Ecological correlates of infraorbital foramen area in primates.
The infraorbital foramen (IOF) transmits the infraorbital nerve (ION) to specialized sensory cells (mechanoreceptors) in the maxillary region. The size of the IOF has been used in numerous paleoecological interpretations of the fossil record. However, these interpretations have been applied without an explicit analysis of the relationship between ecological variables and the IOF. ION and IOF cross-sectional area show a strong positive correlation. As a result, IOF area can be a proxy for ION area, and it is hypothesized that IOF area may be a good measure for maxillary somatosensory acuity. Differences in diet, substrate preference, and/or activity pattern have been shown to correlate with differences in maxillary somatosensory acuity among mammals. This study examines how IOF area covaries with different ecological variables. IOF area was measured for 89 primate species. Ecological profiles were also created for each species and used to evaluate interspecific variation in relative IOF area within each ecological category. The results show a significant relationship between relative IOF area and diet, but not substrate preference or activity pattern. Frugivores have significantly larger relative IOFs than either folivores or insectivores, but the relative IOFs of folivores and insectivores do not differ significantly from one another. These results partially support the hypothesis that maxillary mechanoreception is a critical sensory cue for primates within a feeding context. Results for this study suggest the IOF can be used as an informative character in some paleoecological interpretations of the primate fossil record.


The FICI paradigm: Correcting flaws in antimicrobial in vitro synergy screens at their inception.
Antibiotics have become the corner stone of modern medicine. However, our society is currently facing one of the greatest challenges of its time: the emergence of antimicrobial resistance. It is estimated that if no new therapies are implemented by 2050, 10 million people will die worldwide every year as a result of infections caused by bacteria resistant to current antibiotics; new antimicrobials are thus urgently needed. However, drug development is a tedious and very costly endeavor of hundreds of millions that can take up to 15-20 years from the bench discovery to the bedside. Under this scenario, drug repurposing, which consists in identifying new uses for old, clinically approved drugs, has gathered momentum within the pharmaceutical industry. Because most of these drugs have safety and toxicity information packages available, clinical evaluation could be done in a much shorter period than standard timelines. Synergistic combinations of these clinically approved drugs could also be a promising approach to identify novel antimicrobial therapies that might provide rational choices of available drugs to shorten treatment, increase efficacy, reduce toxicity, prevent resistance and treat infections caused by drug-resistant strains. However, although simple in its conception, translating results from in vitro synergy screens into in vivo efficacy or the clinical practice has proven to be a paramount challenge. In this Commentary, we will discuss common flaws at the inception of synergy research programs, with a special focus on the use of the Fractional Inhibitory Concentration Index (FICI), and evaluate potential interventions that can be made at different developmental pre-clinical stages in order to improve the odds of translation from in vitro studies.


Investigation of a cluster of multiple sclerosis in two elementary school cohorts.
The authors investigated a cluster of multiple sclerosis (MS) among people who had attended two elementary schools in El Paso, Texas, from 1948 through 1970. The community was concerned about the possibility of childhood exposure to heavy metals from a large nearby smelter because historical environmental and biological sampling data demonstrated the potential for study cohort members to have been exposed to heavy metals during their pre-adolescent years. One cohort had no reported cases of MS. In the second cohort, 22 members self-reported a diagnosis of MS, and 16 of these cases were confirmed as MS by an independent board-certified neurologist. The crude MS prevalence estimate was 411 per 100,000 (95 percent confidence interval [CI] = 197-603), Prevalence estimates from four different populations were used for calculation of standardized morbidity ratios (SMRs). At the extremes, the study cohort represents a deficit of cases (SMR= 0.9; 95 percent CI = 0.51-1.44) or a four-fold excess (SMR = 4.0; 95 percent Cl = 2.29-6.5).


Measurement of Intraocular Pressure by Patients With Glaucoma.
The ability of patients to measure their own intraocular pressure (IOP) would allow more frequent measurements and better appreciation of peak IOP and IOP fluctuation. To examine whether patients with glaucoma can perform self-tonometry using a rebound tonometer and examine patient acceptability. An observational study in which IOP was assessed using Goldmann applanation tonometry and a rebound tonometer. Consecutive patients were provided with a patient information sheet and those consenting to take part in the study received standardized self-tonometry training and were then instructed to measure their own IOP under observation. This study was conducted at a glaucoma clinic at a university hospital from March 1, 2016, to December 30, 2016, and included both eyes of 100 patients with glaucoma or ocular hypertension. The percentage of patients who could successfully perform self-tonometry. Complete success was defined by a good technique and an IOP reading within 5 mm Hg of that obtained by a clinician using the same device. A 3-item questionnaire was used to examine perceptions of self-tonometry among patients. Among the 100 patients, the mean (SD) age was 67.5 (10.9) years (53% female). A total 73 of 100 patients (73%) met the complete success criteria. An additional 6 patients could use the device but had IOP readings greater than 5 mm Hg different from those obtained by the clinician. On average, IOP by the rebound tonometer was 2.66 mm Hg lower than Goldmann applanation tonometry (95% limits of agreement, -3.48 to 8.80 mm Hg). The IOPs with the rebound tonometer were similar whether obtained by self-tonometry or investigator, with excellent reproducibility with an intraclass correlation coefficient of 0.903 (95% CI, 0.867-0.928). A total of 56 of 79 successful or partially successful patients (71%) felt self-tonometry was easy, with 73 of 79 (92%) reporting self-tonometry to be comfortable, and a similar number happy to perform self-tonometry in the future. Most patients could perform self-tonometry and the method was acceptable to patients. Self-tonometry has the potential to improve patient engagement, while also providing a more complete picture of IOP changes over time.


Fusion of Enhanced and Synthetic Vision System Images for Runway and Horizon Detection.
Networked operation of unmanned air vehicles (UAVs) demands fusion of information from disparate sources for accurate flight control. In this investigation, a novel sensor fusion architecture for detecting aircraft runway and horizons as well as enhancing the awareness of surrounding terrain is introduced based on fusion of enhanced vision system (EVS) and synthetic vision system (SVS) images. EVS and SVS image fusion has yet to be implemented in real-world situations due to signal misalignment. We address this through a registration step to align EVS and SVS images. Four fusion rules combining discrete wavelet transform (DWT) sub-bands are formulated, implemented, and evaluated. The resulting procedure is tested on real EVS-SVS image pairs and pairs containing simulated turbulence. Evaluations reveal that runways and horizons can be detected accurately even in poor visibility. Furthermore, it is demonstrated that different aspects of EVS and SVS images can be emphasized by using different DWT fusion rules. The procedure is autonomous throughout landing, irrespective of weather. The fusion architecture developed in this study holds promise for incorporation into manned heads-up displays (HUDs) and UAV remote displays to assist pilots landing aircraft in poor lighting and varying weather. The algorithm also provides a basis for rule selection in other signal fusion applications.


High-resolution multimodulation Fourier-transform spectroscopy.
High-resolution double-modulation Fourier-transform (FT) spectroscopy (FTS) is demonstrated for what is, to our knowledge, the first time. Two high-resolution FT interferograms are simultaneously recorded. The first one is nonselective and contains all the spectral information from the observed source, and the other one is made of the samples that are sensitive to only a specific source modulation. General formulations and practical recording procedures are given for phase- and intensity-modulated spectra. The advantage of selectivity is illustrated by velocity-modulated emission spectra of the Dv = 1 sequence of the Doppler-shifted ArH(+) ion. It is also shown that for a source perturbation of small amplitude, only the product of intensity x shift can be retrieved from the selective line shapes obtained in a phase-modulated laser or FT spectra. Thanks to the multimodulation FTS approach, the intensity and the shift of the transitions are measured in a single experiment.


Nanoscale chemical imaging of solid-liquid interfaces using tip-enhanced Raman spectroscopy.
Tip-enhanced Raman spectroscopy (TERS) is a powerful tool for non-destructive and label-free surface molecular mapping at the nanoscale. However, to date nanoscale resolution chemical imaging in a liquid environment has not been possible, in part due to the lack of robust TERS probes that are stable when immersed in a liquid. In this work, we have addressed this challenge by developing plasmonically-active TERS probes with a multilayer metal coating structure that can be successfully used within a liquid environment. Using these novel TERS probes, we have compared the plasmonic enhancement of TERS signals in air and water environments for both gap mode and non-gap mode configurations and show that in both cases the plasmonic enhancement decreases in water. To better understand the signal attenuation in water, we have performed numerical simulations that revealed a negative correlation between the electric field enhancement at the TERS probe-apex and the refractive index of the surrounding medium. Finally, using these robust probes we demonstrate TERS imaging with nanoscale spatial resolution in a water environment for the first time by employing single-wall carbon nanotubes as a model sample. Our findings are expected to broaden the scope of TERS to a range of scientific disciplines in which nanostructured solid-liquid interfaces play a key role.


Activities of types A and B MAO and catechol-o-methyltransferase in blood cells and skin fibroblasts of normal and chronic schizophrenic subjects.
We assayed activities of monoamine oxidase (MAO) type B in blood platelets and type A (and B) in fibroblasts cultured from punch biopsy specimens of skin, as well as of catechol-O-methyltransferase (COMT) in erythrocytes and fibroblasts. Fibroblasts contained moderate amounts of both forms of MAO (types A and B) found in human brain and large amounts of COMT activity. Activities of both enzymes correlated poorly between fibroblasts and blood cells. Comparing carefully diagnosed chronic schizophrenics with age-matched normal young men, we found no difference in these biochemical variables, nor could we distinguish patients with paranoid symptoms. In contrast, we confirmed markedly lower MAO activities in platelet samples from chronic patients provided by colleagues at the National Institute of Mental Health. Results concerning MAO and COMT activities are now sufficiently inconsistently characteristic of schizophrenics as to question their clinical applicability and to indicate a need for further critical evaluation, with special attention to diagnosis, matching of subjects, and effects of possible spurious environmental variables.


