Investigation of lactic acid bacterial strains for meat fermentation and the product's antioxidant and angiotensin-I-converting-enzyme inhibitory activities.
In the lactic acid bacteria (LAB) strains screened from our LAB collection, Lactobacillus (L.) sakei strain no. 23 and L. curvatus strain no. 28 degraded meat protein and tolerated salt and nitrite in vitro. Fermented sausages inoculated strains no. 23 and no. 28 showed not only favorable increases in viable LAB counts and reduced pH, but also the degradation of meat protein. The sausages fermented with these strains showed significantly higher antioxidant activity than those without LAB or fermented by each LAB type strain. Angiotensin-I-converting-enzyme (ACE) inhibitory activity was also significantly higher in the sausages fermented with strain no. 23 than in those fermented with the type strain. Higher ACE inhibitory activity was also observed in the sausages fermented with strain no. 28, but did not differ significantly from those with the type strain. An analysis of the proteolysis and degradation products formed by each LAB in sausages suggested that those bioactivities yielded fermentation products such as peptides. Therefore, LAB starters that can adequately ferment meat, such as strains no. 23 and no. 28, should contribute to the production of bioactive compounds in meat products.


Friction forces position the neural anlage.
During embryonic development, mechanical forces are essential for cellular rearrangements driving tissue morphogenesis. Here, we show that in the early zebrafish embryo, friction forces are generated at the interface between anterior axial mesoderm (prechordal plate, ppl) progenitors migrating towards the animal pole and neurectoderm progenitors moving in the opposite direction towards the vegetal pole of the embryo. These friction forces lead to global rearrangement of cells within the neurectoderm and determine the position of the neural anlage. Using a combination of experiments and simulations, we show that this process depends on hydrodynamic coupling between neurectoderm and ppl as a result of E-cadherin-mediated adhesion between those tissues. Our data thus establish the emergence of friction forces at the interface between moving tissues as a critical force-generating process shaping the embryo.


A randomized clinical trial comparing advanced pneumatic truncal, chest, and arm treatment to arm treatment only in self-care of arm lymphedema.
Treatment of the truncal lymphatics prior to treatment of the lymphedematous arm is an accepted, although not empirically tested, therapeutic intervention delivered during decongestive lymphatic therapy (DLT). Breast cancer survivors with arm lymphedema are encouraged to use these techniques when performing simple lymphatic drainage as part of their life-long lymphedema self-care. Self-massage is at times difficult and pneumatic compression devices are used by many patients to assist with self-care. One such device, the Flexitouch(®) System, replicates the techniques used during DLT; however, the need for application of pneumatic compression in unaffected truncal areas to improve self-care outcomes in arm only lymphedema is not established. The objective of this study was to compare the therapeutic benefit of truncal/chest/arm advanced pneumatic compression therapy (experimental group) verses arm only pneumatic compression (control group) in self-care for arm lymphedema without truncal involvement using the Flexitouch(®) System. Outcomes of interest were self-reported symptoms, function, arm impedance ratios, circumference, volume, and trunk circumference. Forty-two breast cancer survivors, (21 per group), with Stage II lymphedema completed 30 days of home self-care using the Flexitouch(®) System. Findings revealed a statistically significant reduction in both the number of symptoms and overall symptom burden within each group; however, there were no statistically significant differences in these outcomes between the groups. There was no statistically significant overall change or differential pattern of change between the groups in function. A statistically significant reduction in bioelectrical impedance and arm circumference within both of the groups was achieved; however, there was no statistically significant difference in reduction between groups. These findings indicate that both configurations are effective, but that there may be no added benefit to advanced pneumatic treatment of the truncal lymphatics prior to arm massage when the trunk is not also affected. Further research is indicated in a larger sample.


Single-photon nonlinearity at room temperature.
The recent progress in nanotechnology1,2 and single-molecule spectroscopy3-5 paves the way for emergent cost-effective organic quantum optical technologies with potential applications in useful devices operating at ambient conditions. We harness a π-conjugated ladder-type polymer strongly coupled to a microcavity forming hybrid light-matter states, so-called exciton-polaritons, to create exciton-polariton condensates with quantum fluid properties. Obeying Bose statistics, exciton-polaritons exhibit an extreme nonlinearity when undergoing bosonic stimulation6, which we have managed to trigger at the single-photon level, thereby providing an efficient way for all-optical ultrafast control over the macroscopic condensate wavefunction. Here, we utilize stable excitons dressed with high-energy molecular vibrations, allowing for single-photon nonlinear operation at ambient conditions. This opens new horizons for practical implementations like sub-picosecond switching, amplification and all-optical logic at the fundamental quantum limit.


Parental perspectives on the causes of an autism spectrum disorder in their children.
Autism Spectrum Disorders (ASDs) are complex neurodevelopmental disorders with many biological causes, including genetic, syndromic and environmental. Such etiologic heterogeneity impacts considerably upon parents' needs for understanding their child's diagnosis. A descriptive survey was designed to investigate parental views on the cause(s) of ASD in their child. Among the 41 parents who replied to the questionnaire, genetic influences (90.2%), perinatal factors (68.3%), diet (51.2%), prenatal factors (43.9%) and vaccines (40.0%) were considered to be the most significant contributory factors. Parents reported inaccurately high recurrence risks, misperceptions of the contribution of various putative factors, feelings of guilt and blame regarding their child's diagnosis, as well as a lack of advocacy for genetic counseling by non-geneticist professionals. This study offers clinicians and researchers further insight into what parents believe contributed to their child's diagnosis of ASD and will help facilitate genetic counseling for these families.


Increased transplantation of kidneys with multiple renal arteries in the laparoscopic live donor nephrectomy era: surgical technique and surgical and nonsurgical donor and recipient outcomes.
For anatomical and technical reasons, many transplant centers restrict laparoscopic live donor nephrectomy (in contrast with open live donor nephrectomy) to left kidneys. This change in surgical practice increases procurement and transplantation rates of live donor kidneys with multiple renal arteries (RAs), without affecting donor and recipient outcomes. Retrospective review at an academic tertiary care referral center comparing laparoscopically procured single vs multiple-RA kidney grafts (April 1997 to October 2000). Seventy-nine consecutive left laparoscopic live kidney donors and 78 transplant recipients. Donor and recipient complications and postoperative length of stay; cold and warm ischemia time; operating time; short-term and long-term graft function; and survival. We noted multiple RAs in 21 (27%) of all kidneys. The proportion of donors with 1 or more perioperative complications was 19% in the single-RA group vs 10% in the multiple-RA group (P was not significant). For the recipients, we noted no significant differences between groups with respect to surgical complications, quality of early and late graft function, rejection rates, graft losses (all immunologic), and graft survival. Cold and warm ischemia time and length of stay were similar for donors and recipients in both groups. Median operating times were significantly longer for the multiple-RA vs single-RA group (difference, 41 minutes for donors and 45 minutes for recipients; P<.02). While the introduction of laparoscopic live donor nephrectomy has significantly increased the number of grafts with multiple RAs (compared with historical open controls), this change in practice is safe for both donors and recipients from a patient outcome-based perspective. However, from an economic perspective, the longer operating time associated with multiple-RA grafts provides strong added rationale for optimization of surgical instruments and techniques to make right-sided laparoscopic nephrectomy a routine intervention.


A population-based cohort study of KIR genes and genotypes in relation to cervical intraepithelial neoplasia.
Natural killer (NK) cells are involved both in control of virus infections and in elimination of tumor cells. Killer immunoglobulin-like receptors (KIRs) either activate or inhibit NK cell-mediated cytolysis, protecting healthy cells from destruction while enabling killing of abnormal cells. To investigate whether KIR genes or genotypes are associated with cervical carcinogenesis, a nested case-control study of 65 case women with cervical intraepithelial neoplasia (CIN) diagnosed during a 6-year follow-up of 15,234 women and 150 control women from the same cohort that remained healthy was performed. More than 70 different genotypes were observed, and 33 of which had not been described previously. An A-genotype including KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR3DL3, and KIR2DS4 was associated with increased risk of CIN (OR 6.7; 95% CI 1.7-26.3), and KIR2DL5B*002 appeared to have an inverse association with disease (OR 0.5; 95% CI 0.5-2.9). There was no association of CIN with the number of activating KIR genes. There was also no association between KIR genes and type of human papilloma virus or with other CIN-related immune response genes. It was concluded that certain KIR genes and genotypes may associate with cervical neoplasia.


Reaction conditions for laccase catalyzed polymerization of catechol.
Poly(catechol) was synthesized in batch runs with laccase from Trametes versicolor (ATCC 200801). The polymerization reaction was conducted in a closed, temperature controlled system containing acetone and sodium acetate buffer for pH control. The effects of the solvent mixture, monomer (catechol), enzyme, medium pH and temperature on the polymerization rate were investigated with respect to initial reaction conditions and depletion rate of dissolved oxygen in the medium. Maximum initial reaction rate was attained with 10% (v/v) acetone-sodium acetate buffer at pH 5.0, 25 degrees C, 0.02 U/ml enzyme and 250 mg/l initial catechol and 10 mg/l dissolved oxygen. A general saturation enzyme kinetics response was observed for catechol substrate. Temperature rise supported the rate increase up to 45 degrees C, after which the rate tended to be stable due to a drop in dissolved oxygen concentration as well as enzyme instability.


