The thickness of musical pitch: psychophysical evidence for linguistic relativity.
Do people who speak different languages think differently, even when they are not using language? To find out, we used nonlinguistic psychophysical tasks to compare mental representations of musical pitch in native speakers of Dutch and Farsi. Dutch speakers describe pitches as high (hoog) or low (laag), whereas Farsi speakers describe pitches as thin (nazok) or thick (koloft). Differences in language were reflected in differences in performance on two pitch-reproduction tasks, even though the tasks used simple, nonlinguistic stimuli and responses. To test whether experience using language influences mental representations of pitch, we trained native Dutch speakers to describe pitch in terms of thickness, as Farsi speakers do. After the training, Dutch speakers' performance on a nonlinguistic psychophysical task resembled the performance of native Farsi speakers. People who use different linguistic space-pitch metaphors also think about pitch differently. Language can play a causal role in shaping nonlinguistic representations of musical pitch.


Optical control of the Advanced Technology Solar Telescope.
The Advanced Technology Solar Telescope (ATST) is an off-axis Gregorian astronomical telescope design. The ATST is expected to be subject to thermal and gravitational effects that result in misalignments of its mirrors and warping of its primary mirror. These effects require active, closed-loop correction to maintain its as-designed diffraction-limited optical performance. The simulation and modeling of the ATST with a closed-loop correction strategy are presented. The correction strategy is derived from the linear mathematical properties of two Jacobian, or influence, matrices that map the ATST rigid-body (RB) misalignments and primary mirror figure errors to wavefront sensor (WFS) measurements. The two Jacobian matrices also quantify the sensitivities of the ATST to RB and primary mirror figure perturbations. The modeled active correction strategy results in a decrease of the rms wavefront error averaged over the field of view (FOV) from 500 to 19 nm, subject to 10 nm rms WFS noise. This result is obtained utilizing nine WFSs distributed in the FOV with a 300 nm rms astigmatism figure error on the primary mirror. Correction of the ATST RB perturbations is demonstrated for an optimum subset of three WFSs with corrections improving the ATST rms wavefront error from 340 to 17.8 nm. In addition to the active correction of the ATST, an analytically robust sensitivity analysis that can be generally extended to a wider class of optical systems is presented.


Molecular mechanism for opioid dichotomy: bidirectional effect of μ-opioid receptors on P2X₃ receptor currents in rat sensory neurones.
Here, we describe a molecular switch associated with opioid receptors-linked signalling cascades that provides a dual opioid control over P2X3 purinoceptor in sensory neurones. Leu-enkephalin inhibited P2X3-mediated currents with IC50 ~10 nM in ~25% of small nociceptive rat dorsal root ganglion (DRG) neurones. In contrast, in neurones pretreated with pertussis toxin leu-enkephalin produced stable and significant increase of P2X3 currents. All effects of opioid were abolished by selective μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), nonselective inhibitor naloxone, and by PLC inhibitor U73122. Thus, we discovered a dual link between purinoceptors and μ-opioid receptors: the latter exert both inhibitory (pertussis toxin-sensitive) and stimulatory (pertussis toxin-insensitive) actions on P2X3 receptors through phospholipase C (PLC)-dependent pathways. This dual opioid control of P2X3 receptors may provide a molecular explanation for dichotomy of opioid therapy. Pharmacological control of this newly identified facilitation/inhibition switch may open new perspectives for the adequate medical use of opioids, the most powerful pain-killing agents known today.


O-glycosylation expression in fibroadenoma.
Fibroadenomas are human benign breast tumors characterized by proliferation of epithelial and stroma cells of the terminal ductal unit. Expression of O-glycans seems to contribute to the proliferation and transformation events. With this in mind, we evaluated the expression of glycans in fibroadenoma tissue through immunohistochemistry with antibodies against mucin epitopes (Anti CA15-3 and MUC1), as well as with lectins specific for glycans linked to proteins or lipids, and we compared findings with healthy breast specimens. Our results show positive expression of CA15-3 and MUC1 in fibroadenoma tissue, mainly in duct and stroma cells, whereas, in normal samples, staining was observed in duct cells. The lectin from Glycine max recognized equally well duct and stroma cells; this was the only lectin showing co-localization with anti-CA15-3 in healthy and tumor tissues. Dolichos biflorus, Artocarpus integrifolia, and Griffonia simplicifolia lectins recognized duct cells in control healthy tissues as well as in fibroadenoma tissue. The lectin from Amaranthus leucocarpus recognized only duct cells in control samples, whereas, in fibroadenoma tissue, it recognized duct and some stromal cells, suggesting that O-glycans-type mucin linked to proteins and mucin participate in the development of fibroadenomas.


Do trials reduce uncertainty? Assessing impact through cumulative meta-analysis of neonatal RCTs.
To assess the impact of the latest randomized controlled trial (RCT) to each systematic review (SR) in Cochrane Neonatal Reviews. We selected meta-analyses reporting the typical point estimate of the risk ratio for the primary outcome of the latest study (n=130), mortality (n=128) and the mean difference for the primary outcome (n=44). We employed cumulative meta-analysis to determine the typical estimate after each trial was added, and then performed multivariable logistic regression to determine factors predictive of study impact. For the stated primary outcome, 18% of latest RCTs failed to narrow the confidence interval (CI), and 55% failed to decrease the CI by ⩾20%. Only 8% changed the typical estimate directionality, and 11% caused a change to or from significance. Latest RCTs did not change the typical estimate in 18% of cases, and only 41% changed the typical estimate by at least 10%. The ability to narrow the CI by >20% was negatively associated with the number of previously published RCTs (odds ratio 0.707). Similar results were found in analysis of typical estimates for the outcomes of mortality and mean difference. Across a broad range of clinical questions, the latest RCT failed to substantially narrow the CI of the typical estimate, to move the effect estimate or to change its statistical significance in a majority of cases. Investigators and grant peer review committees should consider prioritizing less-studied topics or requiring formal consideration of optimal information size based on extant evidence in power calculations.


Septo-hippocampal deafferentation protects CA1 neurons against ischemic injury.
Excessive synaptic excitation caused by transient cerebral ischemia has been proposed to explain the greater vulnerability of specific neuronal populations to ischemic injury. We tested this hypothesis in rats by cutting, alone or in combination, the afferent fibers that travel in the fimbria/fornix, the perforant, or the Schäffer collateral pathways and innervate the right CA1 hippocampus. Seven to twelve days later the animals were subjected to 30 min of reversible forebrain ischemia. Irreversible damage to the CA1 neurons was assessed with the light microscope after 70-120 h of cerebral reperfusion. The left, unlesioned hippocampus served as a control. Simultaneous cutting of the 3 major afferent pathways significantly reduced CA1 neuronal damage compared to the unlesioned side (P less than 0.001) or to sham-lesioned controls (P less than 0.001). Selective lesions of the fimbria/fornix but not the perforant or the Schäffer collateral pathways also protected against ischemic CA1 damage. These data indicate that afferent fiber input modulates hippocampal damage caused by ischemia, but they are inconsistent with the hypothesis that excitatory afferent fibers, travelling in either the perforant or the Schäffer collateral pathways alone, play a major role. Neurotransmitters, other than those activating excitatory amino acid receptors or yet-to-be-identified synaptic events, may be invoked to explain the spatial and temporal sensitivity of hippocampal CA1 neurons to ischemia.


Perinatal exposure to a high-fat diet is associated with reduced hepatic sympathetic innervation in one-year old male Japanese macaques.
Our group recently demonstrated that maternal high-fat diet (HFD) consumption is associated with non-alcoholic fatty liver disease, increased apoptosis, and changes in gluconeogenic gene expression and chromatin structure in fetal nonhuman primate (NHP) liver. However, little is known about the long-term effects that a HFD has on hepatic nervous system development in offspring, a system that plays an important role in regulating hepatic metabolism. Utilizing immunohistochemistry and Real-Time PCR, we quantified sympathetic nerve fiber density, apoptosis, inflammation, and other autonomic components in the livers of fetal and one-year old Japanese macaques chronically exposed to a HFD. We found that HFD exposure in-utero and throughout the postnatal period (HFD/HFD), when compared to animals receiving a CTR diet for the same developmental period (CTR/CTR), is associated with a 1.7 fold decrease in periportal sympathetic innervation, a 5 fold decrease in parenchymal sympathetic innervation, and a 2.5 fold increase in hepatic apoptosis in the livers of one-year old male animals. Additionally, we observed an increase in hepatic inflammation and a decrease in a key component of the cholinergic anti-inflammatory pathway in one-year old HFD/HFD offspring. Taken together, these findings reinforce the impact that continuous exposure to a HFD has in the development of long-term hepatic pathologies in offspring and highlights a potential neuroanatomical basis for hepatic metabolic dysfunction.


Not all offspring are created equal: variation in larval characteristics in a serially spawning damselfish.
The way organisms allocate their resources to growth and reproduction are key attributes differentiating life histories. Many organisms spawn multiple times in a breeding season, but few studies have investigated the impact of serial spawning on reproductive allocation. This study investigated whether resource allocation was influenced by parental characteristics and prior spawning history in a serial spawning tropical damselfish (Pomacentrus amboinensis). The offspring attributes of isolated parents of known characteristics were monitored over a 6-week breeding period in the field. Smaller females produced larvae of longer length and larger energy reserves at hatching. This finding is contrary to several other studies that found larger females produce offspring of greater quality. We found that resource allocation in the form of reproductive output was not influenced by the number of spawning events within the breeding season, with larger females producing the greatest number of offspring. Larval characteristics changed as spawning progressed. There was a general decline in length of larvae produced, with an increase in the size of the larval yolk-sac, for all females regardless of size as spawning progressed. This trend was accentuated by the smallest females. This change in larval characteristics may reflect a parental ability to forecast unfavourable conditions as the season progresses or a mechanism to ensure that some will survive no matter what conditions they encounter. This study highlights the importance of accounting for temporal changes in reproductive allocation in studies of reproductive trade-offs and investigations into the importance of parental effects.


