A very simple, re-executable neuroimaging publication.
Reproducible research is a key element of the scientific process. Re-executability of neuroimaging workflows that lead to the conclusions arrived at in the literature has not yet been sufficiently addressed and adopted by the neuroimaging community. In this paper, we document a set of procedures, which include supplemental additions to a manuscript, that unambiguously define the data, workflow, execution environment and results of a neuroimaging analysis, in order to generate a verifiable re-executable publication. Re-executability provides a starting point for examination of the generalizability and reproducibility of a given finding.


The Sky Has Its Limits in COVID-19 Testing.
At the time of writing, in July 2020, the COVID-19 pandemic has already inflicted dramatic international restrictions, including airports closing and limiting international travel. It has been suggested that re-opening of airports should involve and even rely on testing travelers for COVID-19. This paper discusses the methodology of estimating the detection and diagnostic accuracy of COVID-19 tests. It explains the clear distinction between the technical characteristics of the tests, the detection measures, and the diagnostic measures that have clinical and public health implications. It demonstrates the importance of the prevalence of COVID-19 in terms of determining the ability of a test to yield a diagnosis. We explain the methodology of evaluating diagnostic tests, using the predictive summary index (PSI), and the minimum number of tests that need to be performed in order to correctly diagnose one person, which is estimated by 1/PSI. In a population with low prevalence, even a high-sensitivity test may lead to a high percentage of false positive diagnoses, resulting in the need for multiple high-cost tests to achieve a correct diagnosis. Thus, basing a policy for opening airports on diagnostic testing, even with the best test for COVID-19, has some limits.


Simultaneous Determination of Protein Structure and Dynamics Using Cryo-Electron Microscopy.
Cryo-electron microscopy is rapidly emerging as a powerful technique to determine the structures of complex macromolecular systems elusive to other techniques. Because many of these systems are highly dynamical, characterizing their movements is also a crucial step to unravel their biological functions. To achieve this goal, we report an integrative modeling approach to simultaneously determine structure and dynamics of macromolecular systems from cryo-electron microscopy density maps. By quantifying the level of noise in the data and dealing with their ensemble-averaged nature, this approach enables the integration of multiple sources of information to model ensembles of structures and infer their populations. We illustrate the method by characterizing structure and dynamics of the integral membrane receptor STRA6, thus providing insights into the mechanisms by which it interacts with retinol binding protein and translocates retinol across the membrane.


Description of a new octoploid frog species (Anura: Pipidae: Xenopus) from the Democratic Republic of the Congo, with a discussion of the biogeography of African clawed frogs in the Albertine Rift.
We describe a new octoploid species of African clawed frog (Xenopus) from the Lendu Plateau in the northern Albertine Rift of eastern Democratic Republic of the Congo. This species is the sister taxon of Xenopus vestitus (another octoploid), but is distinguished by a unique morphology, vocalization and molecular divergence in mitochondrial and autosomal DNA. Using a comprehensive genetic sample, we provide new information on the species ranges and intra-specific diversity of African clawed frogs from the Albertine Rift, including the details of a small range extension for the critically endangered Xenopus itombwensis and previously uncharacterized variation in Xenopus laevis. We also detail a new method for generating cytogenetic preparations in the field that can be stored at room temperature for up to 3 weeks. While extending our understanding of the extant diversity in the Albertine Rift, this new species highlights components of species diversity in ancestral African clawed frogs that are not represented by known extant descendants.


Design and validation of a self-administered test to assess bullying (bull-M) in high school Mexicans: a pilot study.
Bullying (Bull) is a public health problem worldwide, and Mexico is not exempt. However, its epidemiology and early detection in our country is limited, in part, by the lack of validated tests to ensure the respondents' anonymity. The aim of this study was to validate a self-administered test (Bull-M) for assessing Bull among high-school Mexicans. Experts and school teachers from highly violent areas of Ciudad Juarez (Chihuahua, México), reported common Bull behaviors. Then, a 10-item test was developed based on twelve of these behaviors; the students' and peers' participation in Bull acts and in some somatic consequences in Bull victims with a 5-point Likert frequency scale. Validation criteria were: content (CV, judges); reliability [Cronbach's alpha (CA), test-retest (spearman correlation, rs)]; construct [principal component (PCA), confirmatory factor (CFA), goodness-of-fit (GF) analysis]; and convergent (Bull-M vs. Bull-S test) validity. Bull-M showed good reliability (CA = 0.75, rs = 0.91; p < 0.001). Two factors were identified (PCA) and confirmed (CFA): "bullying me (victim)" and "bullying others (aggressor)". GF indices were: Root mean square error of approximation (0.031), GF index (0.97), and normalized fit index (0.92). Bull-M was as good as Bull-S for measuring Bull prevalence. Bull-M has a good reliability and convergent validity and a bi-modal factor structure for detecting Bull victims and aggressors; however, its external validity and sensitivity should be analyzed on a wider and different population.


An Optimal Transport Based Transferable System for Detection of Erroneous Somato-Sensory Feedback from Neural Signals.
This study is aimed at the detection of single-trial feedback, perceived as erroneous by the user, using a transferable classification system while conducting a motor imagery brain-computer interfacing (BCI) task. The feedback received by the users are relayed from a functional electrical stimulation (FES) device and hence are somato-sensory in nature. The BCI system designed for this study activates an electrical stimulator placed on the left hand, right hand, left foot, and right foot of the user. Trials containing erroneous feedback can be detected from the neural signals in form of the error related potential (ErrP). The inclusion of neuro-feedback during the experiments indicated the possibility that ErrP signals can be evoked when the participant perceives an error from the feedback. Hence, to detect such feedback using ErrP, a transferable (offline) decoder based on optimal transport theory is introduced herein. The offline system detects single-trial erroneous trials from the feedback period of an online neuro-feedback BCI system. The results of the FES-based feedback BCI system were compared to a similar visual-based (VIS) feedback system. Using our framework, the error detector systems for both the FES and VIS feedback paradigms achieved an F1-score of 92.66% and 83.10%, respectively, and are significantly superior to a comparative system where an optimal transport was not used. It is expected that this form of transferable and automated error detection system compounded with a motor imagery system will augment the performance of a BCI and provide a better BCI-based neuro-rehabilitation protocol that has an error control mechanism embedded into it.


Stability Limit of Electrified Droplets.
In many physical processes, including cloud electrification, electrospray, and demulsification, droplets and bubbles are exposed to electric fields and may either remain whole or burst in response to electrical stresses. Determining the stability limit of a droplet exposed to an external electric field has been a long-standing mathematical challenge, and the only analytical treatment to date is an approximate calculation for the particular case of a free-floating droplet. Here we demonstrate, experimentally and theoretically, that the stability limit of a conducting droplet or bubble exposed to an external electric field is described by a power law with broad generality that, in practice, applies to the cases in which the droplet or bubble is pinned or sliding on a conducting surface or free floating. This power law can facilitate the design of devices for liquid manipulation via a simple formula that captures the parameter range of bubbles and droplets that can be supported on electrified surfaces.


Elucidating poor decision-making in a rat gambling task.
Although poor decision-making is a hallmark of psychiatric conditions such as attention deficit/hyperactivity disorder, pathological gambling or substance abuse, a fraction of healthy individuals exhibit similar poor decision-making performances in everyday life and specific laboratory tasks such as the Iowa Gambling Task. These particular individuals may provide information on risk factors or common endophenotypes of these mental disorders. In a rodent version of the Iowa gambling task--the Rat Gambling Task (RGT), we identified a population of poor decision makers, and assessed how these rats scored for several behavioral traits relevant to executive disorders: risk taking, reward seeking, behavioral inflexibility, and several aspects of impulsivity. First, we found that poor decision-making could not be well predicted by single behavioral and cognitive characteristics when considered separately. By contrast, a combination of independent traits in the same individual, namely risk taking, reward seeking, behavioral inflexibility, as well as motor impulsivity, was highly predictive of poor decision-making. Second, using a reinforcement-learning model of the RGT, we confirmed that only the combination of extreme scores on these traits could induce maladaptive decision-making. Third, the model suggested that a combination of these behavioral traits results in an inaccurate representation of rewards and penalties and inefficient learning of the environment. Poor decision-making appears as a consequence of the over-valuation of high-reward-high-risk options in the task. Such a specific psychological profile could greatly impair clinically healthy individuals in decision-making tasks and may predispose to mental disorders with similar symptoms.


Medical Council of India's new guidelines on admission of persons with specified disabilities: Unfair, discriminatory and unlawful.
The Medical Council of India (MCI)'s recent guidelines on admission of persons with specified disabilities into the medical course under the disability quota has escalated into a huge controversy. Multiple litigations have been initiated against MCI by successful National Eligibility cum Entrance Test candidates with disabilities across the country. In light of our new Rights of Persons with Disabilities Act, 2016, and the United Nations Convention on the Rights of Persons with Disabilities, I argue in this essay that these guidelines are unfair, discriminatory and unlawful. I quote Supreme Court judgments on reasonable accommodation, equality and discrimination and highlight the exclusion of doctors with disabilities in policy making.


Effectiveness of Face Masks in Preventing Airborne Transmission of SARS-CoV-2.
Guidelines from the CDC and the WHO recommend the wearing of face masks to prevent the spread of coronavirus (CoV) disease 2019 (COVID-19); however, the protective efficiency of such masks against airborne transmission of infectious severe acute respiratory syndrome CoV-2 (SARS-CoV-2) droplets/aerosols is unknown. Here, we developed an airborne transmission simulator of infectious SARS-CoV-2-containing droplets/aerosols produced by human respiration and coughs and assessed the transmissibility of the infectious droplets/aerosols and the ability of various types of face masks to block the transmission. We found that cotton masks, surgical masks, and N95 masks all have a protective effect with respect to the transmission of infective droplets/aerosols of SARS-CoV-2 and that the protective efficiency was higher when masks were worn by a virus spreader. Importantly, medical masks (surgical masks and even N95 masks) were not able to completely block the transmission of virus droplets/aerosols even when completely sealed. Our data will help medical workers understand the proper use and performance of masks and determine whether they need additional equipment to protect themselves from infected patients.IMPORTANCE Airborne simulation experiments showed that cotton masks, surgical masks, and N95 masks provide some protection from the transmission of infective SARS-CoV-2 droplets/aerosols; however, medical masks (surgical masks and even N95 masks) could not completely block the transmission of virus droplets/aerosols even when sealed.