Impact of TCF4 on the genetics of schizophrenia.
Mutations of the transcription factor 4 (TCF4) gene cause mental retardation with or without associated facial dysmorphisms and intermittent hyperventilation. Subsequently, a polymorphism of TCF4 was shown in a genome-wide association study to slightly increase the risk of schizophrenia. We have further analysed the impact of this TCF4 variant rs9960767 on early information processing and cognitive functions in schizophrenia patients. We have shown in a sample of 401 schizophrenia patients that TCF4 influences verbal memory in the Rey Auditory Verbal Learning Test. Contrary to expectations, carriers of the schizophrenia-associated allele showed better recognition, thus indicating that while TCF4 influences verbal memory, the TCF4-mediated schizophrenia risk is not determined by the influence of TCF4 on verbal memory. TCF4 does not impact on various other cognitive functions belonging to the domains of attention and executive functions. Moreover, in a pharmacogenetic approach, TCF4 does not modulate the improvement of positive or negative schizophrenia symptoms during treatment with antipsychotics. Finally, we have assessed a key electrophysiological endophenotype of schizophrenia, sensorimotor gating. As measured by prepulse inhibition, the schizophrenia risk allele C of TCF4 rs9960767 reduces sensorimotor gating. This indicates that TCF4 influences key mechanisms of information processing, which may contribute to the pathogenesis of schizophrenia.


A sectional aerosol model for submicron particles in indoor air.
This study attempted to simulate indoor concentrations and the indoor-to-outdoor (I:O) number concentration ratios of aerosol particles in the submicron size range. The developed model used size-segregated outdoor number concentrations of particles as inputs and produced the indoor aerosol size spectrum. It covered all the major dynamic processes associated with the indoor aerosol concentration: transport and filtration in the air exchange system, deposition, coagulation, nucleation, condensation, and indoor sources. The model results were compared with measured particle concentrations. Numerous sensitivity analyses were also made for testing the effect of different dynamic processes on the model results. No indoor particle sources were considered in the sensitivity simulations. Changes in the air exchange rate had the strongest effect on the simulated I:O ratios of particle number concentrations. Filtration in the air exchange system also had a large effect on the indoor concentrations. Deposition did not significantly change the particle number concentrations within a realistic range of turbulence intensity indoors and the temperature differences between the ambient air and surfaces. Coagulation affected only the smallest particle size ranges. Condensation and nucleation had potentially large effects on the particle size spectrum. The model reproduced the measured I:O ratios of fine and ultrafine particle concentrations with reasonable accuracy. The model can be a valuable tool with which to estimate the I:O ratios for human exposure assessment.


Quantifying the psychological value of goal achievement.
It is often assumed that people put forth the least amount of effort necessary to obtain a reward. This assumption is consistent with so-called "rational" economic models of behavior. Yet these models rarely take into account the motivating effects of goals, which may lead to departures from objective reward maximizing behavior. We present an experiment in which people make a series of prioritization decisions whilst pursuing two approach or avoidance goals. Participants were rewarded $10 if they achieved both goals on a randomly selected trial, and either $0, $2.50, $5, $7.50, or $10 if they achieved only one. Bayesian parameter estimation was used to examine the subjective values that people placed on various goal achievement outcomes. The results suggested that people often discounted the achievement of the first goal, relative to a reward maximizing model, particularly when pursuing avoidance goals. These results were most evident among participants who could obtain the full reward after achieving just one goal, yet behaved as if achieving one goal was only half as valuable as achieving both. Our findings question the notion that people put forth the least amount of effort required to obtain a reward. They suggest that when tasks have explicit goals, people may even sacrifice financial reward to achieve the goals.


Applying Multivariate Segmentation Methods to Human Activity Recognition From Wearable Sensors' Data.
Time-resolved quantification of physical activity can contribute to both personalized medicine and epidemiological research studies, for example, managing and identifying triggers of asthma exacerbations. A growing number of reportedly accurate machine learning algorithms for human activity recognition (HAR) have been developed using data from wearable devices (eg, smartwatch and smartphone). However, many HAR algorithms depend on fixed-size sampling windows that may poorly adapt to real-world conditions in which activity bouts are of unequal duration. A small sliding window can produce noisy predictions under stable conditions, whereas a large sliding window may miss brief bursts of intense activity. We aimed to create an HAR framework adapted to variable duration activity bouts by (1) detecting the change points of activity bouts in a multivariate time series and (2) predicting activity for each homogeneous window defined by these change points. We applied standard fixed-width sliding windows (4-6 different sizes) or greedy Gaussian segmentation (GGS) to identify break points in filtered triaxial accelerometer and gyroscope data. After standard feature engineering, we applied an Xgboost model to predict physical activity within each window and then converted windowed predictions to instantaneous predictions to facilitate comparison across segmentation methods. We applied these methods in 2 datasets: the human activity recognition using smartphones (HARuS) dataset where a total of 30 adults performed activities of approximately equal duration (approximately 20 seconds each) while wearing a waist-worn smartphone, and the Biomedical REAl-Time Health Evaluation for Pediatric Asthma (BREATHE) dataset where a total of 14 children performed 6 activities for approximately 10 min each while wearing a smartwatch. To mimic a real-world scenario, we generated artificial unequal activity bout durations in the BREATHE data by randomly subdividing each activity bout into 10 segments and randomly concatenating the 60 activity bouts. Each dataset was divided into ~90% training and ~10% holdout testing. In the HARuS data, GGS produced the least noisy predictions of 6 physical activities and had the second highest accuracy rate of 91.06% (the highest accuracy rate was 91.79% for the sliding window of size 0.8 second). In the BREATHE data, GGS again produced the least noisy predictions and had the highest accuracy rate of 79.4% of predictions for 6 physical activities. In a scenario with variable duration activity bouts, GGS multivariate segmentation produced smart-sized windows with more stable predictions and a higher accuracy rate than traditional fixed-size sliding window approaches. Overall, accuracy was good in both datasets but, as expected, it was slightly lower in the more real-world study using wrist-worn smartwatches in children (BREATHE) than in the more tightly controlled study using waist-worn smartphones in adults (HARuS). We implemented GGS in an offline setting, but it could be adapted for real-time prediction with streaming data.


Coffee consumption by type and risk of digestive cancer: a large prospective cohort study.
Inverse associations have been observed between coffee consumption and liver cancer, but associations for other digestive cancers are unclear. Few previous studies have investigated coffee type (specifically instant or ground coffee) or a range of digestive cancer types within one cohort. We therefore investigated coffee consumption by type and digestive cancer risks in a population-based cohort. The UK Biobank captured self-reported coffee consumption and cancer-registry recorded incident digestive cancers. Hazard ratios (HRs) and 95% CIs were calculated using Cox regression. The risk of every type of digestive cancer was investigated in association with coffee consumption by dose-response and by coffee type (decaffeinated, instant and ground). Over 7.5 years of follow-up, 3567 developed digestive cancer among 471,779 participants. There were 88 cases of hepatocellular carcinoma and a marked association was observed for hepatocellular carcinoma in coffee drinkers (HR 0.50, 95% CI 0.29, 0.87), which was similar for instant (HR 0.51, 95% CI 0.28, 0.93) and ground coffee (HR 0.47, 95% CI 0.20, 1.08). We did not observe significant consistently reduced risks of other individual digestive cancers amongst coffee drinkers. We found some evidence that coffee consumption was inversely associated with hepatocellular carcinoma which was similar by coffee type.


No evidence of sperm conjugate formation in an Australian mouse bearing sperm with three hooks.
Sperm conjugation occurs when two or more sperm physically unite for motility or transport through the female reproductive tract. In many muroid rodent species, sperm conjugates have been shown to form by a single, conspicuous apical hook located on the sperm head. These sperm "trains" have been reported to be highly variable in size and, despite all the heads pointing in roughly the same direction, exhibit a relatively disordered arrangement. In some species, sperm "trains" have been shown to enhance sperm swimming speed, and thus have been suggested to be advantageous in sperm competition. Here, we assessed the behavior of sperm in the sandy inland mouse (Pseudomys hermannsburgensis), a muroid rodent that bears sperm with three apical hooks. First, we accrued genetic evidence of multiple paternity within "wild" litters to unequivocally show that sperm competition does occur in this species. Following this we utilized both in vitro and in vivo methodologies to determine whether sandy inland mouse sperm conjugate to form motile trains. Our observations of in vitro preparations of active sperm revealed that sandy inland mouse sperm exhibit rapid, progressive motility as individual cells only. Similarly, histological sections of the reproductive tracts of mated females revealed no in vivo evidence of sperm conjugate formation. We conclude that the unique, three-hooked morphology of the sandy inland mouse sperm does not facilitate the formation of motile conjugates, and discuss our findings in relation to the different hypotheses for the evolution of the muroid rodent hook/s.


LE135, a retinoid acid receptor antagonist, produces pain through direct activation of TRP channels.
Retinoids, through their activation of retinoic acid receptors (RARs) and retinoid X receptors, regulate diverse cellular processes, and pharmacological intervention in their actions has been successful in the treatment of skin disorders and cancers. Despite the many beneficial effects, administration of retinoids causes irritating side effects with unknown mechanisms. Here, we demonstrate that LE135 [4-(7,8,9,10-tetrahydro-5,7,7,10,10-pentamethyl-5H-benzo[e]naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid], a selective antagonist of RARβ , is a potent activator of the capsaicin (TRPV1) and wasabi (TRPA1) receptors, two critical pain-initiating cation channels. We performed to investigate the excitatory effects of LE135 on TRPV1 and TRPA1 channels expressed in HEK293T cells and in dorsal root ganglia neurons with calcium imaging and patch-clamp recordings. We also used site-directed mutagenesis of the channels to determine the structural basis of LE135-induced activation of TRPV1 and TRPA1 channels and behavioural testing to examine if pharmacological inhibition and genetic deletion of the channels affected LE135-evoked pain-related behaviours. LE135 activated both the capsaicin receptor (TRPV1) and the allyl isothiocyanate receptor (TRPA1) heterologously expressed in HEK293T cells and endogenously expressed by sensory nociceptors. Mutations disrupting the capsaicin-binding site attenuated LE135 activation of TRPV1 channels and a single mutation (K170R) eliminated TRPA1 activity evoked by LE135. Intraplantar injection of LE135 evoked pain-related behaviours. Both TRPV1 and TRPA1 channels were involved in LE135-elicited pain-related responses, as shown by pharmacological and genetic ablation studies. This blocker of retinoid acid signalling also exerted non-genomic effects through activating the pain-initiating TRPV1 and TRPA1 channels.


