Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism.
Molecular subtyping of breast cancer is necessary for therapy selection and mandatory for all breast cancer patients. Metabolic alterations are considered a hallmark of cancer and several metabolic drugs are currently being investigated in clinical trials. However, the dependence of metabolic alterations on breast cancer subtypes has not been investigated on -omics scale. Thus, 204 estrogen receptor positive (ER+) and 67 estrogen receptor negative (ER-) breast cancer tissues were investigated using GC-TOFMS based metabolomics. 19 metabolites were detected as altered in a predefined training set (2/3 of tumors) and could be validated in a predefined validation set (1/3 of tumors). The metabolite changes included increases in beta-alanine, 2-hydroyglutarate, glutamate, xanthine and decreases in glutamine in the ER- subtype. Beta-alanine demonstrated the strongest change between ER- and ER+ breast cancer (fold change=2.4, p=1.5E-20). In a correlation analysis with genome-wide expression data in a subcohort of 154 tumors, we found a strong negative correlation (Spearman R=-0.62) between beta-alanine and 4-aminobutyrate aminotransferase (ABAT). Immunohistological analysis confirmed down-regulation of the ABAT protein in ER- breast cancer. In a Kaplan-Meier analysis of a large external expression data set, the ABAT transcript was demonstrated to be a positive prognostic marker for breast cancer (HR=0.6, p=3.2E-15). It is well-known for more than a decade that breast cancer exhibits distinct gene expression patterns depending on the molecular subtype defined by estrogen receptor (ER) and HER2 status. Here, we show that breast cancer exhibits distinct metabolomics patterns depending on ER status. Our observation supports the current view of ER+ breast cancer and ER- breast as different diseases requiring different treatment strategies. Metabolic drugs for cancer including glutaminase inhibitors are currently under development and tested in clinical trials. We found glutamate enriched and glutamine reduced in ER- breast cancer compared to ER+ breast cancer and compared to normal breast tissues. Thus, metabolomics analysis highlights the ER- subtype as a preferential target for glutaminase inhibitors. For the first time, we report on a regulation of beta-alanine catabolism in cancer. In breast cancer, ABAT transcript expression was variable and correlated with ER status. Low ABAT transcript expression was associated with low ABAT protein expression and high beta-alanine concentration. In a large external microarray cohort, low ABAT expression shortened recurrence-free survival in breast cancer, ER+ breast cancer and ER- breast cancer.


Direct monitoring of spin transitions in a dinuclear triple-stranded helicate iron(ii) complex through X-ray photoelectron spectroscopy.
A dinuclear helical iron(ii) complex of a new ditopic thiazolylimine ligand (L) has been synthesised via supramolecular assembly. The resulting dinuclear helical cylinder [Fe2L3]·4BF4 was investigated by variable temperature X-ray crystallography, ESI high resolution mass spectrometry, CHN analysis, FT-IR and UV-Vis spectroscopy. The nature of the spin transition was investigated by magnetic susceptibility measurements, and confirmed by VT-SCXRD and X-ray photoelectron spectroscopy. [Fe2L3]·4BF4 displays a complete spin transition with a gradual-abrupt character at T1/2 = 348 K and represents a new example of a dinuclear iron(ii) complex exhibiting a spin transition at high temperature. Both VT-SCXRD and XPS measurements show excellent correlation with the magnetic susceptibility experiments, demonstrating the power of XPS not just to confirm, but also to clearly follow the spin-state transition in Fe(ii) SCO complexes.


Theoretical evaluation of measurement uncertainties of two-color pyrometry applied to optical diagnostics.
We present a theoretical analysis of two-color pyrometry applied to optical diagnostics. A two-color pyrometer built with a single CCD is advantageous due to the simple system design. We evaluate the possibility and degree of ill-conditionness on the basis of measurement uncertainties for different measurement approaches of this two-color system. We classify measurement approaches. The corresponding ill-conditionness criterion is established. The greater the criterion value is, the worse the ill-conditioned degree of solution is. So, the optimum choice of measurement approach for the two-color system is achieved through intercomparison of the criterion values. Numerical examples are also given to illustrate this point. The theoretical analysis not only provides an effective way of evaluating different measurement approaches, but also may help us to better understand the influences that determine the choices between wavelength/waveband measurements and calibration/noncalibration modes for temperature and soot distribution.