IGHV gene usage and mutational status in follicular lymphoma: Correlations with prognosis and patient age.
Follicular lymphoma (FL) is a heterogeneous disease with some patients developing progressively or transformed disease early, whereas others follow an indolent clinical course. We evaluated the prognostic value of immunoglobulin heavy chain variable (IGHV) gene usage and mutational status in FL patients. One hundred and four IGH sequences were obtained in tumour samples from 99 patients. The IGHV3 subgroup had the highest usage frequency (57.7%) with IGHV3-23 being the most common sequence. Patients with the IGHV5 subgroup or IGHV sequences from more than one subgroup had significantly less favourable prognosis with an estimated 5-year survival of 62.5 and 50.0%, respectively, as compared with a 5-year survival of 95.1% for patients with other IGHV subgroups (P=0.013 and P<0.001, log-rank). The poor survival associated with IGHV5 or >1 IGHV subgroup usage was an independent prognostic factor in Cox multivariate analysis (P=0.005). IGHV genes were unmutated showing >98% homology in 15.2% of cases. Contrasting the situation in chronic lymphocytic leukaemia (CLL), the presence of unmutated sequences did not yield prognostic information, although unmutated sequences were associated with age at diagnosis >60 years (P=0.022, Fisher's exact). In conclusion, our results indicate that analysis of IGHV gene usage might aid in predicting prognosis for FL patients.


Hassallidin A, a glycosylated lipopeptide with antifungal activity from the cyanobacterium Hassallia sp.
Hassallidin A (1), a new antifungal glycosylated lipopeptide, was isolated from an epilithic cyanobacterium collected in Bellano, Italy, identified as Tolypothrix (basionym Hassallia) species. Chemical, mass spectrometric, and spectroscopic analyses, including one- and two-dimensional NMR, were performed to determine an esterified eight-residue cyclic peptide linked with a carbohydrate and a fatty acid residue. Chiral GC-MS analysis revealed the occurrence of the nonproteinogenic amino acids D-allo-Thr, D-Thr, D-Tyr, D-Gln, and dehydroaminobutyric acid (Dhb) within the peptide moiety. The additional components of hassallidin A could be identified as alpha,beta-dihydroxytetradecanoic acid (Dht) and mannose. This is the first report on a cyclic peptide of cyanobacterial origin that contains both a fatty acid and a carbohydrate moiety. Compound 1 exhibits antifungal activity against Aspergillus fumigatus and Candida albicans with MIC values of 4.8 microg/mL for both test organisms.


Adenovirus-vectored Ebola vaccines.
The 2014 outbreak of Ebola virus disease in West Africa has highlighted the need for the availability of effective vaccines against outbreak pathogens that are suitable for use in frontline workers who risk their own health in the course of caring for those with the disease, and also for members of the community in the affected area. Along with effective contact tracing and quarantine, use of a vaccine as soon as an outbreak is identified could greatly facilitate rapid control and prevent the outbreak from spreading. This review describes the progress that has been made in producing and testing adenovirus-based Ebola vaccines in both pre-clinical and clinical studies, and considers the likely future use of these vaccines.


Obstetric and neonatal outcomes for women with reversed and non-reversed type III female genital mutilation.
To record and compare obstetric and neonatal complication rates in women with reversed and non-reversed type III female genital mutilation (FGM). A retrospective observational study comparing cesarean delivery rates and neonatal outcomes of primiparous and multiparous women who had or had not undergone reversal of FGM III. Of the 250 women, 230 (92%) had an FGM reversal. Of these, 50 (21.7%) were primiparous (cesarean delivery rate 17/50; 34%) and 180 (78.3%) were multiparous (cesarean delivery rate 28/180; 15.6%). Of the 20 women who had not had an FGM reversal, 7 (35%) were primiparous (cesarean delivery rate 5/7; 71.4%) and 13 (65%) were multiparous (cesarean delivery rate 7/13; 53.8%). The cesarean delivery rates for primiparae and multiparae were 32.9% and 25%, respectively. Multiparous women with FGM III reversal had a lower possibility of cesarean delivery compared with the hospital multiparous population (P=0.003) and multiparae who had not undergone FGM III reversal (P=0.007). There was no significant association between Apgar scores or blood loss at vaginal delivery and FGM reversal. Reversal of FGM III significantly reduced the increased risk of cesarean delivery seen with multiparae who have FGM III.


Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol zeta.
Cell cycle checkpoints and DNA repair act in concert to ensure DNA integrity during perturbation of normal replication or in response to genotoxic agents. Deficiencies in these protective mechanisms can lead to cellular transformation and ultimately tumorigenesis. Here we focused on Rev3, the catalytic subunit of the low-fidelity DNA repair polymerase zeta. Rev3 is believed to play a role in double-strand break (DSB)-induced DNA repair by homologous recombination. In line with this hypothesis, we show the accumulation of chromatin-bound Rev3 protein in late S-G2 of untreated cells and in response to clastogenic DNA damage as well as an gamma-H2AX accumulation in Rev3-depleted cells. Moreover, serine 995 of Rev3 is in vitro phosphorylated by the DSB-inducible checkpoint kinase, Chk2. Our data also disclose a significant reduction of rev3 gene expression in 74 colon carcinomas when compared to the normal adjacent tissues. This reduced expression is independent of the carcinoma stages, suggesting that the downregulation of rev3 might have occurred early during tumorigenesis.


A new role for MCM1 in yeast: cell cycle regulation of SW15 transcription.
In the yeast Saccharomyces cerevisiae cell cycle-regulated SW15 transcription is essential for ensuring that mother and not daughter cells switch mating type. We have identified a 55-bp promoter sequence that appears to be responsible for restricting transcription to the late S, G2, and M phases of the cell cycle. Two proteins, MCM1, a transcription factor described previously, and SFF (SWI five factor, a newly identified factor) bind this sequence in vitro. MCM1 binds the DNA tightly on its own, but SFF will only bind as part of a ternary complex with MCM1. We observe a strong correlation between the ability of mutated SWI5 promoter sequences to form a ternary MCM1-SFF-containing complex in vitro and to activate transcription in vivo, which suggests that efficient transcription requires that both proteins bind DNA. Through its interactions with cell type-specific coactivators and corepressors, MCM1 controls cell type-specific expression of pheromone and receptor genes. By analogy, we propose that SFF enables MCM1 to function as a part of a cell cycle-regulated transcription complex.


Diagnostic evaluation of multiplexed reverse transcription-PCR microsphere array assay for detection of foot-and-mouth and look-alike disease viruses.
A high-throughput multiplexed assay was developed for the differential laboratory detection of foot-and-mouth disease virus (FMDV) from viruses that cause clinically similar diseases of livestock. This assay simultaneously screens for five RNA and two DNA viruses by using multiplexed reverse transcription-PCR (mRT-PCR) amplification coupled with a microsphere hybridization array and flow-cytometric detection. Two of the 17 primer-probe sets included in this multiplex assay were adopted from previously characterized real-time RT-PCR (rRT-PCR) assays for FMDV. The diagnostic accuracy of the mRT-PCR assay was evaluated using 287 field samples, including 247 samples (213 true-positive samples and 35 true-negative samples) from suspected cases of foot-and-mouth disease collected from 65 countries between 1965 and 2006 and 39 true-negative samples collected from healthy animals. The mRT-PCR assay results were compared to those of two singleplex rRT-PCR assays, using virus isolation with antigen enzyme-linked immunosorbent assays as the reference method. The diagnostic sensitivity of the mRT-PCR assay for FMDV was 93.9% (95% confidence interval [CI], 89.8 to 96.4%), and the sensitivity was 98.1% (95% CI, 95.3 to 99.3%) for the two singleplex rRT-PCR assays used in combination. In addition, the assay could reliably differentiate between FMDV and other vesicular viruses, such as swine vesicular disease virus and vesicular exanthema of swine virus. Interestingly, the mRT-PCR detected parapoxvirus (n = 2) and bovine viral diarrhea virus (n = 2) in clinical samples, demonstrating the screening potential of this mRT-PCR assay to identify viruses in FMDV-negative material not previously recognized by using focused single-target rRT-PCR assays.


Correlating Single Crystal Structure, Nanomechanical, and Bulk Compaction Behavior of Febuxostat Polymorphs.
Febuxostat exhibits unprecedented solid forms with a total of 40 polymorphs and pseudopolymorphs reported. Polymorphs differ in molecular arrangement and conformation, intermolecular interactions, and various physicochemical properties, including mechanical properties. Febuxostat Form Q (FXT Q) and Form H1 (FXT H1) were investigated for crystal structure, nanomechanical parameters, and bulk deformation behavior. FXT Q showed greater compressibility, densification, and plastic deformation as compared to FXT H1 at a given compaction pressure. Lower mechanical hardness of FXT Q (0.214 GPa) as compared to FXT H1 (0.310 GPa) was found to be consistent with greater compressibility and lower mean yield pressure (38 MPa) of FXT Q. Superior compaction behavior of FXT Q was attributed to the presence of active slip systems in crystals which offered greater plastic deformation. By virtue of greater compressibility and densification, FXT Q showed higher tabletability over FXT H1. Significant correlation was found with anticipation that the preferred orientation of molecular planes into a crystal lattice translated nanomechanical parameters to a bulk compaction process. Moreover, prediction of compactibility of materials based on true density or molecular packing should be carefully evaluated, as slip-planes may cause deviation in the structure-property relationship. This study supported how molecular level crystal structure confers a bridge between particle level nanomechanical parameters and bulk level deformation behavior.