Would eligible gay, bisexual and other men who have sex with men use PrEP? Awareness, knowledge, eligibility and intention to use PrEP among EMIS-2017 participants in Spain.
Pre-exposure prophylaxis (PrEP) is an efficacious strategy for reducing the incidence of HIV infection. It has been available in Spain since 2019. We aim to report on awareness, knowledge of, intention to use, and eligibility for PrEP and related factors among participants in the European Men-Who-Have-Sex-With-Men Internet Survey (EMIS-2017) in Spain. We used Spanish data from EMIS-2017, a cross-sectional study performed among gay, bisexual, and other men who have sex with mean (GBMSM) from 50 countries. We found that 65.3% of the 10,634 participants were aware of PrEP, some 30.1% of those HIV-negative and ≥ 18 years were eligible and 52.7% of those eligible intended to use it. Regarding knowledge about PrEP, only 15.4% of the participants knew 3 statement with true information about that PrEP meant. Older age, being born in Western Europe (WE) and greater outness were associated with greater awareness. Older age, being born in Latin America or Caribbean or WE, sex work, and living in a large city were associated with greater eligibility. A greater degree of outness was associated with reduced intention to use. Our study point to possible barriers in the implementation of PrEP in Spain and similar countries.


Asia prostate cancer study (A-CaP Study) launch symposium.
The Asian Prostate Cancer (A-CaP) Study is an Asia-wide initiative that has been developed over the course of 2 years. The A-CaP Study is scheduled to begin in 2016, when each participating country or region will begin registration of newly diagnosed prostate cancer patients and conduct prognosis investigations. From the data gathered, common research themes will be identified, such as comparisons among Asian countries of background factors in newly diagnosed prostate cancer patients. This is the first Asia-wide study of prostate cancer and has developed from single country research efforts in this field, including in Japan and Korea. The inaugural Board Meeting of A-CaP was held on December 11, 2015 at the Research Center for Advanced Science and Technology, The University of Tokyo, attended by representatives of all participating countries and regions, who signed a memorandum of understanding concerning registration for A-CaP. Following the Board Meeting an A-CaP Launch Symposium was held. The symposium was attended by representatives of countries and regions participating in A-CaP, who gave presentations. Presentations and a keynote address were also delivered by representatives of the University of California San Francisco, USA, and the Peter MacCallum Cancer Centre, Australia, who provided insight and experience on similar databases compiled in their respective countries.


Development and characterization of a new TILLING population of common bread wheat (Triticum aestivum L.).
Mutagenesis is an important tool in crop improvement. However, the hexaploid genome of wheat (Triticum aestivum L.) presents problems in identifying desirable genetic changes based on phenotypic screening due to gene redundancy. TILLING (Targeting Induced Local Lesions IN Genomes), a powerful reverse genetic strategy that allows the detection of induced point mutations in individuals of the mutagenized populations, can address the major challenge of linking sequence information to the biological function of genes and can also identify novel variation for crop breeding. Wheat is especially well-suited for TILLING due to the high mutation densities tolerated by polyploids. However, only a few wheat TILLING populations are currently available in the world, which is far from satisfying the requirement of researchers and breeders in different growing environments. In addition, current TILLING screening protocols require costly fluorescence detection systems, limiting their use, especially in developing countries. We developed a new TILLING resource comprising 2610 M(2) mutants in a common wheat cultivar 'Jinmai 47'. Numerous phenotypes with altered morphological and agronomic traits were observed from the M(2) and M(3) lines in the field. To simplify the procedure and decrease costs, we use unlabeled primers and either non-denaturing polyacrylamide gels or agarose gels for mutation detection. The value of this new resource was tested using PCR with RAPD and Intron-spliced junction (ISJ) primers, and also TILLING in three selected candidate genes, in 300 and 512 mutant lines, revealing high mutation densities of 1/34 kb by RAPD/ISJ analysis and 1/47 kb by TILLING. In total, 31 novel alleles were identified in the 3 targeted genes and confirmed by sequencing. The results indicate that this mutant population represents a useful resource for the wheat research community. We hope that the use of this reverse genetics resource will provide novel allelic diversity for wheat improvement and functional genomics.


The stimuli evoking the aerial-righting posture of falling pea aphids.
Some wingless insects possess aerial righting reflexes, suggesting that adaptation for controlling body orientation while falling through air could have preceded flight. When threatened by natural enemies, wingless pea aphids (Acyrthosiphon pisum) may drop off their host plant and assume a stereotypic posture that rotates them in midair to land on their feet. The sensory information triggering aphids to assume this posture has so far been unknown. We subjected aphids to a series of tests, isolating the sensory cues experienced during free-fall. Falling aphids assumed the righting posture and landed upright irrespective of whether the experiments were carried out in the light or in complete darkness. Detachment of the tarsi from the substrate triggered the aphids to assume the posture rapidly, but only for a brief period. Rotation (mainly roll and yaw) of the body in air, in the light, caused aphids to assume the posture and remain in it throughout rotation. In contrast, aphids rotated in the dark did not respond. Acceleration associated with falling or airflow over the body per se did not trigger the posture. However, sensing motion relative to air heightened the aphids' responsiveness to rotation in the light. These results suggest that the righting posture of aphids is triggered by a tarsal reflex, but, once the aphid is airborne, vision and a sense of motion relative to air can augment the response. Hence, aerial righting in a wingless insect could have emerged as a basic tarsal response and developed further to include secondary sensory cues typical of falling.


Compliance with trial registration in five core journals of clinical geriatrics: a survey of original publications on randomised controlled trials from 2008 to 2012.
to assess the proportion of registered randomised controlled trials in five core clinical geriatric journals and to analyse whether registered study outcomes correspond with published outcomes. survey of original papers published 2008 to 2012. two independent reviewers retrieved the sample through search in the web-based archives of Age and Ageing, the Journal of the American Geriatric Society, the American Journal of Geriatric Psychiatry, the Journal of the American Medical Directors Association and International Psychogeriatrics. Data extraction was performed by two independent reviewers using a pre-tested 13-item checklist. Registration status was checked and information provided in registers compared with information presented in the original publication. A third reviewer was consulted if no consensus could be reached. the sample comprised 220 original publications on randomised controlled trials. A total of 140 (63.6%) were registered. Registration was in accordance with the ICMJE requirements in 54 out of 140 registered trials (38.6%). Less than one-third of registered papers (n = 40) reported on all study outcomes listed in the study register. In 74 out of the 80 non-registered trials, the missing registration was not declared in the publication. There was no consistent upward trend towards higher registration compliance throughout journals and years. our survey shows that prospective trial registration and compliance between outcomes declared in the registry and reported in the publication is poor. Concerted action of authors, editors and peer-reviewers is overdue aimed to irreversibly implement the imperative of registration of randomised controlled trials and complete outcome reporting.


Health care in Europe for women with genital mutilation.
The increasing number of immigrants from African countries practicing female genital mutilation (FGM) has raised concern in Europe. Health care professionals have developed three main responses: (1) technical guidelines for clinical management; (2) codes of conduct on quality of care; and (3) specialised health services for medical and psychological care and counselling. Much remains to be done, however, to ensure adequate care in Europe: (1) medico-legal/ethical discussions; (2) development of protocols to assist in making informed decisions; and (3) development of guidelines on counselling, communication strategies, and referral procedures. All agencies working in the field of FGM should be interlinked at the national level, in which members of the affected communities should be included. At the European level, a coordinated approach between all agencies should be developed.


On weighting clustering.
Recent papers and patents in iterative unsupervised learning have emphasized a new trend in clustering. It basically consists of penalizing solutions via weights on the instance points, somehow making clustering move toward the hardest points to cluster. The motivations come principally from an analogy with powerful supervised classification methods known as boosting algorithms. However, interest in this analogy has so far been mainly borne out from experimental studies only. This paper is, to the best of our knowledge, the first attempt at its formalization. More precisely, we handle clustering as a constrained minimization of a Bregman divergence. Weight modifications rely on the local variations of the expected complete log-likelihoods. Theoretical results show benefits resembling those of boosting algorithms and bring modified (weighted) versions of clustering algorithms such as k-means, fuzzy c-means, Expectation Maximization (EM), and k-harmonic means. Experiments are provided for all these algorithms, with a readily available code. They display the advantages that subtle data reweighting may bring to clustering.


Pathogenic fungus Batrachochytrium dendrobatidis in marbled water frog Telmatobius marmoratus: first record from Lake Titicaca, Bolivia.
The pathogenic fungus Batrachochytrium dendrobatidis (Bd) has been associated with amphibian declines worldwide but has not been well-studied among Critically Endangered amphibian species in Bolivia. We sampled free-living marbled water frogs Telmatobius marmoratus (Anura: Leptodactylidae) from Isla del Sol, Bolivia, for Bd using skin swabs and quantitative polymerase chain reactions. We detected Bd on 44% of T. marmoratus sampled. This is the first record of Bd in amphibians from waters associated with Lake Titicaca, Bolivia. These results further confirm the presence of Bd in Bolivia and substantiate the potential threat of this pathogen to the Critically Endangered, sympatric Titicaca water frog T. culeus and other Andean amphibians.


Hypokalaemic Periodic Paralysis- A Prospective Study of the Underlying Etiologies.
Hypokalaemic periodic paralysis (HPP) is a rare muscular disorder characterised by episodic weakness associated with hypokalaemia. The disease can either be inherited or acquired and misdiagnosis of the disease is quite common. Most of the data available on the disease is from the western world. Studies reporting aetiological, clinical and metabolic profiles of Indian population are sparse. Hence we tried to provide insights of the disease among the Indian population. To study the aetiological, clinical and metabolic profile of patients diagnosed with Hypokalaemic Periodic Paralysis (HPP). This is an observational and analytical study on HPP diagnosed patients, during September 2011 to September 2014 in Kasturba Hospital, Manipal. A total of 23 patients were studied. Detailed history, clinical evaluation and metabolic workup for secondary causes of HPP were analysed. Of the 23 patients, 57% had primary HPP while 43% had secondary HPP. The group of patients with primary HPP comprised of 92% males and 8% females with mean age of 28 years and the mean duration of symptoms of 18 hours. The group with secondary HPP comprised of 70% males and 30% females with mean age of 38.7 years and the mean duration of symptoms of 60 hours. The secondary causes of HPP were thyrotoxicosis (50%), infective diarrhea (20%), Crohn's disease (10%), renal tubular acidosis (RTA) Type I (10%) and Conn's syndrome (10%). In our study primary HPP was found to be more common than secondary HPP. Males were predominantly affected in both groups. HPP should be ruled out before starting therapy for Guillain-Barré Syndrome (GBS).