Putting Meaning into Meaningful Use: A Roadmap to Successful Integration of Evidence at the Point of Care.
Pressures to contain health care costs, personalize patient care, use big data, and to enhance health care quality have highlighted the need for integration of evidence at the point of care. The application of evidence-based medicine (EBM) has great promise in the era of electronic health records (EHRs) and health technology. The most successful integration of evidence into EHRs has been complex decision tools that trigger at a critical point of the clinical visit and include patient specific recommendations. The objective of this viewpoint paper is to investigate why the incorporation of complex CDS tools into the EMR is equally complex and continues to challenge health service researchers and implementation scientists. Poor adoption and sustainability of EBM guidelines and CDS tools at the point of care have persisted and continue to document low rates of usage. The barriers cited by physicians include efficiency, perception of usefulness, information content, user interface, and over-triggering. Building on the traditional EHR implementation frameworks, we review keys strategies for successful CDSs: (1) the quality of the evidence, (2) the potential to reduce unnecessary care, (3) ease of integrating evidence at the point of care, (4) the evidence's consistency with clinician perceptions and preferences, (5) incorporating bundled sets or automated documentation, and (6) shared decision making tools. As EHRs become commonplace and insurers demand higher quality and evidence-based care, better methods for integrating evidence into everyday care are warranted. We have outlined basic criteria that should be considered before attempting to integrate evidenced-based decision support tools into the EHR.


Structural aspects of surfactant selection for the design of vegetable oil semi-synthetic metalworking fluids.
This paper presents a set of surfactant-selection guidelines that can be used to design bio-based semi-synthetic metalworking fluid (MWF) microemulsions as a renewable alternative to conventional petroleum formulations. Ten surfactant classes (six anionic and four nonionic) with different head and tail structures and three vegetable base oils (canola oil, soybean oil, and a fatty acid trimethylolpropane ester) were investigated as representatives of oil and surfactant options currently under consideration in the MWF industry. All combinations of these surfactants and oils were formulated at the full range of oil to surfactant ratios and surfactant concentrations. The stability of each formulation was evaluated based on visual transparency, light transmittance, and droplet diameter. The experimental results yield the following guidelines that produce stable bio-based MWF microemulsions with minimum necessary concentrations of surfactants: (1) a combination of two surfactants, one nonionic and one water soluble co-surfactant (either nonionic or anionic) is preferred over a single surfactant; (2) the nonionic surfactant should have a carbon tail length greater than or equal to the nominal carbon chain length of the fatty acids in the oil as well as a head group that is not excessively small or large (e.g., 10-20 ethylene oxide groups for a polysorbitan ester, ethoxylated alcohol, or ethoxylated glyceryl ester); (3) the difference in tail lengths between the surfactant and the co-surfactant should be less than 6 to maximize the feasible range of oil to surfactant ratios yielding stable emulsions. These guidelines are consistent with general results of micelle solubilization theory and evidence is provided to suggest that common semi-synthetic MWF systems can be thought of as swollen micelle systems.


One-dimensional electrical contact to a two-dimensional material.
Heterostructures based on layering of two-dimensional (2D) materials such as graphene and hexagonal boron nitride represent a new class of electronic devices. Realizing this potential, however, depends critically on the ability to make high-quality electrical contact. Here, we report a contact geometry in which we metalize only the 1D edge of a 2D graphene layer. In addition to outperforming conventional surface contacts, the edge-contact geometry allows a complete separation of the layer assembly and contact metallization processes. In graphene heterostructures, this enables high electronic performance, including low-temperature ballistic transport over distances longer than 15 micrometers, and room-temperature mobility comparable to the theoretical phonon-scattering limit. The edge-contact geometry provides new design possibilities for multilayered structures of complimentary 2D materials.