Laparoscopic management of urachal cysts in adulthood.
Managing persistent and symptomatic urachal anomalies requires wide surgical excision. Such intervention is recommended to prevent symptom recurrence and complications, most notably malignant degeneration. However, traditional open excision is associated with significant morbidity and prolonged convalescence. We report our experience with the laparoscopic excision of urachal remnants as a less morbid, minimally invasive surgical alternative. Between October 1993 and December 1999, 4 patients with a mean age of 43.3 years who had a symptomatic urachal cyst underwent laparoscopic radical excision of the urachal remnant. Using 2, 10 mm. and 1 or 2, 5 mm. ports the urachus and medial umbilical ligaments were divided at the umbilicus cephalad to the cyst. The specimen, which included the urachus, cyst and medial umbilical ligaments, was then separated from the bladder dome with or without the bladder cuff and removed intact. We reviewed the perioperative records to assess morbidity, recovery and outcome. All 4 procedures were completed successfully. No intraoperative or postoperative complications were reported at a mean followup of 15 months (range 2 to 24). Mean operative time was 180 minutes (range 150 to 210) and average hospital stay was 2.75 days (range 1 to 4). Pathological evaluation confirmed a benign urachal remnant in each case. All patients resumed normal activity within 2 weeks. To minimize the morbidity of radical excision the laparoscopic management of benign urachal remnants in adulthood is efficacious and our preferred method of management.


Host response to microgel coatings on neural electrodes implanted in the brain.
The performance of neural electrodes implanted in the brain is often limited by host response in the surrounding brain tissue, including astrocytic scar formation, neuronal cell death, and inflammation around the implant. We applied conformal microgel coatings to silicon neural electrodes and examined host responses to microgel-coated and uncoated electrodes following implantation in the rat brain. In vitro analyses demonstrated significantly reduced astrocyte and microglia adhesion to microgel-coated electrodes compared to uncoated controls. Microgel-coated and uncoated electrodes were implanted in the rat brain cortex and the extent of activated microglia and astrocytes as well as neuron density around the implant were evaluated at 1, 4, and 24 weeks postimplantation. Microgel coatings reduced astrocytic recruitment around the implant at later time points. However, microglial response indicated persistence of inflammation in the area around the electrode. Neuronal density around the implanted electrodes was also lower for both implant groups compared to the uninjured control. These results demonstrate that microgel coatings do not significantly improve host responses to implanted neural electrodes and underscore the need for further improvements in implantable materials.


Variability of computational fluid dynamics solutions for pressure and flow in a giant aneurysm: the ASME 2012 Summer Bioengineering Conference CFD Challenge.
Stimulated by a recent controversy regarding pressure drops predicted in a giant aneurysm with a proximal stenosis, the present study sought to assess variability in the prediction of pressures and flow by a wide variety of research groups. In phase I, lumen geometry, flow rates, and fluid properties were specified, leaving each research group to choose their solver, discretization, and solution strategies. Variability was assessed by having each group interpolate their results onto a standardized mesh and centerline. For phase II, a physical model of the geometry was constructed, from which pressure and flow rates were measured. Groups repeated their simulations using a geometry reconstructed from a micro-computed tomography (CT) scan of the physical model with the measured flow rates and fluid properties. Phase I results from 25 groups demonstrated remarkable consistency in the pressure patterns, with the majority predicting peak systolic pressure drops within 8% of each other. Aneurysm sac flow patterns were more variable with only a few groups reporting peak systolic flow instabilities owing to their use of high temporal resolutions. Variability for phase II was comparable, and the median predicted pressure drops were within a few millimeters of mercury of the measured values but only after accounting for submillimeter errors in the reconstruction of the life-sized flow model from micro-CT. In summary, pressure can be predicted with consistency by CFD across a wide range of solvers and solution strategies, but this may not hold true for specific flow patterns or derived quantities. Future challenges are needed and should focus on hemodynamic quantities thought to be of clinical interest.


Quinoline Derivative Enhances Human Sperm Motility and Improves the Functional Competence.
In this study, we aimed to explore the beneficial properties of novel quinoline derivatives on human sperm motility and its functional competence. Nine novel quinoline derivatives were screened for their effect on motility in human spermatozoa from normozoospermic ejaculates. Compounds with impressive sperm motility enhancement properties were further assessed for their effect on functional competence of human spermatozoa. To determine the effect on the fertilizing ability of spermatozoa processed with quinoline derivatives and to assess developmental competence of embryos derived, in vitro fertilization (IVF) was performed using mouse model. Among the nine quinoline derivatives, 2 compounds (6MQT and 2,6DQT) exhibited significant enhancement in sperm progressive motility and survival at 24 h. Further, non-significant increase in curvilinear velocity (VCL), straight line velocity (VSL), and amplitude of lateral head displacement (ALH) was observed. Capacitation, intracellular cAMP level and tyrosine phosphorylated sperm proteins were significantly higher in 6MQT (P < 0.05) and 2,6DQT (P < 0.001) compared to control. In vitro fertilization (IVF) experiments using Swiss albino mice revealed that spermatozoa processed with 6MQT had non-significantly higher blastocyst rate and a superior blastocyst quality, while, 2,6DQT resulted in significantly lower blastocyst rate (P < 0.05) compared to control. Quinoline derivative 6MQT has significant motility enhancement property under in vitro conditions. Graphical abstract.


Role of standardized grape polyphenol preparation as a novel treatment to improve synaptic plasticity through attenuation of features of metabolic syndrome in a mouse model.
Metabolic syndrome has become an epidemic and poses tremendous burden on the health system. People with metabolic syndrome are more likely to experience cognitive decline. As obesity and sedentary lifestyles become more common, the development of early prevention strategies is critical. In this study, we explore the potential beneficial effects of a combinatory polyphenol preparation composed of grape seed extract, Concord purple grape juice extract, and resveratrol, referred to as standardized grape polyphenol preparation (SGP), on peripheral as well as brain dysfunction induced by metabolic syndrome. We found dietary fat content had minimal effect on absorption of metabolites of major polyphenols derived from SGP. Using a diet-induced animal model of metabolic syndrome (DIM), we found that brain functional connectivity and synaptic plasticity are compromised in the DIM mice. Treatment with SGP not only prevented peripheral metabolic abnormality but also improved brain synaptic plasticity. Our study demonstrated that SGP, comprised of multiple bioavailable and bioactive components targeting a wide range of metabolic syndrome related pathological features, provides greater global protection against peripheral and central nervous system dysfunctions and can be potentially developed as a novel prevention/treatment for improving brain connectivity and synaptic plasticity important for learning and memory.


Minimally-invasive versus transcatheter aortic valve implantation: systematic review with meta-analysis of propensity-matched studies.
Minimally invasive aortic valve replacement (MiAVR) and transcatheter aortic valve implantation (TAVI) provide aortic valve replacement (AVR) by less invasive methods than conventional surgical AVR, by avoiding complete sternotomy. This study directly compares and analyses the available evidence for early outcomes between these two AVR methods. Electronic databases were searched from inception until August 2019 for studies comparing MiAVR to TAVI, according to predefined search criteria. Propensity-matched studies with sufficient data were included in a meta-analysis. Eight studies with 9,744 patients were included in the quantitative analysis. Analysis of risk-matched patients showed no difference in early mortality (RR 0.76, 95% CI, 0.37-1.54, P=0.44). MiAVR had a signal towards lower rate of postoperative stroke, although this did not reach statistical significance (OR 0.42, 95% CI, 0.13-1.29, P=0.13). MiAVR had significantly lower rates of new pacemaker (PPM) requirement (OR 0.29, 95% CI, 0.16-0.52, P<0.0001) and postoperative aortic insufficiency (AI) or paravalvular leak (PVL) (OR 0.05, 95% CI, 0.01-0.20, P<0.0001) compared to TAVI, (OR 0.42, 95% CI, 0.13-1.29, P=0.13), while acute kidney injury (AKI) was higher in MiAVR compared to TAVI (11.1% vs. 5.2%, OR 2.28, 95% CI, 1.25-4.16, P=0.007). In patients of equivalent surgical risk scores, MiAVR may be performed with lower rates of postoperative PPM requirement and AI/PVL, higher rates of AKI and no statistical difference in postoperative stroke or short-term mortality, compared to TAVI. Further prospective trials are needed to validate these results.


Hypoxia reprograms calcium signaling and regulates myoglobin expression.
Myoglobin is an oxygen storage molecule that is selectively expressed in cardiac and slow-twitch skeletal muscles that have a high oxygen demand. Numerous studies have implicated hypoxia in the regulation of myoglobin expression as an adaptive response to hypoxic stress. However, the details of this relationship remain undefined. In the present study, adult mice exposed to 10% oxygen for periods up to 3 wk exhibited increased myoglobin expression only in the working heart, whereas myoglobin was either diminished or unchanged in skeletal muscle groups. In vitro and in vivo studies revealed that hypoxia in the presence or absence of exercise-induced stimuli reprograms calcium signaling and modulates myoglobin gene expression. Hypoxia alone significantly altered calcium influx in response to cell depolarization or depletion of endoplasmic reticulum calcium stores, which inhibited the expression of myoglobin. In contrast, our whole animal and transcriptional studies indicate that hypoxia in combination with exercise enhanced the release of calcium from the sarcoplasmic reticulum via the ryanodine receptors triggered by caffeine, which increased the translocation of nuclear factor of activated T-cells into the nucleus to transcriptionally activate myoglobin expression. The present study unveils a previously unrecognized mechanism where the hypoxia-mediated regulation of calcium transients from different intracellular pools modulates myoglobin gene expression. In addition, we observed that changes in myoglobin expression, in response to hypoxia, are not dependent on hypoxia-inducible factor-1 or changes in skeletal muscle fiber type. These studies enhance our understanding of hypoxia-mediated gene regulation and will have broad applications for the treatment of myopathic diseases.


