The context-object-manipulation triad: cross talk during action perception revealed by fMRI.
To recognize an action, an observer exploits information about the applied manipulation, the involved objects, and the context where the action occurs. Context, object, and manipulation information are hence expected to be tightly coupled in a triadic relationship (the COM triad hereafter). The current fMRI study investigated the hemodynamic signatures of reciprocal modulation in the COM triad. Participants watched short video clips of pantomime actions, that is, actions performed with inappropriate objects, taking place at compatible or incompatible contexts. The usage of pantomime actions enabled the disentanglement of the neural substrates of context-manipulation (CM) and context-object (CO) associations. There were trials in which (1) both manipulation and objects, (2) only manipulation, (3) only objects, or (4) neither manipulation nor objects were compatible with the context. CM compatibility effects were found in an action-related network comprising ventral premotor cortex, SMA, left anterior intraparietal sulcus, and bilateral occipito-temporal cortex. Conversely, CO compatibility effects were found bilaterally in lateral occipital complex. These effects interacted in subregions of the lateral occipital complex. An overlap of CM and CO effects was observed in the occipito-temporal cortex and the dorsal attention network, that is, superior frontal sulcus/dorsal premotor cortex and superior parietal lobe. Results indicate that contextual information is integrated into the analysis of actions. Manipulation and object information is linked by contextual associations as a function of co-occurrence in specific contexts. Activation of either CM or CO associations shifts attention to either action- or object-related relevant information.


Diagnosis of traumatic brain injury using miRNA signatures in nanomagnetically isolated brain-derived extracellular vesicles.
The accurate diagnosis and clinical management of traumatic brain injury (TBI) is currently limited by the lack of accessible molecular biomarkers that reflect the pathophysiology of this heterogeneous disease. To address this challenge, we developed a microchip diagnostic that can characterize TBI more comprehensively using the RNA found in brain-derived extracellular vesicles (EVs). Our approach measures a panel of EV miRNAs, processed with machine learning algorithms to capture the state of the injured and recovering brain. Our diagnostic combines surface marker-specific nanomagnetic isolation of brain-derived EVs, biomarker discovery using RNA sequencing, and machine learning processing of the EV miRNA cargo to minimally invasively measure the state of TBI. We achieved an accuracy of 99% identifying the signature of injured vs. sham control mice using an independent blinded test set (N = 77), where the injured group consists of heterogeneous populations (injury intensity, elapsed time since injury) to model the variability present in clinical samples. Moreover, we successfully predicted the intensity of the injury, the elapsed time since injury, and the presence of a prior injury using independent blinded test sets (N = 82). We demonstrated the translatability in a blinded test set by identifying TBI patients from healthy controls (AUC = 0.9, N = 60). This approach, which can detect signatures of injury that persist across a variety of injury types and individual responses to injury, more accurately reflects the heterogeneity of human TBI injury and recovery than conventional diagnostics, opening new opportunities to improve treatment of traumatic brain injuries.


Interactive biotic and abiotic regulators of soil carbon cycling: evidence from controlled climate experiments on peatland and boreal soils.
Partially decomposed plant and animal remains have been accumulating in organic soils (i.e. >40% C content) for millennia, making them the largest terrestrial carbon store. There is growing concern that, in a warming world, soil biotic processing will accelerate and release greenhouse gases that further exacerbate climate change. However, the magnitude of this response remains uncertain as the constraints are abiotic, biotic and interactive. Here, we examined the influence of resource quality and biological activity on the temperature sensitivity of soil respiration under different soil moisture regimes. Organic soils were sampled from 13 boreal and peatland ecosystems located in the United Kingdom, Ireland, Spain, Finland and Sweden, representing a natural resource quality range of C, N and P. They were incubated at four temperatures (4, 10, 15 and 20 °C) at either 60% or 100% water holding capacity (WHC). Our results showed that chemical and biological properties play an important role in determining soil respiration responses to temperature and moisture changes. High soil C : P and C : N ratios were symptomatic of slow C turnover and long-term C accumulation. In boreal soils, low bacterial to fungal ratios were related to greater temperature sensitivity of respiration, which was amplified in drier conditions. This contrasted with peatland soils which were dominated by bacterial communities and enchytraeid grazing, resulting in a more rapid C turnover under warmer and wetter conditions. The unexpected acceleration of C mineralization under high moisture contents was possibly linked to the primarily role of fermented organic matter, instead of oxygen, in mediating microbial decomposition. We conclude that to improve C model simulations of soil respiration, a better resolution of the interactions occurring between climate, resource quality and the decomposer community will be required.


Rapid assessment of lamp spectrum to quantify ecological effects of light at night.
For many decades, the spectral composition of lighting was determined by the type of lamp, which also influenced potential effects of outdoor lights on species and ecosystems. Light-emitting diode (LED) lamps have dramatically increased the range of spectral profiles of light that is economically viable for outdoor lighting. Because of the array of choices, it is necessary to develop methods to predict the effects of different spectral profiles without conducting field studies, especially because older lighting systems are being replaced rapidly. We describe an approach to predict responses of exemplar organisms and groups to lamps of different spectral output by calculating an index based on action spectra from behavioral or visual characteristics of organisms and lamp spectral irradiance. We calculate relative response indices for a range of lamp types and light sources and develop an index that identifies lamps that minimize predicted effects as measured by ecological, physiological, and astronomical indices. Using these assessment metrics, filtered yellow-green and amber LEDs are predicted to have lower effects on wildlife than high pressure sodium lamps, while blue-rich lighting (e.g., K ≥ 2200) would have greater effects. The approach can be updated with new information about behavioral or visual responses of organisms and used to test new lighting products based on spectrum. Together with control of intensity, direction, and duration, the approach can be used to predict and then minimize the adverse effects of lighting and can be tailored to individual species or taxonomic groups.


The Protein Information Resource.
The Protein Information Resource (PIR) is an integrated public resource of protein informatics that supports genomic and proteomic research and scientific discovery. PIR maintains the Protein Sequence Database (PSD), an annotated protein database containing over 283 000 sequences covering the entire taxonomic range. Family classification is used for sensitive identification, consistent annotation, and detection of annotation errors. The superfamily curation defines signature domain architecture and categorizes memberships to improve automated classification. To increase the amount of experimental annotation, the PIR has developed a bibliography system for literature searching, mapping, and user submission, and has conducted retrospective attribution of citations for experimental features. PIR also maintains NREF, a non-redundant reference database, and iProClass, an integrated database of protein family, function, and structure information. PIR-NREF provides a timely and comprehensive collection of protein sequences, currently consisting of more than 1 000 000 entries from PIR-PSD, SWISS-PROT, TrEMBL, RefSeq, GenPept, and PDB. The PIR web site (http://pir.georgetown.edu) connects data analysis tools to underlying databases for information retrieval and knowledge discovery, with functionalities for interactive queries, combinations of sequence and text searches, and sorting and visual exploration of search results. The FTP site provides free download for PSD and NREF biweekly releases and auxiliary databases and files.


Biological aspects of gender disorders.
The scientific community is very interested in the biological aspects of gender disorders and sexual orientation. There are different levels to define an individual's sex: chromosomal, gonadic, and phenotypic sex. Concerning the psychological sex, men and women are different by virtue of their own gender identity, which means they recognize themselves as belonging to a determinate sex. They are different also as a result of their own role identity, a set of behaviors, tendencies, and cognitive and emotional attitudes, commonly defined as "male" and "female". Transsexuality is a disorder characterized by the development of a gender identity opposed to phenotypic sex, whereas homosexuality is not a disturbance of gender identity but only of sexual attraction, expressing sexual orientation towards people of the same sex. We started from a critical review of literature on genetic and hormonal mechanisms involved in sexual differentiation. We re-examined the neuro-anatomic and functional differences between men and women, with special reference to their role in psychosexual differentiation and to their possible implication in the genesis of homosexuality and identity gender disorders. Homosexuality and transsexuality are conditions without a well defined etiology. Although the influence of educational and environmental factors in humans is undeniable, it seems that organic neurohormonal prenatal and postnatal factors might contribute in a determinant way in the development of these two conditions. This "organicistic neurohormal theory" might find support in the study of particular situations in which the human fetus is exposed to an abnormal hormonal environment in utero.


Authenticity Anyone? The Enhancement of Emotions via Neuro-Psychopharmacology.
This article will examine how the notion of emotional authenticity is intertwined with the notions of naturalness and artificiality in the context of the recent debates about 'neuro-enhancement' and 'neuro-psychopharmacology.' In the philosophy of mind, the concept of authenticity plays a key role in the discussion of the emotions. There is a widely held intuition that an artificial means will always lead to an inauthentic result. This article, however, proposes that artificial substances do not necessarily result in inauthentic emotions. The literature provided by the philosophy of mind on this subject usually resorts to thought experiments. On the other hand, the recent literature in applied ethics on 'enhancement' provides good reasons to include real world examples. Such case studies reveal that some psychotropic drugs such as antidepressants actually cause people to undergo experiences of authenticity, making them feel 'like themselves' for the first time in their lives. Beginning with these accounts, this article suggests three non-naturalist standards for emotions: the authenticity standard, the rationality standard, and the coherence standard. It argues that the authenticity standard is not always the only valid one, but that the other two ways of assessing emotions are also valid, and that they can even have repercussions on the felt authenticity of emotions. In conclusion, it sketches some of the normative implications if not ethical intricacies that accompany the enhancement of emotions.


Pacing during a cross-country mountain bike mass-participation event according to race performance, experience, age and sex.
This study describes pacing strategies adopted in an 86-km mass-participation cross-country marathon mountain bike race (the 'Birkebeinerrittet'). Absolute (km·h-1) and relative speed (% average race speed) and speed coefficient of variation (%CV) in five race sections (15.1, 31.4, 52.3, 74.4 and 100% of total distance) were calculated for 8182 participants. Data were grouped and analysed according to race performance, age, sex and race experience. The highest average speed was observed in males (21.8 ± 3.7 km/h), 16-24 yr olds (23.0 ± 4.8 km/h) and those that had previously completed >4 Birkebeinerrittet races (22.5 ± 3.4 km/h). Independent of these factors, the fastest performers exhibited faster speeds across all race sections, whilst their relative speed was higher in early and late climbing sections (Cohen's d = 0.45-1.15) and slower in the final descending race section (d = 0.64-0.98). Similar trends were observed in the quicker age, sex and race experience groups, who tended to have a higher average speed in earlier race sections and a lower average speed during the final race section compared to slower groups. In all comparisons, faster groups also had a lower %CV for speed than slower groups (fastest %CV = 24.02%, slowest %CV = 32.03%), indicating a lower variation in speed across the race. Pacing in a cross-country mountain bike marathon is related to performance, age, sex and race experience. Better performance appears to be associated with higher relative speed during climbing sections, resulting in a more consistent overall race speed.