Ceftriaxone-resistant salmonella infection acquired by a child from cattle.
The emergence of resistance to antimicrobial agents within the salmonellae is a worldwide problem that has been associated with the use of antibiotics in livestock. Resistance to ceftriaxone and the fluoroquinolones, which are used to treat invasive salmonella infections, is rare in the United States. We analyzed the molecular characteristics of a ceftriaxone-resistant strain of Salmonella enterica serotype typhimurium isolated from a 12-year-old boy with fever, abdominal pain, and diarrhea. We used pulsed-field gel electrophoresis and analysis of plasmids and beta-lactamases to compare the ceftriaxone-resistant S. enterica serotype typhimurium from the child with four isolates of this strain obtained from cattle during a local outbreak of salmonellosis. The ceftriaxone-resistant isolate from the child was indistinguishable from one of the isolates from cattle, which was also resistant to ceftriaxone. Both ceftriaxone-resistant isolates were resistant to 13 antimicrobial agents; all but one of the resistance determinants were on a conjugative plasmid of 160 kb that encoded the functional group 1 beta-lactamase CMY-2. Both ceftriaxone-resistant isolates were closely related to the three other salmonella isolates obtained from cattle, all of which were susceptible to ceftriaxone. This study provides additional evidence that antibiotic-resistant strains of salmonella in the United States evolve primarily in livestock. Resistance to ceftriaxone, the drug of choice for invasive salmonella disease, is a public health concern, especially with respect to children, since fluoroquinolones, which can also be used to treat this disease, are not approved for use in children.


Avocado Oil Extract Modulates Auditory Hair Cell Function through the Regulation of Amino Acid Biosynthesis Genes.
Sensorineural hearing loss (SNHL) is one of the most common causes of disability, affecting over 466 million people worldwide. However, prevention or therapy of SNHL has not been widely studied. Avocado oil has shown many health benefits but it has not yet been studied in regards to SNHL. Therefore, we aimed to investigate the efficacy of avocado oil on SNHL in vitro and in vivo and elucidate its mode of action. For the present study, we used enhanced functional avocado oil extract (DKB122). DKB122 led to recovery of otic hair cells in zebrafish after neomycin-induced otic cell damage. Also, DKB122 improved auditory sensory transmission function in a mouse model of noise induced-hearing loss and protected sensory hair cells in the cochlea. In addition, RNA sequencing was performed to elucidate the mechanism involved. KEGG pathway enrichment analysis of differentially expressed genes showed that DKB122 protected House Ear Institute-Organ of Corti 1 (HEI-OC1) cells against neomycin-related alterations in gene expression due to oxidative stress, cytokine production and protein synthesis.


Reproductive health of bass in the Potomac, U.S.A., drainage: part 2. Seasonal occurrence of persistent and emerging organic contaminants.
The seasonal occurrence of organic contaminants, many of which are potential endocrine disruptors, entering the Potomac River, USA, watershed was investigated using a two-pronged approach during the fall of 2005 and spring of 2006. Passive samplers (semipermeable membrane device and polar organic chemical integrative sampler [POCIS]) were deployed in tandem at sites above and below wastewater treatment plant discharges within the watershed. Analysis of the samplers resulted in detection of 84 of 138 targeted chemicals. The agricultural pesticides atrazine and metolachlor had the greatest seasonal changes in water concentrations, with a 3.1- to 91-fold increase in the spring compared with the level in the previous fall. Coinciding with the elevated concentrations of atrazine in the spring were increasing concentrations of the atrazine degradation products desethylatrazine and desisopropylatrazine in the fall following spring and summer application of the parent compound. Other targeted chemicals (organochlorine pesticides, polycyclic aromatic hydrocarbons, and organic wastewater chemicals) did not indicate seasonal changes in occurrence or concentration; however, the overall concentrations and number of chemicals present were greater at the sites downstream of wastewater treatment plant discharges. Several fragrances and flame retardants were identified in these downstream sites, which are characteristic of wastewater effluent and human activities. The bioluminescent yeast estrogen screen in vitro assay of the POCIS extracts indicated the presence of chemicals that were capable of producing an estrogenic response at all sampling sites.