Effects of solar UV radiation and climate change on biogeochemical cycling: interactions and feedbacks.
Solar UV radiation, climate and other drivers of global change are undergoing significant changes and models forecast that these changes will continue for the remainder of this century. Here we assess the effects of solar UV radiation on biogeochemical cycles and the interactions of these effects with climate change, including feedbacks on climate. Such interactions occur in both terrestrial and aquatic ecosystems. While there is significant uncertainty in the quantification of these effects, they could accelerate the rate of atmospheric CO(2) increase and subsequent climate change beyond current predictions. The effects of predicted changes in climate and solar UV radiation on carbon cycling in terrestrial and aquatic ecosystems are expected to vary significantly between regions. The balance of positive and negative effects on terrestrial carbon cycling remains uncertain, but the interactions between UV radiation and climate change are likely to contribute to decreasing sink strength in many oceanic regions. Interactions between climate and solar UV radiation will affect cycling of elements other than carbon, and so will influence the concentration of greenhouse and ozone-depleting gases. For example, increases in oxygen-deficient regions of the ocean caused by climate change are projected to enhance the emissions of nitrous oxide, an important greenhouse and ozone-depleting gas. Future changes in UV-induced transformations of aquatic and terrestrial contaminants could have both beneficial and adverse effects. Taken in total, it is clear that the future changes in UV radiation coupled with human-caused global change will have large impacts on biogeochemical cycles at local, regional and global scales.


A cardiopulmonary bypass with deep hypothermic circulatory arrest rat model for the investigation of the systemic inflammation response and induced organ damage.
Cardiopulmonary bypass (CPB) is a commonly used technique in cardiac surgery. CPB is however associated with a strong induction of systemic inflammatory response syndrome (SIRS) which in conjunction with ischemia and reperfusion may lead to multiple organ failure. The aim of the study was to establish and characterize a CPB rat model incorporating deep hypothermic circulatory arrest with a specific focus on the extent of the inflammatory reactions and organ damage as a groundwork for novel therapeutics against SIRS and I/R induced organ injury. Male Wistar rats (n = 6) were cannulated for CPB, connected to a heart-lung-machine (HLM) and cooled to a temperature of 16°C before they underwent 45 minutes of deep hypothermic circulatory arrest with global ischaemia. Arrest was followed by rewarming and 60 minutes of reperfusion. Haemodynamic and vital parameters were recorded throughout the CPB procedure. Only animals displaying sinus rhythm throughout reperfusion were utilized for analysis. Rats were euthanized and tissue samples were harvested. Blood gas analysis was performed and blood samples were taken. Induction of organ damage was examined by analysis of protein levels and phosphorylation status of kinases and stress proteins. Results were compared to animals (n = 6) which did not undergo CPB. CPB induced leucocytosis and an increase of interleukin-6 and TNF-α plasma values indicating an inflammatory response. Markers of tissue damage and dysfunction, such as troponin T, creatinine and AST were elevated. Phosphorylation of STAT3 was induced in all examined organs. Activation of MAPK and induction of heat shock proteins occurred in an organ-specific manner with most pronounced effects in heart, lungs and kidneys. The presented CPB rat model shows the induction of SIRS and activation of specific signalling cascades. SIRS seems not to be provoked during DHCA and is elicited mainly during reperfusion. This model might be suitable to test the efficacy of therapeutics applied in major heart surgery with and without DHCA.


Spatial Rho regulation: Molecular mechanisms controlling the GAP protein DLC3.
The spatial regulation of cellular Rho signaling by GEF and GAP proteins and the molecular mechanisms controlling the Rho regulators themselves are still incompletely understood. We previously reported that the poorly characterized RhoGAP protein DLC3 localizes to cell-cell adhesions and Rab8-positive membrane tubules. However, it was unclear how DLC3 is targeted to these subcellular sites to execute its functions. In our recent work, protein partners of DLC3 were identified by mass spectrometry, identifying the basolateral polarity protein Scribble as a scaffold for DLC3 at cell-cell contacts. We found that the PDZ-mediated interaction of DLC3 and Scribble is essential for junctional DLC3 recruitment and its role as a local regulator of RhoA-ROCK signaling controlling adherens junction integrity and Scribble localization. Furthermore, DLC3 and Scribble depletion interfered with polarized lumen formation in a 3D model of cyst morphogenesis, emphasizing the relevance of both proteins in epithelial polarity. These findings reveal a new mechanism for spatial Rho regulation at adherens junctions in polarized epithelial cells and highlight the necessity to investigate DLC3 localization and function also in cellular contexts that require cell junction remodeling.


Fibroblast adhesion on ECM-derived peptide modified poly(2-hydroxyethyl methacrylate) brushes: ligand co-presentation and 3D-localization.
Polymer brushes prepared via surface-initiated polymerization of 2-hydroxyethyl methacrylate are powerful platforms for the fabrication of model biointerfaces to study cell-substrate interactions. In this manuscript, the versatility of surface-initiated polymerization and the poly(2-hydroxyethyl methacrylate) (PHEMA) polymer brush platform are used to address two fundamental questions, viz. the effects of ligand co-presentation and of the 3D localization of biochemical cues on cell behavior. Using a series of PHEMA brushes that present RGD and PHSRN ligands in various relative surface concentrations, the present study unequivocally demonstrates that: (i) co-presentation of PHSRN cues on an RGD functionalized substrate enhances cell adhesion and (ii) this synergetic effect is highest when the two ligands are presented at equal surface concentrations. In the second part of this study, adhesion of 3T3 fibroblasts on a series of PHEMA brushes that present the RGD ligand at a distance of 12, 23 or 42 nm away from the cell substrate interface is investigated. While cells were found to adhere to surfaces that presented the cell adhesive peptides at distances up to 23 nm from the interface, polymer brushes that contained the RGD ligands 42 nm away from the interface did not support cell adhesion.


Determinants of paramedic response readiness for CBRNE threats.
Paramedics play a pivotal role in the response to major emergencies. Recent evidence indicates that their confidence and willingness to respond to chemical, biological, radiological, nuclear, and explosives-related (CBRNE) incidents differs from that relating to their "routine" emergency work. To further investigate the factors underpinning their readiness to respond to CBRNE incidents, paramedics in New South Wales (NSW), Australia, were asked to complete a validated online survey instrument. Univariate and multivariate analyses were performed to examine associated factors determining readiness. The sample of 663 respondents was weighted to reflect the NSW paramedic population as a whole. The univariate analysis indicated that gender, length of service, deployment concern, perceived personal resilience, CBRNE training, and incident experience were significantly associated with perceived CBRNE response readiness. In the initial multivariate analysis, significantly higher response readiness was associated with male gender, university education, and greater length of service (10-15 years). In the final multivariate model, the combined effect of training/incident experience negated the significant effects observed in the initial model and, importantly, showed that those with recent training reported higher readiness, irrespective of incident experience. Those with lower concern regarding CBRNE deployment and those with higher personal resilience were significantly more likely to report higher readiness (Adjusted Relative Risk [ARR] = 0.91, 95% CI: 0.84-0.99; ARR = 1.40, 95% CI: 1.11-1.72, respectively). These findings will assist emergency medical planners in recognizing occupational and dispositional factors associated with enhanced CBRNE readiness and highlight the important role of training in redressing potential readiness differences associated with these factors.


Using Survival Analysis to Identify Risk Factors for Treatment Interruption among New and Retreatment Tuberculosis Patients in Kenya.
Despite high tuberculosis (TB) treatment success rate, treatment adherence is one of the major obstacles to tuberculosis control in Kenya. Our objective was to identify patient-related factors that were associated with time to TB treatment interruption and the geographic distribution of the risk of treatment interruption by county. Data of new and retreatment patients registered in TIBU, a Kenyan national case-based electronic data recording system, between 2013 and 2014 was obtained. Kaplan-Meier curves and log rank tests were used to assess the adherence patterns. Mixed-effects Cox proportional hazards modeling was used for multivariate analysis. Records from 90,170 patients were included in the study. The cumulative incidence of treatment interruption was 4.5% for new patients, and 8.5% for retreatment patients. The risk of treatment interruption was highest during the intensive phase of treatment. Having previously been lost to follow-up was the greatest independent risk factor for treatment interruption (HR: 4.79 [3.99, 5.75]), followed by being HIV-positive not on ART (HR: 1.96 [1.70, 2.26]) and TB relapse (HR: 1.70 [1.44, 2.00]). Male and underweight patients had high risks of treatment interruption (HR: 1.46 [1.35, 1.58]; 1.11 [1.03, 1.20], respectively). High rates of treatment interruption were observed in counties in the central part of Kenya while counties in the northeast had the lowest risk of treatment interruption. A better understanding of treatment interruption risk factors is necessary to improve adherence to treatment. Interventions should focus on patients during the intensive phase, patients who have previously been lost to follow-up, and promotion of integrated TB and HIV services among public and private facilities.