The single-port concept: combining optical glucose measurement with insulin infusion.
The aim of this study was to develop a single-port system that combines glucose monitoring and insulin infusion. In a preclinical proof-of-concept trial, the performance of the glucose measurement at the site of insulin infusion was assessed. Glucose levels were clamped from 40 to 250 mg/dL by intravenous glucose infusion and subcutaneous insulin infusion via the glucose sensor. Sensor-glucose values correlated well with reference blood-glucose values, despite infusion at the site of glucose measurement. The average median ARE value was 21.6 ± 5.7 % for sensors used for insulin infusion, 18.1 ± 5.8 % for sensors used for NaCl infusion and 19.2 ± 7.9 % for sensors without infusion. These preclinical in vivo results demonstrate that single-port glucose monitoring is feasible at the site of insulin infusion.


Evidence-based algorithms and the management of falls and syncope presenting to acute medical services.
Falls and syncope are symptoms that commonly present to medical services. Detailed international guidelines for their management are available but tend to be aimed at specialists rather than generalists. Novel, evidence-based algorithms for the management of these symptoms when they present to acute medical services were formulated and their impact on patient care audited. The percentage of people admitted with falls and syncope was unexpectedly high (10.6% at baseline); this had decreased to 8.2% at repeat audit. Readmission rates decreased from 12% at baseline audit to 0% in repeat audit, while length of inpatient stay was unchanged. Mortality was strikingly high (12%) in both audits. Although inappropriate use of investigations decreased, the use of appropriate management strategies increased. Easy-to-use algorithms can help reduce the number of patients admitted to acute medical services with falls and syncope while optimising the care of those managed as inpatients. The algorithms are provided for use by interested parties.


Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease.
The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNow P2Y12 were measured predose, 2, and 24 +/- 4 h post-LD and predose during the MD period on Day 14 +/- 3 and Day 29 +/- 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow P2Y(12) reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses. Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y(12) inhibition, but has no significant influence on the response to prasugrel.


The novel PEI-modified biochars and their application for the efficient elimination of Cr(VI) from aqueous solutions.
In this study, the polyethyleneimine (PEI) was grafted onto the biochars from chestnut shells and nori via the cross-linking reaction. Scanning electron microscopy, transmission electron microscopy and Fourier transferred infrared spectroscopy analysis indicated that the PEI was successfully grafted on the surface of biochars. The PEI modified and pristine biochars were used as adsorbents to remove Cr(VI) from aqueous solutions as a function of pH, ionic strength, contact time and initial concentrations of Cr(VI) through batch technique. The strongly pH-dependent and ionic strength-independent of Cr(VI) sorption indicated that the sorption was mainly dominated by electrostatic interaction and inner-sphere surface complexation. The maximum sorption capacities of PEI modified chestnut shell and nori biochars were 141.42 and 222.84 mg/g, respectively, which were significantly higher than those of pristine biochars. The PEI grafted onto the biochars significantly enhanced Cr(VI) sorption capacity because PEI, which contains volumes of amine/imine groups, provided an excellent platform for Cr(VI) ions removal. In addition, the sorption-desorption experimental results indicated that the PEI modified biochars possessed a stable and recyclable performance. All these results manifested that the PEI modified biochars could be applied as environmentally friendly and efficient adsorbents for the removal of Cr(VI) from wastewater.


Harvest models of small populations of a large carnivore using Bayesian forecasting.
Harvesting large carnivores can be a management tool for meeting politically set goals for their desired abundance. However, harvesting carnivores creates its own set of conflicts in both society and among conservation professionals, where one consequence is a need to demonstrate that management is sustainable, evidence-based, and guided by science. Furthermore, because large carnivores often also have high degrees of legal protection, harvest quotas have to be carefully justified and constantly adjusted to avoid damaging their conservation status. We developed a Bayesian state-space model to support adaptive management of Eurasian lynx harvesting in Scandinavia. The model uses data from the annual monitoring of lynx abundance and results from long-term field research on lynx biology, which has provided detailed estimates of key demographic parameters. We used the model to predict the probability that the forecasted population size will be below or above the management objectives when subjected to different harvest quotas. The model presented here informs decision makers about the policy risks of alternative harvest levels. Earlier versions of the model have been available for wildlife managers in both Sweden and Norway to guide lynx harvest quotas and the model predictions showed good agreement with observations. We combined monitoring data with data on vital rates and were able to estimate unobserved additional mortality rates, which are most probably due to poaching. In both countries, the past quota setting strategy suggests that there has been a de facto threshold strategy with increasing proportion, which means that there is no harvest below a certain population size, but above this threshold there is an increasing proportion of the population harvested as the population size increases. The annual assessment of the monitoring results, the use of forecasting models, and a threshold harvest approach to quota setting will all reduce the risk of lynx population sizes moving outside the desired goals. The approach we illustrate could be adapted to other populations of mammals worldwide.


Impact of prevalent fractures on quality of life: baseline results from the global longitudinal study of osteoporosis in women.
To examine several dimensions of health-related quality of life (HRQL) in postmenopausal women who report previous fractures, and to provide perspective by comparing these findings with those in other chronic conditions (diabetes, arthritis, lung disease). Fractures are a major cause of morbidity among older women. Few studies have examined HRQL in women who have had prior fractures and the effect of prior fracture location on HRQL. In this observational study of 57,141 postmenopausal women aged 55 years and older (enrollment from December 2007 to March 2009) from 17 study sites in 10 countries, HRQL was measured using the European Quality of Life 5 Dimensions Index (EQ-5D) and the health status, physical function, and vitality questions of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Reductions in EQ-5D health-utility scores and SF-36-measured health status, physical function, and vitality were seen in association with 9 of 10 fracture locations. Spine, hip, and upper leg fractures resulted in the greatest reductions in quality of life (EQ-5D scores, 0.62, 0.64, and 0.61, respectively, vs 0.79 without prior fracture). Women with fractures at any of these 3 locations, as well as women with a history of multiple fractures (EQ-5D scores, 0.74 for 1 prior fracture, 0.68 for 2, and 0.58 for >/=3), had reductions in HRQL that were similar to or worse than those in women with other chronic diseases (0.67 for diabetes, 0.69 for arthritis, and 0.71 for lung disease). Previous fractures at a variety of bone locations, particularly spine, hip, and upper leg, or involving more than 1 location are associated with significant reductions in quality of life.


Sliding Fibers: Slidable, Injectable, and Gel-like Electrospun Nanofibers as Versatile Cell Carriers.
Designing biomaterial systems that can mimic fibrous, natural extracellular matrix is crucial for enhancing the efficacy of various therapeutic tools. Herein, a smart technology of three-dimensional electrospun fibers that can be injected in a minimally invasive manner was developed. Open surgery is currently the only route of administration of conventional electrospun fibers into the body. Coordinating electrospun fibers with a lubricating hydrogel produced fibrous constructs referred to as slidable, injectable, and gel-like (SLIDING) fibers. These SLIDING fibers could pass smoothly through a catheter and fill any cavity while maintaining their fibrous morphology. Their injectable features were derived from their distinctive rheological characteristics, which were presumably caused by the combinatorial effects of mobile electrospun fibers and lubricating hydrogels. The resulting injectable fibers fostered a highly favorable environment for human neural stem cell (hNSC) proliferation and neurosphere formation within the fibrous structures without compromising hNSC viability. SLIDING fibers demonstrated superior performance as cell carriers in animal stroke models subjected to the middle cerebral artery occlusion (MCAO) stroke model. In this model, SLIDING fiber application extended the survival rate of administered hNSCs by blocking microglial infiltration at the early, acute inflammatory stage. The development of SLIDING fibers will increase the clinical significance of fiber-based scaffolds in many biomedical fields and will broaden their applicability.


TAP mediates import of Mycobacterium tuberculosis-derived peptides into phagosomes and facilitates loading onto HLA-I.
Processing and presentation of antigen on MHC-I class I molecules serves to present peptides derived from cytosolic proteins to CD8(+) T cells. Infection with bacteria that remain in phagosomal compartments, such as Mycobacterium tuberculosis (Mtb), provides a challenge to this immune recognition as bacterial proteins are segregated from the cytosol. Previously we identified the Mtb phagosome itself as an organelle capable of loading MHC Class I molecules with Mtb antigens. Here, we find that the TAP transporter, responsible for importing peptides into the ER for loading in Class I molecules, is both present and functional in Mtb phagosomes. Furthermore, we describe a novel peptide reagent, representing the N-terminal domain of the bovine herpes virus UL49.5 protein, which is capable of specifically inhibiting the lumenal face of TAP. Together, these results provide insight into the mechanism by which peptides from intra-phagosomal pathogens are loaded onto Class I molecules.


GENOMICS SYMPOSIUM: Using genomic approaches to uncover sources of variation in age at puberty and reproductive longevity in sows.
Genetic variants associated with traits such as age at puberty and litter size could provide insight into the underlying genetic sources of variation impacting sow reproductive longevity and productivity. Genomewide characterization and gene expression profiling were used using gilts from the University of Nebraska-Lincoln swine resource population ( = 1,644) to identify genetic variants associated with age at puberty and litter size traits. From all reproductive traits studied, the largest fraction of phenotypic variation explained by the Porcine SNP60 BeadArray was for age at puberty (27.3%). In an evaluation data set, the predictive ability of all SNP from high-ranked 1-Mb windows (1 to 50%), based on genetic variance explained in training, was greater (12.3 to 36.8%) compared with the most informative SNP from these windows (6.5 to 23.7%). In the integrated data set ( = 1,644), the top 1% of the 1-Mb windows explained 6.7% of the genetic variation of age at puberty. One of the high-ranked windows detected (SSC2, 12-12.9 Mb) showed pleiotropic features, affecting both age at puberty and litter size traits. The RNA sequencing of the hypothalami arcuate nucleus uncovered 17 differentially expressed genes (adjusted < 0.05) between gilts that became pubertal early (<155 d of age) and late (>180 d of age). Twelve of the differentially expressed genes are upregulated in the late pubertal gilts. One of these genes is involved in energy homeostasis (), a function in which the arcuate nucleus plays an important contribution, linking nutrition with reproductive development. Energy restriction during the gilt development period delayed age at puberty by 7 d but increased the probability of a sow to produce up to 3 parities ( < 0.05). Identification of pleotropic functional polymorphisms may improve accuracy of genomic prediction while facilitating a reduction in sow replacement rates and addressing welfare concerns.