Assessing changes in cervical epidural pressure during biportal endoscopic lumbar discectomy.
Biportal endoscopic spinal surgery has been performed for several years, and its effectiveness is well known; however, no studies on its safety, specifically intracranial pressure, have been conducted to date. The authors sought to evaluate the effect of biportal endoscopic lumbar discectomy on intracranial pressure by monitoring cervical epidural pressure (CEP) changes throughout the procedure. Twenty patients undergoing single-level biportal endoscopic lumbar discectomy were enrolled in this study. CEPs were monitored throughout the procedure, consisting of phase 1, establishing the surgical portal and working space; phase 2, performing decompression and discectomy; and phase 3, turning off the fluid irrigation system. After discectomy was completed, the authors evaluated changes in CEP as the irrigation pressure increased serially by adding phase 4, increasing irrigation pressure with outflow open; and phase 5, increasing irrigation pressure with outflow closed. The mean baseline CEP was measured as 16.65 mm Hg. In phase 1, the mean CEP was 17.3 mm Hg, which was not significantly different from the baseline CEP. In phase 2, the mean CEP abruptly increased up to 35.1 mm Hg when the epidural space was first connected with the working space, followed by stabilization of the CEP at 31.65 mm Hg. In phase 4, the CEP increased as the inflow pressure increased, showing a linear correlation, but not in phase 5. No patients experienced neurological complications. It is important to ensure that irrigation fluid is not stagnant and is maintained continuously. More attention must be paid to keeping pressures low when opening the epidural space.


Genome-wide analysis of SREBP1 activity around the clock reveals its combined dependency on nutrient and circadian signals.
In mammals, the circadian clock allows them to anticipate and adapt physiology around the 24 hours. Conversely, metabolism and food consumption regulate the internal clock, pointing the existence of an intricate relationship between nutrient state and circadian homeostasis that is far from being understood. The Sterol Regulatory Element Binding Protein 1 (SREBP1) is a key regulator of lipid homeostasis. Hepatic SREBP1 function is influenced by the nutrient-response cycle, but also by the circadian machinery. To systematically understand how the interplay of circadian clock and nutrient-driven rhythm regulates SREBP1 activity, we evaluated the genome-wide binding of SREBP1 to its targets throughout the day in C57BL/6 mice. The recruitment of SREBP1 to the DNA showed a highly circadian behaviour, with a maximum during the fed status. However, the temporal expression of SREBP1 targets was not always synchronized with its binding pattern. In particular, different expression phases were observed for SREBP1 target genes depending on their function, suggesting the involvement of other transcription factors in their regulation. Binding sites for Hepatocyte Nuclear Factor 4 (HNF4) were specifically enriched in the close proximity of SREBP1 peaks of genes, whose expression was shifted by about 8 hours with respect to SREBP1 binding. Thus, the cross-talk between hepatic HNF4 and SREBP1 may underlie the expression timing of this subgroup of SREBP1 targets. Interestingly, the proper temporal expression profile of these genes was dramatically changed in Bmal1-/- mice upon time-restricted feeding, for which a rhythmic, but slightly delayed, binding of SREBP1 was maintained. Collectively, our results show that besides the nutrient-driven regulation of SREBP1 nuclear translocation, a second layer of modulation of SREBP1 transcriptional activity, strongly dependent from the circadian clock, exists. This system allows us to fine tune the expression timing of SREBP1 target genes, thus helping to temporally separate the different physiological processes in which these genes are involved.


Visualization of protein folding funnels in lattice models.
Protein folding occurs in a very high dimensional phase space with an exponentially large number of states, and according to the energy landscape theory it exhibits a topology resembling a funnel. In this statistical approach, the folding mechanism is unveiled by describing the local minima in an effective one-dimensional representation. Other approaches based on potential energy landscapes address the hierarchical structure of local energy minima through disconnectivity graphs. In this paper, we introduce a metric to describe the distance between any two conformations, which also allows us to go beyond the one-dimensional representation and visualize the folding funnel in 2D and 3D. In this way it is possible to assess the folding process in detail, e.g., by identifying the connectivity between conformations and establishing the paths to reach the native state, in addition to regions where trapping may occur. Unlike the disconnectivity maps method, which is based on the kinetic connections between states, our methodology is based on structural similarities inferred from the new metric. The method was developed in a 27-mer protein lattice model, folded into a 3×3×3 cube. Five sequences were studied and distinct funnels were generated in an analysis restricted to conformations from the transition-state to the native configuration. Consistent with the expected results from the energy landscape theory, folding routes can be visualized to probe different regions of the phase space, as well as determine the difficulty in folding of the distinct sequences. Changes in the landscape due to mutations were visualized, with the comparison between wild and mutated local minima in a single map, which serves to identify different trapping regions. The extension of this approach to more realistic models and its use in combination with other approaches are discussed.


Non-linear quantum-classical scheme to simulate non-equilibrium strongly correlated fermionic many-body dynamics.
We propose a non-linear, hybrid quantum-classical scheme for simulating non-equilibrium dynamics of strongly correlated fermions described by the Hubbard model in a Bethe lattice in the thermodynamic limit. Our scheme implements non-equilibrium dynamical mean field theory (DMFT) and uses a digital quantum simulator to solve a quantum impurity problem whose parameters are iterated to self-consistency via a classically computed feedback loop where quantum gate errors can be partly accounted for. We analyse the performance of the scheme in an example case.


Taphonomic information from the modern vertebrate death assemblage of Doñana National Park, Spain.
Modern death assemblages provide insights about the early stages of fossilization and useful ecological information about the species inhabiting the ecosystem. We present the results of taphonomic monitoring of modern vertebrate carcasses and bones from Doñana National Park, a Mediterranean coastal ecosystem in Andalusia, Spain. Ten different habitats were surveyed. Half of them occur in active depositional environments (marshland, lake margin, river margin, beach and dunes). Most of the skeletal remains belong to land mammals larger than 5 kg in body weight (mainly wild and feral ungulates). Overall, the Doñana bone assemblage shows good preservation with little damage to the bones, partly as a consequence of the low predator pressure on large vertebrates. Assemblages from active depositional habitats differ significantly from other habitats in terms of the higher incidence of breakage and chewing marks on bones in the latter, which result from scavenging, mainly by wild boar and red fox. The lake-margin and river-margin death assemblages have high concentrations of well preserved bones that are undergoing burial and offer the greatest potential to produce fossil assemblages. The spatial distribution of species in the Doñana death assemblage generally reflects the preferred habitats of the species in life. Meadows seem to be a preferred winter habitat for male deer, given the high number of shed antlers recorded there. This study is further proof that taphonomy can provide powerful insights to better understand the ecology of modern species and to infer past and future scenarios for the fossil record.


Dissecting intermolecular interactions in the condensed phase of ibuprofen and related compounds: the specific role and quantification of hydrogen bonding and dispersion forces.
Ibuprofen is a well-established non-steroidal anti-inflammatory drug, inhibiting the prostaglandin-endoperoxide synthase. One of the key features defining the ibuprofen structure is the doubly intermolecular O-HO[double bond, length as m-dash]C hydrogen bond in cyclic dimers as know from carboxylic acids and confirmed by X-ray analysis. Until now, there was neither information about the vaporization enthalpy of ibuprofen nor about how this thermal property is determined by the subtle balance between different types of intermolecular interaction. In this study we derive the vaporization enthalpy of ibuprofen from thermochemical experiments to be . We dissected the hydrogen bond energy, EHB = 45.0 kJ mol-1, exclusively from measured vaporization enthalpies of related aliphatic carboxylic acids, their homomorph methyl esters and alkyl acetates, respectively. This contribution from hydrogen bonding could be confirmed almost quantitatively from quantum chemical calculations of ibuprofen clusters, which also suggest dispersion interaction of similar order (Edisp = 47 kJ mol-1). Following the full analysis of the gas-vapor transition enthalpy, we studied the changing structural components from the solid to the liquid phase of ibuprofen by means of Attenuated Total Reflection Infrared (ATR-IR) spectroscopy. The cyclic dimers as observed in the X-ray patterns are essentially preserved in the liquid state just above the melting point. However, with increasing temperature the doubly hydrogen-bonded cyclic dimers are replaced by singly hydrogen-bonded linear dimers in the liquid ibuprofen. The transfer enthalpy from the temperature-dependent equilibria of both dimers as obtained from the IR intensity ratios of the vibrational bands quantifies for the first time the energy of the released, single hydrogen bond to be EHB = 21.0 kJ mol-1. Overall, we show that a combination of thermodynamics, infrared spectroscopy and quantum chemistry provides quantification and detailed understanding of structure and molecular interaction in ibuprofen and related compounds.


Data compression for speckle correlation interferometry temporal fringe pattern analysis.
Temporal fringe pattern analysis is gaining prominence in speckle correlation interferometry, in particular for transient phenomena studies. This form of analysis, nevertheless, necessitates large data storage. Current compression schemes do not facilitate efficient data retrieval and may even result in important data loss. We describe a novel compression scheme that does not result in crucial data loss and allows for the efficient retrieval of data for temporal fringe analysis. In sample tests with digital speckle interferometry on fringe patterns of a plate and of a cantilever beam subjected to temporal phase and load evolution, respectively, we achieved a compression ratio of 1.6 without filtering out any data from discontinuous and low fringe modulation spatial points. By eliminating 38% of the data from discontinuous and low fringe modulation spatial points, we attained a significant compression ratio of 2.4.


National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities.
Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.


Hospital-acquired infections due to multidrug-resistant organisms in Hungary, 2005-2010.
Healthcare-associated infections caused by multidrug-resistant organisms are associated with prolonged medical care, worse outcome and costly therapies. In Hungary, hospital-acquired infections (HAIs) due to epidemiologically important multidrug-resistant organisms are notifiable by law since 2004. Overall, 6,845 case-patients (59.8% men; median age: 65 years) were notified in Hungary from 2005 to 2010. One third of case-patients died in hospital. The overall incidence of infections increased from 5.4 in 2005 to 14.7 per 100,000 patient-days in 2010. Meticillin-resistant Staphylococcus aureus (MRSA) was the most frequently reported pathogen (52.2%), but while its incidence seemed to stabilise after 2007, notifications of multidrug-resistant Gram-negative organisms have significantly increased from 2005 to 2010. Surgical wound and bloodstream were the most frequently reported sites of infection. Although MRSA incidence has seemingly reached a plateau in recent years, actions aiming at reducing the burden of HAIs with special focus on Gram-negative multidrug-resistant organisms are needed in Hungary. Continuing promotion of antimicrobial stewardship, infection control methodologies, reinforced HAI surveillance among healthcare and infection control practitioners, and engagement of stakeholders, hospital managers and public health authorities to facilitate the implementation of existing guidelines and protocols are essential.