Effect of Varicocele and Its Treatment on Testosterone in Hypogonadal Men with Varicocele: Review of the Literature
Varicocele might cause deterioration in Leydig cell functions, and it is a significant risk factor for hypogonadism. Some controversial issues have been raised in the treatment of hypogonadal men with varicoceles. Symptomatic hypogonadal men with varicoceles have two options: testosterone replacement therapy or varicocele treatment. Both approaches have some advantages and disadvantages. This review summarizes the effect of varicoceles on total plasma testosterone level and addresses whether varicocele repair is effective to improve testosterone levels in hypogonadal men with varicoceles. Experience from large clinical studies in the literature suggests that varicocele repair may increase serum testosterone level in men with varicoceles and testosterone deficiency. Varicocele repair could be offered to men with clinically palpable varicocele and hypogonadism. As the treatment method, microsurgical varicocele repair could be preferred to provide the best improvement. Another advantage of varicocele repair for hypogonadism, instead of exogenous testosterone treatment, is its ability to preserve the fertility status in men who may desire a child in the future. However, further studies are required to clarify varicocel-related Leydig cell dysfunction and to advise hypogonadal patients about the sufficient effectiveness of varicocele repair.


Life with hereditary angioedema: then and now.
Originally identified in 1882, hereditary angioedema (HAE) is a debilitating and potentially fatal disorder. Although a number of therapies have been identified, many are relatively ineffective or are associated with significant side effect concerns that limit their efficacy. Fortunately, the 2008 approval of plasma-derived C1 esterase inhibitor concentrate for disease prophylaxis provides clinicians with a novel and effective treatment unencumbered with severe side effect concerns for those with this debilitating disorder. However, despite advances in modern medicine, HAE remains a condition marked by a myriad of symptoms that mimic a range of other disorders, from allergic angioedema to acute abdomen, and accurate diagnosis remains a concern. Using articles from the medical literature from the late nineteenth and early twentieth centuries documenting families with HAE, we will review its history and pathophysiology as well as describe current trends in its diagnosis and treatment. Additionally, we will emphasize the humanistic impact of the disorder by describing the real-life experiences of a contemporary family who has documented their experience with HAE across 7 generations.


A Roadmap Towards Standards for Neurally Controlled End Effectors.
The control and manipulation of various types of end effectors such as powered exoskeletons, prostheses, and 'neural' cursors by brain-machine interface (BMI) systems has been the target of many research projects. A seamless "plug and play" interface between any BMI and end effector is desired, wherein similar user's intent cause similar end effectors to behave identically. This report is based on the outcomes of an IEEE Standards Association Industry Connections working group on End Effectors for Brain-Machine Interfacing that convened to identify and address gaps in the existing standards for BMI-based solutions with a focus on the end-effector component. A roadmap towards standardization of end effectors for BMI systems is discussed by identifying current device standards that are applicable for end effectors. While current standards address basic electrical and mechanical safety, and to some extent, performance requirements, several gaps exist pertaining to unified terminologies, data communication protocols, patient safety and risk mitigation.


Graphene mode-locked Cr:ZnS chirped-pulse oscillator.
We report the first to our knowledge high-energy graphene mode-locked solid-state laser operating in the positive dispersion regime. Pulses with 15.5 nJ energy and 42 nm spectral bandwidth with 0.87 ps duration were obtained at 2.4 μm wavelength. The output can be compressed down to 189 fs. The graphene absorber damage threshold was established at fluence approaching 1 mJ/cm².


Nucleoplasmic bridges and acrocentric chromosome associations as early markers of exposure to low levels of ionising radiation in occupationally exposed hospital workers.
Ionising radiation, with the contribution of telomere shortening, induces DNA double-strand breaks that result in chromosome end fusion, nucleoplasmic bridges (NPBs) and chromosome aberrations (ChAbs) as well as dicentric chromosomes. In order to investigate the chromosomal damage induced by occupational ionising radiation at low exposure levels, and to find early markers of health hazard, peripheral lymphocytes of occupationally exposed hospital workers were cytogenetically analysed. Results showed a significant difference in the frequency of ChAbs in exposed subjects relative to controls. A significant number of NPBs between nuclei of binucleated cultured lymphocytes from exposed subjects were also observed, as well as a consistent amount of acrocentric chromosomes with associations of their short arms. Excluding confounding factors, the frequencies of all these three biological endpoints differed significantly in exposed subjects from those in controls. Because the absence of telomeres and/or their short length could be a common root for both the findings, we utilised fluorescence in situ hybridisation technique with telomeric repeat as probe to demonstrate that, in exposed subjects, chromatin of short arms of involved acrocentric chromosomes did not exhibit a telomeric shortening but appeared strongly decondensed. This finding suggests that NPBs and telomeric acrocentric association should be regarded as early markers of exposure to low levels of ionising radiation and their increase should be seen as an early warning for the health of the involved workers.


"I Don't Feel Like I Have Any Control of My Life at All . . . Everything Overwhelms Me. Everything": Analyzing Caregiver Uncertainty and Control Through Stance Marking.
Informal caregivers immersed in the daily care of loved ones at end-of-life stages face such challenges as medical and household issues, worries, doubts, and uncertainties. Using a macro-mezzo-micro approach to discourse, we analyzed parent study interview data involving 46 caregivers facing end-of-life realities. At the mezzo level, we examined caregivers' expressed perceptions of control. We then more finely analyzed discursive expressions of affective stances pertaining to caregivers' emotions and feelings, and epistemic stances pertaining to their knowledge and belief states. Theories of uncertainty and control inextricably interweave areas of cognition, affect, and behavior regarding how caregivers perceive their realities and how they engage in or disengage from coping mechanisms in the process. The findings in this three-tiered approach make salient specific discursive patterns gleaned from systematic and fastidious attention to caregivers' own ways of using language that methodically afford deeper entry into the emotional, physical, and cognitive challenges in their everyday lived experiences.


Translational promise of the apelin--APJ system.
Apelin, the endogenous ligand for the G-protein-coupled APJ receptor, is emerging as a key hormone in cardiovascular homoeostasis. It is expressed in a diverse range of tissues with particular preponderance for the cardiovascular system, being found in both the heart and vasculature. Apelin is the most potent in vitro inotrope yet identified and causes endothelium- and nitric oxide-dependent vasodilatation. It also appears to have a role in lipid and glucose metabolism as well as fluid homoeostasis. One of the key emerging features of the apelin--APJ system is its interaction with the renin-angiotensin system with the respective receptors sharing marked sequence homology, forming heterodimers, and mediating opposing physiological actions. To date, both preclinical and limited clinical studies suggest that the apelin--APJ system may have an important role in the pathogenesis of heart failure. Although the apelin--APJ system is downregulated, the inotropic actions of apelin persist and are enhanced in failing hearts without inducing ventricular hypertrophy. In combination with its interaction with the renin-angiotensin system, APJ agonism may provide a new therapeutic target in the treatment of acute and chronic heart failure. In this review, we highlight key aspects of the apelin--APJ system in health and disease, and consider its translational and therapeutic potential. The diverse actions of the apelin--APJ system have implications for understanding the pathophysiology of, and development of treatments for, several major cardiovascular diseases.


Staying well during pregnancy and the postpartum: A pilot randomized trial of mindfulness-based cognitive therapy for the prevention of depressive relapse/recurrence.
Clinical decision-making regarding the prevention of depression is complex for pregnant women with histories of depression and their health care providers. Pregnant women with histories of depression report preference for nonpharmacological care, but few evidence-based options exist. Mindfulness-based cognitive therapy has strong evidence in the prevention of depressive relapse/recurrence among general populations and indications of promise as adapted for perinatal depression (MBCT-PD). With a pilot randomized clinical trial, our aim was to evaluate treatment acceptability and efficacy of MBCT-PD relative to treatment as usual (TAU). Pregnant adult women with depression histories were recruited from obstetric clinics at 2 sites and randomized to MBCT-PD (N = 43) or TAU (N = 43). Treatment acceptability was measured by assessing completion of sessions, at-home practice, and satisfaction. Clinical outcomes were interview-based depression relapse/recurrence status and self-reported depressive symptoms through 6 months postpartum. Consistent with predictions, MBCT-PD for at-risk pregnant women was acceptable based on rates of completion of sessions and at-home practice assignments, and satisfaction with services was significantly higher for MBCT-PD than TAU. Moreover, at-risk women randomly assigned to MBCT-PD reported significantly improved depressive outcomes compared with participants receiving TAU, including significantly lower rates of depressive relapse/recurrence and lower depressive symptom severity during the course of the study. MBCT-PD is an acceptable and clinically beneficial program for pregnant women with histories of depression; teaching the skills and practices of mindfulness meditation and cognitive-behavioral therapy during pregnancy may help to reduce the risk of depression during an important transition in many women's lives.


Cellulose Nanocrystals from Forest Residues as Reinforcing Agents for Composites: A Study from Macro- to Nano-Dimensions.
This study investigates for the first time the feasibility of extracting cellulose nanocrystals (CNCs) from softwood forestry logging residues (woody chips, branches and pine needles), with an obtained gravimetric yield of over 13%. Compared with the other residues, woody chips rendered a higher yield of bleached cellulosic fibers with higher hemicellulose, pectin and lignin content, longer diameter, and lower crystallinity and thermal stability. The isolation of CNCs from these bleached cellulosic fibers was verified by the removal of most of their amorphous components, the increase in the crystallinity index, and the nano-dimensions of the individual crystals. The differences in the physico-chemical properties of the fibers extracted from the three logging residues resulted in CNCs with specific physico-chemical properties. The potential of using the resulting CNCs as reinforcements in nanocomposites was discussed in terms of aspect ratio, crystallinity and thermal stability.


The Body That Speaks: Recombining Bodies and Speech Sources in Unscripted Face-to-Face Communication.
This article examines advances in research methods that enable experimental substitution of the speaking body in unscripted face-to-face communication. A taxonomy of six hybrid social agents is presented by combining three types of bodies (mechanical, virtual, and human) with either an artificial or human speech source. Our contribution is to introduce and explore the significance of two particular hybrids: (1) the cyranoid method that enables humans to converse face-to-face through the medium of another person's body, and (2) the echoborg method that enables artificial intelligence to converse face-to-face through the medium of a human body. These two methods are distinct in being able to parse the unique influence of the human body when combined with various speech sources. We also introduce a new framework for conceptualizing the body's role in communication, distinguishing three levels: self's perspective on the body, other's perspective on the body, and self's perspective of other's perspective on the body. Within each level the cyranoid and echoborg methodologies make important research questions tractable. By conceptualizing and synthesizing these methods, we outline a novel paradigm of research on the role of the body in unscripted face-to-face communication.