Guano exposed: Impact of aerobic conditions on bat fecal microbiota.
Bats and their associated guano microbiota provide important terrestrial and subterranean ecosystem services and serve as a reservoir for a wide range of epizootic and zoonotic diseases. Unfortunately, large-scale studies of bats and their guano microbiotas are limited by the time and cost of sample collection, which requires specially trained individuals to work at night to capture bats when they are most active. Indirectly surveying bat gut microbiota through guano deposits could be a more cost-effective alternative, but it must first be established whether the postdefecation exposure to an aerobic environment has a large impact on the guano microbial community. A number of recent studies on mammalian feces have shown that the impact of aerobic exposure is highly species specific; therefore, it is difficult to predict how exposure will affect the bat guano microbiota without empirical data. In our study, we collected fresh guano samples from 24 individuals of 10 bat species that are common throughout the arid environments of the American southwest and subjected the samples to 0, 1, and 12 hr of exposure. The biodiversity decreased rapidly after the shift from an anaerobic to an aerobic environment-much faster than previously reported in mammalian species. However, the relative composition of the core guano microbiota remained stable and, using highly sensitive targeted PCR methods, we found that pathogens present in the original, non-exposed samples could still be recovered after 12 hr of exposure. These results suggest that with careful sample analysis protocols, a more efficient passive collection strategy is feasible; for example, guano could be collected on tarps placed near the roost entrance. Such passive collection methods would greatly reduce the cost of sample collection by allowing more sites or roosts to be surveyed with a fraction of trained personnel, time, and effort investments needed.


Microbial Community Structure and Functional Potential Along a Hypersaline Gradient.
Salinity is one of the strongest environmental drivers of microbial evolution and community composition. Here we aimed to determine the impact of salt concentrations (2.5, 7.5, and 33.2%) on the microbial community structure of reclaimed saltern ponds near San Francisco, California, and to discover prospective enzymes with potential biotechnological applications. Community compositions were determined by 16S rRNA amplicon sequencing revealing both higher richness and evenness in the pond sediments compared to the water columns. Co-occurrence network analysis additionally uncovered the presence of microbial seed bank communities, potentially primed to respond to rapid changes in salinity. In addition, functional annotation of shotgun metagenomic DNA showed different capabilities if the microbial communities at different salinities for methanogenesis, amino acid metabolism, and carbohydrate-active enzymes. There was an overall shift with increasing salinity in the functional potential for starch degradation, and a decrease in degradation of cellulose and other oligosaccharides. Further, many carbohydrate-active enzymes identified have acidic isoelectric points that have potential biotechnological applications, including deconstruction of biofuel feedstocks under high ionic conditions. Metagenome-assembled genomes (MAGs) of individual halotolerant and halophilic microbes were binned revealing a variety of carbohydrate-degrading potential of individual pond inhabitants.


Histological verification of microaneurysms as a cause of cerebral haemorrhage in surgical specimens.
Surgical specimens taken from 14 patients with lobar intracerebral haemorrhage or cerebellar haemorrhage without vascular abnormalities on angiograms were examined histologically. In seven of the 14 patients, arteriovenous malformation or amyloid angiopathy were found by ordinary pathological examinations. Among the remaining seven patients, definite microaneurysms were verified in five and possible ones in two patients by using the technique of serial sectioning of the solid nodular tissues removed from the presumed bleeding site, where an arterial connection between the tissues and the surrounding brain was noted. Four of these seven patients had no history of hypertension and showed normal blood pressure before and after surgery. To verify microaneurysms in surgical specimens, it seems important to search the presumed bleeding site properly by a meticulous microsurgical technique and to section the tissues serially for the histological examination.


Pseudogenes as regulators of biological function.
A pseudogene arises when a gene loses the ability to produce a protein, which can be due to mutation or inaccurate duplication. Previous dogma has dictated that because the pseudogene no longer produces a protein it becomes functionless and evolutionarily inert, being neither conserved nor removed. However, recent evidence has forced a re-evaluation of this view. Some pseudogenes, although not translated into protein, are at least transcribed into RNA. In some cases, these pseudogene transcripts are capable of influencing the activity of other genes that code for proteins, thereby altering expression and in turn affecting the phenotype of the organism. In the present chapter, we will define pseudogenes, describe the evidence that they are transcribed into non-coding RNAs and outline the mechanisms by which they are able to influence the machinery of the eukaryotic cell.


The ancient history of the structure of ribonuclease P and the early origins of Archaea.
Ribonuclease P is an ancient endonuclease that cleaves precursor tRNA and generally consists of a catalytic RNA subunit (RPR) and one or more proteins (RPPs). It represents an important macromolecular complex and model system that is universally distributed in life. Its putative origins have inspired fundamental hypotheses, including the proposal of an ancient RNA world. To study the evolution of this complex, we constructed rooted phylogenetic trees of RPR molecules and substructures and estimated RPP age using a cladistic method that embeds structure directly into phylogenetic analysis. The general approach was used previously to study the evolution of tRNA, SINE RNA and 5S rRNA, the origins of metabolism, and the evolution and complexity of the protein world, and revealed here remarkable evolutionary patterns. Trees of molecules uncovered the tripartite nature of life and the early origin of archaeal RPRs. Trees of substructures showed molecules originated in stem P12 and were accessorized with a catalytic P1-P4 core structure before the first substructure was lost in Archaea. This core currently interacts with RPPs and ancient segments of the tRNA molecule. Finally, a census of protein domain structure in hundreds of genomes established RPPs appeared after the rise of metabolic enzymes at the onset of the protein world. The study provides a detailed account of the history and early diversification of a fundamental ribonucleoprotein and offers further evidence in support of the existence of a tripartite organismal world that originated by the segregation of archaeal lineages from an ancient community of primordial organisms.


Drug-induced thrombotic microangiopathy: a systematic review of published reports.
Many patients with syndromes of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, have been reported to have a drug-induced etiology, and many different drugs have been suspected as a cause of TMA. We established criteria to assess the strength of evidence for a causal association of a drug with TMA and systematically searched for all published reports of drug-induced TMA. We identified 1569 articles: 604 were retrieved for review, 344 reported evaluable data for 586 individual patients, 43 reported evaluable data on 46 patient groups. Seventy-eight drugs were described; 22 had evidence supporting a definite causal association with TMA. Three drugs accounted for 61 of the 104 patient reports with definite evidence (quinine, 34; cyclosporine, 15; tacrolimus, 12). Twenty additional drugs had evidence supporting a probable association with TMA. These criteria and data can provide support for clinicians evaluating patients with suspected TMA.


The role of the amino-terminal beta-barrel domain of the alpha and beta subunits in the yeast F1-ATPase.
The crystal structure of mitochondrial F1-ATPase indicates that the alpha and beta subunits fold into a structure defined by three domains: the top beta-barrel domain, the middle nucleotide-binding domain, and the C-terminal alpha-helix bundle domain (Abrahams et al., 1994); Bianchet et al., 1998). The beta-barrel domains of the alpha and beta subunits form a crown structure at the top of F1, which was suggested to stabilize it (Abrahams et al. 1994). In this study, the role of the beta-barrel domain in the alpha and beta subunits of the yeast Saccharomyces cerevisiae F1, with regard to its folding and assembly, was investigated. The beta-barrel domains of yeast F1alpha and beta subunits were expressed individually and together in Escherichia coli. When expressed separately, the beta-barrel domain of the beta subunit formed a large aggregate structure, while the domain of the alpha subunit was predominately a monomer or dimer. However, coexpression of the beta-barrel domain of alpha subunit with the beta-barrel domain of beta subunit, greatly reduced the aggregation of the beta subunit domain. Furthermore, the two domains copurified in complexes with the major portion of the complex found in a small molecular weight form. These results indicate that the beta-barrel domain of the alpha and beta subunits interact specifically with each other and that these interactions prevent the aggregation of the beta-barrel domain of the beta subunit. These results mimic in vivo results and suggest that the interactions of the beta-barrel domains may be critical during the folding and assembly of F1.


Complete genome sequence of the aerobic CO-oxidizing thermophile Thermomicrobium roseum.
In order to enrich the phylogenetic diversity represented in the available sequenced bacterial genomes and as part of an "Assembling the Tree of Life" project, we determined the genome sequence of Thermomicrobium roseum DSM 5159. T. roseum DSM 5159 is a red-pigmented, rod-shaped, Gram-negative extreme thermophile isolated from a hot spring that possesses both an atypical cell wall composition and an unusual cell membrane that is composed entirely of long-chain 1,2-diols. Its genome is composed of two circular DNA elements, one of 2,006,217 bp (referred to as the chromosome) and one of 919,596 bp (referred to as the megaplasmid). Strikingly, though few standard housekeeping genes are found on the megaplasmid, it does encode a complete system for chemotaxis including both chemosensory components and an entire flagellar apparatus. This is the first known example of a complete flagellar system being encoded on a plasmid and suggests a straightforward means for lateral transfer of flagellum-based motility. Phylogenomic analyses support the recent rRNA-based analyses that led to T. roseum being removed from the phylum Thermomicrobia and assigned to the phylum Chloroflexi. Because T. roseum is a deep-branching member of this phylum, analysis of its genome provides insights into the evolution of the Chloroflexi. In addition, even though this species is not photosynthetic, analysis of the genome provides some insight into the origins of photosynthesis in the Chloroflexi. Metabolic pathway reconstructions and experimental studies revealed new aspects of the biology of this species. For example, we present evidence that T. roseum oxidizes CO aerobically, making it the first thermophile known to do so. In addition, we propose that glycosylation of its carotenoids plays a crucial role in the adaptation of the cell membrane to this bacterium's thermophilic lifestyle. Analyses of published metagenomic sequences from two hot springs similar to the one from which this strain was isolated, show that close relatives of T. roseum DSM 5159 are present but have some key differences from the strain sequenced.