Comparative assessment of vaccine vectors encoding ten malaria antigens identifies two protective liver-stage candidates.
The development of an efficacious Plasmodium falciparum malaria vaccine remains a top priority for global health. Vaccination with irradiated sporozoites is able to provide complete sterile protection through the action of CD8(+) T cells at the liver-stage of infection. However, this method is currently unsuitable for large-scale deployment and focus has instead turned to the development of sub-unit vaccines. Sub-unit vaccine efforts have traditionally focused on two well-known pre-erythrocytic antigens, CSP and TRAP, yet thousands of genes are expressed in the liver-stage. We sought to assess the ability of eight alternative P. falciparum pre-erythrocytic antigens to induce a high proportion of CD8(+) T cells. We show that all antigens, when expressed individually in the non-replicating viral vectors ChAd63 and MVA, are capable of inducing an immune response in mice. Furthermore, we also developed chimeric P. berghei parasites expressing the cognate P. falciparum antigen to enable assessment of efficacy in mice. Our preliminary results indicate that vectors encoding either PfLSA1 or PfLSAP2 are capable of inducing sterile protection dependent on the presence of CD8(+) T cells. This work has identified two promising P. falciparum liver-stage candidate antigens that will now undergo further testing in humans.


Spectroscopy-based characterization of Hb-NO adducts in human red blood cells exposed to NO-donor and endothelium-derived NO.
The work presents the complementary approach to characterize the formation of various Hb species inside isolated human RBCs exposed to NO, with a focus on the formed Hb-NO adducts. This work presents a complementary approach based on Resonance Raman Spectroscopy (RRS) supported by Blood Gas Analysis, Electron Paramagnetic Resonance Spectroscopy, UV-Vis Absorption Spectroscopy and Mössbauer Spectroscopy to characterize the formation of various Hb species, with a focus on the Hb-NO adducts formed inside isolated human RBCs exposed to NO, under the experimental conditions of low and high levels of oxygen Hb saturation. In the present work, we induced Hb-NO adducts using PAPA-NONOate, a NO-donor with known chemistry and kinetics of NO release, and confirmed the formation of Hb-NO adducts in RBCs incubated with Human Aortic Endothelial Cells (HAECs) stimulated to produce NO. Our results provide a new insight into the formation of Hb-NO adducts after the exposure of RBCs with high oxyHb content to exogenous NO with special attention to the formation of LSHbIIINO in addition to LSHbIINO and metHb (HS/LSHbIIIH2O). We also point out that reliable characterization of Hb-NO adducts requires complementary techniques. Among them, RRS, as a label-free and non-destructive tool, appears to be an important discrimination technique in the studies of Hb-NO adducts inside intact RBCs.


Post-lesion up-regulation of 5-HT1B binding sites in the suprachiasmatic nucleus may be reversed after spontaneous or graft-induced serotonin reinnervation.
We have previously reported that selective axotomy of serotoninergic neurons produced by an intraventricular injection of 5, 7-dihydroxytryptamine is followed by an increase in 5-HT1B binding sites in the suprachiasmatic nucleus of the hypothalamus. This post-lesion up-regulation is shown here to be spontaneously reversed after long-term survival in spite of an incomplete reinnervation of the nucleus. Recovery may be accelerated by fetal raphe transplants that produce more rapid reinnervation.


Roles of salt and conformation in the biological and physicochemical behavior of protegrin-1 and designed analogues: correlation of antimicrobial, hemolytic, and lipid bilayer-perturbing activities.
Protegrins are short (16-18 residues) cationic peptides from porcine leukocytes that display potent, broad-spectrum antimicrobial activity. Protegrin-1 (PG-1), one of five natural homologues, adopts a rigid beta-hairpin structure that is stabilized by two disulfide bonds. We have previously employed the principles of beta-hairpin design to develop PG-1 variants that lack disulfide bonds but nevertheless display potent antimicrobial activity [Lai, J. R., Huck, B. R., Weisblum, B., and Gellman, S. H. (2002) Biochemistry 41, 12835-12842.]. The activity of these disulfide-free variants, however, is attenuated in the presence of salt, and the activity of PG-1 itself is not. Salt-induced inactivation of host-defense peptides, such as human defensins, is thought to be important in some pathological situations (e.g., cystic fibrosis), and the variation in salt-sensitivity among our PG-1 analogues offers a model system with which to explore the origins of these salt effects. We find that the variations in antimicrobial activity among our peptides are correlated with the folding propensities of these molecules and with the extent to which the peptides induce leakage of contents from synthetic liposomes. Comparable correlations were observed between folding and hemolytic activity. The extent to which added salt reduces antimicrobial activity parallels salt effects on vesicle perturbation, which suggests that the biological effects of high salt concentrations arise from modulation of peptide-membrane interactions.


Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate.
The aim of the present phase I/II study was to evaluate the safety, immune responses and clinical activity of a vaccine based on autologous dendritic cells (DC) loaded with an allogeneic tumor cell lysate in advanced melanoma patients. DC derived from monocytes were generated in serum-free medium containing GM-CSF and IL-13 according to Good Manufacturing Practices. Fifteen patients with metastatic melanoma (stage III or IV) received four subcutaneous, intradermal, and intranodal vaccinations of both DC loaded with tumor cell lysate and DC loaded with hepatitis B surface protein (HBs) and/or tetanus toxoid (TT). No grade 3 or 4 adverse events related to the vaccination were observed. Enhanced immunity to the allogeneic tumor cell lysate and to TAA-derived peptides were documented, as well as immune responses to HBs/TT antigens. Four out of nine patients who received the full treatment survived for more than 20 months. Two patients showed signs of clinical response and received 3 additional doses of vaccine: one patient showed regression of in-transit metastases leading to complete remission. Eighteen months later, the patient was still free of disease. The second patient experienced stabilization of lung metastases for approximately 10 months. Overall, our results show that vaccination with DC loaded with an allogeneic melanoma cell lysate was feasible in large-scale and well-tolerated in this group of advanced melanoma patients. Immune responses to tumor-related antigens documented in some treated patients support further investigations to optimize the vaccine formulation.


When to press on or turn back: dispersal strategies for reef fish larvae.
Events that occur during the pelagic larval stage are thought to be important determinants of reef fish population dynamics. Recent research contradicts the early paradigm of larvae being advected as passive propagules and indicates that many late stage larvae have well-developed sensory and locomotory capabilities. Whether and how larvae use these capabilities to influence their dispersal is unknown. We compare alternative hypotheses regarding larval behavior. Contrary to the trend in dispersal modeling, we focus on larval biology rather than physical oceanographic considerations. Specifically, we present two streams of models: one that describes a return-based strategy and one in which dispersal is a central component. The models depend on different sets of behavioral assumptions for a pomacentrid species and for acanthurids, two groups with contrasting early life histories. Whether dispersal or return-based strategies are favored depends on the efficiency and sustainability of larval swimming methods and the environmental conditions experienced during dispersal. We argue that dispersal models should consider a variety of behavioral hypotheses and that the sensitivity of results to the behavioral assumptions made should be quantified.


Characterization of papillomavirus polypeptides from bovine cutaneous fibropapillomas.
Virions of bovine papilloma virus (BPV) were isolated from a pool of cutaneous bovine fibropapillomas and purified by CsCl gradient centrifugation. SDS-PAGE revealed several polypeptides with an Mr ranging from 76K to 19K. Western blot analysis of the viral isolate identified additional polypeptides when a rabbit anti-BPV serum was used, but only the main capsid component of 57K when a rabbit antiserum raised against human papillomavirus was used. The viral preparation was then 125I-labelled and further purified by gel filtration. SDS-PAGE of immunoprecipitates of the anti-BPV serum with different fractions from the chromatographic column revealed the polypeptides of 76K, 57K and 28K to be viral structural components. The 28K polypeptide, not previously characterized, was shown to be composed of several molecular forms, migrating over a pH range of 3.5 to 4.6 when analysed by two-dimensional PAGE. Following SDS-PAGE performed under non-reducing conditions, the 28K and 76K polypeptides and the main capsid component of 57K appeared to be linked by disulphide bridges to form hetero- or homopolymers.


Parallel ClickSeq and Nanopore sequencing elucidates the rapid evolution of defective-interfering RNAs in Flock House virus.
Defective-Interfering RNAs (DI-RNAs) have long been known to play an important role in virus replication and transmission. DI-RNAs emerge during virus passaging in both cell-culture and their hosts as a result of non-homologous RNA recombination. However, the principles of DI-RNA emergence and their subsequent evolution have remained elusive. Using a combination of long- and short-read Next-Generation Sequencing, we have characterized the formation of DI-RNAs during serial passaging of Flock House virus (FHV) in cell-culture over a period of 30 days in order to elucidate the pathways and potential mechanisms of DI-RNA emergence and evolution. For short-read RNAseq, we employed 'ClickSeq' due to its ability to sensitively and confidently detect RNA recombination events with nucleotide resolution. In parallel, we used the Oxford Nanopore Technologies's (ONT) MinION to resolve full-length defective and wild-type viral genomes. Together, these accurately resolve both rare and common RNA recombination events, determine the correlation between recombination events, and quantifies the relative abundance of different DI-RNAs throughout passaging. We observe the formation of a diverse pool of defective RNAs at each stage of viral passaging. However, many of these 'intermediate' species, while present in early stages of passaging, do not accumulate. After approximately 9 days of passaging we observe the rapid accumulation of DI-RNAs with a correlated reduction in specific infectivity and with the Nanopore data find that DI-RNAs are characterized by multiple RNA recombination events. This suggests that intermediate DI-RNA species are not competitive and that multiple recombination events interact epistatically to confer 'mature' DI-RNAs with their selective advantage allowing for their rapid accumulation. Alternatively, it is possible that mature DI-RNA species are generated in a single event involving multiple RNA rearrangements. These insights have important consequences for our understanding of the mechanisms, determinants and limitations in the emergence and evolution of DI-RNAs.