Fluxomics with ratiometric metabolite dyes.
Today's major excitement in biology centers on signaling: How can a cell or organism measure the myriad of environmental cues, integrate it, and acclimate to the new conditions? Hormonal signals and second messengers are in the focus of most of these studies, e.g., regulation of glucose transporter GLUT4 cycling by insulin, or regulation of plant growth by auxin or brassinosteroids.1-3 In comparison, we generally assume that we know almost everything about basic metabolism since it has been studied for many decades; for example we know since the early 80s that allosteric regulation by fructose-2,6-bisphophate plays an important role in regulating glycolysis in plants and animals.4 This may be the reason why studies of metabolism appear to be a bit out of fashion. But if we look to other organisms such as E. coli or yeast, we rapidly realize that metabolism is controlled by complex interconnected signaling networks, and that we understand little of these signaling networks in humans and plants.5,6 As it turns out, the cell registers many metabolites, and flux through the pathways is regulated using complex signaling networks that involve calcium as well as hormones.


A post-marketing assessment of major bleeding in total hip and total knee replacement surgery patients receiving rivaroxaban.
Rivaroxaban is a novel oral anticoagulant indicated for prophylaxis against deep vein thrombosis and pulmonary embolism in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery. To evaluate major bleeding (MB) in THR/TKR patients receiving post-operative rivaroxaban. Electronic medical records of nearly 10 million US Department of Defense (DoD) beneficiaries were queried from 1 January 2013 through 30 June 2015. Using the validated Cunningham case-finding algorithm, post-surgical MB events in rivaroxaban users were identified and analyzed. The incidence of MB was determined, and descriptive statistics were used to compare patient characteristics and other covariates in those with and without MB. Two additional methods were used to explore and identify bleeding cases that were not considered MB events per the study case-finding algorithm. A total of 12,429 patients received THR and/or TKR surgery, and were post-operatively prescribed rivaroxaban. Nine patients had MB, yielding an incidence proportion of 0.07% (95% CI 0.02-0.13). The alternative case-finding methods found bleeding incidences of 0.46% and 0.21%, though it is not clear whether these are clinical MB cases, since the alternative methods were not validated. The incidence of MB in this retrospective analysis is lower than that observed in the clinical trials of rivaroxaban. Whether this is due to lower real-world MB rates or challenges with case-finding algorithms is unclear.


To eat or not to eat an endangered species: views of local residents and physicians on the safety of sea turtle consumption in northwestern Mexico.
Sea turtles have historically been an important food resource for many coastal inhabitants of Mexico. Today, the consumption of sea turtle meat and eggs continues in northwestern Mexico despite well-documented legal protection and market conditions providing easier access to other more reliable protein sources. Although there is growing evidence that consuming sea turtles may be harmful to human health due to biotoxins, environmental contaminants, viruses, parasites, and bacteria, many at-risk individuals, trusted information sources, and risk communicators may be unaware of this information. Therefore, we interviewed 134 residents and 37 physicians in a region with high rates of sea turtle consumption to: (1) examine their knowledge and perceptions concerning these risks, as a function of sex, age, occupation, education and location; (2) document the occurrence of illness resulting from consumption; and (3) identify information needs for effective risk communication. We found that 32% of physicians reported having treated patients who were sickened from sea turtle consumption. Although physicians believed sea turtles were an unhealthy food source, they were largely unaware of specific health hazards found in regional sea turtles, regardless of location. By contrast, residents believed that sea turtles were a healthy food source, regardless of sex, age, occupation, and education, and they were largely unaware of specific health hazards found in regional sea turtles, regardless of age, occupation, and education. Although most residents indicated that they would cease consumption if their physician told them it was unhealthy, women were significantly more likely to do so than men. These results suggest that residents may lack the necessary knowledge to make informed dietary decisions and physicians do not have enough accurate information to effectively communicate risks with their patients.


How children and adults learn to intercept moving gaps.
We used an immersive virtual environment to examine how children and adults learn to intercept moving gaps and whether children and adults benefit from variability of practice. Children (10- and 12-year-olds) and adults attempted to bicycle between two moving vehicle-size blocks without stopping. In Experiment 1, block motions were timed such that if participants maintained a constant speed, they would intercept the gap between the blocks. By the last set of intersections, adults learned to maintain a constant speed throughout the approach to the intersection, 12-year-olds exhibited less variability in time-to-spare when they intercepted the blocks, and 10-year-olds exhibited no significant change across intersection sets. In Experiment 2, block motions during the first eight intersections were timed such that participants needed to either speed up or slow down on all intersections or needed to speed up on half and slow down on half of the intersections. On the last four intersections, all age groups encountered a novel block timing in which no adjustment in speed was necessary to intercept the blocks. The adults performed well regardless of whether they experienced consistent or variable block timings. The 10-year-olds in the variable condition performed better on slow-down trials than their peers in the slow-down condition but performed worse on speed-up trials than their peers in the speed-up condition. Discussion focuses on possible developmental changes in reliance on perceptually available and remembered information in complex perception-action tasks.


The area postrema modulates hypothalamic fos responses to intragastric hypertonic saline in conscious rats.
We have recently reported that an acute intragastric hypertonic saline load increases Fos immunoreactivity in several central nuclei, including the supraoptic nucleus (SON), paraventricular nucleus (PVN), nucleus of the solitary tract (NTS), area postrema (AP), and lateral parabrachial nucleus (LPBN). We have also shown that these responses are mediated by stimulation of peripheral osmoreceptors with splanchnic and vagal afferent projections. However, it is unclear whether the primary projections of peripheral osmoreceptors terminate in the NTS or the AP, both of which project to the SON and PVN. This study tested the hypothesis that efferent projections from the AP were necessary for the Fos responses in the SON, PVN, and LPBN. We examined the effect of AP lesion on the response of central Fos immunoreactivity to intragastric hypertonic saline infusion in conscious rats. Compared with sham-lesioned rats (n = 5), Fos expression in AP-lesioned rats (n = 6) was similar in the SON following the intragastric sodium load. However, in contrast to the sham group, Fos expression was significantly reduced in the PVN of AP-lesioned rats. Fos levels observed in the NTS and LPBN were similar in both groups. These results suggest that the PVN response to intragastric hypertonic saline is dependent on efferent projections from the AP. In contrast, Fos responses to this stimulus in the NTS, SON, and LPBN are independent of the activity of the AP.


The cognitive and neural correlates of tactile memory.
Tactile memory systems are involved in the storage and retrieval of information about stimuli that impinge on the body surface and objects that people explore haptically. Here, the authors review the behavioral, neuropsychological, neurophysiological, and neuroimaging research on tactile memory. This body of research reveals that tactile memory can be subdivided into a number of functionally distinct neurocognitive subsystems, just as is the case with auditory and visual memory. Some of these subsystems are peripheral and short lasting and others are more central and long lasting. The authors highlight evidence showing that the representation of tactile information interacts with information about other sensory attributes (e.g., visual, auditory, and kinaesthetic) of objects/events that people perceive. This fact suggests that at least part of the neural network involved in the memory for touch might be shared among different sensory modalities. In particular, multisensory/amodal information-processing networks seem to play a leading role in the storage of tactile information in the brain. (PsycINFO Database Record (c) 2009 APA, all rights reserved).


Preconditioning the immature lung with enhanced Nrf2 activity protects against oxidant-induced hypoalveolarization in mice.
Bronchopulmonary dysplasia (BPD) is a chronic disease of preterm babies with poor clinical outcomes. Nrf2 transcription factor is crucial for cytoprotective response, whereas Keap1-an endogenous inhibitor of Nrf2 signaling-dampens these protective responses. Nrf2-sufficient (wild type) newborn mice exposed to hyperoxia develop hypoalveolarization, which phenocopies human BPD, and Nrf2 deficiency worsens it. In this study, we used PND1 pups bearing bearing hypomorphic Keap1 floxed alleles (Keap1f/f) with increased levels of Nrf2 to test the hypothesis that constitutive levels of Nrf2 in the premature lung are insufficient to mitigate hyperoxia-induced hypoalveolarization. Both wildtype and Keap1f/f pups at PND1 were exposed to hyperoxia for 72 h and then allowed to recover at room air for two weeks (at PND18), sacrificed, and lung hypoalveolarization and inflammation assessed. Hyperoxia-induced lung hypoalveolarization was remarkably lower in Keap1f/f pups than in wildtype counterparts (28.9% vs 2.4%, wildtype vs Keap1f/f). Likewise, Keap1f/f pups were protected against prolonged (96 h) hyperoxia-induced hypoalveolarization. However, there were no differences in hyperoxia-induced lung inflammatory response immediately after exposure or at PND18. Lack of hypoalveolarization in Keap1f/f pups was accompanied by increased levels of expression of antioxidant genes and GSH as assessed immediately following hyperoxia. Keap1 knockdown resulted in upregulation of lung cell proliferation postnatally but had opposing effects following hyperoxia. Collectively, our study demonstrates that augmenting endogenous Nrf2 activation by targeting Keap1 may provide a physiological way to prevent hypoalveolarization associated with prematurity.


Increased Complement Factor B and Bb Levels Are Associated with Mortality in Patients with Severe Aortic Stenosis.
Inflammation is involved in initiation and progression of aortic stenosis (AS). However, the role of the complement system, a crucial component of innate immunity in AS, is unclear. We hypothesized that circulating levels of complement factor B (FB), an important component of the alternative pathway, are upregulated and could predict outcome in patients with severe symptomatic AS. Therefore, plasma levels of FB, Bb, and terminal complement complex were analyzed in three cohorts of patients with severe symptomatic AS and mild-to-moderate or severe asymptomatic AS (population 1, n = 123; population 2, n = 436; population 3, n = 61) and in healthy controls by enzyme immunoassays. Compared with controls, symptomatic AS patients had significantly elevated levels of FB (2.9- and 2.8-fold increase in population 1 and 2, respectively). FB levels in symptomatic and asymptomatic AS patients were comparable (population 2 and 3), and in asymptomatic patients FB correlated inversely with valve area. FB levels in population 1 and 2 correlated with terminal complement complex levels and measures of systemic inflammation (i.e., CRP), cardiac function (i.e., NT-proBNP), and cardiac necrosis (i.e., Troponin T). High FB levels were significantly associated with mortality also after adjusting for clinical and biochemical covariates (hazard ratio 1.37; p = 0.028, population 2). Plasma levels of the Bb fragment showed a similar pattern in relation to mortality. We concluded that elevated levels of FB and Bb are associated with adverse outcome in patients with symptomatic AS. Increased levels of FB in asymptomatic patients suggest the involvement of FB from the early phase of the disease.