Use of motivational interviewing in smoking cessation at nurse-led chronic obstructive pulmonary disease clinics.
This paper is a report of a study to describe to what extent Registered Nurses, with a few days of education in motivational interviewing based communication, used motivational interviewing in smoking cessation communication at nurse-led chronic obstructive pulmonary disease clinics in primary health care. For smokers with chronic obstructive pulmonary disease the most crucial and evidence-based intervention is smoking cessation. Motivational interviewing is often used in healthcare to support patients to quit smoking. The study included two videotaped consultations, the first and third of three at the clinic, with each of 13 smokers. Data were collected from March 2006 to April 2007. The nurses' smoking cessation communication was analysed using the Motivational Interviewing Treatment Integrity scale. To get an impression of the consultation, five parameters were judged on a five-point Likert-scale, with five indicating best adherence to Motivational Interviewing. Evocation', 'collaboration', 'autonomy-support' and 'empathy' averaged between 1·31 and 2·23 whereas 'direction' scored five in all consultations. Of communication behaviours, giving information was the most frequently used, followed by 'closed questions', 'motivational interviewing non-adherent' and 'simple reflections'. 'Motivational int erviewing adherent', 'open questions' and 'complex reflections' occurred rarely. There were no important individual or group-level differences in any of the ratings between the first and the third consultations. In smoking cessation communication the nurses did not employ behaviours that are important in motivational interviewing.


Cheaters in mutualism networks.
Mutualism-network studies assume that all interacting species are mutualistic partners and consider that all links are of one kind. However, the influence of different types of links, such as cheating links, on network organization remains unexplored. We studied two flower-visitation networks (Malpighiaceae and Bignoniaceae and their flower visitors), and divide the types of link into cheaters (i.e. robbers and thieves of flower rewards) and effective pollinators. We investigated if there were topological differences among networks with and without cheaters, especially with respect to nestedness and modularity. The Malpighiaceae network was nested, but not modular, and it was dominated by pollinators and had much fewer cheater species than Bignoniaceae network (28% versus 75%). The Bignoniaceae network was mainly a plant-cheater network, being modular because of the presence of pollen robbers and showing no nestedness. In the Malpighiaceae network, removal of cheaters had no major consequences for topology. In contrast, removal of cheaters broke down the modularity of the Bignoniaceae network. As cheaters are ubiquitous in all mutualisms, the results presented here show that they have a strong impact upon network topology.


Meal rich in rapeseed oil increases 24-h fat oxidation more than meal rich in palm oil.
The fatty acid composition of the diet has been linked to the prevalence of diabetes and cardiovascular diseases. Compared with monounsaturated fatty acids, saturated fatty acids decrease fat oxidation and diet-induced thermogenesis. A potential limitation of previous studies was the short duration (≦5h) of calorimetry used. The present study compared the effects of a meal rich in saturated and unsaturated fatty acids on 24-h of fat oxidation. Ten males participated in two sessions of indirect calorimetry in a whole-room metabolic chamber. At each session, subjects consumed three meals rich in palm oil (44.3% as saturated, 42.3% as monounsaturated and 13.4% as polyunsaturated fatty acid) or rapeseed oil (11.7% as saturated, 59.3% as monounsaturated and 29.0% as polyunsaturated fatty acid). Fat oxidation over 24-h was significantly higher in the meal rich in rapeseed oil (779 ± 202 kcal/day) than that rich in palm oil (703 ± 158 kcal/day, P < 0.05), although energy expenditure was similar between both meal conditions. Meal rich in unsaturated fatty acids increased the oxidation of exogenous and/or endogenous fat. The results of a long calorimetry period indicate that rapeseed oil offered an advantage toward increased 24-h fat oxidation in healthy young males.


Immune dysfunction in patients with functional gastrointestinal disorders.
There is increasing evidence for involvement of the immune system in functional gastrointestinal disorder (FGID), including onset after acute gastrointestinal infections, genotypes resulting in altered cytokine expression and abnormal presence of immune cells. Our aim was to assess cellular and humoral immune responses in (i) FGIDs, compared to healthy subjects and (ii) acute vs unspecified onset FGIDs. Lymphocytic [interleukin (IL)-5, IL-10, IL-13 and interferon gamma (IFN-gamma)] and monocytic [IL-10, IL-12, tumour necrosis factor (TNF)-alpha] cytokine production was characterized at baseline and after stimulation with phytohemagglutinine and anti-CD28 or lipopolysaccharide (LPS) in controls (n = 32), irritable bowel syndrome (IBS) (n = 30), functional dyspepsia (FD) (n = 23) and non-cardiac chest pain (NCCP) (n = 15). Serum IL-6 and IL-10 concentrations were compared, and the immunophenotype was assessed using fluorescent-activated cell sorter. Findings were compared for acute vs unspecified onset FGID. Compared to controls, stimulated lymphocyte expression of IL-5 and IL-13 was enhanced in IBS, FD and NCCP (all P < 0.05). Conversely, the stimulated monocytic IL-12 and lymphocytic IL-10 expression were reduced in IBS and FD, while IFN-gamma expression was also reduced in FD patients. Except for an increase in the numbers of CD3(+)CD45RA(+)CD45RO(+) cells, no distinct cellular profile was detected. Patients with a presumed acute onset of their symptoms had higher serum IL-10 levels and more CD3(+)CD45RA(+)CD45RO(+) cells, while TNF-alpha levels following stimulation with LPS were higher in FD patients reporting an acute onset. A shift towards a Th2 cytokine profile is present in FGID, while the cellular immunophenotype remains largely unchanged. Further research is indicated and could provide new therapeutic strategies for these disorders.


A psychophysical investigation into the preview benefit in visual search.
In preview search, half of the distracters are presented ahead of the remaining distracters and the target. Search under these conditions is more efficient than when all the items appear together (Watson & Humphreys, 1997). We investigated the mechanisms contributing to this preview benefit using an orientation discrimination task. In a display of vertical Gabors (all equidistant from fixation) one Gabor (chosen at random) was tilted (left or right). When half the non-tilted Gabors were previewed, thresholds increased less with the number of Gabors, relative to when all the Gabors appeared together (a preview benefit). In a further experiment, orientation noise was added to some of the Gabors. When all Gabors were presented simultaneously, orientation thresholds for the target increased. The effects of noise on thresholds was reduced, however, when the noisy Gabors were presented as a preview. Furthermore, there was less effect of noise in the preview condition than when observers were cued to a subset of Gabors (with a cue presented prior to the Gabors, adjacent to their positions). Visual information can be effectively excluded from the previewed locations to a greater degree than when attention is directed to a subset of display items. The implications for understanding the mechanisms involved in preview search are discussed.


Wnts, signaling and sulfates.
Questions remain about the signaling pathways that control pattern formation during development. Blair describes how sulfated glycosaminoglycans affect several developmentally important signaling pathways, including Wnt-Wingless, Fibroblast growth factor, Hedgehog, and Bone morphogenetic protein-4 signaling. A new secreted sulfatase, Qsulf1, regulates the sensitivity of vertebrate cells to Wnts, possibly by modifying the sulfation of glycosaminoglycans.


Modification of the Gastric Mucosal Microbiota by a Strain-Specific Helicobacter pylori Oncoprotein and Carcinogenic Histologic Phenotype.
Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma; however, most infected individuals never develop this malignancy. Strain-specific microbial factors, such as the oncoprotein CagA, as well as environmental conditions, such as iron deficiency, augment cancer risk. Importantly, dysbiosis of the gastric microbiota is also associated with gastric cancer. To investigate the combinatorial effects of these determinants in an in vivo model of gastric cancer, Mongolian gerbils were infected with the carcinogenic cag+H. pylori strain 7.13 or a 7.13 cagA isogenic mutant, and microbial DNA extracted from gastric tissue was analyzed by 16S rRNA sequencing. Infection with H. pylori significantly increased gastric inflammation and injury, decreased α-diversity, and altered microbial community structure in a cagA-dependent manner. The effect of iron deficiency on gastric microbial communities was also investigated within the context of infection. H. pylori-induced injury was augmented under conditions of iron deficiency, but despite differences in gastric pathology, there were no significant differences in α- or β-diversity, phyla, or operational taxonomic unit (OTU) abundance among infected gerbils maintained on iron-replete or iron-depleted diets. However, when microbial composition was stratified based solely on the severity of histologic injury, significant differences in α- and β-diversity were present among gerbils harboring premalignant or malignant lesions compared to gerbils with gastritis alone. This study demonstrates that H. pylori decreases gastric microbial diversity and community structure in a cagA-dependent manner and that as carcinogenesis progresses, there are corresponding alterations in community structure that parallel the severity of disease.IMPORTANCE Microbial communities are essential for the maintenance of human health, and when these communities are altered, hosts can become susceptible to inflammation and disease. Dysbiosis contributes to gastrointestinal cancers, and specific bacterial species are associated with this phenotype. This study uses a robust and reproducible animal model to demonstrate that H. pylori infection induces gastric dysbiosis in a cagA-dependent manner and further that dysbiosis and altered microbial community structure parallel the severity of H. pylori-induced gastric injury. Ultimately, such models of H. pylori infection and cancer that can effectively evaluate multiple determinants simultaneously may yield effective strategies for manipulating the gastric microbiota to prevent the development of gastric cancer.