Concepts of Illness Among the Swahili of Lamu, Kenya.
The Swahili of Lamu, Kenya, understand illness as the result of a spiritual imbalance caused by personal transgression or an attack by harmful forces directed by an envious person. Another underlying component of the Swahili concept of illness is that each person's physical body operates in conjunction with personal attributes that are fixed at birth and determine moral character, behavior, and predisposition to ailments. When physical symptoms occur, the Swahili focus on identifying the human or supernatural entity that caused the illness in consultation with a range of healers who specialize in a variety of curing strategies. Two case studies illustrate how culturally congruent nursing care can be achieved when health care providers understand the Swahili framework of diagnosing and treating illness.


Shifts in spatial attention affect the perceived duration of events.
We investigated the relationship between attention and perceived duration of visual events with a double-task paradigm. The primary task was to discriminate the size change of a 2 degree circle presented 10 degrees left, right, above, or below fixation; the secondary task was to judge the temporal separation (from 133 ms to 633 ms) of two equiluminant horizontal bars (10 deg x 2 deg) briefly flashed 12 degrees above or below fixation. The stimulus onset asynchrony (SOA) between primary and secondary task ranged from -1300 ms to +1000 ms. Temporal intervals in proximity of the onset of the primary task stimuli were perceived strongly compressed by up to 40%. The effect was proportional to the size of the interval with a maximum effect at 100 ms SOA. Control experiments show that neither primary-task difficulty, nor the type of primary task discrimination (form or motion, or equiluminant or luminance contrast) nor spatial congruence between primary and secondary task alter the effect. Interestingly, the compression occurred only when the intervals are marked by bars presented in separated spatial locations: when the interval is marked by two bars flashed in the same spatial position no temporal distortion was found. These data indicate that attention can alter perceived duration when the brain has to compare the passage of time at two different spatial positions, corroborating earlier findings that mechanisms of time perception may monitor separately the various spatial locations possibly at high level of analysis.


Mapping of quantitative trait loci controlling adaptive traits in coastal Douglas fir. III. Quantitative trait loci-by-environment interactions.
Quantitative trait loci (QTL) were mapped in the woody perennial Douglas fir (Pseudotsuga menziesii var. menziesii [Mirb.] Franco) for complex traits controlling the timing of growth initiation and growth cessation. QTL were estimated under controlled environmental conditions to identify QTL interactions with photoperiod, moisture stress, winter chilling, and spring temperatures. A three-generation mapping population of 460 cloned progeny was used for genetic mapping and phenotypic evaluations. An all-marker interval mapping method was used for scanning the genome for the presence of QTL and single-factor ANOVA was used for estimating QTL-by-environment interactions. A modest number of QTL were detected per trait, with individual QTL explaining up to 9.5% of the phenotypic variation. Two QTL-by-treatment interactions were found for growth initiation, whereas several QTL-by-treatment interactions were detected among growth cessation traits. This is the first report of QTL interactions with specific environmental signals in forest trees and will assist in the identification of candidate genes controlling these important adaptive traits in perennial plants.


Thermophilic anaerobic oxidation of methane by marine microbial consortia.
The anaerobic oxidation of methane (AOM) with sulfate controls the emission of the greenhouse gas methane from the ocean floor. AOM is performed by microbial consortia of archaea (ANME) associated with partners related to sulfate-reducing bacteria. In vitro enrichments of AOM were so far only successful at temperatures ≤25 °C; however, energy gain for growth by AOM with sulfate is in principle also possible at higher temperatures. Sequences of 16S rRNA genes and core lipids characteristic for ANME as well as hints of in situ AOM activity were indeed reported for geothermally heated marine environments, yet no direct evidence for thermophilic growth of marine ANME consortia was obtained to date. To study possible thermophilic AOM, we investigated hydrothermally influenced sediment from the Guaymas Basin. In vitro incubations showed activity of sulfate-dependent methane oxidation between 5 and 70 °C with an apparent optimum between 45 and 60 °C. AOM was absent at temperatures ≥75 °C. Long-term enrichment of AOM was fastest at 50 °C, yielding a 13-fold increase of methane-dependent sulfate reduction within 250 days, equivalent to an apparent doubling time of 68 days. The enrichments were dominated by novel ANME-1 consortia, mostly associated with bacterial partners of the deltaproteobacterial HotSeep-1 cluster, a deeply branching phylogenetic group previously found in a butane-amended 60 °C-enrichment culture of Guaymas sediments. The closest relatives (Desulfurella spp.; Hippea maritima) are moderately thermophilic sulfur reducers. Results indicate that AOM and ANME archaea could be of biogeochemical relevance not only in cold to moderate but also in hot marine habitats.


Second-hand smoke-induced cardiac fibrosis is related to the Fas death receptor apoptotic pathway without mitochondria-dependent pathway involvement in rats.
Exposure to environmental tobacco smoke has been epidemiologically linked to heart disease among nonsmokers. However, the molecular mechanism behind the pathogenesis of cardiac disease is unknown. In this study, we found that Wistar rats, exposed to tobacco cigarette smoke at doses of 5, 10, or 15 cigarettes for 30 min twice a day for 1 month, had a dose-dependently reduced heart weight to body weight ratio and enhanced interstitial fibrosis as identified by histopathologic analysis. The mRNA and activity of matrix metalloprotease-2 (MMP-2), representing the progress of cardiac remodeling, were also elevated in the heart. In addition, we used reverse-transcriptase polymerase chain reaction and Western blotting to demonstrate significantly increased levels of the apoptotic effecter caspase-3 in treated animal hearts. Dose-dependently elevated mRNA and protein levels of Fas, and promoted apoptotic initiator caspase-8 (active form), a molecule of a death-receptor-dependent pathway, coupled with unaltered or decreased levels of cytosolic cytochrome c and the apoptotic initiator caspase-9 (active form), molecules of mitochondria-dependent pathways, may be indicative of cardiac apoptosis, which is Fas death-receptor apoptotic-signaling dependent, but not mitochondria pathway dependent in rats exposed to second-hand smoke (SHS). With regard to the regulation of survival pathway, using dot blotting, we found cardiac insulin-like growth factor-1 (IGF-1) and IGF-1 receptor mRNA levels to be significantly increased, indicating that compensative effects of IGF-1 survival signaling could occur. In conclusion, we found that the effects of SHS on cardiomyocyte are mediated by the Fas death-receptor-dependent apoptotic pathway and might be related to the epidemiologic incidence of cardiac disease of SHS-exposed nonsmokers.


Kinetic modeling of hyperpolarized (13)C pyruvate metabolism in tumors using a measured arterial input function.
Mathematical models are required to estimate kinetic parameters of [1-(13)C] pyruvate-lactate interconversion from magnetic resonance spectroscopy data. One- or two-way exchange models utilizing a hypothetical approximation to the true arterial input function (AIF), (e.g. an ideal 'box-car' function) have been used previously. We present a method for direct measurement of the AIF in the rat. The hyperpolarized [1-(13)C] pyruvate signal was measured in arterial blood as it was continuously withdrawn through a small chamber. The measured signal was corrected for T1 relaxation of pyruvate, RF pulses and dispersion of blood in the chamber to allow for the estimation of the direct AIF. Using direct AIF, rather than the commonly used box-car AIF, provided realistic estimates of the rate constant of conversion of pyruvate to lactate, kpl, the rate constant of conversion of lactate to pyruvate klp, the clearance rate constant of pyruvate from blood to tissue, Kip, and the relaxation rate of lactate T1la. Since no lactate signal was present in blood, it was possible to use a simple precursor-product relationship, with the tumor tissue pyruvate time-course as the input for the lactate time-course. This provided a robust estimate of kpl, similar to that obtained using a directly measured AIF.


Chronic psychological stress and lower urinary tract symptoms.
It is well established that lower urinary tract symptoms (LUTS), particularly urinary urgency and incontinence, cause stress and anxiety for patients. However, there is mounting evidence that the relationship between these two factors is bidirectional and that chronic psychological stress itself can result in the development of symptoms such as urinary frequency, urgency, incontinence, and pelvic pain. This review considers the evidence that such a relationship exists and reviews the literature from clinical and animal studies to identify some of the mechanisms that might be involved. Inflammatory responses induced by chronic stress appear to offer the strongest link to bladder dysfunction. There is overwhelming evidence, both in patients and animal models, for a release of pro-inflammatory cytokines and chemokines during periods of chronic stress. Furthermore, cytokines have been shown to cause bladder dysfunction and pain via actions in the central nervous system and locally in the bladder. In the brain and spinal cord, pro-inflammatory cytokines influence the regulation of micturition pathways by corticotropin-releasing factor (CRF) and its receptors, while peripherally cytokines affect bladder function, directly causing detrusor hypertrophy and afferent nerve hypersensitivity. There is little information on which treatments may have most benefit for stressed/anxious patients with LUTS, but animal studies suggest traditional drugs for overactive bladder (solifenacin, mirabegron) are more effective on LUTS than anxiolytic drugs (fluoxetine, imipramine). The preliminary preclinical data for CRF receptor antagonists is not consistent. A clearer understanding of the mechanisms involved in stress-induced LUTS should provide a basis for improved treatment of this condition.