Nabilone for the Management of Pain.
Nabilone, a synthetic cannabinoid, is approved in many countries including, but not limited to, Canada, the United States, Mexico, and the United Kingdom for the treatment of severe nausea and vomiting associated with chemotherapy. Clinical evidence is emerging for its use in managing pain conditions with different etiologies. We review the efficacy and safety of nabilone for various types of pain as well as its abuse potential, precautions and contraindications, and drug interactions; summarize pertinent clinical practice guidelines; and provide recommendations for dosing, monitoring, and patient education. Citations involving nabilone were identified through systematic reviews evaluating cannabinoids for pain. A systematic search (updated July 23, 2015) of the Ovid MEDLINE, EMBASE, PubMed, and Cochrane Library databases was performed. Eight randomized controlled trials, two prospective cohort trials, and one retrospective chart review were retrieved. Cancer pain, chronic noncancer pain, neuropathic pain, fibromyalgia, and pain associated with spasticity were the pain conditions evaluated. Nabilone was most commonly used as adjunctive therapy and led to small but significant reductions in pain. The most common adverse drug reactions included euphoria, drowsiness, and dizziness. Nabilone was rarely associated with severe adverse drug reactions requiring drug discontinuation, and the likelihood of abuse was thought to be low. Although the optimal role of nabilone in the management of pain is yet to be determined, certain clinical practice guidelines consider nabilone as a third-line agent.


Antimicrobial Effect of Ozone Made by KP Syringe of High-Frequency Ozone Generator.
The aim of this study was to evaluate in vitro the antibacterial effect of ozone on suspension of three different bacteria inoculated in prepared canals of extracted human teeth. Ozone was produced by special KP syringe of high frequency ozone generator Ozonytron (Biozonix, München, Germany) from aspirated atmospheric air by dielectric barrier discharge and applied through the tip of the syringe to the prepared root canal. The microorganisms used were Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis. However, none of the methods was 100% effective against the three bacterial types in suspension. Application of ozone significantly decreased the absolute count of microorganisms (89.3%), as well as the count of each type of bacteria separately (Staphylococcus aureus 94.0%; Staphylococcus epidermidis 88.6% and Enterococcus faecalis 79.7%). Ozone generated by KP syringe was statistically more effective compared to NaOCl as positive control, for Staphylococcus aureus and Staphylococcus epidermidis. The absolute count of Enterococcus faecalis was statistically decreased without a statistically significant difference between the tested group and positive control, respectively. Among the three types of bacteria in suspension, KP probe had the lowest antimicrobial effect against Enterococcus faecalis.


Design, synthesis and biological assessment of a triazine dendrimer with approximately 16 Paclitaxel groups and 8 PEG groups.
The synthesis and characterization of a generation three triazine dendrimer that displays a phenolic group at the core for labeling, up to eight 5 kDa PEG chains for solubility, and 16 paclitaxel groups is described. Three different diamine linkers--dipiperidine trismethylene, piperazine, and aminomethylpiperidine--were used within the dendrimer. To generate the desired stoichiometric ratio of 8 PEG chains to 16 paclitaxel groups, a monochlorotriazine was prepared with two paclitaxel groups attached through their 2'-hydroxyls using a linker containing a labile disulfide. This monochlorotriazine was linked to a dichlorotriazine with aminomethylpiperidine. The resulting dichlorotriazine bearing two paclitaxel groups could be reacted with the eight amines of the dendrimer. NMR and MALDI-TOF confirm successful reaction. The eight monochlorotriazines of the resulting material are used as the site for PEGylation affording the desired 2:1 stoichiometry. The target and intermediates were amenable to characterization by (1)H and (13)C NMR, and mass spectrometry. Analysis revealed that 16 paclitaxel groups were installed along with 5-8 PEG chains. The final construct is 63% PEG, 22% paclitaxel, and 15% triazine dendrimer. Consistent with previous efforts and computational models, 5 kDa PEG groups were essential for making the target water-soluble. Molecular dynamics simulations showed a high degree of hydration of the core, and a radius of gyration of 2.8 ± 0.2 nm. The hydrodynamic radius of the target was found to be 15.8 nm by dynamic light scattering, an observation indicative of aggregation. Drug release studies performed in plasma showed slow and identical release in mouse and rat plasma (8%, respectively). SPECT/CT imaging was used to follow biodistribution and tumor uptake. Using a two component model, the elimination and distribution half-lives were 2.65 h and 38.2 h, respectively. Compared with previous constructs, this dendrimer persists in the vasculature longer (17.33 ± 0.88% ID/g at 48 h postinjection), and showed higher tumor uptake. Low levels of dendrimer were observed in lung, liver, and spleen (~6% ID/g). Tumor saturation studies of small prostate cancer tumors (PC3) suggest that saturation occurs at a dose between 23.2 mg/kg and 70.9 mg/kg.


Intracellular trafficking of interleukin-1 receptor I requires Tollip.
Interleukin-1 receptor (IL-1RI) is a master regulator of inflammation and innate immunity. When triggered by IL-1beta, IL-1RI aggregates with IL-1R-associated protein (IL-1RAcP) and forms a membrane proximal signalosome that potently activates downstream signaling cascades. IL-1beta also rapidly triggers endocytosis of IL-1RI. Although internalization of IL-1RI significantly impacts signaling, very little is known about trafficking of IL-1RI and therefore about precisely how endocytosis modulates the overall cellular response to IL-1beta. Upon internalization, activated receptors are often sorted through endosomes and delivered to lysosomes for degradation. This is a highly regulated process that requires ubiquitination of cargo proteins as well as protein-sorting complexes that specifically recognize ubiquitinated cargo. Here, we show that IL-1beta induces ubiquitination of IL-1RI and that via these attached ubiquitin groups, IL-1RI interacts with the ubiquitin-binding protein Tollip. By using an assay to follow trafficking of IL-1RI from the cell surface to late endosomes and lysosomes, we demonstrate that Tollip is required for sorting of IL-1RI at late endosomes. In Tollip-deficient cells and cells expressing only mutated Tollip (incapable of binding IL-1RI and ubiquitin), IL-1RI accumulates on late endosomes and is not efficiently degraded. Furthermore, we show that IL-1RI interacts with Tom1, an ubiquitin-, clathrin-, and Tollip-binding protein, and that Tom1 knockdown also results in the accumulation of IL-1RI at late endosomes. Our findings suggest that Tollip functions as an endosomal adaptor linking IL-1RI, via Tom1, to the endosomal degradation machinery.


Distribution, relative importance and effect of lepidopterous borers on maize yields in the forest zone and mid-altitude of Cameroon.
Geographic distribution, relative importance, and effect of lepidopterous stem and ear borers on maize, Zea mays L., were studied in the humid forest and the mid-altitude zones of Cameroon from 1994 to 1997. Six villages were chosen in the forest zone and grouped into three blocks representing gradients in human population density. A single block with three villages was chosen in the mid-altitude. Farmers' maize fields were surveyed during the vegetative growth phase for Busseola fusca (Fuller) egg batches, and at harvest for number of larvae and pupae by species, plant damage, and ear weight. There was no significant block effect for any of the variables measured, and most of the overall variance (72-99%) was attributed to within-field variability. In the forest zone, the noctuid B. fusca and the pyralid Eldana saccharina (Walker) accounted for >80% of all species in almost all locations, followed by the pyralid Mussidia nigrivenella (Ragonot) and the tortricid Cryptophlebia leucotreta (Meyrick). The noctuid Sesamia calamistis (Hampson) was found in almost all locations during the first season but disappeared in most locations in the second season. B. fusco egg infestation was significantly higher during the second compared with the first season, whereas larval and pupal densities were much higher during the first season. E. saccharina was the predominant species during the second season, when densities increased fourfold. In the mid-altitude, B. fusca was the predominant species. No significant differences in pest densities, plant damage, and ear weight were found between years. Results of stepwise regression of stem and ear damage on pest densities verified the relative importance of the individual species. In the forest zone, ear and stem damage significantly reduced ear weight, whereas in the mid-altitude only stem tunneling was significant.


The incidence and clinical characteristics by gender differences in patients with Kikuchi-Fujimoto disease.
Kikuchi-Fujimoto disease (KFD) is a rare, self-limiting disorder that typically affects the cervical lymph nodes (LNs). Although initially described in young women, KFD also occurs in men. There are no reports on the clinical manifestations and characteristics of male KFD patients. Therefore, this study was conducted to assess the incidence of KFD among males, as well as the most frequent clinical characteristics of these patients. A retrospective, cross-sectional study was performed at a tertiary hospital of patients pathologically confirmed as having KFD from LN biopsy specimens. Clinical and laboratory data, and treatment outcomes of the enrolled patients, were analyzed by gender. A total of 254 patients diagnosed with KFD were enrolled. There were 189 females and 65 males (2.9:1). The mean age was 32.6 ± 11.3 years. Compared to the female patients, the males had more frequent manifestations of fever (48% vs 67%, P = 0.008), headache (9% vs 20%, P = 0.013), bilateral lymphadenopathy (31% vs 46%, P = 0.029), thrombocytopenia (14% vs 29%, P = 0.014), elevated C-reactive protein (CRP) (35% vs 78.4%, P < 0.001), elevated liver enzymes (15% vs 41%, P < 0.001), and elevated lactate dehydrogenase (LDH) (61% vs 80%, P = 0.021). Male patients had fewer autoimmune features (9% vs 2%, P = 0.043) and fewer positive antinuclear antibodies (32% vs 10%, P = 0.006). In this study, 25.6% of the enrolled patients were male, with a 2.9:1 female-to-male sex ratio. Male patients showed a distinctive profile characterized by a higher frequency of fever, headache, bilateral lymphadenopathy, and thrombocytopenia, as well as elevated liver enzymes, CRP, and LDH.