Analysis of the bacterial strains isolated from urine samples of hospitalized and ambulatory patients.
Bacteria of Enterococcus spp. are now much more often isolated from various diagnostic materials in systemic infection, both in hospitalized and in ambulatory patients. The study included 571 enterococci strains isolated from urine in 1997. Species identification was performed by rapid ID32 STREP test (bioMérieux) for 327 analyzed strains. Enterococcus faecalis and Enterococcus faecium dominated (46.1% and 11.2%, respectively). Over 42% of strains were isolated from urine of patients with non-significant bacteriuria or as concomitant flora. In such cases, simplified identification was performed and the strains were determined as Enterococcus spp. The microorganisms analyzed originated primarily from the urine samples of patients hospitalized at the Department of Urology (41.8%), the Department of Neurology (11.9%) and the Department of Internal Medicine and Nephrology (9.9%). Enterococcus faecalis strains were second with respect to population count (263--10.6%), after Escherichia coli strains (464--18.8%), while Enterococcus faecium strains were the sixth (64--2.5%). Enterococcus genus took the first place among all microorganisms isolated from the urine samples. Antibiotic-sensitivity was determined for 323 enterococci strains originating from hospitalized and ambulatory patients. Enterococcus faecium strains, naturally resistant to beta-lactam antibiotics, were sensitive to nitrofuranoin in more than 50% and to norfloxacin in about 20%. Among 254 analyzed Enterococcus faecalis strains, 80.0% were sensitive to ampicillin, nitrofurantoin and high concentrations of gentamicin as well as streptomycin. Enterococci strains isolated from hospitalized patients proved sensitive to ampicillin and carbapenems in 76.8%, while strains isolated from ambulatory patients were 100% sensitive to these drugs. Examination of enterococci isolated from urine of patients hospitalized showed 33.8% sensitive to norfloxacin and 84.6% sensitive to nitrofurantoin. All the enterococci strains were sensitive to glycopeptide antibiotics: vancomycin, teicoplanin.


Study Protocol of Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro).
The ongoing Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Microcarcinoma (MAeSTro) aims to observe the natural course of papillary thyroid microcarcinoma (PTMC), develop a protocol for active surveillance (AS), and compare the long-term prognosis, quality of life, and medical costs between the AS and immediate surgery groups. This multicenter prospective cohort study of PTMC started in June 2016. The inclusion criteria were suspicious of malignancy or malignancy based on fine needle aspiration or core needle biopsy, age of ≥18 years, and a maximum diameter of ≤1 cm. If there was no major organ involvement, no lymph node/distant metastasis, and no variants with poor prognosis, the patients were explained of the pros and cons of immediate surgery and AS before selecting AS or immediate surgery. Follow-up visits (physical examination, ultrasonography, thyroid function, and questionnaires) are scheduled every 6 months during the first 2 years, and then every 1 year thereafter. Progression was defined as a maximum diameter increase of ≥3, ≥2 mm in two dimensions, suspected organ involvement, or lymph node/distant metastasis. Among 439 enrolled patients, 290 patients (66.1%) chose AS and 149 patients (33.9%) chose immediate surgery. The median follow-up was 6.7 months (range, 0.2 to 11.9). The immediate surgery group had a larger maximum tumor diameter, compared to the AS group (7.1±1.9 mm vs. 6.6±2.0 mm, respectively; P=0.014). The results will be useful for developing an appropriate PTMC treatment policy based on its natural course and risk factors for progression.


Distinct signaling molecules control Hoxa-11 and Hoxa-13 expression in the muscle precursor and mesenchyme of the chick limb bud.
The limb muscles, originating from the ventrolateral portion of the somites, exhibit position-specific morphological development through successive splitting and growth/differentiation of the muscle masses in a region-specific manner by interacting with the limb mesenchyme and the cartilage elements. The molecular mechanisms that provide positional cues to the muscle precursors are still unknown. We have shown that the expression patterns of Hoxa-11 and Hoxa-13 are correlated with muscle patterning of the limb bud (Yamamoto et al., 1998) and demonstrated that muscular Hox genes are activated by signals from the limb mesenchyme. We dissected the regulatory mechanisms directing the unique expression patterns of Hoxa-11 and Hoxa-13 during limb muscle development. HOXA-11 protein was detected in both the myogenic cells and the zeugopodal mesenchymal cells of the limb bud. The earlier expression of HOXA-11 in both the myogenic precursor cells and the mesenchyme was dependent on the apical ectodermal ridge (AER), but later expression was independent of the AER. HOXA-11 expression in both myogenic precursor cells and mesenchyme was induced by fibroblast growth factor (FGF) signal, whereas hepatocyte growth factor/scatter factor (HGF/SF) maintained HOXA-11 expression in the myogenic precursor cells, but not in the mesenchyme. The distribution of HOXA-13 protein expression in the muscle masses was restricted to the posterior region. We found that HOXA-13 expression in the autopodal mesenchyme was dependent on the AER but not on the polarizing region, whereas expression of HOXA-13 in the posterior muscle masses was dependent on the polarizing region but not on the AER. Administration of BMP-2 at the anterior margin of the limb bud induced ectopic HOXA-13 expression in the anterior region of the muscle masses followed by ectopic muscle formation close to the source of exogenous BMP-2. In addition, NOGGIN/CHORDIN, antagonists of BMP-2 and BMP-4, downregulated the expression of HOXA-13 in the posterior region of the muscle masses and inhibited posterior muscle development. These results suggested that HOXA-13 expression in the posterior muscle masses is activated by the posteriorizing signal from the posterior mesenchyme via BMP-2. On the contrary, the expression of HOXA-13 in the autopodal mesenchyme was affected by neither BMP-2 nor NOGGIN/CHORDIN. Thus, mesenchymal HOXA-13 expression was independent of BMP-2 from polarizing region, but was under the control of as yet unidentified signals from the AER. These results showed that expression of Hox genes is regulated differently in the limb muscle precursor and mesenchymal cells.


Foundations for evidence-based intraoperative neurophysiological monitoring.
In this review, we recommend means to enhance the evidence-base for intraoperative neurophysiological monitoring (IONM). We address two preliminary issues: (1) whether IONM should be evaluated as a diagnostic test or an intervention, and (2) the state of the evidence for IONM (as presented in systematic reviews, for example). Three reasons may be suggested to evaluate at least some IONM applications as interventions (or as part of an "interventional cascade"). First, practical barriers limit our ability to measure IONM diagnostic accuracy. Second, IONM results are designed to be correlated with interventions during surgery. Third, IONM should improve patient outcomes when IONM-directed intervention alters the course of surgery. Observational evidence for IONM is growing yet more is required to understand the conditions under which IONM, in its variety of settings, can benefit patients. A multi-center observational cohort study would represent an important initial compromise between the pragmatic difficulties with conducting controlled trials in IONM and the Evidence-Based Medicine (EBM) view that large scale randomized trials are required. Such a cohort study would improve the evidence base and (if justified) provide the rationale for controlled trials.


B cell biology: an overview.
In this review we summarize recent insights into the development of human B cells primarily by studying immunodeficiencies. Development and differentiation of B cells can be considered as a paradigm for many other developmental processes in cell biology. However, it differs from the development of many other cell types by phases of extremely rapid cell division and by defined series of somatic recombination and mutation events required to assemble and refine the B cell antigen receptors. Both somatic DNA alteration and proliferation phases take place in defined sites but in different organs. Thus, cell migration and timely arrival at defined sites are additional features of B cell development. By comparing experimental mouse models with insights gained from studying defined genetic defects leading to primary immunodeficiencies and hypogammaglobulinemia, we address important features that are characteristic for human B cells. We also summarize recent advances made by developing improved in vitro and in vivo systems allowing the development of human B cells from hematopoietic stem cells. Combined with genetic and functional studies of immunodeficiencies, these models will contribute not only to a better understanding of disease affecting the B lymphocyte compartment, but also to designing better and safer novel B cell-targeted therapies in autoimmunity and allergy.


Systematic Review of the Use of Patient Reported Outcome Measures in Studies of Electively-Managed Hand Conditions.
Background: Electively-managed conditions account for over 100 000 inpatient surgeries a year in the English National Health Service alone, with further procedures in other regions of the UK, or performed on an outpatient basis. To quality assure this care and to conduct research, effective outcome measurement is critical. Traditional surgeon-centric outcome measures correlate poorly with hand function and are seldom important to patients. There has been an advent in the use of patient reported outcome measures (PROMs) in hand surgery although consensus of PROM choice appears to be lacking. This systematic review aimed to describe the use of relevant PROMs in clinical research of electively-managed hand conditions. Methods: A PRISMA-compliant methodology was used. A bespoke search strategy was developed in conjunction with a search strategist, and applied to Medline, EMBASE, CINAHL and PSYCHINFO from 1992 to June 2017. Pre-specified stepwise inclusion criteria were used to identify studies describing adult patients undergoing treatment for electively-managed hand conditions distal to the distal radius, with clinical outcomes measured using one or more PROMs. Results: Of 4554 results, 834 met inclusion criteria. PROMs identified included 9 disease-specific, 8 site-specific and 4 generic quality of life measures. Across all, the Disabilities of the Arm, Shoulder and Hand (DASH) was the most commonly used (overall frequency 41.0%). The most commonly reported disease-specific measure was the Boston Carpal Tunnel Questionnaire (overall frequency 23.0%). The most commonly reported generic quality of life of measure was the SF-36 (overall frequency 4%). Time-analysis demonstrated predominance of site-specific PROMs since the year 2000. Conclusions: Various PROMs have been used to study electively-managed hand conditions, with site-specific PROMs most popular. However, there appears to be limited consensus on choices. A future systematic evaluation of the published psychometric properties of identified PROMs may inform standardisation of measurement.


The evolution of sex chromosomes.
Structurally distinct sex chromosomes (X and Y) are the most familiar mode of genetic sex determination and have evolved independently in many different taxa. The evolutionary paths by which their characteristic properties may have evolved are reviewed. These properties include the failure of X and Y to recombine through much or all of their length, the genetic inertness of much of the Y chromosome, dosage compensation of the activity of X chromosomal loci, and the accumulation of repeated DNA sequences on the Y chromosome.