Increased resting heart rate with pollutants in a population based study.
Air pollution is associated with cardiovascular mortality. Changes in the autonomic nervous system may contribute to cardiac arrhythmias and cardiovascular mortality. This study investigated the relations between air pollutant concentrations of sulphur dioxide (SO(2)), ozone (O(3)), nitric dioxide (NO(2)), and resting heart rate (RHR) in a population based study. A sample of 863 middle aged men and women, living in Toulouse (MONICA centre) area, was randomly recruited. A cross sectional survey on cardiovascular risk factors was carried. RHR was measured twice in a sitting position after a five minute rest. Multivariate analyses with quintiles of RHR were performed using polytomous logistic regression. Models were adjusted for temperature, season, relative humidity, sex, physical activity, blood pressure, C reactive protein, and cardiovascular drugs. For NO(2), the OR (odds ratio) (95% CI) associated with an increase of 5 microg/m(3) in the current day of medical examination was 1.14 (1.03 to 1.25) in quintile Q5 of RHR compared with Q1, p for trend = 0.003. For SO(2), OR was 1.16 (0.94 to 1.44) in Q5 compared with Q1, p for trend = 0.05, and for O(3), OR was 0.96 (0.91 to 1.01) in Q5 compared with Q1, p for trend = 0.11. No significant association was seen when the daily mean concentration of NO(2), SO(2), and O(3) was considered during the previous day as well as when day lag 2 or 3 was considered. The cumulative concentration (three consecutive days) of O(3) is negatively associated with RHR (p for trend = 0.02). Changes in pulse rate could reflect cardiac rhythm changes and may be part of the pathophysiological link between pollution and cardiovascular mortality.


A quantitative model for ordered Cdk substrate dephosphorylation during mitotic exit.
After sister chromatid splitting at anaphase onset, exit from mitosis comprises an ordered series of events. Dephosphorylation of numerous mitotic substrates, which were phosphorylated by cyclin-dependent kinase (Cdk), is thought to bring about mitotic exit, but how temporal ordering of mitotic exit events is achieved is poorly understood. Here, we show, using budding yeast, that dephosphorylation of Cdk substrates involved in sequential mitotic exit events occurs with ordered timing. We test different models of how ordering might be achieved by modulating Cdk and Cdk-counteracting phosphatase Cdc14 activities in vivo, as well as by kinetic analysis of Cdk substrate phosphorylation and dephosphorylation in vitro. Our results suggest that the gradual change of the phosphatase to kinase ratio over the course of mitotic exit is read out by Cdk substrates that respond by dephosphorylation at distinct thresholds. This provides an example and a mechanistic explanation for a quantitative model of cell-cycle progression.


Echocardiographic features of post-transcatheter aortic valve implantation thrombosis and endocarditis.
Transcatheter heart valve thrombosis (THV-t) and endocarditis (THV-e) are relevant complications after transcatheter aortic valve implantation (TAVI). Transcatheter heart valve (THV) dysfunction definition is mostly based on Doppler (stenosis/regurgitation) without considering leaflets characteristics. To evaluate the additional diagnostic value of leaflets echocardiographic features over Doppler when prosthetic valve complication is suspected. Among 621 post-TAVI patients, 128 cases with probable valve complication were identified. THV-t was finally diagnosed in 13 patients (10%) and THV-e in 8 (6%), while the remaining 107 (84%) had no definitive diagnosis of thrombosis/endocarditis (THV-no). We analyzed at 2 time points (baseline and follow-up) both traditional Doppler parameters and leaflets morpho-functional features. Both Doppler and leaflets parameters showed high sensitivity (sensitivity 92%) and low specificity (ranging from specificity 32% to 74%) in detecting THV-t. Interestingly, the combination of mean aortic pressure gradient ≥20 mm Hg and leaflet thickening significantly improved the specificity of echocardiography for diagnosis of THV thrombosis (specificity 94%). On the other hand, echocardiographic diagnosis of THV endocarditis remained limited by very low sensitivity despite showing high specificity. The combination of Doppler and leaflets parameters can improve the echocardiographic diagnosis of THV thrombosis in post-TAVI patients with suspicious symptoms, via a significant increase in the overall test specificity. This would potentially allow more rational gatekeeping to more expensive/invasive diagnostic examinations (eg, CT scan) or therapeutic trials (eg, unnecessary anticoagulation).


On the Convergence of the LMS Algorithm with Adaptive Learning Rate for Linear Feedforward Networks.
We consider the problem of training a linear feedforward neural network by using a gradient descent-like LMS learning algorithm. The objective is to find a weight matrix for the network, by repeatedly presenting to it a finite set of examples, so that the sum of the squares of the errors is minimized. Kohonen showed that with a small but fixed learning rate (or stepsize) some subsequences of the weight matrices generated by the algorithm will converge to certain matrices close to the optimal weight matrix. In this paper, we show that, by dynamically decreasing the learning rate during each training cycle, the sequence of matrices generated by the algorithm will converge to the optimal weight matrix. We also show that for any given ∊ > 0 the LMS algorithm, with decreasing learning rates, will generate an ∊-optimal weight matrix (i.e., a matrix of distance at most ∊ away from the optimal matrix) after O(1/∊) training cycles. This is in contrast to Ω(1/∊log 1/∊) training cycles needed to generate an ∊-optimal weight matrix when the learning rate is kept fixed. We also give a general condition for the learning rates under which the LMS learning algorithm is guaranteed to converge to the optimal weight matrix.


Tissue-specific functions in the fatty acid-binding protein family.
The intracellular fatty acid-binding proteins (FABPs) are abundantly expressed in almost all tissues. They exhibit high affinity binding of a single long-chain fatty acid, with the exception of liver FABP, which binds two fatty acids or other hydrophobic molecules. FABPs have highly similar tertiary structures consisting of a 10-stranded antiparallel β-barrel and an N-terminal helix-turn-helix motif. Research emerging in the last decade has suggested that FABPs have tissue-specific functions that reflect tissue-specific aspects of lipid and fatty acid metabolism. Proposed roles for FABPs include assimilation of dietary lipids in the intestine, targeting of liver lipids to catabolic and anabolic pathways, regulation of lipid storage and lipid-mediated gene expression in adipose tissue and macrophages, fatty acid targeting to β-oxidation pathways in muscle, and maintenance of phospholipid membranes in neural tissues. The regulation of these diverse processes is accompanied by the expression of different and sometimes multiple FABPs in these tissues and may be driven by protein-protein and protein-membrane interactions.


Gold Nanoparticles in Diagnostics and Therapeutics for Human Cancer.
The application of nanotechnology for the treatment of cancer is mostly based on early tumor detection and diagnosis by nanodevices capable of selective targeting and delivery of chemotherapeutic drugs to the specific tumor site. Due to the remarkable properties of gold nanoparticles, they have long been considered as a potential tool for diagnosis of various cancers and for drug delivery applications. These properties include high surface area to volume ratio, surface plasmon resonance, surface chemistry and multi-functionalization, facile synthesis, and stable nature. Moreover, the non-toxic and non-immunogenic nature of gold nanoparticles and the high permeability and retention effect provide additional benefits by enabling easy penetration and accumulation of drugs at the tumor sites. Various innovative approaches with gold nanoparticles are under development. In this review, we provide an overview of recent progress made in the application of gold nanoparticles in the treatment of cancer by tumor detection, drug delivery, imaging, photothermal and photodynamic therapy and their current limitations in terms of bioavailability and the fate of the nanoparticles.


The effect of physiotherapy in addition to testosterone replacement therapy on the efficiency of the motor system in men with hypogonadism.
The aim of this study was to analyze whether the addition of physiotherapy to testosterone replacement therapy provides added benefit in improving functional capacity of the motor system in men with hypogonadism. The study involved 3 groups of subjects: group 1, healthy men (n=20); group 2, men with hypogonadism who underwent testosterone replacement therapy with physiotherapy (TRT+PT) (n=8); and group 3, men with hypogonadism who underwent testosterone replacement therapy alone (TRT) (n=10). Physical activity (International Physical Activity Questionnaire [IPAQ]) and body composition (X-SCAN analysis) were analyzed; the vertical jump test (Leonardo Mechanography®) was applied. The application of testosterone replacement therapy together with physiotherapy for 6 months significantly increased the maximum and relative power of jump in the subjects in the TRT+PT group; however, in the TRT group, no statistically significant difference was observed. The maximum jump height for the subjects in the TRT+PT group significantly increased 6 months after the intervention; however, in the TRT group, this index remained unaltered. The lean body mass of the subjects in the TRT+PT group increased (P<0.05); however, in the TRT group, it did not change. The relative fat body mass in the TRT+PT group decreased significantly (P<0.05), but, in the TRT group, it had a tendency to increase, though insignificantly. Our results suggest that the application of testosterone replacement therapy together with physiotherapy (1 hour twice weekly) in men with hypogonadism may lead to earlier and better results in comparison with testosterone replacement therapy applied alone.


Ectoparasite Burdens of the Damaraland Mole-Rat (Fukomys damarensis) from Southern Africa.
Damaraland mole-rats (Fukomys damarensis) of the family Bathyergidae are widely distributed subterranean rodents in sub-Saharan Africa. No parasites have ever been reported for this species and only 1 ectoparasite is described for the entire genus. In the current study ectoparasites were collected from individuals captured at 3 localities in South Africa and Namibia to document the ectoparasite community of F. damarensis, investigate their aggregation patterns, and evaluate the influence of season on ectoparasite burden. A total of 2,071 arthropods from 9 mite taxa and 1 louse species (Eulinognathus hilli) were collected from 293 hosts sampled. Of these, 5 mite species (Androlaelaps scapularis, Androlaelaps capensis, Androlaelaps tauffliebi, Radfordia sp., and unidentified chiggers) and the louse were parasites while the remainder was soil mites. All ectoparasites were highly aggregated and the species richness as well as the prevalence and abundance of 4 of them were significantly greater in summer compared to winter, possibly as a result of seasonal changes in rainfall patterns affecting the ectoparasites, host behavior, or both.


The charged linker of the molecular chaperone Hsp90 modulates domain contacts and biological function.
The heat shock protein 90 (Hsp90) is a dimeric molecular chaperone essential in numerous cellular processes. Its three domains (N, M, and C) are connected via linkers that allow the rearrangement of domains during Hsp90's chaperone cycle. A unique linker, called charged linker (CL), connects the N- and M-domain of Hsp90. We used an integrated approach, combining single-molecule techniques and biochemical and in vivo methods, to study the unresolved structure and function of this region. Here we show that the CL facilitates intramolecular rearrangements on the milliseconds timescale between a state in which the N-domain is docked to the M-domain and a state in which the N-domain is more flexible. The docked conformation is stabilized by 1.1 kBT (2.7 kJ/mol) through binding of the CL to the N-domain of Hsp90. Docking and undocking of the CL affects the much slower intermolecular domain movement and Hsp90's chaperone cycle governing client activation, cell viability, and stress tolerance.