Combining fractal image compression and vector quantization.
In fractal image compression, the code is an efficient binary representation of a contractive mapping whose unique fixed point approximates the original image. The mapping is typically composed of affine transformations, each approximating a block of the image by another block (called domain block) selected from the same image. The search for a suitable domain block is time-consuming. Moreover, the rate distortion performance of most fractal image coders is not satisfactory. We show how a few fixed vectors designed from a set of training images by a clustering algorithm accelerates the search for the domain blocks and improves both the rate-distortion performance and the decoding speed of a pure fractal coder, when they are used as a supplementary vector quantization codebook. We implemented two quadtree-based schemes: a fast top-down heuristic technique and one optimized with a Lagrange multiplier method. For the 8 bits per pixel (bpp) luminance part of the 512 x 512 Lena image, our best scheme achieved a peak-signal-to-noise ratio of 32.50 dB at 0.25 bpp.


Simulated learning in musculoskeletal assessment and rehabilitation education: comparing the effect of a simulation-based learning activity with a peer-based learning activity.
Musculoskeletal disorders and diseases are leading causes of pain, physical disability, and doctor visits throughout the world. Health professionals must be trained to assess, treat through rehabilitation and monitor patients with these disorders. Yet, due to overcrowded curricula, some health education programs struggle to accommodate more than minimal training in musculoskeletal conditions. Consequently, educators in these professions must consider how traditional instruction could be complemented effectively to enhance students' preparation for the diverse musculoskeletal disorders and pathologies they may encounter. The purpose of this study was to explore the benefits that can be obtained from laboratory practice in musculoskeletal conditions with a standardised patient, rather than a peer patient, in a condensed time frame. Two groups of students were assigned to either a standardised or a peer patient condition for 2 × 2 hours musculoskeletal assessment and rehabilitation lab sessions. All students completed a pre-post matched questionnaire measuring their clinical knowledge, confidence in clinical skills and motivation for further learning. Their clinical skills were tested at the end. Students and standardised patients' perceptions of the simulated learning environment to practise musculoskeletal assessment and rehabilitation were also elicited. A t-test for independent samples revealed that students working with standardised patients displayed significantly higher standards of practical clinical skills than those working with peer patients (p=0.018). Using MANOVAs with repeated measures, no interaction effect for clinical knowledge, confidence in clinical skills, and motivation for future learning were found, both groups displaying significantly enhanced cognition and motivation. Three positive and two negative themes emerged from the analysis of students' perceptions of the simulated learning environments. These were consistent with the simulated patients' perceptions. The findings of this study provide support for the value of using standardised patients to enhance clinical skills in musculoskeletal assessment and rehabilitation when the timeframe for laboratory practice is limited. Students' perceptions of their experience contributed to explain why confidence in clinical skills might not necessarily improve when practising with standardised patients. Suggestions are made for optimising learning with standardised patients and for addressing the economic challenge on health education programs of hiring standardised patients.


The LKB1-AMPK pathway: metabolism and growth control in tumour suppression.
In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity. LKB1 encodes a serine-threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes. The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.


Evaluation of Implementing a Home-Based Fall Prevention Program among Community-Dwelling Older Adults.
We aimed to describe and evaluate the implementation of a home-based exercise program among community-dwelling adults aged ≥65 years. In an observational study, the twelve-week program was implemented in a community setting. The implementation plan consisted of dialogues with healthcare professionals and older adults, development of an implementation protocol, recruitment of participants, program implementation, and implementation evaluation. The dialogues consisted of a Delphi survey among healthcare professionals, and of individual and group meetings among older adults. The implementation of the program was evaluated using the framework model RE-AIM. In the dialogues with healthcare professionals and older adults, it was found that negative consequences of a fall and positive effects of preventing a fall should be emphasized to older adults, in order to get them engaged in fall prevention activities. A total of 450 older adults enrolled in the study, of which 238 started the program. The process evaluation showed that the majority of older adults were recruited by a community nurse. Also, a good collaboration between the research team and the local primary healthcare providers was accomplished, which was important in the recruitment. Future fall prevention studies may use this information in order to translate an intervention in a research project into a community-based program.


[Itching in dialysis, from the patient's point of view].
Itching is an annoying symptom, which afflicts patients with chronic renal failure. To assess the diffusion of itching in the dialysis population in Italy, we carried out a questionnaire, which was distributed to patients of various Italian dialysis centers. The purpose of this investigation was to bring out all those aspects, which make itching a state of chronic suffering, which daily undermines the quality of life of patients. The questionnaire had 16 questions on the intensity of itching, the timing of appearance, the report to doctors and nurses, and any suggested remedies, in addition to some other concerning age, sex, and dialysis age. The questionnaires were distributed to 153 Dialysis Centers and received 1905 responses. In 46.7% of the answered questionnaires, the patients declared the absence of itching. Instead, 53.3% of the patients interviewed reported having itching with varying degrees of intensity. We used for quantifying the intensity of itching the numerical rating scale (NRS). Among the interviewees, those (20.4%) who reported a greater intensity and severity of the symptom described it as often present always, even at night, so as to heavily condition sleep. Only 32.5% of patients solved the problem by contacting their nephrologist or dialysis nurse, and a lower percentage by contacting the dermatologist or general practitioner.


Spike-Centered Jitter Can Mistake Temporal Structure.
Jitter-type spike resampling methods are routinely applied in neurophysiology for detecting temporal structure in spike trains (point processes). Several variations have been proposed. The concern has been raised, based on numerical experiments involving Poisson spike processes, that such procedures can be conservative. We study the issue and find it can be resolved by reemphasizing the distinction between spike-centered (basic) jitter and interval jitter. Focusing on spiking processes with no temporal structure, interval jitter generates an exact hypothesis test, guaranteeing valid conclusions. In contrast, such a guarantee is not available for spike-centered jitter. We construct explicit examples in which spike-centered jitter hallucinates temporal structure, in the sense of exaggerated false-positive rates. Finally, we illustrate numerically that Poisson approximations to jitter computations, while computationally efficient, can also result in inaccurate hypothesis tests. We highlight the value of classical statistical frameworks for guiding the design and interpretation of spike resampling methods.


X-ray illumination of the ejecta of supernova 1987A.
When a massive star explodes as a supernova, substantial amounts of radioactive elements--primarily (56)Ni, (57)Ni and (44)Ti--are produced. After the initial flash of light from shock heating, the fading light emitted by the supernova is due to the decay of these elements. However, after decades, the energy powering a supernova remnant comes from the shock interaction between the ejecta and the surrounding medium. The transition to this phase has hitherto not been observed: supernovae occur too infrequently in the Milky Way to provide a young example, and extragalactic supernovae are generally too faint and too small. Here we report observations that show this transition in the supernova SN 1987A in the Large Magellanic Cloud. From 1994 to 2001, the ejecta faded owing to radioactive decay of (44)Ti as predicted. Then the flux started to increase, more than doubling by the end of 2009. We show that this increase is the result of heat deposited by X-rays produced as the ejecta interacts with the surrounding material. In time, the X-rays will penetrate farther into the ejecta, enabling us to analyse the structure and chemistry of the vanished star.


Endothelial progenitor cell dysfunction in cardiovascular diseases: role of reactive oxygen species and inflammation.
Endothelial progenitor cells (EPCs) move towards injured endothelium or inflamed tissues and incorporate into foci of neovascularisation, thereby improving blood flow and tissue repair. Patients with cardiovascular diseases have been shown to exhibit reduced EPC number and function. It has become increasingly apparent that these changes may be effected in response to enhanced oxidative stress, possibly as a result of systemic and localised inflammatory responses. The interplay between inflammation and oxidative stress affects the initiation, progression, and complications of cardiovascular diseases. Recent studies suggest that inflammation and oxidative stress modulate EPC bioactivity. Clinical medications with anti-inflammatory and antioxidant properties, such as statins, thiazolidinediones, angiotensin II receptor 1 blockers, and angiotensin-converting enzyme inhibitors, are currently administered to patients with cardiovascular diseases. These medications appear to exert beneficial effects on EPC biology. This review focuses on EPC biology and explores the links between oxidative stress, inflammation, and development of cardiovascular diseases.


Divergence of the diapause transcriptome in apple maggot flies: winter regulation and post-winter transcriptional repression.
The duration of dormancy regulates seasonal timing in many organisms and may be modulated by day length and temperature. Though photoperiodic modulation has been well studied, temperature modulation of dormancy has received less attention. Here, we leverage genetic variation in diapause in the apple maggot fly, Rhagoletis pomonella, to test whether gene expression during winter or following spring warming regulates diapause duration. We used RNAseq to compare transcript abundance during and after simulated winter between an apple-infesting population and a hawthorn-infesting population where the apple population ends pupal diapause earlier than the hawthorn-infesting population. Marked differences in transcription between the two populations during winter suggests that the 'early' apple population is developmentally advanced compared with the 'late' hawthorn population prior to spring warming, with transcripts participating in growth and developmental processes relatively up-regulated in apple pupae during the winter cold period. Thus, regulatory differences during winter ultimately drive phenological differences that manifest themselves in the following summer. Expression and polymorphism analysis identify candidate genes in the Wnt and insulin signaling pathways that contribute to population differences in seasonality. Both populations remained in diapause and displayed a pattern of up- and then down-regulation (or vice versa) of growth-related transcripts following warming, consistent with transcriptional repression. The ability to repress growth stimulated by permissive temperatures is likely critical to avoid mismatched phenology and excessive metabolic demand. Compared with diapause studies in other insects, our results suggest some overlap in candidate genes/pathways, though the timing and direction of changes in transcription are likely species specific.