Facet-dependent trapping and dynamics of excess electrons at anatase TiO2 surfaces and aqueous interfaces.
Excess electrons from intrinsic defects, dopants and photoexcitation play a key role in many of the properties of TiO2. Understanding their behaviour is important for improving the performance of TiO2 in energy-related applications. We focus on anatase, the TiO2 polymorph most relevant in photocatalysis and solar energy conversion. Using first-principles simulations, we investigate the states and dynamics of excess electrons from different donors near the most common anatase (101) and (001) surfaces and aqueous interfaces. We find that the behaviour of excess electrons depends strongly on the exposed anatase surface, the environment and the character of the electron donor. Whereas no electron trapping is observed on the (101) surface in vacuo, an excess electron at the aqueous (101) interface can trigger water dissociation and become trapped into a stable surface Ti(3+)-bridging OH complex. By contrast, electrons avoid the (001) surface, indicating that oxidation reactions are favoured on this surface. Our results provide a bridge between surface science experiments and observations of crystal-face-dependent photocatalysis on anatase, and support the idea that optimization of the ratio between {101} and {001} facets could provide a way to enhance the photocatalytic activity of this material.


Childhood Obesity Is a Chronic Disease Demanding Specific Health Care--a Position Statement from the Childhood Obesity Task Force (COTF) of the European Association for the Study of Obesity (EASO).
Childhood obesity is one of the greatest health challenges of the 21st century. The EASO COTF is convinced that classifying obesity as a chronic disease in children and adolescents is a crucial step for increasing individual and societal awareness, and for improving early diagnosis and intervention. Such a classification will enhance the development of novel preventive and treatment approaches, health care policies and systems, and the education of healthcare workers. The management of obesity prior to the appearance of co-morbidities may prevent their escalation into significant medical and psychosocial problems, and reduce their economic and societal impact. Childhood is a unique window of opportunity to influence lifetime effects on health, quality of life, prevention of non-communicable chronic diseases and disabilities. The Convention on the Rights of the Child by UNICEF states that parties shall strive to ensure that no child is deprived of his or her right of access to health care services. The EASO COTF is aiming to address these issues via educational activities for health care workers, identification of research agendas, and the promotion of collaborations among clinicians, researchers, health institutions, organizations and states across Europe.


What makes a smiling face look happy? Visual saliency, distinctiveness, and affect.
We investigated the relative contribution of (a) perceptual (eyes and mouth visual saliency), (b) conceptual or categorical (eye expression distinctiveness), and (c) affective (rated valence and arousal) factors, and (d) specific morphological facial features (Action Units; AUs), to the recognition of facial happiness. The face stimuli conveyed truly happy expressions with a smiling mouth and happy eyes, or blended expressions with a smile but non-happy eyes (neutral, sad, fearful, disgusted, surprised, or angry). Saliency, distinctiveness, affect, and AUs served as predictors; the probability of judging a face as happy was the criterion. Both for truly happy and for blended expressions, the probability of perceiving happiness increased mainly as a function of positive valence of the facial configuration. In addition, for blended expressions, the probability of being (wrongly) perceived as happy increased as a function of (a) delayed saliency and (b) reduced distinctiveness of the non-happy eyes, and (c) enhanced AU 6 (cheek raiser) or (d) reduced AUs 4, 5, and 9 (brow lowerer, upper lid raiser, and nose wrinkler, respectively). Importantly, the later the eyes become visually salient relative to the smiling mouth, the more likely it is that faces will look happy.


Turnover of low density lipoproteins during inhibition of cholesterol absorption by neomycin.
The mechanisms for the hypocholesterolemic actin of neomycin were examined in six patients with various levels of plasma total cholesterol and triglycerides. All patients were studied on a metabolic ward. The first period of 6 weeks was for control. Thereafter, neomycin (1.5 g/day) was started, and the patients were readmitted for another 6-week period after 2 to 3 months of treatment with the drug. Cholesterol balance studies showed that neomycin increased fecal excretion of neutral steroids by an average of 45%; the drug also inhibited absorption of exogenous cholesterol by an average of 44%. During treatment with neomycin, the plasma total cholesterol fell by an average of 20%, low density lipoproteins (LDL) fell by 25%, and high density lipoproteins, by 16%. Neomycin did not change plasma triglyceride levels. Turnover of the apoprotein of LDL (apoLDL) was measured following injection of 125I-apoLDL. Neomycin decreased synthesis of apoLDL by 28%. The decrease in plasma apoLDL level was correlated positively with the decrease in apoLDL synthetic rate. The effect of the drug on clearance of LDL was less constant; four of six patients had an increase in fractional clearance rates of apoLDL, but the change for the whole group was not statistically significant. These data suggest that a decrease in production of LDL is a major factor in the lowering of LDL following inhibition of cholesterol absorption; however, an increase in clearance rates may occur in some patients.


The Essentials of Multiomics.
Within the last decade, the science of molecular testing has evolved from single gene and single protein analysis to broad molecular profiling as a standard of care, quickly transitioning from research to practice. Terms such as genomics, transcriptomics, proteomics, circulating omics, and artificial intelligence are now commonplace, and this rapid evolution has left us with a significant knowledge gap within the medical community. In this paper, we attempt to bridge that gap and prepare the physician in oncology for multiomics, a group of technologies that have gone from looming on the horizon to become a clinical reality. The era of multiomics is here, and we must prepare ourselves for this exciting new age of cancer medicine.


Effect of troglitazone on leptin production. Studies in vitro and in human subjects.
Leptin, the product of the ob gene, is a hormone secreted by adipocytes. Animals with mutations in the ob gene are obese and lose weight when given leptin, but little is known about the physiological role of leptin in humans. Obese subjects have higher concentrations of leptin than lean subjects, the strongest correlation being with percentage body fat. Thus, it appears that obese subjects are resistant to the effects of endogenously secreted leptin. We have also shown that insulin stimulates leptin production, chronically but not acutely, presumably through its trophic effect on adipocytes. Troglitazone is an insulin-sensitizing thiazolidinedione, which improves hepatic and skeletal muscle insulin resistance in NIDDM and obesity. This study was undertaken to investigate the effects of troglitazone on leptin production in vitro and in vivo. In the presence and absence of 100 nmol/l insulin and 10 umol/l troglitazone, 72-h primary cultures of isolated abdominal adipocytes were studied. Insulin led to an almost twofold increase in leptin in vitro, and this increase was completely abolished by coincubation with troglitazone. Incubation with troglitazone alone led to a 40% decrease in leptin production. In obese patients administered troglitazone 200 mg twice daily for 12 weeks, there was no significant change in fasting plasma leptin concentrations, despite a 40-50% reduction in fasting and postmeal plasma insulin concentrations. Troglitazone treatment led to a significant increase in insulin sensitivity, and there was a positive correlation between the change in insulin sensitivity and the change in plasma leptin concentration in these subjects. In conclusion, troglitazone treatment had no net effect on plasma leptin concentrations, possibly because of improvement in insulin sensitivity and reduction in plasma insulin concentrations.


Application of Microfluidics in Experimental Ecology: The Importance of Being Spatial.
Microfluidics is an emerging technology that is used more and more in biology experiments. Its capabilities of creating precisely controlled conditions in cellular dimensions make it ideal to explore cell-cell and cell-environment interactions. Thus, a wide spectrum of problems in microbial ecology can be studied using engineered microbial habitats. Moreover, artificial microfluidic ecosystems can serve as model systems to test ecology theories and principles that apply on a higher level in the hierarchy of biological organization. In this mini review we aim to demonstrate the versatility of microfluidics and the diversity of its applications that help the advance of microbiology, and in more general, experimental ecology.


Significant association between Helicobacter pylori infection and serum C-reactive protein.
Helicobacter pylori (H. pylori) infection in gastric mucosa may cause systemic inflammatory reaction. This study aimed to examine the association between the infection and serum high sensitivity C-reactive protein (hsCRP). Subjects were comprised of three groups; 453 health checkup examinees from Yakumo town inhabitants in Hokkaido, Japan (YTI, 153 males and 300 females), 449 health checkup examinees (ENUH, 273 males and 176 females), and 255 female patients of an infertility clinic (PIC), Nagoya University Hospital. Twenty participants with hsCRP more than 1 mg/dl were excluded from the analysis. Those with hsCRP more than 0.1mg/dl were defined as high hsCRP individuals. H. pylori infection status was examined with a serum IgG antibody test. When the three groups were combined, the geometric mean of hsCRP concentration was significantly higher among the seropositives (0.047 mg/dl) than among the seronegatives (0.035 mg/dl); p<0.0001 by a t-test. The percentage of high hsCRP individuals was also higher in the seropositives than in the seronegatives among any group; 23.3% and 20.1% in YTI, 22.0% and 16.0% in ENUH, and 32.7% and 18.7% in PIC, respectively, although the difference was significant only in ENUH. The summary odds ratio of the high hsCRP for the seropositives relative to the seronegatives was 1.38 (95% confidence interval, 1.01-1.89), when age, sex, body mass index, smoking, and subject group were adjusted by a logistic model. In three groups, hsCRP was higher among the infected individuals. The summary odd ratio indicated that H. pylori infection could influence the serum hsCRP level.


New vascular ring connectors in surgery for intramural haematoma of the abdominal aorta progressing to rupture.
Aortic intramural haematoma is similar to classic aortic dissection, which causes a life-threatening medical condition, and immediate diagnosis and treatment are crucial. The optimal therapy for intramural haematoma of the abdominal aorta remains controversial. Conservative medical management is usually the first choice of treatment for uncomplicated cases. Surgical intervention is usually required for complicated intramural haematomas of the abdominal aorta, including conventional open repair and endovascular treatment with stent-grafts. A new vascular ring connector that achieves a quick, blood-sealed and sutureless anastomosis has been designed for aortic dissection. We herein report a case of intramural haematoma of the abdominal aorta, progressing to rupture on day 14 after onset, which had successful aortic repair with the new vascular ring connector. The new vascular ring connector could be an alternative method for the treatment of complicated intramural haematomas of the abdominal aorta.