Digestive tract morphology and enzyme activities of juvenile diploid and triploid Atlantic salmon (Salmo salar) fed fishmeal-based diets with or without fish protein hydrolysates.
Triploid, sterile Atlantic salmon (Salmo salar) could make a contribution to the development of the farming industry, but uncertainties about the performance and welfare of triploids have limited their adoption by farmers. In this study, we compared the ontogeny of digestive tract morphology and enzyme activities (pepsin, trypsin, chymotrypsin, alkaline phosphatase and aminopeptidase) of diploid and triploid Atlantic salmon. Fish were fed diets based on fishmeal (STD) or a mix of fishmeal and hydrolysed fish proteins (HFM) whilst being reared at low temperature from start-feeding to completion of the parr-smolt transformation. Fish weights for each ploidy and feed combination were used to calculate thermal growth coefficients (TGCs) that spanned this developmental period, and the data were used to examine possible relationships between enzyme activities and growth. At the end of the experiment, faeces were collected and analyzed to determine the apparent digestibility coefficients (ADCs) of the dietary amino acids (AAs). Digestive tract histo-morphology did not differ substantially between ploidies and generally reflected organ maturation and functionality. There were no consistent differences in proteolytic enzyme activities resulting from the inclusion of HFM in the diet, nor was there improved digestibility and AA bioavailability of the HFM feed in either diploid or triploid fish. The triploid salmon had lower ADCs than diploids for most essential and non-essential AAs in both diets (STD and HFM), but without there being any indication of lower intestinal protease activity in triploid fish. When trypsin-to-chymotrypsin activity and trypsin and alkaline phosphatase (ALP) ratios (T:C and T:ALP, respectively) were considered in combination with growth data (TGC) low T:C and T:ALP values coincided with times of reduced fish growth, and vice versa, suggesting that T:C and T:ALP may be used to predict recent growth history and possible growth potential.


Inactivation of Myosin binding protein C homolog in zebrafish as a model for human cardiac hypertrophy and diastolic dysfunction.
Sudden cardiac death due to malignant ventricular arrhythmia is a devastating manifestation of cardiac hypertrophy. Sarcomere protein myosin binding protein C is functionally related to cardiac diastolic function and hypertrophy. Zebrafish is a better model to study human electrophysiology and arrhythmia than rodents because of the electrophysiological characteristics similar to those of humans. We established a zebrafish model of cardiac hypertrophy and diastolic dysfunction by genetic knockdown of myosin binding protein C gene (mybpc3) and investigated the electrophysiological phenotypes in this model. We found expression of zebrafish mybpc3 restrictively in the heart and slow muscle, and mybpc3 gene was evolutionally conservative with sequence homology between zebrafish and human mybpc3 genes. Zebrafish with genetic knockdown of mybpc3 by morpholino showed ventricular hypertrophy with increased myocardial wall thickness and diastolic heart failure, manifesting as decreased ventricular diastolic relaxation velocity, pericardial effusion, and dilatation of the atrium. In terms of electrophysiological phenotypes, mybpc3 knockdown fish had a longer ventricular action potential duration and slower ventricular diastolic calcium reuptake, both of which are typical electrophysiological features in human cardiac hypertrophy and heart failure. Impaired calcium reuptake resulted in increased susceptibility to calcium transient alternans and action potential duration alternans, which have been proved to be central to the genesis of malignant ventricular fibrillation and a sensitive marker of sudden cardiac death. mybpc3 knockdown in zebrafish recapitulated the morphological, mechanical, and electrophysiological phenotypes of human cardiac hypertrophy and diastolic heart failure. Our study also first demonstrated arrhythmogenic cardiac alternans in cardiac hypertrophy.


Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2A-H2B acidic pocket.
Interleukin-33 (IL-33) is an IL-1-like ligand for the ST2 receptor that stimulates the production of Th2-associated cytokines. Recently, we showed that IL-33 is a chromatin-associated factor in the nucleus of endothelial cells in vivo. Here, we report the identification of a short IL-33 chromatin-binding peptide that shares striking similarities with a motif found in Kaposi sarcoma herpesvirus LANA (latency-associated nuclear antigen), which is responsible for the attachment of viral genomes to mitotic chromosomes. Similar to LANA, the IL-33 peptide docks into the acidic pocket formed by the H2A-H2B dimer at the nucleosomal surface and regulates chromatin compaction by promoting nucleosome-nucleosome interactions. Taken together, our data provide important new insights into the nuclear roles of IL-33, and show a unique example of molecular mimicry of a chromatin-associated cytokine by a DNA tumour virus. In addition, the data provide, to the best of our knowledge, the first demonstration of the existence of non-histone cellular factors that bind to the acidic pocket of the nucleosome.


A Multiplexed Cas13-Based Assay with Point-of-Care Attributes for Simultaneous COVID-19 Diagnosis and Variant Surveillance.
Point-of-care (POC) nucleic acid detection technologies are poised to aid gold-standard technologies in controlling the COVID-19 pandemic, yet shortcomings in the capability to perform critically needed complex detection-such as multiplexed detection for viral variant surveillance-may limit their widespread adoption. Herein, we developed a robust multiplexed clustered regularly interspaced short palindromic repeats (CRISPR)-based detection using LwaCas13a and PsmCas13b to simultaneously diagnose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pinpoint the causative SARS-CoV-2 variant of concern (VOC)-including globally dominant VOCs Delta (B.1.617.2) and Omicron (B.1.1.529)-all the while maintaining high levels of accuracy upon the detection of multiple SARS-CoV-2 gene targets. The platform has several attributes suitable for POC use: premixed, freeze-dried reagents for easy use and storage; convenient direct-to-eye or smartphone-based readouts; and a one-pot variant of the multiplexed detection. To reduce reliance on proprietary reagents and enable sustainable use of such a technology in low- and middle-income countries, we locally produced and formulated our own recombinase polymerase amplification reaction and demonstrated its equivalent efficiency to commercial counterparts. Our tool-CRISPR-based detection for simultaneous COVID-19 diagnosis and variant surveillance that can be locally manufactured-may enable sustainable use of CRISPR diagnostics technologies for COVID-19 and other diseases in POC settings.


Lymph-node resident CD8α+ dendritic cells capture antigens from migratory malaria sporozoites and induce CD8+ T cell responses.
Malaria infection begins when a female Anopheles mosquito injects Plasmodium sporozoites into the skin of its host during blood feeding. Skin-deposited sporozoites may enter the bloodstream and infect the liver, reside and develop in the skin, or migrate to the draining lymph nodes (DLNs). Importantly, the DLN is where protective CD8(+) T cell responses against malaria liver stages are induced after a dermal route of infection. However, the significance of parasites in the skin and DLN to CD8(+) T cell activation is largely unknown. In this study, we used genetically modified parasites, as well as antibody-mediated immobilization of sporozoites, to determine that active sporozoite migration to the DLNs is required for robust CD8(+) T cell responses. Through dynamic in vivo and static imaging, we show the direct uptake of parasites by lymph-node resident DCs followed by CD8(+) T cell-DC cluster formation, a surrogate for antigen presentation, in the DLNs. A few hours after sporozoite arrival to the DLNs, CD8(+) T cells are primed by resident CD8α(+) DCs with no apparent role for skin-derived DCs. Together, these results establish a critical role for lymph node resident CD8α(+) DCs in CD8(+) T cell priming to sporozoite antigens while emphasizing a requirement for motile sporozoites in the induction of CD8(+) T cell-mediated immunity.


Chemical oxidation for mitigation of UV-quenching substances (UVQS) from municipal landfill leachate: Fenton process versus ozonation.
UV-quenching substance (UVQS), as an emerging municipal solid waste (MSW)-derived leachate contaminant, has a potential to interfere with UV disinfection when leachate is disposed of at publicly owned treatment works (POTWs). The objective of this study was to evaluate and compare two chemical oxidation processes under different operational conditions, i.e. Fenton process and ozonation, for alleviation of UV254 absorbance of a biologically pre-treated landfill leachate. Results showed that leachate UV254 absorbance was reduced due to the UVQS decomposition by hydroxyl radicals (·OH) during Fenton treatment, or by ozone (O3) and ·OH during ozonation. Fenton process exhibited a better treatment performance than ozonation under their respective optimal conditions, because ·OH could effectively decompose both hydrophobic and hydrophilic dissolved organic matter (DOM), but O3 tended to selectively oxidize hydrophobic compounds alone. Different analytical techniques, including molecular weight (MW) fractionation, hydrophobic/hydrophilic isolation, UV spectra scanning, parallel factor (PARAFAC) analysis, and fluorescence excitation-emission matrix spectrophotometry, were used to characterize UVQS. After either oxidation treatment, residual UVQS was more hydrophilic with a higher fraction of low MW molecules. It should be noted that the removed UV254 absorbance (ΔUV254) was directly proportional to the removed COD (ΔCOD) for the both treatments (Fenton process: ΔUV254 = 0.011ΔCOD; ozonation: ΔUV254 = 0.016ΔCOD). A greater ΔUV254/ΔCOD was observed for ozonation, suggesting that oxidant was more efficiently utilized during ozonation than in Fenton treatment for mitigation of the UV absorbance.


Using the self-select paradigm to delineate the nature of speech motor programming.
The authors examined the involvement of 2 speech motor programming processes identified by S. T. Klapp (1995, 2003) during the articulation of utterances differing in syllable and sequence complexity. According to S. T. Klapp, 1 process, INT, resolves the demands of the programmed unit, whereas a second process, SEQ, oversees the serial order demands of longer sequences. A modified reaction time paradigm was used to assess INT and SEQ demands. Specifically, syllable complexity was dependent on syllable structure, whereas sequence complexity involved either repeated or unique syllabi within an utterance. INT execution was slowed when articulating single syllables in the form CCCV compared to simpler CV syllables. Planning unique syllables within a multisyllabic utterance rather than repetitions of the same syllable slowed INT but not SEQ. The INT speech motor programming process, important for mental syllabary access, is sensitive to changes in both syllable structure and the number of unique syllables in an utterance.