Flexible resources and experiences of racism among a multi-ethnic adolescent population in Aotearoa, New Zealand: an intersectional analysis of health and socioeconomic inequities using survey data.
As societies become increasingly diverse, understanding the complex nature of racism for multiple ethnic, social, and economic identities of minority youth is required. Here we explore the experience of racism between and among privileged majority adolescent groups and targeted minority (Indigenous and ethnic) adolescents in New Zealand. Using the concept of structural and embodiment flexible resources, which act as risk and protective factors, we examine the social and health effects on minority youth. In this intersectional analysis, we use self-reported data from the Youth2000 survey series administered in 2001, 2007, 2012, and 2019 to large, representative samples of students from mainstream state and private schools in the Auckland, Tai Tokerau, and Waikato regions of New Zealand. Students were in school years 9-13 and mostly aged 13-17 years. Ethnic or migrant group, income level of country of origin, and migrant generation were used as measures of structural resources and perceived ethnicity as a measure of embodiment resource. Racism and its effects were measured as socioeconomic inequities (household, neighbourhood, and school-level deprivation); interpersonal discrimination (unfair treatment, bullying, and safety); and health inequities (forgone health care, symptoms of depression, and attempted suicide). We used generalised linear models to explore variations in economic, interpersonal, and health outcomes for Indigenous and migrant youth, adjusting for mediating effects of household deprivation and measures of flexible resources (migration generation, income level of country of origin, and perceived ethnicity). We collected data from a total of 20 410 adolescents from the four survey waves between 2001 and 2019. Participants had a median age of 15 years (IQR 14-16). Socioeconomic, interpersonal, and health inequities varied with access to flexible resources among Māori and racialised migrant youth. Māori and racialised migrants from low-income and middle-income countries in particular experienced high levels of socioeconomic inequities. Racialised migrant youth experienced persistent socioeconomic inequities extending over three generations, especially Pasifika migrant adolescents. Minorities perceived as White experienced less discrimination and had more advantages than visibly racialised groups. Regression models showed that embodiment resources, and to a lesser extent structural resources, mediated, but did not eliminate ethnic disparities in socioeconomic status and interpersonal discrimination; these resources did not strongly mediate ethnic disparities in health. Trend analyses indicate consistency in these patterns with ethnicity-based inequities persisting or increasing over time. Indigenous and ethnic minority experiences of racism are heterogeneous. Structural flexible resources (wealth) and, more substantially, embodiment flexible resources (perceived Whiteness) mitigate individual experiences of racism. In multi-ethnic western societies, anti-racist interventions and policies must address both structural deprivation and associated intergenerational mobility and colourism (ie, implicit and explicit bias against non-White youth). Health Research Council of New Zealand.


Synergistic effect of aged garlic extract and naltrexone on improving immune responses to experimentally induced fibrosarcoma tumor in BALB/c mice.
Garlic, a medicinal plant, and Naltrexone (NTX), an opioid receptor antagonist, both have immunomodulatory and antitumor effects. Current study was designed to evaluate synergistic antitumor effects of aged garlic extract (AGE) and NTX. WEHI-164 fibrosarcoma cells were implanted subcutaneously on day 0 into right flank of 80 BALB/c mice at age of 8 weeks. Mice were randomly categorized in four separate groups: The first group received AGE (100 mg/kg, i.p.), the second group received NTX (0.5 mg/kg, i.p.), the third group received both of them, and the fourth group received phosphate buffered saline as control group. Treatments were administered three times per week. Tumor growth was measured and morbidity was recorded. Subpopulations of CD4+/CD8+ T cells were determined using flowcytometery. WEHI-164 cell specific cytotoxicity of splenocytes and in vitro production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) cytokines were measured. All statistical analyses were conducted with SPSS 16 software and P < 0.05 was considered to be statistically significant. The mice who received AGE+NTX had significantly longer survival time compared with the mice treated with AGE or NTX alone. An enhanced inhibitory effect on tumor growth was seen in combination therapy group. The CD4+/CD8+ ratio and in vitro IFN-γ production of splenocytes were significantly increased in AGE+NTX and NTX groups. WEHI-164 specific cytotoxicity of splenocytes was also significantly increased at 25:1 E:T ratio in AGE+NTX treated mice. Coadministration of AGE with NTX resulted in improvement of immune responses against experimentally implanted fibrosarcoma tumors in BALB/c mice. AGE showed synergistic effects with NTX on inhibition of tumor growth and increment of survival times.


Examination of Treatment Effects on Hazardous Drinking Among Service Members With Posttraumatic Stress Disorder.
Posttraumatic stress disorder (PTSD) and alcohol use disorder are frequently comorbid and present significant treatment challenges. Unfortunately, since the September 11, 2001, terrorist attacks in the United States, the rates of PTSD and hazardous drinking among active duty service members have increased significantly. Previous research on PTSD has typically excluded participants with current substance abuse. However, there is some research examining independent treatments for PTSD and substance abuse provided consecutively, concurrently, or as enhancements to other treatment. The current study examined the association between current hazardous drinking and PTSD treatment among 108 active duty service members with PTSD in a randomized controlled trial of group cognitive processing therapy and group present-centered therapy. Total scores above 8 on the Alcohol Use Disorders Identification Test defined hazardous alcohol use. At baseline, 25.0% of the sample was categorized as hazardous drinkers, and the hazardous and nonhazardous drinking groups did not differ in PTSD symptom severity, F(1, 106) = 0.08, p = .777, d = 0.06. Over the course of treatment, the two groups also did not differ significantly in PTSD symptom severity change on the PTSD Checklist, F(1, 106) = 1.20, p = .280, d = 0.33. Treatment for PTSD did not exacerbate hazardous drinking, and the hazardous drinking group showed significant reductions in drinking following PTSD treatment. Limitations and implications for treatment considerations are discussed.


Barriers to Telephone Quitline Use Among Methadone-Maintained Smokers.
Drug users have high rates of tobacco use and tobacco-related disease. Telephone quitlines promote smoking cessation, but their reach among drug users is unknown. We thus aimed to assess utilization of and barriers to telephone quitlines among methadone-maintained smokers. Subjects were opioid-dependent smokers in Bronx, New York, methadone treatment programs who were enrolled in a clinical trial of varenicline. All subjects were offered referral to a free, proactive quitline. We examined quitline records, surveyed barriers to quitline use, and queried reasons for declining referral. Of the 112 subjects enrolled, 47% were male, 54% were Hispanic, and 28% were Black. All subjects were offered referral, and 25 (22% of study participants) utilized the quitline. Quitline utilizers (vs. nonutilizers) were significantly more likely to have landline phone service (72 vs. 42%, p = .01), interest in quitline participation (92 vs. 62%, p < .01), and willingness to receive calls (96 vs. 76%, p = .02). Nonutilizers were significantly more likely to report cell phone service lapse (38 vs. 14%, p = .04), and difficulty charging cell phones (19 vs. 0%, p = .02). Reasons for quitline refusal included: (a) skepticism of quitline efficacy; (b) aversion to telephone communication; (c) competing life demands (e.g., drug treatment, shelter); and (d) problems with cell phone service or minutes. Despite several limitations to quitline access among methadone-maintained smokers, routine quitline referral was associated with 22% utilization. To expand provision of smoking cessation treatment to opioid-dependent smokers, interventions to promote routine quitline referral in substance abuse treatment programs warrant investigation.


Use of high dose cyproterone acetate and risk of intracranial meningioma in women: cohort study.
To assess the risk of meningioma associated with use of high dose cyproterone acetate, a progestogen indicated for clinical hyperandrogenism. Observational cohort study. Data from SNDS, the French administrative healthcare database, between 2007 and 2015. 253 777 girls and women aged 7-70 years living in France who started cyproterone acetate between 2007 and 2014. Participants had at least one reimbursement for high dose cyproterone acetate and no history of meningioma or benign brain tumour, or long term disease status. Participants were considered to be exposed when they had received a cumulative dose of at least 3 g during the first six months (139 222 participants) and very slightly exposed (control group) when they had received a cumulative dose of less than 3 g (114 555 participants). 10 876 transgender participants (male to female) were included in an additional analysis. Surgery (resection or decompression) or radiotherapy for one or more intracranial meningiomas. Overall, 69 meningiomas in the exposed group (during 289 544 person years of follow-up) and 20 meningiomas in the control group (during 439 949 person years of follow-up) were treated by surgery or radiotherapy. The incidence of meningioma in the two groups was 23.8 and 4.5 per 100 000 person years, respectively (crude relative risk 5.2, 95% confidence interval 3.2 to 8.6; adjusted hazard ratio 6.6, 95% confidence interval 4.0 to 11.1). The adjusted hazard ratio for a cumulative dose of cyproterone acetate of more than 60 g was 21.7 (10.8 to 43.5). After discontinuation of cyproterone acetate for one year, the risk of meningioma in the exposed group was 1.8-fold higher (1.0 to 3.2) than in the control group. In a complementary analysis, 463 women with meningioma were observed among 123 997 already using cyproterone acetate in 2006 (risk of 383 per 100 000 person years in the group with the highest exposure in terms of cumulative dose). Meningiomas located in the anterior skull base and middle skull base, particularly the medial third of the middle skull base, involving the spheno-orbital region, appeared to be specific to cyproterone acetate. An additional analysis of transgender participants showed a high risk of meningioma (three per 14 460 person years; 20.7 per 100 000 person years). A strong dose-effect relation was observed between use of cyproterone acetate and risk of intracranial meningiomas. A noticeable reduction in risk was observed after discontinuation of treatment.