Role of fluorescence in situ hybridization in lung cancer cytology.
There are several challenges in lung cytology including equivocal cytological findings, lung cancer subclassification, and predictive marker analysis. Fluorescence in situ hybridization (FISH) detects chromosomal alterations that underlie the development and progression of cancer, and pinpoints targets of new anticancer drugs. Detection of such targets by FISH can be of diagnostic utility in morphologically difficult cases. Multitarget FISH with four different chromosomal probes improves the sensitivity of cytology in the diagnosis of lung cancer and clarifies equivocal cytological findings. FISH is becoming increasingly important in the field of predictive marker analysis. FISH is the gold standard to identify ALK rearrangements for treatment with the ALK inhibitor crizotinib (Xalkori). EGFR mutation analysis is the method of choice for selecting patients for therapy with EGFR tyrosine kinase inhibitors (TKIs), whereas the EGFR gene copy number has not been confirmed as a reliable predictive marker. MET amplification is an important mechanism of secondary resistance to EGFR TKIs and a candidate predictive marker for targeted second-line treatment of TKI-resistant non-squamous non-small cell lung cancer. FGFR1 amplification is a promising new marker in squamous cell carcinoma that may predict the response to FGFR1 inhibitors. In conclusion, there are an increasing number of clinically relevant FISH applications in lung cytology. We provide an overview on the current role of FISH in respiratory cytology.


The relation between adiposity throughout the life course and variation in IGFs and IGFBPs: evidence from the ProtecT (Prostate testing for cancer and Treatment) study.
Adiposity is positively associated with advanced, metastatic, and fatal prostate cancer. Obesity-related variations in insulin-like growth factors (IGF-I and -II) and their binding proteins (IGFBPs) could underlie these associations. We investigated associations of adiposity throughout the life course (determined retrospectively) with serum levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in a population-based study of 1,106 healthy men. IGF-I and IGF-II showed inverted U-shaped associations with adult body mass index (BMI) (p quadratic model = 0.04 and 0.06, respectively), although differences between quartiles with the highest and lowest IGF-I levels were small (no more than 5 ng/ml). IGFBP-2 was strongly inversely related to adult BMI (-22% change per SD increase in BMI; 95% confidence interval (CI) -24% to -19%) and waist circumference (-18% change per SD increase in waist circumference; 95% CI -20% to -15%) (p < 0.001). IGFBP-3 was positively related to BMI (63.5 ng/ml increase per SD increase in BMI; 95% CI -2.69 to 129.8, p = 0.06). IGFBP-2 and IGFBP-3 were strongly related to body shape change from childhood to adulthood, with men who gained the most weight having the lowest IGFBP-2 (9% lower per category body shape change; 95% CI -11% to -7%, p < 0.001) and the highest IGFBP-3 (50 ng/ml increase per category; 95% CI 8 to 92, p = 0.02). We provide evidence that adiposity and change in body shape through the life course are related to the IGF system, with the largest effect of adiposity being to lower IGFBP-2, a possible marker of insulin resistance. The results suggest that circulating IGF-I levels may not be important mediators of the association of adiposity with aggressive prostate cancer, but the role of IGFBP-2 deserves further investigation.


Participation of heparin binding proteins from the surface of Leishmania (Viannia) braziliensis promastigotes in the adhesion of parasites to Lutzomyia longipalpis cells (Lulo) in vitro.
Leishmania (V.) braziliensis is a causative agent of cutaneous leishmaniasis in Brazil. During the parasite life cycle, the promastigotes adhere to the gut of sandflies, to avoid being eliminated with the dejection. The Lulo cell line, derived from Lutzomyia longipalpis (Diptera: Psychodidae), is a suitable in vitro study model to understand the features of parasite adhesion. Here, we analyze the role of glycosaminoglycans (GAGs) from Lulo cells and proteins from the parasites in this event. Flagellar (Ff) and membrane (Mf) fractions from promastigotes were obtained by differential centrifugation and the purity of fractions confirmed by western blot assays, using specific antibodies for cellular compartments. Heparin-binding proteins (HBP) were isolated from both fractions using a HiTrap-Heparin column. In addition, binding of promastigotes to Lulo cells or to a heparin-coated surface was assessed by inhibition assays or surface plasmon resonance (SPR) analysis. The success of promastigotes subcellular fractionation led to the obtainment of Ff and Mf proteins, both of which presented two main protein bands (65.0 and 55.0 kDa) with affinity to heparin. The contribution of HBPs in the adherence of promastigotes to Lulo cells was assessed through competition assays, using HS or the purified HBPs fractions. All tested samples presented a measurable inhibition rate when compared to control adhesion rate (17 ± 2.0% of culture cells with adhered parasites): 30% (for HS 20 μg/ml) and 16% (for HS 10 μg/ml); HBP Mf (35.2% for 10 μg/ml and 25.4% for 20 μg/ml) and HBP Ff (10.0% for 10 μg/ml and 31.4% for 20 μg/ml). Additionally, to verify the presence of sulfated GAGs in Lulo cells surface and intracellular compartment, metabolic labeling with radioactive sulfate was performed, indicating the presence of an HS and chondroitin sulfate in both cell sections. The SPR analysis performed further confirmed the presence of GAGs ligands on L. (V.) braziliensis promastigote surfaces. The data presented here point to evidences that HBPs present on the surface of L. (V.) braziliensis promastigotes participate in adhesion of these parasites to Lulo cells through HS participation.


Interplay of individual interactions and turbidity affects the functional response of three-spined sticklebacks Gasterosteus aculeatus.
The effects of turbidity, size and the presence of conspecifics on the functional response, feeding latency and activity in the three-spined stickleback Gasterosteus aculeatus were examined. A significant interaction between standard length and presence of conspecifics demonstrated an increase in attack rates of larger individuals in the presence of conspecifics. Attack rate was also higher in turbid water. Feeding latency decreased with prey concentration and presence of conspecifics, but was not affected by turbidity. Activity level did not change with prey levels, but increased with turbidity. These results can help to better understand how individual flexibility in the functional response can affect prey mortality according to environmental perturbation and social interaction at the level of the predator.


Synthesis and biophysical evaluation of 2',4'-constrained 2'O-methoxyethyl and 2',4'-constrained 2'O-ethyl nucleic acid analogues.
We have recently shown that combining the structural elements of 2'O-methoxyethyl (MOE) and locked nucleic acid (LNA) nucleosides yielded a series of nucleoside modifications (cMOE, 2',4'-constrained MOE; cEt, 2',4'-constrained ethyl) that display improved potency over MOE and an improved therapeutic index relative to that of LNA antisense oligonucleotides. In this report we present details regarding the synthesis of the cMOE and cEt nucleoside phosphoramidites and the biophysical evaluation of oligonucleotides containing these nucleoside modifications. The synthesis of the cMOE and cEt nucleoside phosphoramidites was efficiently accomplished starting from inexpensive commercially available diacetone allofuranose. The synthesis features the use of a seldom used 2-naphthylmethyl protecting group that provides crystalline intermediates during the synthesis and can be cleanly deprotected under mild conditions. The synthesis was greatly facilitated by the crystallinity of a key mono-TBDPS-protected diol intermediate. In the case of the cEt nucleosides, the introduction of the methyl group in either configuration was accomplished in a stereoselective manner. Ring closure of the 2'-hydroxyl group onto a secondary mesylate leaving group with clean inversion of stereochemistry was achieved under surprisingly mild conditions. For the S-cEt modification, the synthesis of all four (thymine, 5-methylcytosine, adenine, and guanine) nucleobase-modified phosphoramidites was accomplished on a multigram scale. Biophysical evaluation of the cMOE- and cEt-containing oligonucleotides revealed that they possess hybridization and mismatch discrimination attributes similar to those of LNA but greatly improved resistance to exonuclease digestion.


Unveiling self-assembled monolayers' potential for molecular spintronics: spin transport at high voltage.
Molecular magnetic tunnel junctions using self-assembled monolayers (SAMs) as tunnel barriers show stable and efficient spin transport properties. Large tunnel magnetoresistance with a flat bias voltage dependence of the magnetoresistance is observed in La(2/3) Sr(1/3) MnO(3) /dodecylphosphonic acid SAM/Co nanocontacts. This opens the door to spintronic tailoring though SAM engineering and could also lead to new venues for spin injection in organic devices.


The backtracking survey propagation algorithm for solving random K-SAT problems.
Discrete combinatorial optimization has a central role in many scientific disciplines, however, for hard problems we lack linear time algorithms that would allow us to solve very large instances. Moreover, it is still unclear what are the key features that make a discrete combinatorial optimization problem hard to solve. Here we study random K-satisfiability problems with K=3,4, which are known to be very hard close to the SAT-UNSAT threshold, where problems stop having solutions. We show that the backtracking survey propagation algorithm, in a time practically linear in the problem size, is able to find solutions very close to the threshold, in a region unreachable by any other algorithm. All solutions found have no frozen variables, thus supporting the conjecture that only unfrozen solutions can be found in linear time, and that a problem becomes impossible to solve in linear time when all solutions contain frozen variables.


Bladder paraganglioma with renal agenesis: A possible new association and its implications in the light of REarranged in transfection gene genetics.
Pheochromocytoma/paraganglioma and renal agenesis are commonly reported conditions. Their coexistence, however, is rare, with few cases reported. We report the case of a 21-year-old male who presented with painless hematuria. He was found to have congenital absent right kidney along with bladder mass on imaging. Examination including blood pressure was normal. He underwent cystoscopy that showed a solid looking tumor on the anterior wall. Paraganglioma was suspected due to intraoperative rise in blood pressure during resection and was confirmed on histopathology. Subsequently after work up and preoperative alpha blockade, patient underwent partial cystectomy and excision of the paravesical mass. Histopathology showed paraganglioma confined to bladder wall with surgical margins free and a paravesical mass that was seminal vesicle cyst. On follow-up, patient is normotensive and asymptomatic. This coexistence of paraganglioma and renal agenesis may have a common genetic mechanism in the form of REarranged in Transfection (RET) gene mutation. This is a well-characterized gene, mutations of which are known to be associated with both conditions. Current knowledge of the role of RET gene in both conditions is reviewed to put forth RET mutation as the possible common underlying genetic mechanism along with possible clinical implications of the combination.