Influence of vector-encoded cytokines on anti-Salmonella immunity: divergent effects of interleukin-2 and tumor necrosis factor alpha.
Attenuated Salmonella strains are of interest as new vaccine candidates and as vectors of cloned genes of other organisms. Attenuated strains expressing specific cytokines were constructed as a means of manipulating the immune response in various disease settings. In the present study, interleukin-2 (IL-2)-expressing (GIDIL2) or tumor necrosis factor alpha (TNF-alpha)-expressing (GIDTNF) strains were compared with the parent strain (BRD509) for the effect of cytokines on anti-Salmonella immunity. Expression of IL-2 resulted in a rapid clearance of the organism soon after vaccination. The reduction in GIDIL2 CFU was 50- to 300-fold higher than that of BRD509 and correlated with a markedly decreased splenomegaly. Furthermore, no evidence for any significant activation, including upregulation of surface markers and production of nitric oxide (NO), was observed in spleens of GIDIL2-injected mice. In contrast, the host response to GIDTNF was marked by an early, strong, splenic cellular influx, but surprisingly, the degree of induced splenomegaly and NO secretion was only 50% of that observed in BRD509-treated mice. Despite this, bacterial colonization of the spleen in GIDTNF-immunized animals was either slightly decreased from or equivalent to that of the BRD509-treated group, suggesting the induction of additional antimicrobial mechanisms by TNF-alpha. In vivo protection studies demonstrated that, at limiting doses, GIDIL2 was inferior to GIDTNF and BRD509 in its capacity to protect against virulent challenge. At high doses, however, all three strains exhibited equal protective efficacy. These results demonstrate that the immune response against intracellular bacteria can be manipulated by pathogen-expressed cytokines and open the way for further fine tuning of immune responses not only to Salmonella strains themselves but also to the heterologous gene(s) carried by them.


Extended depth of focus with induced spherical aberration in light-adjustable intraocular lenses.
To evaluate the quality of vision and depth of focus induced by controlled amounts of negative spherical aberration in patients implanted bilaterally with light-adjustable intraocular lenses. Prospective, nonrandomized clinical trial. Seventeen patients were implanted and treated with appropriate spatial irradiance light profiles. One eye was set for emmetropia, and the fellow eye received an additional aspheric light treatment to induce controlled amounts of negative spherical aberration. We used a Hartmann-Shack sensor to measure the eye's refraction and aberrations for a 4-mm pupil diameter. Decimal visual acuity (VA) was measured using a micro-display placed at 10 m, 60 cm, 40 cm, and 30 cm. Eyes treated with aspheric profiles were divided into 2 groups depending on the final amount of induced negative spherical aberration: low [-0.05, -0.10 μm] and high [-0.13, -0.23 μm]. In both groups, the mean uncorrected decimal VA at 60 cm was over 0.90. In the first group, distance VA was 0.97 ± 0.16, but in the second group it was lower (0.76 ± 0.16). As expected, the VA for nearer distances is higher in the eyes with a larger magnitude of spherical aberration (P value < .01): 0.94 ± 0.10 and 0.73 ± 0.16 at 40 and 30 cm, respectively, in comparison with 0.71 ± 0.15 and 0.50 ± 0.14. Binocular summation with the fellow eye, adjusted for emmetropia, produces an excellent binocular distance VA (>1.10) in both groups. Controlled amounts of negative spherical aberration and defocus can be induced in eyes implanted with adjustable intraocular lenses to enhance near vision.


Dark Classics in Chemical Neuroscience: Δ9-Tetrahydrocannabinol.
Cannabis ( Cannabis sativa) is the most widely used illicit drug in the world, with an estimated 192 million users globally. The main psychoactive component of cannabis is (-)- trans-Δ9-tetrahydrocannabinol (Δ9-THC), a compound with a diverse range of pharmacological actions. The unique and distinctive intoxication caused by Δ9-THC primarily reflects partial agonist action at central cannabinoid type 1 (CB1) receptors. Δ9-THC is an approved therapeutic treatment for a range of conditions, including chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis, and is being investigated in indications such as anorexia nervosa, agitation in dementia, and Tourette's syndrome. It is available as a regulated pharmaceutical in products such as Marinol, Sativex, and Namisol as well as in an ever-increasing range of unregistered medicinal and recreational cannabis products. While cannabis is an ancient medicament, contemporary use is embroiled in legal, scientific, and social controversy, much of which relates to the potential hazards and benefits of Δ9-THC itself. Robust contemporary debate surrounds the therapeutic value of Δ9-THC in different diseases, its capacity to produce psychosis and cognitive impairment, and the addictive and "gateway" potential of the drug. This review will provide a profile of the chemistry, pharmacology, and therapeutic uses of Δ9-THC as well as the historical and societal import of this unique, distinctive, and ubiquitous psychoactive substance.


Progress toward global eradication of dracunculiasis--January 2011-June 2012.
Dracunculiasis (Guinea worm disease) is caused by Dracunculus medinensis, a parasitic worm. Approximately 1 year after initial infection from contaminated drinking water, the worm emerges through the skin of the infected person, usually on the lower limb. Pain and secondary bacterial wound infection can cause temporary or permanent disability that disrupts work and schooling for the entire family. In 1986, the World Health Assembly (WHA) called for dracunculiasis elimination and the Guinea Worm Eradication Program, supported by The Carter Center, World Health Organization (WHO), United Nations Children's Fund (UNICEF), CDC, and other partners, was coalesced to assist ministries of health of endemic countries in meeting this goal. At that time, an estimated 3.5 million cases occurred annually in 20 countries in Africa and Asia. This report updates published and previously unpublished surveillance data reported by ministries of health and describes progress toward global dracunculiasis eradication. In 2011, a total of 1,058 cases were reported. As of 2012, dracunculiasis remained endemic in only four countries. Through June 2012, worldwide reductions in reported cases continued, compared with the first 6 months of 2011. Failures in surveillance and containment, lack of clean drinking water, and insecurity in Mali and parts of South Sudan continue to challenge dracunculiasis eradication efforts.


Blood-pressure lowering efficacy of winged bean seed hydrolysate in spontaneously hypertensive rats, peptide characterization and a toxicity study in Sprague-Dawley rats.
Winged bean seed (WBS) is an underutilized tropical crop. The current study evaluates its potential to reduce blood pressure (BP) in spontaneously hypertensive rats and finds that it reduces BP significantly, in a dose-dependent manner. Five peptides with the sequences, RGVFPCLK, TQLDLPTQ, EPALVP, MRSVVT and DMKP, have been characterized in terms of their stability against ACE via in vitro and in silico modelling. All peptides exhibited IC50 values between 0.019 and 6.885 mM and various inhibitory modes, including substrate, prodrug and true inhibitor modes. The toxicity status of non-Current Good Manufacturing Practice (non-CGMP) peptides is evaluated and the results show that such peptides are toxic, and thus are not suitable to be tested in animals, particularly in repeated-dose studies. In short, WBS hydrolysate demonstrated in vitro ACE inhibitory properties and in vivo blood pressure lowering efficacy in rat models, fostering its potential as a functional food ingredient. Non-CGMP grade peptides are toxic and unfit for testing in animal models.


Stereoacuity degradation by experimental and real monocular and binocular amblyopia.
Fourteen normal adult volunteers with normal binocular single vision and normal stereoacuity submitted to monocular and binocular degradation of their stereoacuity by cycloplegia and fogging with spherical lenses. Stereoacuity (SA) was reduced as soon as visual acuity (VA), both monocular and binocular, was reduced. There was a marked similarity in the degree of SA reduction produced by monocular and binocular amblyopia. The degree of SA reduction was slightly more marked with monocular decrements than with binocular at VAs between 20/25 and 20/50. Significant intersubject variation was noted. The majority of subjects maintained gross SA at 20/200 monocular or binocular. One subject was reduced to gross stereopsis at 20/30 monocular and 20/50 binocular VAs. Two subjects were able to retain 40 sec of SA until vision was degraded to 20/50. Conversely, 40 sec of SA was not achieved by any subject at monocular or binocular vision less than 20/40 (test for malingering). Thirteen patients with real monocular and binocular organic or functional amblyopia were then compared with the experimental group. On the whole, patients scored somewhat better than normals but their scores fell within the range of responses found in the normal group.


Akt2 causes TGFβ-induced deptor downregulation facilitating mTOR to drive podocyte hypertrophy and matrix protein expression.
TGFβ promotes podocyte hypertrophy and expression of matrix proteins in fibrotic kidney diseases such as diabetic nephropathy. Both mTORC1 and mTORC2 are hyperactive in response to TGFβ in various renal diseases. Deptor is a component of mTOR complexes and a constitutive inhibitor of their activities. We identified that deptor downregulation by TGFβ maintains hyperactive mTOR in podocytes. To unravel the mechanism, we found that TGFβ -initiated noncanonical signaling controls deptor inhibition. Pharmacological inhibitor of PI 3 kinase, Ly 294002 and pan Akt kinase inhibitor MK 2206 prevented the TGFβ induced downregulation of deptor, resulting in suppression of both mTORC1 and mTORC2 activities. However, specific isoform of Akt involved in this process is not known. We identified Akt2 as predominant isoform expressed in kidney cortex, glomeruli and podocytes. TGFβ time-dependently increased the activating phosphorylation of Akt2. Expression of dominant negative PI 3 kinase and its signaling inhibitor PTEN blocked Akt2 phosphorylation by TGFβ. Inhibition of Akt2 using a phospho-deficient mutant that inactivates its kinase activity, as well as siRNA against the kinase markedly diminished TGFβ -mediated deptor suppression, its association with mTOR and activation of mTORC1 and mTORC2. Importantly, inhibition of Akt2 blocked TGFβ -induced podocyte hypertrophy and expression of the matrix protein fibronectin. This inhibition was reversed by the downregulation of deptor. Interestingly, we detected increased phosphorylation of Akt2 concomitant with TGFβ expression in the kidneys of diabetic rats. Thus, our data identify previously unrecognized Akt2 kinase as a driver of TGFβ induced deptor downregulation and sustained mTORC1 and mTORC2 activation. Furthermore, we provide the first evidence that deptor downstream of Akt2 contributes to podocyte hypertrophy and matrix protein expression found in glomerulosclerosis in different renal diseases.