Neuroprotection of Neuro2a cells and the cytokine suppressive and anti-inflammatory mode of action of resveratrol in activated RAW264.7 macrophages and C8-B4 microglia.
Chronic inflammation is a hallmark of neurodegenerative disease and cytotoxic levels of nitric oxide (NO) and pro-inflammatory cytokines can initiate neuronal death pathways. A range of cellular assays were used to assess the anti-inflammatory and neuroprotective action of resveratrol using murine microglial (C8-B4), macrophage (RAW264.7) and neuronal-like (Neuro2a) cell lines. We examined the release of NO by Griess assay and used a Bioplex array to measure a panel of pro- and anti-inflammatory cytokines and chemokines, in response to the inflammatory stimuli lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Resveratrol was a potent inhibitor of NO and cytokine release in activated macrophages and microglia. The activity of resveratrol increased marginally in potency with longer pre-incubation times in cell culture that was not due to cytotoxicity. Using an NO donor we show that resveratrol can protect Neuro2a cells from cytotoxic concentrations of NO. The protective effect of resveratrol from pro-inflammatory signalling in RAW264.7 cells was confirmed in co-culture experiments leading to increased survival of Neuro2a cells. Together our data are indicative of the potential neuroprotective effect of resveratrol during nitrosative stress and neuroinflammation.


Duplication of Drosophila melanogaster mitochondrial EF-Tu: pre-adaptation to T-arm truncation and exclusion of bulky aminoacyl residues.
Translation elongation factor Tu (EF-Tu) delivers aminoacyl-tRNA (aa-tRNA) to ribosomes in protein synthesis. EF-Tu generally recognizes aminoacyl moieties and acceptor- and T-stems of aa-tRNAs. However, nematode mitochondrial (mt) tRNAs frequently lack all or part of the T-arm that is recognized by canonical EF-Tu. We previously reported that two distinct EF-Tu species, EF-Tu1 and EF-Tu2, respectively, recognize mt tRNAs lacking T-arms and D-arms in the mitochondria of the chromadorean nematode Caenorhabditis elegansC. elegans EF-Tu2 specifically recognizes the seryl moiety of serylated D-armless tRNAs. Mitochondria of the enoplean nematode Trichinella possess three structural types of tRNAs: T-armless tRNAs, D-armless tRNAs, and cloverleaf tRNAs with a short T-arm. Trichinella mt EF-Tu1 binds to all three types and EF-Tu2 binds only to D-armless Ser-tRNAs, showing an evolutionary intermediate state from canonical EF-Tu to chromadorean nematode (e.g. C. elegans) EF-Tu species. We report here that two EF-Tu species also participate in Drosophila melanogaster mitochondria. Both D. melanogaster EF-Tu1 and EF-Tu2 bound to cloverleaf and D-armless tRNAs. D. melanogaster EF-Tu1 has the ability to recognize T-armless tRNAs that do not evidently exist in D. melanogaster mitochondria, but do exist in related arthropod species. In addition, D. melanogaster EF-Tu2 preferentially bound to aa-tRNAs carrying small amino acids, but not to aa-tRNAs carrying bulky amino acids. These results suggest that the Drosophila mt translation system could be another intermediate state between the canonical and nematode mitochondria-type translation systems.


Device failures associated with patient injuries during robot-assisted laparoscopic surgeries: a comprehensive review of FDA MAUDE database.
Robot-assisted laparoscopic surgery has increased in the areas of cardiac and urologic surgery. We sought to determine the number of reported device malfunctions leading to patient injuries. We performed a review of the MAUDE database of the FDA. Adverse events (AE) were defined as potential and actual product use errors and product quality problems. All incidents involving the ZEUS and da Vinci surgical robots were analyzed. The MAUDE database was last accessed on August 27, 2007. A total of 189 AEs were reported from 2000 to August 27, 2007. Assuming that 50,000 robotic-assisted laparoscopic cases have been performed, this represents 0.38% overall estimated failure rate. Twenty-one malfunctions were reported for the ZEUS robotic system between 2001 and 2003, while 168 malfunctions were reported for the da Vinci robotic system between 2000 and 2007. The rate of open conversions due to device malfunction decreased from 94% in 2003 to 16% in 2007. Of the 189 reported device malfunctions, only 9 (4.8%) were associated with patient injury. The increasing use of robotic-assisted surgery has led to an increase in the number of reported device malfunctions, albeit at a very small estimated rate of 0.38%. With experience, the rate of open conversions due to device malfunction decreased. Only a small percentage of these adverse occurrences were associated with patient injury.


Proprioceptive control of interjoint coordination.
This paper reviews a series of experiments comparing intact controls with functionally deafferented patients to determine the role of proprioception in controlling dynamic interactions between limb segments during movement. We examine the control of hand path in a planar movement-reversal task and in a familiar three-dimensional gesture with similar biomechanical characteristics. In the planar task subjects had to move their hand out and back along a series of straight-line segments in the horizontal plane without visual feedback. The lengths and directions of the target line segments were chosen to require different amounts of shoulder motion while requiring the same elbow excursion. In controls, hand paths were, as required, straight with sharp bends at the outermost point. In patients, however, distinctive errors appeared at movement reversals, consisting of widened hand paths resulting from desynchronization in the reversals of elbow and shoulder motions. These errors reflected an inability to program elbow muscle contractions in accord with interaction torques produced at the elbow by variations in acceleration of the shoulder. The reversal errors were substantially reduced after patients had practiced for a few trials while visually monitoring movements of their arm. The improvement was not limited to the direction where they had practiced with vision, but also extended to other directions in which the elbow torques were different. This suggests that practice with vision of the arm served to improve the general rules that subjects used to plan movement, rather than simply improving the performance of a specific response. Similar to their performance on the planar task, the patients made errors in interjoint coordination during unconstrained three-dimensional gestures with movement reversals. We conclude (i) that both the planning and the learning of movement required an internal model of the dynamic properties of the limb that takes account of interaction torques acting at different joints; (ii) that this internal model is normally established and updated using proprioceptive information; but (iii) that when proprioception is lacking, vision of the limb in motion partially substitutes for proprioception.


The many faces of SAM.
Protein-protein interactions are essential for the assembly, regulation, and localization of functional protein complexes in the cell. SAM domains are among the most abundant protein-protein interaction motifs in organisms from yeast to humans. Although SAM domains adopt similar folds, they are remarkably versatile in their binding properties. Some identical SAM domains can interact with each other to form homodimers or polymers. In other cases, SAM domains can bind to other related SAM domains, to non-SAM domain-containing proteins, and even to RNA. Such versatility earns them functional roles in myriad biological processes, from signal transduction to transcriptional and translational regulation. In this review, we describe the structural basis of SAM domain interactions and highlight their roles in the scaffolding of protein complexes in normal and pathological processes.


Comparison of Fundus-Guided Microperimetry and Multifocal Electroretinography for Evaluating Hydroxychloroquine Maculopathy.
To compare retinal function by using fundus-guided microperimetry (MP) and multifocal electroretinography (mfERG) for detecting hydroxychloroquine (HCQ) maculopathy. Forty-six eyes of 25 patients referred to our clinical practice for HCQ maculopathy assessment and 3 groups of normal control subjects were evaluated by mfERG and MP. Macular structure was assessed using spectral-domain optical coherence tomography (SD-OCT). Ring ratios from the three innermost mERG rings were compared with average sensitivity of each MP ring at approximately equivalent distances from the fovea. HCQ toxicity was defined as an mfERG ring ratio or mean MP ring sensitivity >2 standard deviations below the normal mean. The sensitivity and specificity of MP to detect HCQ toxicity relative to mfERG were evaluated. MP rings MR2 and MR3 were positively correlated with corresponding mfERG ring ratios (r = 0.52, P = 0.002 and r = 0.56, P < 0.001 respectively). Ring 2 and ring 3 measures of MP and mfERG were significantly worse in HCQ eyes than controls (P < 0.001). The sensitivity of MP to detect toxicity for MR1 through MR3 ranged from 33% to 88%, whereas specificity ranged from 72% to 85%. Through rings 1 to 3, the frequency of abnormal function ranged from 20% to 48% for MP, 11% to 35% for mfERG, and 41% to 45% for SD-OCT. The frequency of detection of HCQ toxicity with MP was greater than with mfERG. MP showed an overall good sensitivity and moderate specificity in detecting HCQ-induced functional deficits. Results from this study may allow clinicians to improve screening accuracy for HCQ toxicity by using the alternative modality of MP.


Treatment of urticaria pigmentosa with corticosteroids.
Based on a previous observation that the long-term application of potent topical corticosteroids under occlusion to normal skin resulted in the loss of mast cells, we investigated the effects of intralesional and topical steroids in urticaria pigmentosa (UP). Three patients with UP had lesions that were injected with triamcinolone acetonide. Four weeks after injection, all patients showed a loss of Darier's sign, and, by eight weeks after injection, there was a dramatic clearing of the plaques and a decrease in brown hyperpigmentation. By 12 weeks, mast cells were undetectable by light microscopy and transmission electron microscopy (TEM). The injection sites remained dramatically improved for as long as one year after treatment, and histamine content was reduced 95% in one patient 48 weeks after injection. In six patients, the topical application of 0.05% betamethasone dipropionate under occlusion to limited areas induced almost complete clearing of UP lesions. Lesions treated with an emollient under occlusion, as a control, demonstrated no change. After treatment, no mast cells were seen by light microscopy or TEM, and this persisted for at least 24 weeks. There was also a significant decrease in tissue histamine levels in the treated areas. The treated areas remained clinically improved for at least nine to 12 months. These data indicate that steroid therapy dramatically decreases the excess number of normal-appearing mast cells in UP as well as induces a prolonged resolution of UP lesions. Local corticosteroids thus are a useful therapeutic modality for UP.