Salvage Carbon Ion Radiation Therapy for Locally Recurrent or Radiation-Induced Second Primary Sarcoma of the Head and Neck.
Purpose: Salvage radiation therapy (RT) is a potentially curative treatment option for head and neck sarcomas (HNS) that did not respond to previous treatment(s). We report the first clinical experience of carbon ion radiotherapy (CIRT) for salvage treatment of locally recurrent (LR) or RT-induced secondary HNS after surgery and/or radiotherapy. Methods and Materials: A retrospective analysis of the ongoing prospective data registries from the Shanghai Proton and Heavy Ion Center was conducted. Patients with LR-HNS who underwent surgery and/or RT and those with RT-induced second primary HNS were included. Acute and late toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0 and the Radiation Therapy Oncology Group late radiation toxicity scoring system, respectively. The actuarial 12-month local progression-free and overall survival rates (LPFS and OS) were calculated using the Kaplan-Meier method. Results: Between 10/2015 and 7/2017, 19 consecutive and non-selected patients with LR-HNS or RT-induced secondary HNS received definitive doses of CIRT delivered with pencil beam scanning technology for salvage. Six patients had locally recurrent soft-tissue sarcoma, and another 6 had chondrosarcoma. Among these 12 patients, 4 had received one prior course of RT. Seven additional patients had an RT-induced second primary soft tissue sarcoma (STS)/osteosarcoma after RT. The median time between the completion of initial treatment (either surgery only or surgery followed by adjuvant RT) and salvage CIRT was 30.6 months. The median follow-up time was 13.1 (range 1.6-41.1) months. All patients except one (for re-irradiation) completed the planned CIRT for salvage. The median dose of salvage CIRT was 60 GyE. Three patients developed local progression, and another 3 developed distant metastasis after salvage CIRT. Deaths occurred (3 patients) only in patients with radiation-induced second primary sarcoma at the time of analysis. The actuarial 12-month LPFS, DMFS and OS rates were 74.6%, 82.6% and 86.5%, respectively. Two patients irradiated for a second primary sarcoma had Grade 4 bleeding during CIRT, including one who experienced the rupture of an optic artery aneurysm unrelated to his disease or the salvage treatment. No patient had Grade 5 toxicity during treatment. Except for one patient who died of hemorrhage 3.5 months after the completion of CIRT, no moderate or severe late toxicities were observed. Conclusions: With few observed acute and late toxicities, salvage CIRT can provide effective short-term tumor control. Further research, preferably in a prospective fashion, will be required to confirm the efficacy and safety of salvage CIRT in this patient population.


Effects of Triclosan on Neural Stem Cell Viability and Survival.
Triclosan is an antimicrobial or sanitizing agent used in personal care and household products such as toothpaste, soaps, mouthwashes and kitchen utensils. There are increasing evidence of the potentially harmful effects of triclosan in many systemic and cellular processes of the body. In this study, we investigated the effects of triclosan in the survivability of cultured rat neural stem cells (NSCs). Cortical cells from embryonic day 14 rat embryos were isolated and cultured in vitro. After stabilizing the culture, triclosan was introduced to the cells with concentrations ranging from 1 μM to 50 μM and in varied time periods. Thereafter, cell viability parameters were measured using MTT assay and PI staining. TCS decreased the cell viability of treated NSC in a concentration-dependent manner along with increased expressions of apoptotic markers, cleaved caspase-3 and Bax, while reduced expression of Bcl2. To explore the mechanisms underlying the effects of TCS in NSC, we measured the activation of MAPKs and intracellular ROS. TCS at 50 μM induced the activations of both p38 and JNK, which may adversely affect cell survival. In contrast, the activities of ERK, Akt and PI3K, which are positively correlated with cell survival, were inhibited. Moreover, TCS at this concentration augmented the ROS generation in treated NSC and depleted the glutathione activity. Taken together, these results suggest that TCS can induce neurodegenerative effects in developing rat brains through mechanisms involving ROS activation and apoptosis initiation.


Resource-poor settings: response, recovery, and research: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement.
Planning for mass critical care in resource-poor and constrained settings has been largely ignored, despite large, densely crowded populations who are prone to suffer disproportionately from natural disasters. As a result, disaster response has been suboptimal and in many instances hampered by lack of planning, education and training, information, and communication. The Resource-Poor Settings panel developed five key question domains; defining the term resource poor and using the traditional phases of the disaster cycle (mitigation/preparedness/response/recovery). Literature searches were conducted to identify evidence to answer the key questions in these areas. Given a lack of data on which to develop evidence-based recommendations, expert-opinion suggestions were developed, and consensus was achieved using a modified Delphi process. The five key questions were as follows: definition, capacity building and mitigation, what resources can we bring to bear to assist/surge, response, and reconstitution and recovery of host nation critical care capabilities. Addressing these led the panel to offer 33 suggestions. Because of the large number of suggestions, the results have been separated into two sections: part I, Infrastructure/Capacity in the accompanying article, and part II, Response/Recovery/Research in this article. A lack of rudimentary ICU resources and capacity to enhance services plagues resource-poor or constrained settings. Capacity building therefore entails preventative strategies and strengthening of primary health services. Assistance from other countries and organizations is often needed to mount a surge response. Moreover, the disengagement of these responding groups and host country recovery require active planning. Future improvements in all phases require active research activities.


e-Photosynthesis: a comprehensive dynamic mechanistic model of C3 photosynthesis: from light capture to sucrose synthesis.
Photosynthesis is arguably the most researched of all plant processes. A dynamic model of leaf photosynthesis that includes each discrete process from light capture to carbohydrate synthesis, e-photosynthesis, is described. It was developed by linking and extending our previous models of photosystem II (PSII) energy transfer and photosynthetic C3 carbon metabolism to include electron transfer processes around photosystem I (PSI), ion transfer between the lumen and stroma, ATP synthesis and NADP reduction to provide a complete representation. Different regulatory processes linking the light and dark reactions are also included: Rubisco activation via Rubisco activase, pH and xanthophyll cycle-dependent non-photochemical quenching mechanisms, as well as the regulation of enzyme activities via the ferredoxin-theoredoxin system. Although many further feedback and feedforward controls undoubtedly exist, it is shown that e-photosynthesis effectively mimics the typical kinetics of leaf CO₂ uptake, O₂ evolution, chlorophyll fluorescence emission, lumen and stromal pH, and membrane potential following perturbations in light, [CO₂] and [O₂] observed in intact C3 leaves. The model provides a framework for guiding engineering of improved photosynthetic efficiency, for evaluating multiple non-invasive measures used in emerging phenomics facilities, and for quantitative assessment of strengths and weaknesses within the understanding of photosynthesis as an integrated process.


Integral and peripheral association of proteins and protein complexes with Yersinia pestis inner and outer membranes.
Yersinia pestis proteins were sequentially extracted from crude membranes with a high salt buffer (2.5 M NaBr), an alkaline solution (180 mM Na2CO3, pH 11.3) and membrane denaturants (8 M urea, 2 M thiourea and 1% amidosulfobetaine-14). Separation of proteins by 2D gel electrophoresis was followed by identification of more than 600 gene products by MS. Data from differential 2D gel display experiments, comparing protein abundances in cytoplasmic, periplasmic and all three membrane fractions, were used to assign proteins found in the membrane fractions to three protein categories: (i) integral membrane proteins and peripheral membrane proteins with low solubility in aqueous solutions (220 entries); (ii) peripheral membrane proteins with moderate to high solubility in aqueous solutions (127 entries); (iii) cytoplasmic or ribosomal membrane-contaminating proteins (80 entries). Thirty-one proteins were experimentally associated with the outer membrane (OM). Circa 50 proteins thought to be part of membrane-localized, multi-subunit complexes were identified in high Mr fractions of membrane extracts via size exclusion chromatography. This data supported biologically meaningful assignments of many proteins to the membrane periphery. Since only 32 inner membrane (IM) proteins with two or more predicted transmembrane domains (TMDs) were profiled in 2D gels, we resorted to a proteomic analysis by 2D-LC-MS/MS. Ninety-four additional IM proteins with two or more TMDs were identified. The total number of proteins associated with Y. pestis membranes increased to 456 and included representatives of all six beta-barrel OM protein families and 25 distinct IM transporter families.


Strategy-dependent encoding of planned arm movements in the dorsal premotor cortex.
The kinematic strategy encoded in motor cortical areas for classic straight-line reaching is remarkably simple and consistent across subjects, despite the complicated musculoskeletal dynamics that are involved. As tasks become more challenging, however, different conscious strategies may be used to improve perceived behavioral performance. We identified additional spatial information that appeared both in single neurons and in the population code of monkey dorsal premotor cortex when obstacles impeded direct reach paths. The neural correlate of movement planning varied between subjects in a manner consistent with the use of different strategies to optimize task completion. These distinct planning strategies were manifested in the timing and strength of the information contained in the neural population code.


Lucitanib for the Treatment of HR+/HER2- Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study.
The FGFR1 gene is amplified in 14% of patients with HR + /HER2 - breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/β, were assessed. Patients with HR + /HER2 - metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) FGFR1 amplified, (ii) FGFR1 nonamplified, 11q13 amplified, and (iii) FGFR1 and 11q13 nonamplified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. FGFR1 copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC. Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%-35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%-18%) and 15% (95% CI, 6%-34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high FGFR1 amplification (≥4 CNV) than those without high amplification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers. Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR + /HER2 - MBC. Although based on small sample sizes, exploratory biomarker analyses suggested that patients with high FGFR1 amplification or expression might derive greater benefit.