An adaptive sharing elitist evolution strategy for multiobjective optimization.
Almost all approaches to multiobjective optimization are based on Genetic Algorithms (GAs), and implementations based on Evolution Strategies (ESs) are very rare. Thus, it is crucial to investigate how ESs can be extended to multiobjective optimization, since they have, in the past, proven to be powerful single objective optimizers. In this paper, we present a new approach to multiobjective optimization, based on ESs. We call this approach the Multiobjective Elitist Evolution Strategy (MEES) as it incorporates several mechanisms, like elitism, that improve its performance. When compared with other algorithms, MEES shows very promising results in terms of performance.


Alignment of multiradiation isocenters for megavoltage photon beam.
The accurate measurement of the linear accelerator (linac) radiation isocenter is critical, especially for stereotactic treatment. Traditional quality assurance (QA) procedure focuses on the measurement of single radiation isocenter, usually of 6 megavoltage (MV) photon beams. Single radiation isocenter is also commonly assumed in treatment planning systems (TPS). Due to different flattening filters and bending magnet and steering parameters, the radiation isocenter of one energy mode can deviate from another if no special effort was devoted. We present the first experience of the multiradiation isocenters alignment on an Elekta linac, as well as its corresponding QA procedure and clinical impact. An 8 mm ball-bearing (BB) phantom was placed at the 6 MV radiation isocenter using an Elekta isocenter search algorithm, based on portal images. The 3D radiation isocenter shifts of other photon energy modes relative to the 6 MV were determined. Beam profile scanning for different field sizes was used as an independent method to determine the 2D multiradiation isocenters alignment. To quantify the impact of radiation isocenter offset on targeting accuracy, the 10 MV radiation isocenter was manually offset from that for 6 MV by adjusting the bending magnet current. Because our table isocenter was mechanically aligned to the 6 MV radiation isocenter, the deviation of the table isocentric rotation from the "shifted" 10 MV radiation isocenter after bending magnet adjustment was assessed. Winston-Lutz test was also performed to confirm the overall radiation isocenter positioning accuracy for all photon energies. The portal image method showed the radiation isocenter of the 10 MV flattening filter-free mode deviated from others before beam parameter adjustment. After the adjustment, the deviation was greatly improved from 0.96 to 0.35 mm relative to the 6 MV radiation isocenter. The same finding was confirmed by the profile-scanning method. The maximum deviation of the table isocentric rotation from the 10 MV radiation isocenter was observed to linearly increase with the offset between 6 and 10 MV radiation isocenter; 1 mm radiation isocenter offset can translate to almost 2 mm maximum deviation of the table isocentric rotation from the 10 MV radiation isocenter. The alignment of the multiradiation isocenters is particularly important for high-precision radiotherapy. Our study provides the medical physics community with a quantitative measure of the multiradiation isocenters alignment. A routine QA method should be considered, to examine the radiation isocenters alignment during the linac acceptance.


Improving recruitment to a study of telehealth management for long-term conditions in primary care: two embedded, randomised controlled trials of optimised patient information materials.
Patient understanding of study information is fundamental to gaining informed consent to take part in a randomised controlled trial. In order to meet the requirements of research ethics committees, patient information materials can be long and need to communicate complex messages. There is concern that standard approaches to providing patient information may deter potential participants from taking part in trials. The Systematic Techniques for Assisting Recruitment to Trials (MRC-START) research programme aims to test interventions to improve trial recruitment. The aim of this study was to investigate the effect on recruitment of optimised patient information materials (with improved readability and ease of comprehension) compared with standard materials. The study was embedded within two primary care trials involving patients with long-term conditions. The Healthlines Study involves two linked trials evaluating a telehealth intervention in patients with depression (Healthlines Depression) or raised cardiovascular disease risk (Healthlines CVD). We conducted two trials of a recruitment intervention, embedded within the Healthlines host trials. Patients identified as potentially eligible in each of the Healthlines trials were randomised to receive either the original patient information materials or optimised versions of these materials. Primary outcomes were the proportion of participants randomised (Healthlines Depression) and the proportion expressing interest in taking part (Healthlines CVD). In Healthlines Depression (n = 1364), 6.3% of patients receiving the optimised patient information materials were randomised into the study compared to 4.0% in those receiving standard materials (OR = 1.63, 95% CI = 1.00 to 2.67). In Healthlines CVD (n = 671) 24.0% of those receiving optimised patient information materials responded positively to the invitation to participate, compared to 21.9% in those receiving standard materials (OR = 1.12, 95% CI = 0.78 to 1.61). Evidence from these two embedded trials suggests limited benefits of optimised patient information materials on recruitment rates, which may only be apparent in some patient populations, with no effects on other outcomes. Further embedded trials are needed to provide a more precise estimate of effect, and to explore further how effects vary by trial context, intervention, and patient population. Current Controlled Trials: Healthlines Depression (ISRCTN27508731) on 26 June 2012; and Healthlines CVD (ISRCTN14172341) on 5 July 2012.


Evaluation of U.S. Manufacturing Subsectors at Risk of Physical Water Shortages.
The potential impact of water shortages on U.S. manufacturing is unknown. While water for manufacturing constitutes an estimated 6% of U.S. water intake, the data (i.e., location, quantity, and purpose of water intake) needed to determine this impact does not exist. This paper will identify manufacturing subsectors at risk of physical water shortages by applying a method for estimating U.S. manufacturing water intake at the necessary spatial and sectoral resolutions. First, the data requirements to quantify a manufacturing facility's water footprint within the context of the watershed are developed. Second, using international data, water intake at the national, state, and county-levels by each U.S. manufacturing subsector is estimated. Third, manufacturing subsectors that are most vulnerable to risks of physical water shortages are identified. Based on the results, the Paper, Primary Metals, Chemical, Petroleum and Coal Products, and Food subsectors have the largest intake, respectively. However, the Primary Metals, Fabricated Metals, Transportation Equipment, Petroleum and Coal Products, and Plastics and Rubber subsectors are at the greatest risk of physical water shortages based on concentrations of water intake in water-stressed regions. The results can be used to develop strategies to mitigate the risks of water shortages on the U.S. manufacturing sector.


Sad mood promotes self-initiated mental contrasting of future and reality.
Self-regulation by mentally contrasting a positive future with negative reality leads people to differentiate in their goal commitments: They commit to goals when expectations of success are high and let go when expectations of success are low. On the contrary, when indulging in the positive future or dwelling on negative reality, people fail to consider expectations of success and do not form selective goal commitments (Oettingen, Pak, & Schnetter, 2001). Whereas prior research has examined the effects of experimentally induced mental contrasting, we address sad mood as a contextual influence promoting self-initiated mental contrasting. Across various mood inductions, sad moods--which are associated with problem solving strategies--facilitated self-initiated mental contrasting more than neutral moods (Studies 1, 5) or happy moods (Studies 2, 3, 4, 6). Importantly, mood did not affect the relation between mental contrasting and selective formation of goal commitment (Studies 5, 6). The results suggest that sad moods aid in self-regulation by making people self-initiate goal commitments that are sensitive to their expectations of success.


Accuracy in Wrist-Worn, Sensor-Based Measurements of Heart Rate and Energy Expenditure in a Diverse Cohort.
The ability to measure physical activity through wrist-worn devices provides an opportunity for cardiovascular medicine. However, the accuracy of commercial devices is largely unknown. The aim of this work is to assess the accuracy of seven commercially available wrist-worn devices in estimating heart rate (HR) and energy expenditure (EE) and to propose a wearable sensor evaluation framework. We evaluated the Apple Watch, Basis Peak, Fitbit Surge, Microsoft Band, Mio Alpha 2, PulseOn, and Samsung Gear S2. Participants wore devices while being simultaneously assessed with continuous telemetry and indirect calorimetry while sitting, walking, running, and cycling. Sixty volunteers (29 male, 31 female, age 38 ± 11 years) of diverse age, height, weight, skin tone, and fitness level were selected. Error in HR and EE was computed for each subject/device/activity combination. Devices reported the lowest error for cycling and the highest for walking. Device error was higher for males, greater body mass index, darker skin tone, and walking. Six of the devices achieved a median error for HR below 5% during cycling. No device achieved an error in EE below 20 percent. The Apple Watch achieved the lowest overall error in both HR and EE, while the Samsung Gear S2 reported the highest. In conclusion, most wrist-worn devices adequately measure HR in laboratory-based activities, but poorly estimate EE, suggesting caution in the use of EE measurements as part of health improvement programs. We propose reference standards for the validation of consumer health devices (http://precision.stanford.edu/).


Coronary event and case fatality rates in an English population: results of the Oxford myocardial infarction incidence study. The Oxford Myocardial Infarction Incidence Study Group.
To determine coronary event and case fatality rates in an English population aged less than 80 years in Oxfordshire, and to compare these rates with those reported by the UK monitoring trends and determinants of cardiovascular disease (MONICA) centres in Scotland and Northern Ireland and those ascertained in Oxfordshire in 1966-67. A population wide surveillance study conducted in 1994-95 using prospective and retrospective case ascertainment. A resident population in Oxfordshire of 568,800. Patients with suspected myocardial infarction or coronary death. A diagnosis of definite or possible myocardial infarction or coronary death using WHO MONICA diagnostic criteria based on symptoms, electrocardiograms, cardiac enzymes, necropsy findings, and past medical history. The annual rate for a first or recurrent coronary event per 100,000 population aged less than 65 years in 1994-95 was 273 for men and 66 for women after age adjustment to a standard world population. Rates in the age group 65-79 years were 1350 for men and 677 for women. Between 1966-67 and 1994-95, the age standardised event rate in the age group 30-69 years decreased significantly by 33% (95% confidence interval (CI) 44 to 21) in men, and there was a non-significant reduction of 8% (95% CI -33 to 17) in women. The age standardised 28 day case fatality rates also decreased significantly by 28% (95% CI 41 to 15) in men and by 32% (95% CI 55 to 9) in women. The coronary event rate in Oxfordshire was much lower than rates reported by MONICA centres in Glasgow and Belfast, and similar to rates reported by MONICA centres in France and northern Italy. The substantially lower event rate accounts for lower coronary heart disease mortality in Oxfordshire than in Scotland and Northern Ireland. The reduced coronary mortality in this region is attributable to declines in coronary event and case fatality rates.