Full-genome evolutionary histories of selfing, splitting, and selection in Caenorhabditis.
The nematode Caenorhabditis briggsae is a model for comparative developmental evolution with C. elegans. Worldwide collections of C. briggsae have implicated an intriguing history of divergence among genetic groups separated by latitude, or by restricted geography, that is being exploited to dissect the genetic basis to adaptive evolution and reproductive incompatibility; yet, the genomic scope and timing of population divergence is unclear. We performed high-coverage whole-genome sequencing of 37 wild isolates of the nematode C. briggsae and applied a pairwise sequentially Markovian coalescent (PSMC) model to 703 combinations of genomic haplotypes to draw inferences about population history, the genomic scope of natural selection, and to compare with 40 wild isolates of C. elegans. We estimate that a diaspora of at least six distinct C. briggsae lineages separated from one another approximately 200,000 generations ago, including the "Temperate" and "Tropical" phylogeographic groups that dominate most samples worldwide. Moreover, an ancient population split in its history approximately 2 million generations ago, coupled with only rare gene flow among lineage groups, validates this system as a model for incipient speciation. Low versus high recombination regions of the genome give distinct signatures of population size change through time, indicative of widespread effects of selection on highly linked portions of the genome owing to extreme inbreeding by self-fertilization. Analysis of functional mutations indicates that genomic context, owing to selection that acts on long linkage blocks, is a more important driver of population variation than are the functional attributes of the individually encoded genes.


Protein synthesis in the early stages of cardiac hypertrophy.
Cardiac hypertrophy, induced in rats by either tri-iodothyronine or isoproterenol, administered daily for 7 days, was monitored using several parameters. Both treatments increased RNA concentrations 24 hr after the first injection, while heart weight increased following 2 injections to 46% above control after 7 days. Cardiac protein synthetic activity, as determined by the rate of peptidyl-puromycin formation, was increased by both tri-iodothyronine and isoproterenol 24 hr after a single injection, implying an increase in the number of functional ribosomes. RNA activity (the rate of peptidyl-puromycin formation per unit RNA) remained constant, suggesting that neither accelerated rates of initiation or translation nor increased activation of pre-existing, non-translating ribosomes was involved in the observed increase in protein synthetic activity. In contrast, constant infusion of [14C] tyrosine indicated no change in protein synthetic rate 24 hr after a single tri-iodothyronine injection and decreased protein synthetic rate after isoproterenol injection. It is concluded that the use of [3H]puromycin to estimate protein synthetic activity may be a more sensitive procedure for detecting early changes in protein synthesis in cardiac hypertrophy than constant isotope infusion, owing to the problems associated with determining the precise precursor pool for protein synthesis in this latter method.


Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop.
New therapies are urgently needed for hematologic malignancies, especially in patients with relapsed acute myelogenous leukemia (AML) and multiple myeloma. We and others have previously shown that FDA-approved statins, which are used to control hypercholesterolemia and target the mevalonate pathway (MVA), can trigger tumor-selective apoptosis. Our goal was to identify other FDA-approved drugs that synergize with statins to further enhance the anticancer activity of statins in vivo. Using a screen composed of other FDA approved drugs, we identified dipyridamole, used for the prevention of cerebral ischemia, as a potentiator of statin anticancer activity. The statin-dipyridamole combination was synergistic and induced apoptosis in multiple myeloma and AML cell lines and primary patient samples, whereas normal peripheral blood mononuclear cells were not affected. This novel combination also decreased tumor growth in vivo. Statins block HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the MVA pathway. Dipyridamole blunted the feedback response, which upregulates HMGCR and HMG-CoA synthase 1 (HMGCS1) following statin treatment. We further show that dipyridamole inhibited the cleavage of the transcription factor required for this feedback regulation, sterol regulatory element-binding transcription factor 2 (SREBF2, SREBP2). Simultaneously targeting the MVA pathway and its restorative feedback loop is preclinically effective against hematologic malignancies. This work provides strong evidence for the immediate evaluation of this novel combination of FDA-approved drugs in clinical trials.


How will surface treatments affect the translucency of porcelain laminate veneers?
The purpose of this study was to evaluate whether surface treatments affect the translucency of laminate veneers with different shades and thicknesses. A total of 224 disc-shaped ceramic veneers were prepared from A1, A3, HT (High Translucent) and HO (High Opaque) shades of IPS e.max Press (Ivoclar Vivadent) with 0.5 mm and 1.0 mm thicknesses. The ceramics were divided into four groups for surface treatments. Group C: no surface treatments; Group HF: etched with hydrofluoric acid; Group SB: sandblasted with 30-µm Al2O3 [corrected]; and Group L; irradiated with an Er;YAG laser. A translucent shade of resin cement (Rely X Veneer, 3M ESPE) was chosen for cementation. The color values of the veneers were measured with a colorimeter and translucency parameter (TP) values were calculated. A three-way ANOVA with interactions for TP values was performed and Bonferroni tests were used when appropriate (α=0.05). There were significant interactions between the surface treatments, ceramic shades and thicknesses (P=.001). For the 0.5-mm-thick specimens there were significant differences after the SB and L treatments. There was no significant difference between the HF and C treatments for any shades or thicknesses (P>.05). For the 1-mm-thick ceramics, there was only a significant difference between the L and C treatments for the HT shade ceramics (P=.01). There were also significant differences between the SB and C treatments except not for the HO shades (P=.768). The SB and L treatments caused laminate veneers to become more opaque; however, HF treatment did not affect the TP values. When the laminate veneers were thinner, both the shade of the ceramic and the SB and laser treatments had a greater effect on the TP values.


Cross talk between EBV and telomerase: the role of TERT and NOTCH2 in the switch of latent/lytic cycle of the virus.
Epstein-Barr virus (EBV)-associated malignancies, as well as lymphoblastoid cell lines (LCLs), obtained in vitro by EBV infection of B cells, express latent viral proteins and maintain their ability to grow indefinitely through inappropriate activation of telomere-specific reverse transcriptase (TERT), the catalytic component of telomerase. Our previous studies demonstrated that high levels of TERT expression in LCLs prevent the activation of EBV lytic cycle, which is instead triggered by TERT silencing. As lytic infection promotes the death of EBV-positive tumor cells, understanding the mechanism(s) by which TERT affects the latent/lytic status of EBV may be important for setting new therapeutic strategies. BATF, a transcription factor activated by NOTCH2, the major NOTCH family member in B cells, negatively affects the expression of BZLF1, the master regulator of viral lytic cycle. We therefore analyzed the interplay between TERT, NOTCH and BATF in LCLs and found that high levels of endogenous TERT are associated with high NOTCH2 and BATF expression levels. In addition, ectopic expression of TERT in LCLs with low levels of endogenous telomerase was associated with upregulation of NOTCH2 and BATF at both mRNA and protein levels. By contrast, infection of LCLs with retroviral vectors expressing functional NOTCH2 did not alter TERT transcript levels. Luciferase reporter assays, demonstrated that TERT significantly activated NOTCH2 promoter in a dose-dependent manner. We also found that NF-κB pathway is involved in TERT-induced NOTCH2 activation. Lastly, pharmacologic inhibition of NOTCH signaling triggers the EBV lytic cycle, leading to the death of EBV-infected cells. Overall, these results indicate that TERT contributes to preserve EBV latency in B cells mainly through the NOTCH2/BAFT pathway, and suggest that NOTCH2 inhibition may represent an appealing therapeutic strategy against EBV-associated malignancies.


Plasma adiponectin concentrations are associated with body composition and plant-based dietary factors in female twins.
Circulating adiponectin is emerging as an important link between obesity, type 2 diabetes, and cardiovascular disease (CVD). However, the spectrum of lifestyle factors that modulate the adiponectin concentration remains to be elucidated, particularly among women. We conducted a cross-sectional study of 877 female twin pairs from the TwinsUK adult twin registry. Using a co-twin design, we examined dietary and body composition influences on adiponectin by conducting matched, within-pair analyses to eliminate confounding. Following multivariable adjustment within-twin pairs, significant influences on adiponectin (log-transformed, percent change per SD of the dietary/body composition variable) were observed for nonstarch polysaccharides (3.25%; 95% CI: 0.06, 6.54; P < 0.05) and magnesium intake (3.80%; 95%CI: 0.17, 7.57; P < 0.05), with a trend toward an association for fruit and vegetable (F&V) intakes (2.55%; 95% CI: -0.26, 5.45; P = 0.08). These modest positive associations cannot be explained by confounding through other lifestyle factors shared by the twins. A significant relationship between adiponectin and 3 derived dietary patterns (F&V, dieting, traditional English), carbohydrate, protein, trans fat, and alcohol intake was also observed. Strong inverse associations with adiponectin were observed for BMI (-10.72%; 95% CI: -13.78, -7.55), total (-6.89%: 95% CI: -10.34, -3.30; P < 0.05), and central fat mass (-12.50%; 95% CI: -15.82, -9.05; P < 0.05); these relationships were significant both when twins were analyzed as individuals and when characteristics were contrasted within-twin pairs, suggesting a direct effect. We observed modest associations between dietary factors and adiponectin in female twins, independent of adiposity, and report strong inverse associations with body composition. These data reinforce the importance of weight maintenance and increasing consumption of diets rich in plant-based foods to prevent CVD and type 2 diabetes.