Iron supplementation of breast-fed Honduran and Swedish infants from 4 to 9 months of age.
The objective was to study the effects of iron supplementation on hemoglobin and iron status in 2 different populations. In a randomized, placebo-controlled, masked clinical trial, we assigned term Swedish (n = 101) and Honduran (n = 131) infants to 3 groups at 4 months of age: (1) iron supplements, 1 mg/kg/d, from 4 to 9 months, (2) placebo, 4 to 6 months and iron, 6 to 9 months, and (3) placebo, 4 to 9 months. All infants were breast-fed exclusively to 6 months and partially to 9 months. From 4 to 6 months, the effect of iron (group 1 vs 2 + 3) was significant and similar in both populations for hemoglobin, ferritin, and zinc protoporphyrin. From 6 to 9 months, the effect (group 2 vs group 3) was significant and similar at both sites for all iron status variables except hemoglobin, for which there was a significant effect only in Honduras. In Honduras, the prevalence of iron deficiency anemia at 9 months was 29% in the placebo group and 9% in the supplemented groups. In Sweden, iron supplements caused no reduction in the already low prevalence of iron deficiency anemia at 9 months (<3%). Iron supplementation from 4 to 9 months or 6 to 9 months significantly reduced iron deficiency anemia in Honduran breast-fed infants. The unexpected hemoglobin response at 4 to 6 months in both populations suggests that regulation of hemoglobin synthesis is immature at this age.


Self-healing properties of optical Airy beams.
We investigate both theoretically and experimentally the self-healing properties of accelerating Airy beams. We show that this class of waves tends to reform during propagation in spite of the severity of the imposed perturbations. In all occasions the reconstruction of these beams is interpreted through their internal transverse power flow. The robustness of these optical beams in scattering and turbulent environments is also studied experimentally. Our observations are in excellent agreement with numerical simulations.


Transmembrane helix prediction using amino acid property features and latent semantic analysis.
Prediction of transmembrane (TM) helices by statistical methods suffers from lack of sufficient training data. Current best methods use hundreds or even thousands of free parameters in their models which are tuned to fit the little data available for training. Further, they are often restricted to the generally accepted topology "cytoplasmic-transmembrane-extracellular" and cannot adapt to membrane proteins that do not conform to this topology. Recent crystal structures of channel proteins have revealed novel architectures showing that the above topology may not be as universal as previously believed. Thus, there is a need for methods that can better predict TM helices even in novel topologies and families. Here, we describe a new method "TMpro" to predict TM helices with high accuracy. To avoid overfitting to existing topologies, we have collapsed cytoplasmic and extracellular labels to a single state, non-TM. TMpro is a binary classifier which predicts TM or non-TM using multiple amino acid properties (charge, polarity, aromaticity, size and electronic properties) as features. The features are extracted from sequence information by applying the framework used for latent semantic analysis of text documents and are input to neural networks that learn the distinction between TM and non-TM segments. The model uses only 25 free parameters. In benchmark analysis TMpro achieves 95% segment F-score corresponding to 50% reduction in error rate compared to the best methods not requiring an evolutionary profile of a protein to be known. Performance is also improved when applied to more recent and larger high resolution datasets PDBTM and MPtopo. TMpro predictions in membrane proteins with unusual or disputed TM structure (K+ channel, aquaporin and HIV envelope glycoprotein) are discussed. TMpro uses very few free parameters in modeling TM segments as opposed to the very large number of free parameters used in state-of-the-art membrane prediction methods, yet achieves very high segment accuracies. This is highly advantageous considering that high resolution transmembrane information is available only for very few proteins. The greatest impact of TMpro is therefore expected in the prediction of TM segments in proteins with novel topologies. Further, the paper introduces a novel method of extracting features from protein sequence, namely that of latent semantic analysis model. The success of this approach in the current context suggests that it can find potential applications in other sequence-based analysis problems. http://linzer.blm.cs.cmu.edu/tmpro/ and http://flan.blm.cs.cmu.edu/tmpro/


Congenital heart disease affects local gyrification in 22q11.2 deletion syndrome.
22q11.2 deletion syndrome (22q11.2DS) is a common genetic condition associated with cognitive and learning impairments. In this study, we applied a three-dimensional method for quantifying gyrification at thousands of points over the cortical surface to imaging data from 44 children, adolescents, and young adults with 22q11.2DS (17 males, 27 females; mean age 17y 2mo [SD 9y 1mo], range 6-37y), and 53 healthy participants (21 males, 32 females; mean age 15y 4mo [SD 8y 6mo]; range 6-40y). Several clusters of reduced gyrification were observed, further substantiating the pattern of cerebral alterations presented by children with the syndrome. Comparisons within 22q11.2DS demonstrated an effect of congenital heart disease (CHD) on cortical gyrification, with reduced gyrification at the parieto-temporo-occipital junction in patients with CHD, as compared with patients without CHD. Reductions in gyrification can resemble mild polymicrogyria, suggesting early abnormal neuronal proliferation or migration and providing support for an effect of hemodynamic factors on brain development in 22q11.2DS. The results also shed light on the pathophysiology of acquired brain injury in other populations with CHD.


Cancer: Mitochondrial Origins.
The primacy of glucose derived from photosynthesis as an existential source of chemical energy across plant and animal phyla is universally accepted as a core principle in the biological sciences. In mammalian cells, initial processing of glucose to triose phosphate intermediates takes place within the cytosolic glycolytic pathway and terminates with temporal transport of reducing equivalents derived from pyruvate metabolism by membrane-associated respiratory complexes in the mitochondrial matrix. The intra-mitochondrial availability of molecular oxygen as the ultimate electron acceptor drives the evolutionary fashioned chemiosmotic production of ATP as a high-efficiency biological process. The mechanistic bases of carcinogenesis have demonstrated profound alteration of normative mitochondrial function, notably dysregulated respiratory processes. Accordingly, the classic Warburg effect functionally links aerobic glycolysis, aberrant production and release of lactate, and metabolic down-regulation of mitochondrial oxidative processes with the carcinogenetic phenotype. We surmise, however, that aerobic fermentation by cancer cells may also represent a developmental re-emergence of an evolutionarily conserved early phenotype, which was "sidelined" with the emergence of mitochondrial oxidative phosphorylation as a primary mechanism for ATP production in normal cells. Regardless of state-dependent physiological status in mixed populations of cancer cells, it has been established that mitochondria are functionally linked to the initiation of cancer and its progression. Biochemical, molecular, and physiological differences in cancer cell mitochondria, notably mtDNA heteroplasmy and allele-specific expression of selected nuclear genes, may represent major focal points for novel targeting and elimination of cancer cells in metastatic disease afflicting human populations. To date, and despite considerable research efforts, the practical realization of advanced mitochondrial targeted therapies has not been forthcoming.


p-Chloroamphetamine releases both serotonin and dopamine into rat brain dialysates in vivo.
The effect of p-chloroamphetamine (PCA) on extracellular levels of endogenous 5-hydroxytryptamine (5-HT) and dopamine (DA) in the striatum and frontal cortex of the halothane-anesthetized rat was studied using an intracerebral dialysis method. PCA (5 mg/kg s.c.) induced an immediate, marked release of 5-HT into dialysates collected from the frontal cortex and striatum, an effect which lasted over 2 h. This treatment also caused a marked release of DA in the striatum. The results further emphasize the need to carefully assess the involvement of brain DA as well as 5-HT in PCA-induced behaviors.


Anthropogenic cycles of the elements: a critical review.
A cycle is the quantitative characterization of the flows of a specific material into, within, and from a given system. An anthropogenic elemental cycle can be static (for a point in time) or dynamic (over a time interval). The about 350 publications collected for this review contain a total of 1074 individual cycle determinations, 989 static and 85 dynamic, for 59 elements; more than 90% of the publications have appeared since 2000. The cycles are of varying quality and completeness, with about 80% at country- or territory-level, addressing 45 elements, and 5% at global-level, addressing 30 elements. Despite their limitations, cycles have often been successful in revealing otherwise unknown information. Most of the elements for which no cycles exist are radioactively unstable or are used rarely and in small amounts. For a variety of reasons, the anthropogenic cycles of only perhaps a dozen elements are well characterized. For all the others, with cycles limited or nonexistent, our knowledge of types of uses, lifetimes in those uses, international trade, losses to the environment, and rates of recycling is quite limited, thereby making attempts to evaluate resource sustainability particularly problematic.


Structural insight into inhibitor of apoptosis proteins recognition by a potent divalent smac-mimetic.
Genetic alterations enhancing cell survival and suppressing apoptosis are hallmarks of cancer that significantly reduce the efficacy of chemotherapy or radiotherapy. The Inhibitor of Apoptosis Protein (IAP) family hosts conserved proteins in the apoptotic pathway whose over-expression, frequently found in tumours, potentiates survival and resistance to anticancer agents. In humans, IAPs comprise eight members hosting one or more structural Baculoviral IAP Repeat (BIR) domains. Cellular IAPs (cIAP1 and 2) indirectly inhibit caspase-8 activation, and regulate both the canonical and the non-canonical NF-κB signaling pathways. In contrast to cIAPs, XIAP (X chromosome-linked Inhibitor of Apoptosis Protein) inhibits directly the effector caspases-3 and -7 through its BIR2 domain, and initiator caspase-9 through its BIR3 domain; molecular docking studies suggested that Smac/DIABLO antagonizes XIAP by simultaneously targeting both BIR2 and BIR3 domains. Here we report analytical gel filtration, crystallographic and SAXS experiments on cIAP1-BIR3, XIAP-BIR3 and XIAP-BIR2BIR3 domains, alone and in the presence of compound 9a, a divalent homodimeric Smac mimetic. 9a is shown to bind two BIR domains inter- (in the case of two BIR3) and intra-molecularly (in the case of XIAP-BIR2BIR3), with higher affinity for cIAP1-BIR3, relative to XIAP-BIR3. Despite the different crystal lattice packing, 9a maintains a right handed helical conformation in both cIAP1-BIR3 and XIAP-BIR3 crystals, that is likely conserved in solution as shown by SAXS data. Our structural results demonstrate that the 9a linker length, its conformational degrees of freedom and its hydrophobicity, warrant an overall compact structure with optimal solvent exposure of its two active moieties for IAPs binding. Our results show that 9a is a good candidate for pre-clinical and clinical studies, worth of further investigations in the field of cancer therapy.