Detailed high-accuracy megavoltage transmission measurements: a sensitive experimental benchmark of EGSnrc.
There are three goals for this study: (a) to perform detailed megavoltage transmission measurements in order to identify the factors that affect the measurement accuracy, (b) to use the measured data as a benchmark for the EGSnrc system in order to identify the computational limiting factors, and (c) to provide data for others to benchmark Monte Carlo codes. Transmission measurements are performed at the National Research Council Canada on a research linac whose incident electron parameters are independently known. Automated transmission measurements are made on-axis, down to a transmission value of ∼1.7%, for eight beams between 10 MV (the lowest stable MV beam on the linac) and 30 MV, using fully stopping Be, Al, and Pb bremsstrahlung targets and no fattening filters. To diversify energy differentiation, data are acquired for each beam using low-Z and high-Z attenuators (C and Pb) and Farmer chambers with low-Z and high-Z buildup caps. Experimental corrections are applied for beam drifts (2%), polarity (2.5% typical maximum, 6% extreme), ion recombination (0.2%), leakage (0.3%), and room scatter (0.8%)-the values in parentheses are the largest corrections applied. The experimental setup and the detectors are modeled using EGSnrc, with the newly added photonuclear attenuation included (up to a 5.6% effect). A detailed sensitivity analysis is carried out for the measured and calculated transmission data. The developed experimental protocol allows for transmission measurements with 0.4% uncertainty on the smallest signals. Suggestions for accurate transmission measurements are provided. Measurements and EGSnrc calculations agree typically within 0.2% for the sensitivity of the transmission values to the detector details, to the bremsstrahlung target material, and to the incident electron energy. Direct comparison of the measured and calculated transmission data shows agreement better than 2% for C (3.4% for the 10 MV beam) and typically better than 1% for Pb. The differences can be explained by acceptable photon cross section changes of ≤0.4%. Accurate transmission measurements require accounting for a number of influence quantities which, if ignored, can collectively introduce errors larger than 10%. Accurate transmission calculations require the use of the most accurate data and physics options available in EGSnrc, particularly the more accurate bremsstrahlung angular sampling option and the newly added modeling of photonuclear attenuation. Comparison between measurements and calculations implies that EGSnrc is accurate within 0.2% for relative ion chamber response calculations. Photon cross section uncertainties are the ultimate limiting factor for the accuracy of the calculated transmission data (Monte Carlo or analytical).


Male reproductive senescence causes potential for sexual conflict over mating.
The realization that senescence, age-dependent declines in survival and reproductive performance, pervades natural populations has brought its evolutionary significance into sharper focus. However, reproductive senescence remains poorly understood because it is difficult to separate male and female mechanisms underpinning reproductive success. We experimentally investigated male reproductive senescence in feral fowl, Gallus gallus domesticus, where socially dominant males monopolize access to females and the ejaculates of multiple males compete for fertilization. We detected the signal of senescence on multiple determinants of male reproductive success. The effect of age on status was dependent upon the intensity of intrasexual competition: old males were less likely to dominate male-biased groups where competition is intense but were as likely as young males to dominate female-biased groups. Mating and fertilization success declined sharply with male age largely as a result of population-level patterns. These age-dependent declines translated into sexually antagonistic payoffs: old males fertilized more eggs when they were dominant, but this resulted in females suffering a drastic reduction in fertility. Thus, male senescence causes potential for sexual conflict over mating, and the intensity of this conflict is modulated socially, by the probability of old males dominating reproductive opportunities.


The pathways connecting the hippocampal formation, the thalamic reuniens nucleus and the thalamic reticular nucleus in the rat.
Most dorsal thalamic nuclei send axons to specific areas of the neocortex and to specific sectors of the thalamic reticular nucleus; the neocortex then sends reciprocal connections back to the same thalamic nucleus, directly as well indirectly through a relay in the thalamic reticular nucleus. This can be regarded as a 'canonical' circuit of the sensory thalamus. For the pathways that link the thalamus and the hippocampal formation, only a few comparable connections have been described. The reuniens nucleus of the thalamus sends some of its major cortical efferents to the hippocampal formation. The present study shows that cells of the hippocampal formation as well as cells in the reuniens nucleus are retrogradely labelled following injections of horseradish peroxidase or fluoro-gold into the rostral part of the thalamic reticular nucleus in the rat. Within the hippocampal formation, labelled neurons were localized in the subiculum, predominantly on the ipsilateral side, with fewer neurons labelled contralaterally. Labelled neurons were seen in the hippocampal formation and nucleus reuniens only after injections made in the rostral thalamic reticular nucleus (1.6-1.8 mm caudal to bregma). In addition, the present study confirmed the presence of afferent connections to the rostral thalamic reticular nucleus from cortical (cingulate, orbital and infralimbic, retrosplenial and frontal), midline thalamic (paraventricular, anteromedial, centromedial and mediodorsal thalamic nuclei) and brainstem structures (substantia nigra pars reticularis, ventral tegmental area, periaqueductal grey, superior vestibular and pontine reticular nuclei). These results demonstrate a potential for the thalamo-hippocampal circuitry to influence the functional roles of the thalamic reticular nucleus, and show that thalamo-hippocampal connections resemble the circuitry that links the sensory thalamus and neocortex.


Inhibitory effects of low molecular weight polyphenolics from Inonotus obliquus on human DNA topoisomerase activity and cancer cell proliferation.
Low molecular weight (LMW) polyphenolics containing a polyhydroxylated benzyl moiety are abundant in medicinal plants. In the present study, we report on the activities of seven LMW polyphenolics isolated from Inonotus obliquus, a medicinal mushroom. The isolated compounds included caffeic acid (CA), 3,4-dihydroxybenzalacetone (DBL), gallic acid, syringic acid, protocatechuic acid, 3,4-dihydroxybenzaldehyde and 2,5-dihydroxyterephthalic acid. We analyzed their inhibitory effects on DNA polymerase (pol) and DNA topoisomerase (topo), and their effects on human cancer cell growth. All isolated compounds inhibited human topo II activity; the most potent were DBL and CA, which contain a catechol propanoid moiety. CA and DBL inhibited the activity of human topo I, whereas other compounds had no effect. No compound modulated the activities of 11 mammalian pol species or other DNA metabolic enzymes, including T7 RNA polymerase, mouse IMP dehydrogenase (type II), T4 polynucleotide kinase and bovine deoxyribonuclease I. CA and DBL markedly suppressed the proliferation of human colon HCT116 carcinoma cells with an LD50 of 70.0 and 49.4 µM, respectively, and halted the cell cycle in the G2/M phase. The suppressive effect of these compounds on cancer cell growth correlated with their ability to inhibit topo II. These results suggest that CA- and DBL-dependent decreases in cell proliferation are due to the inhibition of cellular topo II. The mechanism of action of these catechol propanoid compounds and the implication for their use as anticancer agents are discussed.


Neonatal coagulation: normal physiology and pathophysiology.
The newborn infant, particularly when premature, has a haemostatic mechanism which may not be entirely capable of withstanding the onslaughts of trauma, infection, asphyxia or other complications of the neonatal period. He is at risk of local or diffuse haemorrhage, which may at times be serious or even life-threatening. The cause of haemorrhage during the newborn period can generally be ascertained by a careful history and brief physical examination directed toward recognition of any predisposing factors or underlying diseases. Screening laboratory tests can usually be correctly interpreted as long as certain laboratory artifacts and physiological peculiarities of the neonatal coagulation mechanism are kept in mind. Diagnosis of and therapy for vitamin K deficiency and haemophilia in the healthy-appearing neonate is generally carried out with little difficulty. The seriously ill neonate with bacterial sepsis, respiratory distress syndrome, or extreme immaturity presents greater problems, for laboratory tests may be more difficult to obtain and interpret and underlying conditions may be untreatable. DIC occurs commonly in such neonates, and transfusion therapy, with or without heparin, is often unsuccessful. A persistent dilemma are those neonates with fatal intravascular haemorrhage, in whom definable haemostatic abnormalities are few and transfusion therapy is futile.


Excitatory and inhibitory effects of gastrin peptides on gastric motility in sheep.
In conscious sheep, tetragastrin, pentagastrin, and synthetic human gastrin I, injected either subcutaneously or intravenously in doses of 156-5,200 pmol/kg body wt, inhibited the vagally dependent cyclical motility of the reticulum and rumen, whereas in vitro pentagastrin (10(-12) to 10(-6) M) had no demonstrable inhibitory or excitatory effects on intrinsically active or quiescent muscle of the reticulum, rumen, and omasal leaves. In vitro pentagastrin (10(-18) to 10(-4) M) stimulated quiescent and intrinsically active longitudinal and circular muscles of the body of the omasum and the body and antrum of the abomasum and potentiated contractile responses of antral muscle to electrical stimulation of intramural cholinergic nerves. Responses in the presence of hexamethonium, atropine, and tetrodotoxin indicated that the excitatory effects on mixed nerve-muscle preparations of omasal and abomasal tissue were mediated both through stimulation of cholinergic neurones and by direct actions on the muscle. In vitro the ovine stomach shows marked regional differences in both its response and sensitivity to gastrin peptides, and their inhibitory effects on reticuloruminal motility in vivo appear to be other than direct.


ALG-1 Influences Accurate mRNA Splicing Patterns in the Caenorhabditis elegans Intestine and Body Muscle Tissues by Modulating Splicing Factor Activities.
MicroRNAs (miRNAs) are known to modulate gene expression, but their activity at the tissue-specific level remains largely uncharacterized. To study their contribution to tissue-specific gene expression, we developed novel tools to profile putative miRNA targets in the Caenorhabditis elegans intestine and body muscle. We validated many previously described interactions and identified ∼3500 novel targets. Many of the candidate miRNA targets curated are known to modulate the functions of their respective tissues. Within our data sets we observed a disparity in the use of miRNA-based gene regulation between the intestine and body muscle. The intestine contained significantly more putative miRNA targets than the body muscle highlighting its transcriptional complexity. We detected an unexpected enrichment of RNA-binding proteins targeted by miRNA in both tissues, with a notable abundance of RNA splicing factors. We developed in vivo genetic tools to validate and further study three RNA splicing factors identified as putative miRNA targets in our study (asd-2, hrp-2, and smu-2), and show that these factors indeed contain functional miRNA regulatory elements in their 3'UTRs that are able to repress their expression in the intestine. In addition, the alternative splicing pattern of their respective downstream targets (unc-60, unc-52, lin-10, and ret-1) is dysregulated when the miRNA pathway is disrupted. A reannotation of the transcriptome data in C. elegans strains that are deficient in the miRNA pathway from past studies supports and expands on our results. This study highlights an unexpected role for miRNAs in modulating tissue-specific gene isoforms, where post-transcriptional regulation of RNA splicing factors associates with tissue-specific alternative splicing.