Anti-homosexual legislation and HIV-related stigma in African nations: what has been the role of PEPFAR?
Gay men and other men who have sex with men are disproportionately burdened by HIV infection. Laws that penalize same-sex intercourse contribute to a cycle of stigma, homonegativity and discrimination. In many African nations, laws criminalizing homosexuality may be fueling the epidemic, as they dissuade key populations from seeking treatment and health care providers from offering it. We analyzed the ways in which policies and practices of the US President's Emergency Plan for AIDS Relief (PEPFAR) program addressed pervasively harsh anti-homosexuality laws across Africa. Given the aim of the US PEPFAR program to reduce stigma surrounding HIV, we explored how PEPFAR may have used its influence to reduce the criminalization of homosexuality in the countries where it operated. We assessed homosexuality laws in 21 African countries where PEPFAR funding sought to reduce the HIV epidemic. We examined PEPFAR Policy Framework agreements associated with those countries, and other PEPFAR documents, for evidence of attempts to reduce stigma by decriminalizing homosexuality. We found 16 of Africa's 21 PEPFAR-funded countries had laws characterized as harsh in relation to homosexuality. Among the top eight PEPFAR-funded countries in Africa, seven had harsh anti-homosexuality laws. Most (14) of the 16 African 'Partnership Framework' (PEPFAR) policy agreements between African governments and the US State Department call for stigma reduction; however, none call for reducing penalties on individuals who engage in homosexual behavior. We conclude that while PEPFAR has acknowledged the negative role of stigma in fueling the HIV epidemic, it has, so far, missed opportunities to explicitly address the role of the criminalization of homosexuality in feeding stigmatizing attitudes. Our analysis suggests mechanisms like PEPFAR Partnership Framework agreements could be ideal vehicles to call for removal of anti-homosexuality legislation.


Intracellular pattern-recognition receptors.
The last ten years of research in the field of innate immunity have been incredibly fertile: the transmembrane Toll-like receptors (TLRs) were discovered as guardians protecting the host against microbial attacks and the emerging pathways characterized in detail. More recently, cytoplasmic sensors were identified, which are capable of detecting not only microbial, but also self molecules. Importantly, while such receptors trigger crucial host responses to microbial insult, over-activity of some of them has been linked to autoinflammatory disorders, hence demonstrating the importance of tightly regulating their actions over time and space. Here, we provide an overview of recent findings covering this area of innate and inflammatory responses that originate from the cytoplasm.


The use of regenerative medicine in the management of invasive bladder cancer.
Muscle invasive and recurrent nonmuscle invasive bladder cancers have been traditionally treated with a radical cystectomy and urinary diversion. The urinary diversion is generally accomplished through the creation of an incontinent ileal conduit, continent catheterizable reservoir, or orthotopic neobladder utilizing small or large intestine. While radical extirpation of the bladder is often successful from an oncological perspective, there is a significant morbidity associated with enteric interposition within the genitourinary tract. Therefore, there is a great opportunity to decrease the morbidity of the surgical management of bladder cancer through utilization of novel technologies for creating a urinary diversion without the use of intestine. Clinical trials using neourinary conduits (NUC) seeded with autologous smooth muscle cells are currently in progress and may represent a significant surgical advance, potentially eliminating the complications associated with the use of gastrointestinal segments in the urinary reconstruction, simplifying the surgical procedure, and greatly facilitating recovery from cystectomy.


AC Insulator-Based Dielectrophoretic Focusing of Particles and Cells in an "Infinite" Microchannel.
It is often necessary to prefocus particles and cells into a tight stream for subsequent separation and/or analysis in microfluidic devices. A DC electric field has been widely used for particle and cell focusing in insulator-based dielectrophoretic (iDEP) microdevices, where a large field magnitude, a high constriction ratio, and/or a long microchannel are usually required to enhance the iDEP effect. We demonstrate, in this work, an AC iDEP focusing technique, which utilizes a low-frequency AC electric field to generate both an oscillatory electrokinetic flow of the particle/cell suspension and a field direction-independent dielectrophoretic force for particle/cell focusing in a virtually "infinite" microchannel. We also develop a theoretical analysis to evaluate this focusing in terms of the AC voltage frequency, amplitude, and particle size, which are each validated through both experimental demonstration and numerical simulation. The effectiveness of AC iDEP focusing increases with the second order of electric field magnitude, superior to DC iDEP focusing with only a first-order dependence. This feature and the "infinite" channel length together remove the necessity of large electric field and/or small constriction in DC iDEP focusing of small particles.


Real-time imaging of Pt3Fe nanorod growth in solution.
The growth of colloidal nanocrystal architectures by nanoparticle attachment is frequently reported as an alternative to the conventional growth by monomer attachment. However, the mechanism whereby nanoparticle attachment proceeds microscopically remains unclear. We report real-time transmission electron microscopy (TEM) imaging of the solution growth of Pt(3)Fe nanorods from nanoparticle building blocks. Observations revealed growth of winding polycrystalline nanoparticle chains by shape-directed nanoparticle attachment followed by straightening and orientation and shape corrections to yield single-crystal nanorods. Tracking nanoparticle growth trajectories allowed us to distinguish the force fields exerted by single nanoparticles and nanoparticle chains. Such quantification of nanoparticle interaction and understanding the growth pathways are important for the design of hierarchical nanomaterials and controlling nanocrystal self-assembly for functional devices.


Beyond tokenistic involvement of older people in research - a framework for future development and understanding.
Research and development work in health and social care are increasingly required to involve users at all stages of the research process yet there is scant empirical evidence to support the justification of this laudable aim. Evidence does suggest that at present efforts to achieve this are primarily tokenistic and that more work is needed, both to examine what user involvement in research activity actually means, and how this can best be supported. This paper sets out to describe developments to support involvement of older people through work at the Royal Bank of Scotland Centre for the Older Person's Agenda and to identify a number of challenges that this has raised for researchers. These challenges have arisen out of a number of assumptions that underpin the process of user involvement. The paper discusses some of the benefits of working in partnership with older people and identifies strategic issues for consideration in order to promote future partnership working.


Optimal wavelength band clustering for multispectral iris recognition.
This work explores the possibility of clustering spectral wavelengths based on the maximum dissimilarity of iris textures. The eventual goal is to determine how many bands of spectral wavelengths will be enough for iris multispectral fusion and to find these bands that will provide higher performance of iris multispectral recognition. A multispectral acquisition system was first designed for imaging the iris at narrow spectral bands in the range of 420 to 940 nm. Next, a set of 60 human iris images that correspond to the right and left eyes of 30 different subjects were acquired for an analysis. Finally, we determined that 3 clusters were enough to represent the 10 feature bands of spectral wavelengths using the agglomerative clustering based on two-dimensional principal component analysis. The experimental results suggest (1) the number, center, and composition of clusters of spectral wavelengths and (2) the higher performance of iris multispectral recognition based on a three wavelengths-bands fusion.


Pre-exposure rabies vaccination among US international travelers: findings from the global TravEpiNet consortium.
People who travel to areas with high rabies endemicity and have animal contact are at increased risk for rabies exposure. We examined characteristics of international travelers queried regarding rabies vaccination during pretravel consultations at Global TravEpiNet (GTEN) practices during 2009-2010. We performed bivariate and multivariable analyses of data collected from 18 GTEN clinics. Travel destinations were classified by strength level of rabies vaccination recommendation. Of 13,235 travelers, 226 (2%) reported previous rabies vaccination, and 406 (3%) received rabies vaccine at the consultation. Common travel purposes for these 406 travelers were leisure (26%), research/education (17%), and nonmedical service work (14%). Excluding the 226 who were previously vaccinated, 8070 (62%) of 13,009 travelers intended to visit one or more countries with a strong recommendation for rabies vaccination; 1675 (21%) of these 8070 intended to travel for 1 month or more. Among these 1675 travelers, 145 (9%) were vaccinated, 498 (30%) declined vaccination, 832 (50%) had itineraries that clinicians determined did not indicate vaccination, and 200 (12%) remained unvaccinated for other reasons. In both bivariate and multivariate analyses, travelers with trip durations >6 months versus 1-3 months (adjusted odds ratio [OR]=4.9 [95% confidence interval [CI] 2.1, 11.4]) and those traveling for "research/education" or to "provide medical care" (adjusted OR=5.1 [95% CI 1.9, 13.7] and 9.5 [95% CI 2.2, 40.8], respectively), compared with leisure travelers, were more likely to receive rabies vaccination. Few travelers at GTEN clinics received rabies vaccine, although many planned trips 1 month long or more to a strong-recommendation country. Clinicians often determined that vaccine was not indicated, and travelers often declined vaccine when it was offered. The decision to vaccinate should take into account the strength of the vaccine recommendation at the destination country, duration of stay, availability of postexposure prophylaxis, potential for exposure to animals, and likelihood of recurrent travel to high-risk destinations.


Polarization entanglement generation at 1.5 μm based on walk-off effect due to fiber birefringence.
In this Letter, a linear scheme to generate polarization entanglement at 1.5 μm based on commercial polarization maintained dispersion shifted fiber (PM-DSF) is proposed. The birefringent walk-off effect of the pulsed pump light in the PM-DSF provides an effective way to suppress the vector scattering processes of spontaneous four-wave mixing. A 90 deg offset of fiber polarization axes is introduced at the midpoint of the fiber to realize the quantum superposition of the two correlated photon states generated by the two scalar processes on different fiber polarization axes, leading to polarization entanglement generation. Experiments of the indistinguishable property on single-side and two-photon interference in two nonorthogonal polarization bases are demonstrated. A two-photon interference fringe visibility of 89±3% is achieved without subtracting the background counts, demonstrating its great potential in developing highly a efficient and stable fiber based polarization-entangled quantum light source at the optical communication band.


Transferability of Training Benefits Differs across Neural Events: Evidence from ERPs.
Humans can show striking capacity limitations in sensorimotor processing. Fortunately, these limitations can be attenuated with training. However, less fortunately, training benefits often remain limited to trained tasks. Recent behavioral observations suggest that the extent to which training transfers may depend on the specific stage of information processing that is being executed. Training benefits for a task that taps the consolidation of sensory information (sensory encoding) transfer to new stimulus-response mappings, whereas benefits for selecting an appropriate action (decision-making/response selection) remain specific to the trained mappings. Therefore, training may have dissociable influences on the neural events underlying subsequent sensorimotor processing stages. Here, we used EEG to investigate this possibility. In a pretraining baseline session, participants completed two four-alternative-choice response time tasks, presented both as a single task and as part of a dual task (with another task). The training group completed a further 3,000 training trials on one of the four-alternative-choice tasks. Hence, one task became trained, whereas the other remained untrained. At test, a negative-going component that is sensitive to sensory-encoding demands (N2) showed increased amplitudes and reduced latencies for trained and untrained mappings relative to a no-train control group. In contrast, the onset of the stimulus-locked lateralized readiness potential, a component that reflects the activation of motor plans, was reduced only for tasks that employed trained stimulus-response mappings, relative to untrained stimulus-response mappings and controls. Collectively, these results show that training benefits are dissociable for the brain events that reflect distinct sensorimotor processing stages.