Measuring the Impacts of Water Safety Plans in the Asia-Pacific Region.
This study investigated the effectiveness of Water Safety Plans (WSP) implemented in 99 water supply systems across 12 countries in the Asia-Pacific region. An impact assessment methodology including 36 indicators was developed based on a conceptual framework proposed by the Center for Disease Control (CDC) and before/after data were collected between November 2014 and June 2016. WSPs were associated with infrastructure improvements at the vast majority (82) of participating sites and to increased financial support at 37 sites. In addition, significant changes were observed in operations and management practices, number of water safety-related meetings, unaccounted-for water, water quality testing activities, and monitoring of consumer satisfaction. However, the study also revealed challenges in the implementation of WSPs, including financial constraints and insufficient capacity. Finally, this study provided an opportunity to test the impact assessment methodology itself, and a series of recommendations are made to improve the approach (indicators, study design, data collection methods) for evaluating WSPs.


The evolution of body size and shape in the human career.
Body size is a fundamental biological property of organisms, and documenting body size variation in hominin evolution is an important goal of palaeoanthropology. Estimating body mass appears deceptively simple but is laden with theoretical and pragmatic assumptions about best predictors and the most appropriate reference samples. Modern human training samples with known masses are arguably the 'best' for estimating size in early bipedal hominins such as the australopiths and all members of the genus Homo, but it is not clear if they are the most appropriate priors for reconstructing the size of the earliest putative hominins such as Orrorin and Ardipithecus The trajectory of body size evolution in the early part of the human career is reviewed here and found to be complex and nonlinear. Australopith body size varies enormously across both space and time. The pre-erectus early Homo fossil record from Africa is poor and dominated by relatively small-bodied individuals, implying that the emergence of the genus Homo is probably not linked to an increase in body size or unprecedented increases in size variation. Body size differences alone cannot explain the observed variation in hominin body shape, especially when examined in the context of small fossil hominins and pygmy modern humans.This article is part of the themed issue 'Major transitions in human evolution'.


Isolation of intermediate filament assemblies from human hair follicles.
We used developing human hair follicle cells for the isolation of hard alpha-keratin structural components. Intracellular dispersions examined by electron microscopy contained both individual alpha-keratin filaments and the tactoid-like filament assemblies observed in situ organized along subfibrillar arms of macrofibrils. The assemblies of average width 47 nm were composed of closely packed alpha-keratin filaments and originated from the initial filament arrays observed in sections of developing mammalian hair follicles. We have distinguished two types of assemblies: the para-like or hexagonally packed and the ortho-like spiral or whorl type. Axial banding extended across the width of filament assemblies, which suggested that hard alpha-keratin filaments pack in lateral register and form a lattice that contains interfilamentous bridges. We observed axial banding patterns with periods ranging from 20 to 22 nm, consistent with the 22-nm periodic structure deduced from x-ray diffraction studies and present in models proposed for hard alpha-keratin and other intermediate filaments. Preliminary biochemical studies of filaments and filament assemblies indicate that they consist of the closely related group of proteins (low-sulfur proteins) ubiquitous among extracts of hard mammalian keratins. Isolated hard alpha-keratin filament assemblies provide a new and valuable structural entity for investigating the assembly mechanisms involved in the formation of the filament-matrix framework found in hard mammalian keratin appendages.


Neoadjuvant Trials in ER+ Breast Cancer: A Tool for Acceleration of Drug Development and Discovery.
Neoadjuvant therapy trials offer an excellent strategy for drug development and discovery in breast cancer, particularly in triple-negative and HER2-overexpressing subtypes, where pathologic complete response is a good surrogate of long-term patient benefit. For estrogen receptor-positive (ER+) breast cancers, however, use of this strategy has been challenging because of the lack of validated surrogates of long-term efficacy and the overall good prognosis of the majority of patients with this cancer subtype. We review below the clinical benefits of neoadjuvant endocrine therapy for ER+/HER2-negative breast cancer, its use and limitations for drug development, prioritization of adjuvant and metastatic trials, and biomarker discovery.Significance: Neoadjuvant endocrine therapy is an excellent platform for the development of investigational drugs, triaging of novel combinations, biomarker validation, and discovery of mechanisms of drug resistance. This review summarizes the clinical and investigational benefits of this approach, with a focus on how to best integrate predictive biomarkers into novel clinical trial designs. Cancer Discov; 7(6); 561-74. ©2017 AACR.


Formal analysis, hardness, and algorithms for extracting internal structure of test-based problems.
Problems in which some elementary entities interact with each other are common in computational intelligence. This scenario, typical for coevolving artificial life agents, learning strategies for games, and machine learning from examples, can be formalized as a test-based problem and conveniently embedded in the common conceptual framework of coevolution. In test-based problems, candidate solutions are evaluated on a number of test cases (agents, opponents, examples). It has been recently shown that every test of such problem can be regarded as a separate objective, and the whole problem as multi-objective optimization. Research on reducing the number of such objectives while preserving the relations between candidate solutions and tests led to the notions of underlying objectives and internal problem structure, which can be formalized as a coordinate system that spatially arranges candidate solutions and tests. The coordinate system that spans the minimal number of axes determines the so-called dimension of a problem and, being an inherent property of every problem, is of particular interest. In this study, we investigate in-depth the formalism of a coordinate system and its properties, relate them to properties of partially ordered sets, and design an exact algorithm for finding a minimal coordinate system. We also prove that this problem is NP-hard and come up with a heuristic which is superior to the best algorithm proposed so far. Finally, we apply the algorithms to three abstract problems and demonstrate that the dimension of the problem is typically much lower than the number of tests, and for some problems converges to the intrinsic parameter of the problem--its a priori dimension.


What are the prospects for citizen science in agriculture? Evidence from three continents on motivation and mobile telephone use of resource-poor farmers.
As the sustainability of agricultural citizen science projects depends on volunteer farmers who contribute their time, energy and skills, understanding their motivation is important to attract and retain participants in citizen science projects. The objectives of this study were to assess 1) farmers' motivations to participate as citizen scientists and 2) farmers' mobile telephone usage. Building on motivational factors identified from previous citizen science studies, a questionnaire based methodology was developed which allowed the analysis of motivational factors and their relation to farmers' characteristics. The questionnaire was applied in three communities of farmers, in countries from different continents, participating as citizen scientists. We used statistical tests to compare motivational factors within and among the three countries. In addition, the relations between motivational factors and farmers characteristics were assessed. Lastly, Principal Component Analysis (PCA) was used to group farmers based on their motivations. Although there was an overlap between the types of motivations, for Indian farmers a collectivistic type of motivation (i.e., contribute to scientific research) was more important than egoistic and altruistic motivations. For Ethiopian and Honduran farmers an egoistic intrinsic type of motivation (i.e., interest in sharing information) was most important. While fun has appeared to be an important egoistic intrinsic factor to participate in other citizen science projects, the smallholder farmers involved in this research valued 'passing free time' the lowest. Two major groups of farmers were distinguished: one motivated by sharing information (egoistic intrinsic), helping (altruism) and contribute to scientific research (collectivistic) and one motivated by egoistic extrinsic factors (expectation, expert interaction and community interaction). Country and education level were the two most important farmers' characteristics that explain around 20% of the variation in farmers motivations. For educated farmers, contributing to scientific research was a more important motivation to participate as citizen scientists compared to less educated farmers. We conclude that motivations to participate in citizen science are different for smallholders in agriculture compared to other sectors. Citizen science does have high potential, but easy to use mechanisms are needed. Moreover, gamification may increase the egoistic intrinsic motivation of farmers.


Tau immunotherapy modulates both pathological tau and upstream amyloid pathology in an Alzheimer's disease mouse model.
In Alzheimer's disease (AD), the pathological accumulation of tau appears to be a downstream effect of amyloid β protein (Aβ). However, the relationship between these two proteins and memory loss is unclear. In this study, we evaluated the specific removal of pathological tau oligomers in aged Tg2576 mice by passive immunotherapy using tau oligomer-specific monoclonal antibody. Removal of tau oligomers reversed memory deficits and accelerated plaque deposition in the brain. Surprisingly, Aβ*56 levels decreased, suggesting a link between tau and Aβ oligomers in the promotion of cognitive decline. The results suggest that tau oligomerization is not only a consequence of Aβ pathology but also a critical mediator of the toxic effects observed afterward in AD. Overall, these findings support the potential of tau oligomers as a therapeutic target for AD.


The GLIVEC international patient assistance programme: the Nairobi experience.
Glivec is a drug used in the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GISI). It is an expensive drug which would be out of reach for most patients in Kenya. Norvatis Pharmaceutical together with Axios International a healthcare management company and Max Foundation have made it possible for patients in developing countries to get access to the drug at no cost. Patients meet the cost of the confirmatory test and are recruited into the programme to receive the drug at no cost. A total of 201 patients are in the programme in Nairobi, mainly drawn from Kenyatta National Hospital the major referral hospital in Kenya. The age range is nine years to 75 years with a mean age of 39.5 years. Males make up 56.5% while females are 43.5%. CML are 173 (86%) while GIST patients are 28 (13.9%). Most of the CML cases are referred in the chronic stable phase (87.8%) and 85.7% have been on hydroxyurea as the initial treatment. Compliance rates are approximately 80%.


Copper:caeruloplasmin ratio.
Investigation of copper status can be a diagnostic challenge. The non-caeruloplasmin-bound copper (NCC) has deficiencies; accordingly, the copper:caeruloplasmin ratio has been suggested as an alternative index of copper status. A reference interval for this index was derived. In addition to making the interpretation of copper easier, the copper:caeruloplasmin ratio should also enable adjustment for relatively high caeruloplasmin concentrations without recourse to producing gender- and age-derived intervals. The copper:caeruloplasmin ratio has weaknesses similar to those identified for NCC in that immunological methods used for caeruloplasmin can cross react with apocaeruloplasmin and there is no standardised method for caeruloplasmin. Caeruloplasmin assays also have uncertainty from precision, bias and specificity and, accordingly, method-related differences may have a large effect on the copper:caeruloplasmin ratio in a manner similar to the NCC.