Learning-enhanced coupling between ripple oscillations in association cortices and hippocampus.
Consolidation of declarative memories requires hippocampal-neocortical communication. Although experimental evidence supports the role of sharp-wave ripples in transferring hippocampal information to the neocortex, the exact cortical destinations and the physiological mechanisms of such transfer are not known. We used a conducting polymer-based conformable microelectrode array (NeuroGrid) to record local field potentials and neural spiking across the dorsal cortical surface of the rat brain, combined with silicon probe recordings in the hippocampus, to identify candidate physiological patterns. Parietal, midline, and prefrontal, but not primary cortical areas, displayed localized ripple (100 to 150 hertz) oscillations during sleep, concurrent with hippocampal ripples. Coupling between hippocampal and neocortical ripples was strengthened during sleep following learning. These findings suggest that ripple-ripple coupling supports hippocampal-association cortical transfer of memory traces.


Characterization of an epilepsy-associated variant of the human Cl-/HCO3(-) exchanger AE3.
Anion exchanger 3 (AE3), expressed in the brain, heart, and retina, extrudes intracellular HCO(3)(-) in exchange for extracellular Cl(-). The SLC4A3 gene encodes two variants of AE3, brain or full-length AE3 (AE3(fl)) and cardiac AE3 (cAE3). Epilepsy is a heterogeneous group of disorders characterized by recurrent unprovoked seizures that affect about 50 million people worldwide. The AE3-A867D allele in humans has been associated with the development of IGE (IGE), which accounts for approximately 30% of all epilepsies. To examine the molecular basis for the association of the A867D allele with IGE, we characterized wild-type (WT) and AE3(fl)-A867D in transfected human embryonic kidney (HEK)-293 cells. AE3(fl)-A867D had significantly reduced transport activity relative to WT (54 +/- 4%, P < 0.01). Differences in expression levels or the degree of protein trafficking to the plasma membrane did not account for the defect of AE3(fl)-A867D. Treatment with 8-bromo-cAMP (8-Br-cAMP) increased Cl(-)/HCO(3)(-) exchange activity of WT and AE3(fl)-A867D to a similar degree, which was abolished by preincubation with the protein kinase A (PKA)-specific inhibitor H89. This indicates that PKA regulates WT and AE3(fl)-A867D Cl(-)/HCO(3)(-) exchange activity. No difference in Cl(-)/HCO(3)(-) exchange activity was found between cultures of mixed populations of neonatal hippocampal cells from WT and slc4a3(-/-) mice. We conclude that the A867D allele is a functional (catalytic) mutant of AE3 and that the decreased activity of AE3(fl)-A867D may cause changes in cell volume and abnormal intracellular pH. In the brain, these alterations may promote neuron hyperexcitability and the generation of seizures.


Recruitment to the nuclear periphery can alter expression of genes in human cells.
The spatial organisation of the genome in the nucleus has a role in the regulation of gene expression. In vertebrates, chromosomal regions with low gene-density are located close to the nuclear periphery. Correlations have also been made between the transcriptional state of some genes and their location near the nuclear periphery. However, a crucial issue is whether this level of nuclear organisation directly affects gene function, rather than merely reflecting it. To directly investigate whether proximity to the nuclear periphery can influence gene expression in mammalian cells, here we relocate specific human chromosomes to the nuclear periphery by tethering them to a protein of the inner nuclear membrane. We show that this can reversibly suppress the expression of some endogenous human genes located near the tethering sites, and even genes further away. However, the expression of many other genes is not detectably reduced and we show that location at the nuclear periphery is not incompatible with active transcription. The dampening of gene expression around the nuclear periphery is dependent on the activity of histone deacetylases. Our data show that the radial position within the nucleus can influence the expression of some, but not all, genes. This is compatible with the suggestion that re-localisation of genes relative to the peripheral zone of the nucleus could be used by metazoans to modulate the expression of selected genes during development and differentiation.


Angioedema.
Angioedema is a potentially life-threatening occurrence that is encountered by critical care providers. The mechanistic understanding of angioedema syndromes has improved in recent years, and novel medications are available that improve outcomes from these syndromes. This clinically focused review will describe the underlying genetics, pathophysiology, classification and treatment of angioedema syndromes, with an emphasis on the novel pharmacologic agents that have recently become available for acute treatment. A MEDLINE search was conducted with the MeSH terms angioedema, acquired angioedema, hereditary angioedema type III, and angiotensin converting enzyme inhibitor-induced angioedema. Selected publications describing angioedema, clinical trials, diagnosis, management, and genetics were retrieved (reviews, guidelines, clinical trials, case series), and their bibliographies were also reviewed to identify relevant publications. Data from the relevant publications were reviewed, summarized and the information synthesized. The data obtained were used to describe the current state of diagnosis and management of various angioedema syndromes. Angioedema is a life-threatening syndrome with multiple subtypes, each with a distinct pathophysiology. We present an evidence-based approach to the diagnosis and suggested management of various subtypes of angioedema. Securing the airway remains the most important intervention, followed by administration of both established and more novel pharmacologic interventions based on disease pathology.


Shrinkage of the entorhinal cortex over five years predicts memory performance in healthy adults.
Lesions in the hippocampus (HC), the entorhinal cortex (EC), and the prefrontal cortex (PFC) are associated with impairment of episodic memory; reduced HC volume is linked to memory declines in dementia; and decline in EC volume predicts progression from mild cognitive impairment to dementia. However, in healthy adults, the relationship between memory and regional volumes is unclear, and no data are available on the relationship of longitudinal regional shrinkage to memory performance in a cognitively intact population. The objective of this study was to examine whether shrinkage of the EC, HC, and PFC over a 5 year period can predict declarative memory performance in healthy adults. The volumes of three brain regions were measured on magnetic resonance images that were acquired twice, 5 years apart. Multiple measures of episodic memory were administered at follow-up. Results indicated that the volume of HC and PFC (but not EC) correlated with age at baseline and follow-up. However, after age differences in memory were taken into account, none of the regional volumes was associated with memory performance at follow-up. In contrast, greater annual rate of shrinkage in EC (but not HC or PFC) predicted poorer memory performance. Thus, in a healthy and educated population, even mild age-related shrinkage of the EC may be a sensitive predictor of memory decline.


CXCR4 promotes B cell egress from Peyer's patches.
Peyer's patches (PPs) play a central role in supporting B cell responses against intestinal antigens, yet the factors controlling B cell passage through these mucosal lymphoid tissues are incompletely understood. We report that, in mixed chimeras, CXCR4-deficient B cells accumulate in PPs compared with their representation in other lymphoid tissues. CXCR4-deficient B cells egress from PPs more slowly than wild-type cells, whereas CXCR5-deficient cells egress more rapidly. The CXCR4 ligand, CXCL12, is expressed by cells adjacent to lymphatic endothelial cells in a zone that abuts but minimally overlaps with the CXCL13(+) follicle. CXCR4-deficient B cells show reduced localization to these CXCL12(+) perilymphatic zones, whereas CXCR5-deficient B cells preferentially localize in these regions. By photoconverting KikGR-expressing cells within surgically exposed PPs, we provide evidence that naive B cells transit PPs with an approximate residency half-life of 10 h. When CXCR4 is lacking, KikGR(+) B cells show a delay in PP egress. In summary, we identify a CXCL12(hi) perilymphatic zone in PPs that plays a role in overcoming CXCL13-mediated retention to promote B cell egress from these gut-associated lymphoid tissues.


Microbe observation and cultivation array (MOCA) for cultivating and analyzing environmental microbiota.
The use of culture-independent nucleic acid techniques, such as ribosomal RNA gene cloning library analysis, has unveiled the tremendous microbial diversity that exists in natural environments. In sharp contrast to this great achievement is the current difficulty in cultivating the majority of bacterial species or phylotypes revealed by molecular approaches. Although recent new technologies such as metagenomics and metatranscriptomics can provide more functionality information about the microbial communities, it is still important to develop the capacity to isolate and cultivate individual microbial species or strains in order to gain a better understanding of microbial physiology and to apply isolates for various biotechnological applications. We have developed a new system to cultivate bacteria in an array of droplets. The key component of the system is the microbe observation and cultivation array (MOCA), which consists of a Petri dish that contains an array of droplets as cultivation chambers. MOCA exploits the dominance of surface tension in small amounts of liquid to spontaneously trap cells in well-defined droplets on hydrophilic patterns. During cultivation, the growth of the bacterial cells across the droplet array can be monitored using an automated microscope, which can produce a real-time record of the growth. When bacterial cells grow to a visible microcolony level in the system, they can be transferred using a micropipette for further cultivation or analysis. MOCA is a flexible system that is easy to set up, and provides the sensitivity to monitor growth of single bacterial cells. It is a cost-efficient technical platform for bioassay screening and for cultivation and isolation of bacteria from natural environments.


Do facial movements express emotions or communicate motives?
This article addresses the debate between emotion-expression and motive-communication approaches to facial movements, focusing on Ekman's (1972) and Fridlund's (1994) contrasting models and their historical antecedents. Available evidence suggests that the presence of others either reduces or increases facial responses, depending on the quality and strength of the emotional manipulation and on the nature of the relationship between interactants. Although both display rules and social motives provide viable explanations of audience "inhibition" effects, some audience facilitation effects are less easily accommodated within an emotion-expression perspective. In particular, emotion is not a sufficient condition for a corresponding "expression," even discounting explicit regulation, and, apparently, "spontaneous" facial movements may be facilitated by the presence of others. Further, there is no direct evidence that any particular facial movement provides an unambiguous expression of a specific emotion. However, information communicated by facial movements is not necessarily extrinsic to emotion. Facial movements not only transmit emotion-relevant information but also contribute to ongoing processes of emotional action in accordance with pragmatic theories.


Sugars of the unfermented sap and the wine from the oil palm, Elaeis guinensis, tree.
The sugar composition of the unfermented sap from oil palm (Elaeis guinensis) trees growing in the plantations of the Nigerian Institute for Oil Palm Research, Benin City, has been determined. While sucrose concentration ranges from 9.59 to 10.59% (w/v) in the pure unfermented sap, that of either glucose or fructose is much less than 1% (w/v) (0.13-0.73% w/v). Raffinose occurs in traces only (0.13-0.35 w/v). These results were derived from our improved methods which eliminate completely, or reduce to a bare minimum, fermentation of the sap during collection. The variation with time of storage of the individual sugars in the sap during fermentation to form palm wine reveals that, as sucrose steadily decreases, fructose reaches a peak at 1.51% (w/v) at the 9th hour, and thereafter declines, while glucose and raffinose remain continuously low; all sugars disappear beyond the 33rd hour. Concomittantly, pH decreases from pH 6.60 at zero time and stabilizes at pH 3.30 after 48 h, while titrable acidity increases continuously up until the 96th hour. These changes account for the variations in the quality of palm wine during storages.