K-ras mutation in focal proliferative lesions of human pancreas.
The K-ras gene is mutated in > or =75% of human pancreatic adenocarcinomas and in a number of hyperplastic ductal lesions from noncarcinoma patients. In this study, the incidence of K-ras mutation was determined in a spectrum of focal proliferative pancreatic lesions to evaluate their preneoplastic significance. PCR-based mutation-enriched RFLP analysis was used to identify mutations in codon 12. Immunostaining for Ki67 and p53 was also performed. Forty-seven % of intraductal nonpapillary hyperplasias (8 of 17) contained codon 12 mutations, as did 55% of adenomatoid hyperplasias (6 of 11). This rate increased to 61% in papillary hyperplasias (27 of 44) and to 78% when there was severe dysplasia (7 of 9). The fraction of cells staining for the Ki67 proliferation marker showed a general correlation with the rate of K-ras mutation. Nuclear staining for p53 protein was seen only in two ductal lesions with severe dysplasia. No mutations were found in normal acinar tissue (n = 38), squamous metaplasia (n = 13), ductal complexes (n = 8), or focal acinar cell dysplasia (n = 5). There seemed to be a general correlation of proliferative potential with the presence of K-ras mutation in ductal lesions. However, because of the high prevalence of lesions with K-ras mutations, we conclude that this mutation alone cannot be taken as proof of significant risk for progression to carcinoma. Efforts to use the presence of K-ras mutations in DNA harvested from pancreatic juice or duodenal aspirates as an approach for diagnosis of occult pancreatic carcinoma seem vulnerable to a high false-positive rate.


Computer model for the cardiovascular system: development of an e-learning tool for teaching of medical students.
This study combined themes in cardiovascular modelling, clinical cardiology and e-learning to create an on-line environment that would assist undergraduate medical students in understanding key physiological and pathophysiological processes in the cardiovascular system. An interactive on-line environment was developed incorporating a lumped-parameter mathematical model of the human cardiovascular system. The model outputs were used to characterise the progression of key disease processes and allowed students to classify disease severity with the aim of improving their understanding of abnormal physiology in a clinical context. Access to the on-line environment was offered to students at all stages of undergraduate training as an adjunct to routine lectures and tutorials in cardiac pathophysiology. Student feedback was collected on this novel on-line material in the course of routine audits of teaching delivery. Medical students, irrespective of their stage of undergraduate training, reported that they found the models and the environment interesting and a positive experience. After exposure to the environment, there was a statistically significant improvement in student performance on a series of 6 questions based on cardiovascular medicine, with a 33% and 22% increase in the number of questions answered correctly, p < 0.0001 and p < 0.001 respectively. Considerable improvement was found in students' knowledge and understanding during assessment after exposure to the e-learning environment. Opportunities exist for development of similar environments in other fields of medicine, refinement of the existing environment and further engagement with student cohorts. This work combines some exciting and developing fields in medical education, but routine adoption of these types of tool will be possible only with the engagement of all stake-holders, from educationalists, clinicians, modellers to, most importantly, medical students.


Robotic interfaces for cognitive psychology and embodiment research: A research roadmap.
Advanced human-machine interfaces render robotic devices applicable to study and enhance human cognition. This turns robots into formidable neuroscientific tools to study processes such as the adaptation between a human operator and the operated robotic device and how this adaptation modulates human embodiment and embodied cognition. We analyze bidirectional human-machine interface (bHMI) technologies for transparent information transfer between a human and a robot via efferent and afferent channels. Even if such interfaces have a tremendous positive impact on feedback loops and embodiment, advanced bHMIs face immense technological challenges. We critically discuss existing technical approaches, mainly focusing on haptics, and suggest extensions thereof, which include other aspects of touch. Moreover, we point out other potential constraints such as limited functionality, semi-autonomy, intent-detection, and feedback methods. From this, we develop a research roadmap to guide understanding and development of bidirectional human-machine interfaces that enable robotic experiments to empirically study the human mind and embodiment. We conclude the integration of dexterous control and multisensory feedback to be a promising roadmap towards future robotic interfaces, especially regarding applications in the cognitive sciences. This article is categorized under: Computer Science > Robotics Psychology > Motor Skill and Performance Neuroscience > Plasticity.


A new algorithm for identification of components in a mixture: application to Raman spectra of solid amino acids.
The procedure for identifying components in a mixture was developed and tested on Raman spectra of mixtures of solid amino acids, using the spectra of single amino acids as templates. The method is based on finding the optimum scaling coefficients of the linear combination of template spectra that minimize the Canberra distance between measured and reconstructed spectra. The Canberra distance, used here as a measure of dissimilarity between spectra, defines the non-convex objective function in the related optimization process. In view of the possibility of the presence of local minima, differential evolution, which is a non-gradient stochastic method for finding the global minimum, was chosen for optimization. The method was tested on twenty measured spectra of mixtures of solid powders containing one to eight amino acids taken from the collection of twenty that are coded in living organisms. The results show that the procedure can successfully identify several amino acids, and, in general, several components in a mixture. The method was shown to compare favorably against the least squares and partial least squares methods, the procedures used in commercially available chemometrics packages.


Neutron imaging of laser fusion targets.
Along-term goal of inertial-confinement fusion research is the generation of energy by imploding capsules containing deuterium-tritium fuel. Progress in designing the capsules is aided by accurate imaging of the fusion burn. Penumbral coded-aperture techniques have been used to obtain neutron images that are a direct measurement of the fusion burn region in the capsules.


Identification of a specific site required for rapid heterologous desensitization of the beta-adrenergic receptor by cAMP-dependent protein kinase.
The molecular basis for heterologous desensitization of the beta-adrenergic receptor (beta AR) was investigated by site-directed mutagenesis of the beta AR protein. Rapid heterologous desensitization of agonist-stimulated adenylyl cyclase activity was observed when L cells expressing the wild-type beta AR were incubated with 50 nM epinephrine. This desensitization response could be mimicked in a cell-free system by incubation with cAMP-dependent protein kinase (cA.PK). Deletion of amino acid residues 259-262 from the beta AR, removing one of the two consensus sequences in the receptor for phosphorylation by cA.PK, abolished the ability of the receptor to undergo rapid heterologous desensitization. In contrast, deletion of the other cA.PK consensus sequence (residues 343-348) or truncation of the Ser/Thr-rich C-terminal tail of the beta AR (deletion of residues 354-418) did not affect this heterologous desensitization process. These results suggest that the action of cA.PK on amino acid residue(s) contained within the sequence 259-262 of the beta AR is required for rapid heterologous desensitization of the receptor in response to agonists.


Within-Trial Cost-Effectiveness of a Structured Lifestyle Intervention in Adults With Overweight/Obesity and Type 2 Diabetes: Results From the Action for Health in Diabetes (Look AHEAD) Study.
To assess the cost-effectiveness (CE) of an intensive lifestyle intervention (ILI) compared with standard diabetes support and education (DSE) in adults with overweight/obesity and type 2 diabetes, as implemented in the Action for Health in Diabetes study. Data were from 4,827 participants during their first 9 years of study participation from 2001 to 2012. Information on Health Utilities Index Mark 2 (HUI-2) and HUI-3, Short-Form 6D (SF-6D), and Feeling Thermometer (FT), cost of delivering the interventions, and health expenditures was collected during the study. CE was measured by incremental CE ratios (ICERs) in costs per quality-adjusted life year (QALY). Future costs and QALYs were discounted at 3% annually. Costs were in 2012 U.S. dollars. Over the 9 years studied, the mean cumulative intervention costs and mean cumulative health care expenditures were $11,275 and $64,453 per person for ILI and $887 and $68,174 for DSE. Thus, ILI cost $6,666 more per person than DSE. Additional QALYs gained by ILI were not statistically significant measured by the HUIs and were 0.07 and 0.15, respectively, measured by SF-6D and FT. The ICERs ranged from no health benefit with a higher cost based on HUIs to $96,458/QALY and $43,169/QALY, respectively, based on SF-6D and FT. Whether ILI was cost-effective over the 9-year period is unclear because different health utility measures led to different conclusions.


Chemical Composition, Cytotoxic, Apoptotic and Antioxidant Activities of Main Commercial Essential Oils in Palestine: A Comparative Study.
Background: Essential oils (EOs) are complex mixtures of several components gifted with a wide array of biological activities. The present research was designed to evaluate whether commercial essential oils could be effective by examining their in vitro antioxidant, cytotoxic, and apoptotic properties of nine commercially available EOs in Palestine, namely, African rue, basil, chamomile, fennel, fenugreek, ginger, spearmint, sage, and thyme, and to assure their effective use. Methods: The cytotoxic activity was determined using HT29-19(A) non-muco secreting and HT29-muco secreting (MS) cell lines. MTT, and trypan blue tests, and DPPH radical scavenging have also been assayed on the studied EOs. Results: In this work chamomile oil showed the lowest IC50 at the content of 60 µL/mL, while all other EOs reached such a decrease when 70-80 µL/mL was used on HT-29 (MS) cell lines. In HT-29 19(A) cells, 50% of viability was obtained when 80 µL/mL of ginger and African rue was used, while all other EOs needed more than 80 µL/mL to reach such a decline in viability. Otherwise, an MTT assay on HT-29 (MS) displayed ginger EO with the lowest IC50, followed by African rue and sage, with 40, 48 and 53 µL/mL, respectively. Otherwise, for the rest of the EOs, the IC50 was obtained by assaying around 80 µL/mL. Ginger showed the lowest IC50 with 60 µL/mL and thyme was the highest with 77 µL/mL when HT-29 19(A) cells were used. Conclusion: The most active EOs were found to be ginger, chamomile oil, and African rue. In general, the results demonstrate that most commercial EOs tested in this work possess low, or no biological activities; this may be due to processing, storage conditions, and handling or other reasons, which may cause losses in the biological and pharmacological properties that endemically exist in the Eos; hence, more investigation is still required on commercial EOs before they are recommended to the public.