Is the presence of abnormal prion protein in the renal glomeruli of feline species presenting with FSE authentic?
In a recent paper written by Hilbe et al (BMC vet res, 2009), the nature and specificity of the prion protein deposition in the kidney of feline species affected with feline spongiform encephalopathy (FSE) were clearly considered doubtful. This article was brought to our attention because we published several years ago an immunodetection of abnormal prion protein in the kidney of a cheetah affected with FSE. At this time we were convinced of its specificity but without having all the possibilities to demonstrate it. As previously published by another group, the presence of abnormal prion protein in some renal glomeruli in domestic cats affected with FSE is indeed generally considered as doubtful mainly because of low intensity detected in this organ and because control kidneys from safe animals present also a weak prion immunolabelling. Here we come back on these studies and thought it would be helpful to relay our last data to the readers of BMC Vet res for future reference on this subject.Here we come back on our material as it is possible to study and demonstrate the specificity of prion immunodetection using the PET-Blot method (Paraffin Embedded Tissue--Blot). It is admitted that this method allows detecting the Proteinase K (PK) resistant form of the abnormal prion protein (PrPres) without any confusion with unspecific immunoreaction. We re-analysed the kidney tissue versus adrenal gland and brain samples from the same cheetah affected with TSE using this PET-Blot method. The PET-Blot analysis revealed specific PrPres detection within the brain, adrenal gland and some glomeruli of the kidney, with a complete identicalness compared to our previous detection using immunohistochemistry. In conclusion, these new data enable us to confirm with assurance the presence of specific abnormal prion protein in the adrenal gland and in the kidney of the cheetah affected with FSE. It also emphasizes the usefulness for the re-examination of any available tissue blocks with the PET-Blot method as a sensitive complementary tool in case of doubtful PrP IHC results.


Cash and in-kind transfers in poor rural communities in Mexico increase household fruit, vegetable, and micronutrient consumption but also lead to excess energy consumption.
Conditional transfer programs are increasingly popular, but the impact on household nutrient consumption has not been studied. We evaluated the impact of the Programa de Apoyo Alimentario (PAL), a cash and in-kind transfer program, on the energy and nutrient consumption of poor rural households in Mexico. The program has been shown to reduce poverty. Beneficiary households received either a food basket (including micronutrient-fortified milk) or cash. A random sample of 206 rural communities in Southern Mexico was randomly assigned to 1 of 4 groups: a monthly food basket with or without health and nutrition education, a cash transfer with a cost to the government equivalent to the food basket (14 USD/mo) with education, or control. The impact after 14 mo of exposure was estimated in a panel of 5823 households using a double difference regression model with household fixed effects. PAL was associated with increases (P < 0.01) in the consumption of total energy (5-9%), energy from fruits and vegetables (24-28%), and energy from animal source foods (24-39%). It also affected iron, zinc, and vitamin A and C consumption (P < 0.05). The consumption of energy and all nutrients was greater in the food basket group (P < 0.05). Cash and in-kind transfers in populations that are not energy-deficient should be carefully redesigned to ensure that pulling poor families out of poverty leads to improved micronutrient intake but not to increased energy consumption.


Do people with Parkinson's disease look at task relevant stimuli when walking? An exploration of eye movements.
Eye movements are impaired by Parkinson's disease (PD) although limited research has explored if PD affects the relevance of visual fixations when walking. Visual fixations may provide crucial contextual information for safe navigation and important insights into fall risk. This study aimed to: investigate visual fixations made while walking under a range of conditions in PD; identify their task relevance; and explore their relationship with clinical features. Thirty-eight people with mild-moderate PD and forty age-matched control participants completed a straight walk with (i) no additional stimuli and (ii) with additional stimuli (visual cues or a high contrast obstacle), whilst wearing a mobile eye-tracker. Fixations were extracted and classified by location and relevance. PD participants made proportionally fewer task-relevant fixations (floor, walls and additional stimuli ahead), caused by significantly more task-irrelevant fixations (floor, walls and ceiling away from waking path) during normal walking (p = 0.014). These group differences were not apparent with visual cues (p = 0.359). During obstacle crossing trials, PD made significantly more task-relevant fixations than controls (p = 0.007). Reduced bilateral visual acuity was associated with fewer fixations in PD. Our findings suggest that people with PD visually explore complex environments less efficiently likely owing to underlying PD pathology. Visual exploration improved with the addition of salient stimuli (for example visual cues or an obstacle) and thus developing and optimising visual interventions could prove critical to improving locomotor safety and reducing falls risk in home environments.


The synthesis of a corrole analogue of aquacobalamin (vitamin B12a) and its ligand substitution reactions.
The synthesis of a Co(III) corrole, [10-(2-[[4-(1H-imidazol-1-ylmethyl)benzoyl]amino]phenyl)-5,15-diphenylcorrolato]cobalt(III), DPTC-Co, bearing a tail motif terminating in an imidazole ligand that coordinates Co(III), is described. The corrole therefore places Co(III) in a similar environment to that in aquacobalamin (vitamin B12a, H2OCbl(+)) but with a different equatorial ligand. In coordinating solvents, DPTC-Co is a mixture of five- and six-coordinate species, with a solvent molecule occupying the axial coordination site trans to the proximal imidazole ligand. In an 80:20 MeOH/H2O solution, allowed to age for about 1 h, the predominant species is the six-coordinate aqua species [H2O-DPTC-Co]. It is monomeric at least up to concentrations of 60 μM. The coordinated H2O has a pKa = 9.76(6). Under the same conditions H2OCbl(+) has a pKa = 7.40(2). Equilibrium constants for the substitution of coordinated H2O by exogenous ligands are reported as log K values for neutral N-, P-, and S-donor ligands, and CN(-), NO2(-), N3(-), SCN(-), I(-), and Cys in 80:20 MeOH/H2O solution at low ionic strength. The log K values for [H2O-DPTC-Co] correlate reasonably well with those for H2OCbl(+); therefore, Co(III) displays a similar behavior toward these ligands irrespective of whether the equatorial ligand is a corrole or a corrin. Pyridine is an exception; it is poorly coordinated by H2OCbl(+) because of the sterically hindered coordination site of the corrin. With few exceptions, [H2O-DPTC-Co] has a higher affinity for neutral ligands than H2OCbl(+), but the converse is true for anionic ligands. Density functional theory (DFT) models (BP86/TZVP) show that the Co-ligand bonds tend to be longer in corrin than in corrole complexes, explaining the higher affinity of the latter for neutral ligands. It is argued that the residual charge at the metal center (+2 in corrin, 0 in corrole) increases the affinity of H2OCbl(+) for anionic ligands through an electrostatic attraction. The topological properties of the electron density in the DFT-modeled compounds are used to explore the nature of the bonding between the metal and the ligands.


Insights Into the Microbiology of the Chaotropic Brines of Salar de Atacama, Chile.
Microbial life inhabiting hypersaline environments belong to a limited group of extremophile or extremotolerant taxa. Natural or artificial hypersaline environments are not limited to high concentrations of NaCl, and under such conditions, specific adaptation mechanisms are necessary to permit microbial survival and growth. Argentina, Bolivia, and Chile include three large salars (salt flats) which globally, represent the largest lithium reserves, and are commonly referred to as the Lithium Triangle Zone. To date, a large amount of information has been generated regarding chemical, geological, meteorological and economical perspectives of these salars. However, there is a remarkable lack of information regarding the biology of these unique environments. Here, we report the presence of two bacterial strains (isolates LIBR002 and LIBR003) from one of the most hypersaline lithium-dominated man-made environments (total salinity 556 g/L; 11.7 M LiCl) reported to date. Both isolates were classified to the Bacillus genera, but displayed differences in 16S rRNA gene and fatty acid profiles. Our results also revealed that the isolates are lithium-tolerant and that they are phylogenetically differentiated from those Bacillus associated with high NaCl concentration environments, and form a new clade from the Lithium Triangle Zone. To determine osmoadaptation strategies in these microorganisms, both isolates were characterized using morphological, metabolic and physiological attributes. We suggest that our characterization of bacterial isolates from a highly lithium-enriched environment has revealed that even at such extreme salinities with high concentrations of chaotropic solutes, scope for microbial life exists. These conditions have previously been considered to limit the development of life, and our work extends the window of life beyond high concentrations of MgCl2, as previously reported, to LiCl. Our results can be used to further the understanding of salt tolerance, most especially for LiCl-dominated brines, and likely have value as models for the understanding of putative extra-terrestrial (e.g., Martian) life.


Postdischarge community pharmacist-provided home services for patients after hospitalization for heart failure.
To establish a community pharmacist-provided home health service to improve medication adherence and reduce 30-day heart failure-related hospital readmissions. Visiting Nurse Services of Newport and Bristol Counties located in Portsmouth, RI, from December 2013 to April 2014. Each patient received one in-home visit provided by a Postgraduate Year 1 community pharmacy resident within 1 week of admission to visiting nurse services followed by two follow-up telephone calls, 1 week and 4 weeks after the visit. The in-home visit consisted of a baseline assessment of medication adherence using the Morisky 8-Item Medication Adherence Questionnaire as well as pharmacist-provided education regarding chronic heart failure management. The follow-up telephone calls were used to reassess patient adherence and to monitor for hospital readmission within 30 days of the initial in-home visit. Community pharmacist-provided in-home medication reconciliation and medication teaching has not been described in the literature previously. In addition, pharmacists are often not included on home health care teams placing patients undergoing transitions in care at risk for potential medication-related errors. Improvement in medication adherence and reduction in 30-day heart failure-related hospital readmission rates. Ten patients were enrolled from December 2013 through April 2014. Following intervention, all patients saw improvements in adherence questionnaire scores during follow-up. Hospital readmission rates for patients seen by the pharmacist were lower compared with agencywide figures over a similar time period. A community pharmacist-provided in-home medication teaching service for patients following recent hospital discharge helps facilitate successful transitions of care from an inpatient to outpatient setting, improves medication adherence and has produced lower observed 30-day heart failure-related hospital readmission rates. Expansion of this or a similar service within the community pharmacy to reach as many patients as possible, including those not using visiting nurse services, could serve to only augment these benefits.