The preparation of magnetic molecularly imprinted nanoparticles for the recognition of bovine hemoglobin.
The protein imprinted technique combining surface imprinting and nano-sized supports materials is an attractive strategy for protein recognition and rapid separation. In this work, we imprinted bovine hemoglobin (BHb) on magnetic nanoparticles. With itaconic acid (IA) and acrylamide (AAm) as the monomers, the experiment was carried out in aqueous media via surface-imprinting technique. The effects of initial concentration and adsorption time over the adsorption capacity of both imprinted and non-imprinted nanoparticles were analyzed. The maximum adsorption capability of imprinted nanoparticles was found to be 77.6 mg g(-1), which was 3.1-4.3 times higher than that of the non-imprinted nanoparticles prepared at the same conditions. This resulted in the successful formation of imprinting cavities. Moreover, in selective adsorption experiment and competitive batch rebinding test, imprinted nanoparticles exhibited a high specific recognition of the template protein over the non-imprinted protein.


Nutrition interventions for healthy ageing across the lifespan: a conference report.
Thanks to advances in modern medicine over the past century, the world's population has experienced a marked increase in longevity. However, disparities exist that lead to groups with both shorter lifespan and significantly diminished health, especially in the aged. Unequal access to proper nutrition, healthcare services, and information to make informed health and nutrition decisions all contribute to these concerns. This in turn has hastened the ageing process in some and adversely affected others' ability to age healthfully. Many in developing as well as developed societies are plagued with the dichotomy of simultaneous calorie excess and nutrient inadequacy. This has resulted in mental and physical deterioration, increased non-communicable disease rates, lost productivity and quality of life, and increased medical costs. While adequate nutrition is fundamental to good health, it remains unclear what impact various dietary interventions may have on improving healthspan and quality of life with age. With a rapidly ageing global population, there is an urgent need for innovative approaches to health promotion as individual's age. Successful research, education, and interventions should include the development of both qualitative and quantitative biomarkers and other tools which can measure improvements in physiological integrity throughout life. Data-driven health policy shifts should be aimed at reducing the socio-economic inequalities that lead to premature ageing. A framework for progress has been proposed and published by the World Health Organization in its Global Strategy and Action Plan on Ageing and Health. This symposium focused on the impact of nutrition on this framework, stressing the need to better understand an individual's balance of intrinsic capacity and functional abilities at various life stages, and the impact this balance has on their mental and physical health in the environments they inhabit.


Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma.
1) To correlate the methylation status of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter to its gene and protein expression levels in glioblastoma and 2) to determine the most reliable method for using MGMT to predict the response to adjuvant therapy in patients with glioblastoma. The MGMT gene is epigenetically silenced by promoter hypermethylation in gliomas, and this modification has emerged as a relevant predictor of therapeutic response. Fifty-one cases of glioblastoma were analyzed for MGMT promoter methylation by methylation-specific PCR and pyrosequencing, gene expression by real time polymerase chain reaction, and protein expression by immunohistochemistry. MGMT promoter methylation was found in 43.1% of glioblastoma by methylation-specific PCR and 38.8% by pyrosequencing. A low level of MGMT gene expression was correlated with positive MGMT promoter methylation (p = 0.001). However, no correlation was found between promoter methylation and MGMT protein expression (p = 0.297). The mean survival time of glioblastoma patients submitted to adjuvant therapy was significantly higher among patients with MGMT promoter methylation (log rank = 0.025 by methylation-specific PCR and 0.004 by pyrosequencing), and methylation was an independent predictive factor that was associated with improved prognosis by multivariate analysis. MGMT promoter methylation status was a more reliable predictor of susceptibility to adjuvant therapy and prognosis of glioblastoma than were MGMT protein or gene expression levels. Methylation-specific polymerase chain reaction and pyrosequencing methods were both sensitive methods for determining MGMT promoter methylation status using DNA extracted from frozen tissue.


Modeling the Drosophila gene cluster regulation network for muscle development.
The development of accurate and reliable dynamical modeling procedures that describe the time evolution of gene expression levels is a prerequisite to understanding and controlling the transcription process. We focused on data from DNA microarray time series for 20 Drosophila genes involved in muscle development during the embryonic stage. Genes with similar expression profiles were clustered on the basis of a translation-invariant and scale-invariant distance measure. The time evolution of these clusters was modeled using coupled differential equations. Three model structures involving a transcription term and a degradation term were tested. The parameters were identified in successive steps: network construction, parameter optimization, and parameter reduction. The solutions were evaluated on the basis of the data reproduction and the number of parameters, as well as on two biology-based requirements: the robustness with respect to parameter variations and the values of the expression levels not being unrealistically large upon extrapolation in time. Various solutions were obtained that satisfied all our evaluation criteria. The regulatory networks inferred from these solutions were compared with experimental data. The best solution has half of the experimental connections, which compares favorably with previous approaches. Biasing the network toward the experimental connections led to the identification of a model that is only slightly less good on the basis of the evaluation criteria. The non-uniqueness of the solutions and the variable agreement with experimental connections were discussed in the context of the different hypotheses underlying this type of approach.


Temperature dependence of transport properties of spiro-MeOTAD as a hole transport material in solid-state dye-sensitized solar cells.
The internal transport and recombination parameters of solid-state dye-sensitized solar cells (ssDSCs) using the amorphous organic semiconductor 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (spiro-MeOTAD) as a hole transport material (HTM) are investigated using electrical impedance spectroscopy. Devices were fabricated using flat and nanostructured TiO2 and compared to systems using nanostructured ZrO2 to differentiate between the transport processes within the different components of the ssDSC. The effect of chemically p-doping the HTM on its transport was investigated, and its temperature dependence was examined and analyzed using the Arrhenius equation. Using this approach the activation energy of the hole hopping transport within the undoped spiro-MeOTAD film was determined to be 0.34 ± 0.02 and 0.40 ± 0.02 eV for the mesoporous TiO2 and ZrO2 systems, respectively.


Assessment of the potential impact of a reminder system on the reduction of diagnostic errors: a quasi-experimental study.
Computerized decision support systems (DSS) have mainly focused on improving clinicians' diagnostic accuracy in unusual and challenging cases. However, since diagnostic omission errors may predominantly result from incomplete workup in routine clinical practice, the provision of appropriate patient- and context-specific reminders may result in greater impact on patient safety. In this experimental study, a mix of easy and difficult simulated cases were used to assess the impact of a novel diagnostic reminder system (ISABEL) on the quality of clinical decisions made by various grades of clinicians during acute assessment. Subjects of different grades (consultants, registrars, senior house officers and medical students), assessed a balanced set of 24 simulated cases on a trial website. Subjects recorded their clinical decisions for the cases (differential diagnosis, test-ordering and treatment), before and after system consultation. A panel of two pediatric consultants independently provided gold standard responses for each case, against which subjects' quality of decisions was measured. The primary outcome measure was change in the count of diagnostic errors of omission (DEO). A more sensitive assessment of the system's impact was achieved using specific quality scores; additional consultation time resulting from DSS use was also calculated. 76 subjects (18 consultants, 24 registrars, 19 senior house officers and 15 students) completed a total of 751 case episodes. The mean count of DEO fell from 5.5 to 5.0 across all subjects (repeated measures ANOVA, p < 0.001); no significant interaction was seen with subject grade. Mean diagnostic quality score increased after system consultation (0.044; 95% confidence interval 0.032, 0.054). ISABEL reminded subjects to consider at least one clinically important diagnosis in 1 in 8 case episodes, and prompted them to order an important test in 1 in 10 case episodes. Median extra time taken for DSS consultation was 1 min (IQR: 30 sec to 2 min). The provision of patient- and context-specific reminders has the potential to reduce diagnostic omissions across all subject grades for a range of cases. This study suggests a promising role for the use of future reminder-based DSS in the reduction of diagnostic error.


Clathrin-mediated endocytosis and recycling of autocrine motility factor receptor to fibronectin fibrils is a limiting factor for NIH-3T3 cell motility.
Autocrine motility factor receptor (AMF-R) is internalized via a clathrin-independent pathway to smooth endoplasmic reticulum tubules. This endocytic pathway is shown here to be inhibited by methyl-(beta)-cyclodextrin (m(beta)CD) implicating caveolae or caveolae-like structures in AMF internalization to smooth ER. AMF-R is also internalized via a clathrin-dependent pathway to a transferrin receptor-negative, LAMP-1/lgpA-negative endocytic compartment identified by electron microscopy as a multivesicular body (MVB). Endocytosed AMF recycles to cell surface fibrillar structures which colocalize with fibronectin; AMF-R recycling is inhibited at 20 degrees C, which blocks endocytosis past the early endosome, but not by m(beta)CD demonstrating that AMF-R recycling to fibronectin fibrils is mediated by clathrin-dependent endocytosis to MVBs. Microtubule disruption with nocodazole did not affect delivery of bAMF to cell surface fibrils indicating that recycling bAMF traverses the MVB but not a later endocytic compartment. Plating NIH-3T3 cells on an AMF coated substrate did not specifically affect cell adhesion but prevented bAMF delivery to cell surface fibronectin fibrils and reduced cell motility. AMF-R internalization and recycling via the clathrin-mediated pathway are therefore rate-limiting for cell motility. This recycling pathway to the site of deposition of fibronectin may be implicated in the de novo formation of cellular attachments or the remodeling of the extracellular matrix during cell movement.


Association of new loci identified in European genome-wide association studies with susceptibility to type 2 diabetes in the Japanese.
Several novel susceptibility loci for type 2 diabetes have been identified through genome-wide association studies (GWAS) for type 2 diabetes or quantitative traits related to glucose metabolism in European populations. To investigate the association of the 13 new European GWAS-derived susceptibility loci with type 2 diabetes in the Japanese population, we conducted a replication study using 3 independent Japanese case-control studies. We examined the association of single nucleotide polymorphisms (SNPs) within 13 loci (MTNR1B, GCK, IRS1, PROX1, BCL11A, ZBED3, KLF14, TP53INP1, KCNQ1, CENTD2, HMGA2, ZFAND6 and PRC1) with type 2 diabetes using 4,964 participants (2,839 cases and 2,125 controls) from 3 independent Japanese samples. The association of each SNP with type 2 diabetes was analyzed by logistic regression analysis. Further, we performed combined meta-analyses for the 3 studies and previously performed Japanese GWAS data (4,470 cases vs. 3,071 controls). The meta-analysis revealed that rs2943641 in the IRS1 locus was significantly associated with type 2 diabetes, (P = 0.0034, OR = 1.15 95% confidence interval; 1.05-1.26) and 3 SNPs, rs10930963 in the MTNR1B locus, rs972283 in the KLF14 locus, and rs231362 in the KCNQ1 locus, had nominal association with type 2 diabetes in the present Japanese samples (P<0.05). These results indicate that IRS1 locus may be common locus for type 2 diabetes across different ethnicities.


Src mediates cigarette smoke-induced resistance to tyrosine kinase inhibitors in NSCLC cells.
The EGF receptor (EGFR) is a proto-oncogene commonly dysregulated in several cancers including non-small cell lung carcinoma (NSCLC) and, thus, is targeted for treatment using tyrosine kinase inhibitors (TKI) such as erlotinib. However, despite the efficacy observed in patients with NSCLC harboring oncogenic variants of the EGFR, general ineffectiveness of TKIs in patients with NSCLC who are current and former smokers necessitates identification of novel mechanisms to overcome this phenomenon. Previously, we showed that NSCLC cells harboring either wild-type (WT) EGFR or oncogenic mutant (MT) L858R EGFR become resistant to the effects of TKIs when exposed to cigarette smoke, evidenced by their autophosphorylation and prolonged downstream signaling. Here, we present Src as a target mediating cigarette smoke-induced resistance to TKIs in both WT EGFR- and L858R MT EGFR-expressing NSCLC cells. First, we show that cigarette smoke exposure of A549 cells leads to time-dependent activation of Src, which then abnormally binds to the WT EGFR causing TKI resistance, contrasting previous observations of constitutive binding between inactive Src and TKI-sensitive L858R MT EGFR. Next, we show that Src inhibition restores TKI sensitivity in cigarette smoke-exposed NSCLC cells, preventing EGFR autophosphorylation in the presence of erlotinib. Furthermore, we show that overexpression of a dominant-negative Src (Y527F/K295R) restores TKI sensitivity to A549 exposed to cigarette smoke. Importantly, the TKI resistance that emerges even in cigarette smoke-exposed L858R EGFR-expressing NSCLC cells could be eliminated with Src inhibition. Together, these findings offer new rationale for using Src inhibitors for treating TKI-resistant NSCLC commonly observed in smokers.


Syncopation affects free body-movement in musical groove.
One of the most immediate and overt ways in which people respond to music is by moving their bodies to the beat. However, the extent to which the rhythmic complexity of groove-specifically its syncopation-contributes to how people spontaneously move to music is largely unexplored. Here, we measured free movements in hand and torso while participants listened to drum-breaks with various degrees of syncopation. We found that drum-breaks with medium degrees of syncopation were associated with the same amount of acceleration and synchronisation as low degrees of syncopation. Participants who enjoyed dancing made more complex movements than those who did not enjoy dancing. While for all participants hand movements accelerated more and were more complex, torso movements were more synchronised to the beat. Overall, movements were mostly synchronised to the main beat and half-beat level, depending on the body-part. We demonstrate that while people do not move or synchronise much to rhythms with high syncopation when dancing spontaneously to music, the relationship between rhythmic complexity and synchronisation is less linear than in simple finger-tapping studies.


An epidemiological overview of malaria in Bangladesh.
Bangladesh is one of the four major malaria-endemic countries in South-East Asia having approximately 34% of its population at risk of malaria. This paper aims at providing an overview of the malaria situation in this country. Relevant information was retrieved from published articles and reports in PubMed and Google Scholar. Malaria in Bangladesh is concentrated in 13 districts with a prevalence ranging between 3.1% and 36%, and is mostly caused by Plasmodium falciparum. Geographical conditions pose a potential risk for Plasmodium knowlesi malaria. Resistance to a number of drugs previously recommended for treatment has been reported. Low socio-economic status, poor schooling and close proximity to water bodies and forest areas comprise important risk factors. Despite the significant steps in Long Lasting Insecticide Net (LLIN)/Insecticide Treated Net (ITN) coverage in Bangladesh, there are still many challenges including the extension of malaria support to the remote areas of Bangladesh, where malaria prevalence is higher, and further improvements in the field of referral system and treatment.


Linguistic correlates of self in deceptive oral autobiographical narratives.
The current study collected orally-delivered autobiographical narratives from a sample of 44 undergraduate students. Participants were asked to produce both deceptive and non-deceptive versions of their narrative to two specific autobiographical question prompts while standing in front of a video camera. Narratives were then analyzed with Coh-Metrix software on 33 indices of linguistic cohesion. Following a Bonferroni correction for the large number of linguistic variables (p<.002), results indicated that the deceptive narratives contained more explicit action verbs, less linguistic complexity, and less referential coherence (sentences being cohesive with each other). The results support a theory that, in deceptive narratives, there is greater narrative distance between the self that narrates and the self that is narrated about. This suggests that narrative selves are constituted not as autonomous selves, but are subject to processes (e.g., psychological, linguistic, social) that are likely operating on a subconscious level.


When two become one: the role of oxytocin in interpersonal coordination and cooperation.
Cooperation involves intentional coordinated acts performed to achieve potentially positive outcomes. Here we present a novel explanatory model of cooperation, which focuses on the role of the oxytocinergic system in promoting interpersonal coordination and synchrony. Cooperation was assessed using a novel computerized drawing task that may be performed individually or cooperatively by two participants who coordinate their actions. Using a within-subject crossover design, 42 participants performed the task alone and with a partner following the administration of placebo and oxytocin 1 week apart. The data indicate that following placebo administration, participants performed better alone than in pairs. Yet, the administration of oxytocin improved paired performance up to the level of individual performance. This effect depended on the personality traits of cooperativeness or competitiveness. It is concluded that oxytocin may play a key role in enhancing social synchrony and coordination of behaviors required for cooperation.


Protocol for the Cultural Translation and Adaptation of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project Endometriosis Participant Questionnaire (EPHect).
Endometriosis affects 10% of women worldwide and is one of the most common causes of chronic pelvic pain and infertility. However, causal mechanisms of this disease remain unknown due to its heterogeneous presentation. In order to successfully study its phenotypic variation, large sample sizes are needed. Pooling of data across sites is not always feasible given the large variation in the complexity and quality of the data collected. The World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect) have developed an endometriosis participant questionnaire (EPQ) to harmonize non-surgical clinical participant characteristic data relevant to endometriosis research, allowing for large-scale collaborations in English-speaking populations. Although the WERF EPHect EPQs have been translated into different languages, no study has examined the cross-cultural translation and adaptation for content and face validity. In order to investigate this, we followed the standard guidelines for cross-cultural adaptation and translation of the minimum version of the EPQ (EPQ-M) using 40 patients who underwent laparoscopic surgery in Turkey and 40 women in Northern Cyprus, aged between 18 and 55. We assessed the consistency by using cognitive testing and found the EPHect EPQ-M to be comprehensive, informative, and feasible in these two Turkish-speaking populations. The translated and adapted questionnaire was found to be epidemiologically robust, taking around 30-60 min to complete; furthermore, participants reported a similar understanding of the questions, showing that common perspectives were explored. Results from the cognitive testing process led to minor additions to some items such as further descriptive and/or visuals in order to clarify medical terminology. This paper illustrates the first successful cross-cultural translation and adaptation of the EPHect EPQ-M and should act as a tool to allow for further studies that wish to use this questionnaire in different languages. Standardized tools like this should be adopted by researchers worldwide to facilitate collaboration and aid in the design and conduction of global studies to ultimately help those affected by endometriosis and its associated symptoms.


Focal adhesion kinase: at the crossroads of signal transduction.
Morphogenetic processes during development, including cell migration, depend on signals from both the extracellular matrix (ECM) and soluble signaling factors. Extensive evidence has shown that the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), is activated in response to both kind of signal. The most definitive evidence that FAK is directly downstream of signals initiated by the ECM comes from comparing the phenotypes of mice deficient for FAK and the ECM molecule, fibronectin: in both cases embryos die at about E8.5 and display almost identical severe vascular and other mesodermal defects. It is now clear that there are additional FAK-like proteins, indicating the existence of a FAK family. Furthermore, FAK is not located at adhesive sites in all cells where it is expressed. This, plus extensive data indicating that FAK becomes activated in response to several soluble signaling factors, suggests that the FAK family may be at the crossroads of multiple signaling pathways that affect cell and developmental processes.


Car-Parrinello Monitor for More Robust Born-Oppenheimer Molecular Dynamics.
Born-Oppenheimer molecular dynamics (BOMD) is a promising simulation method for exploring the possible reaction pathways of a chemical system, but one significant challenge is the increased difficulty of converging the self-consistent field (SCF) calculation that often accompanies the breaking and forming of chemical bonds. To address this challenge, we developed an enhancement to the BOMD simulation method called the Car-Parrinello monitor (CPMonitor) that uses Car-Parrinello molecular dynamics (CPMD) to recover from SCF convergence failures. CPMonitor works by detecting SCF convergence failures in BOMD and switching to a CPMD Hamiltonian to propagate through the region of configuration space where the SCF calculation is unable to converge, then switching back to BOMD when good convergence behavior is re-established. We present a series of simulation studies that use CPMonitor, including detailed studies of the thermodynamic and dynamical properties of simple systems, as well as ab initio nanoreactor simulations containing transition metal atoms that were previously not possible to simulate using standard BOMD methods. Our studies show that CPMonitor can make BOMD simulations robust to SCF convergence difficulties and improve simulation performance and stability in reaction discovery applications.