A role for Ca2+-sensitive nonselective cation channels in regulating the membrane potential of pancreatic beta-cells.
The incretin hormones, glucagon-like peptide 1 and pituitary adenylyl cyclase-activating polypeptide, are proposed to activate a maitotoxin (MTX)-sensitive, Ca2+-dependent nonselective cation current in pancreatic beta-cells and insulinoma cells. This MTX-sensitive current is present in human beta-cells as well as in mouse and rat beta-cells, and is accompanied by a rise in cytosolic Ca2+ in voltage-clamped cells in which the activation of voltage-dependent Ca2+ channels is prevented. Activation of the nonselective cation current is inhibited by reduction of disulfide bonds with intracellular, but not extracellular, dithiothreitol, and is also abolished by intracellular dialysis with trypsin. The nonselective cation channels that carry this current have a conductance of about 30 pS, with Na+ as the major extracellular cation. We estimate that these cation channels are expressed on beta-cells at a density similar to that of ATP-sensitive potassium channels (K(ATP) channels) and exhibit spontaneous activity at basal glucose concentrations. We propose that this spontaneous cation channel activity constitutes at least part of the depolarizing background conductance that permits changes in the activity of K(ATP) channels to regulate the resting potential of beta-cells.


The pathogenesis of primary internodal demyelination produced by acetyl ethyl tetramethyl tetralin: evidence for preserved Schwann cell somal function.
The pathogenesis of primary internodal PNS demyelination produced by acetyl ethyl tetramethyl tetralin (AETT) has been studied using subchronically intoxicated rats with intact sciatic nerves (right side), and with focally traumatized nerves (left side) undergoing myelin breakdown and repair. Sixteen Sprague-Dawley rats were given approximately 50 mg/kg/d of AETT, dissolved in ethanol and placed in food. Six age-matched control animals received daily an equivalent amount of food treated with the same volume of alcohol. After six weeks and prior to the onset of demyelination, AETT treatment had increased the number of visible Schmidt-Lanterman incisures per internode of large-diameter fibers in tibial nerves. By ten weeks, the same group of fibers had begun to develop juxtanodal and internodal myelin bubbles. Subsequently, intramyelinic phagocytes of hematogenous derivation removed entire internodes of edematous myelin. Schwann cell response to injury was studied in control and AETT-intoxicated animals which had undergone left hindlimb surgery 1 to 2 days after beginning toxin treatment: (a) a perineurial window was placed in the peroneal nerve to induce focal demyelination and remyelination, (b) the tibial nerve was transected between ligatures to study Wallerian degeneration of the distal stump, and (c) the sural nerve was focally crushed to induce axonal regeneration and myelination. Qualitatively similar responses to nerve injury were seen 1 to 16 weeks later in AETT-treated and control animals. These results are compatible with the view that AETT damages myelin directly, that Schwann cell somal functions are not seriously affected by AETT, and that Schmidt-Lanterman incisures undergo changes prior to demyelination, which may represent a physiological response of the Schwann cell to toxic attack on its myelin sheath. Taken in concern, these observations challenge the long-held view that primary internodal demyelination is necessarily indicative of metabolic dysfunction of the Schwann cell soma.


Healthcare Utilization and End-of-Life Outcomes in Patients Receiving CAR T-Cell Therapy.
CAR T-cell therapy has revolutionized the treatment of patients with hematologic malignancies, but it can result in prolonged hospitalizations and serious toxicities. However, data on the impact of CAR T-cell therapy on healthcare utilization and end-of-life (EoL) outcomes are lacking. We conducted a retrospective analysis of 236 patients who received CAR T-cell therapy at 2 tertiary care centers from February 2016 through December 2019. We abstracted healthcare utilization and EoL outcomes from the electronic health record, including hospitalizations, receipt of ICU care, hospitalization and receipt of systemic therapy in the last 30 days of life, palliative care, and hospice referrals. Most patients (81.4%; n=192) received axicabtagene ciloleucel. Overall, 28.1% of patients experienced a hospital readmission and 15.5% required admission to the ICU within 3 months of CAR T-cell therapy. Among the deceased cohort, 58.3% (49/84) were hospitalized and 32.5% (26/80) received systemic therapy in the last 30 days of life. Rates of palliative care and hospice referrals were 47.6% and 30.9%, respectively. In multivariable logistic regression, receipt of bridging therapy (odds ratio [OR], 3.15; P=.041), index CAR-T hospitalization length of stay >14 days (OR, 4.76; P=.009), hospital admission within 3 months of CAR T-cell infusion (OR, 4.29; P=.013), and indolent lymphoma transformed to diffuse large B-cell lymphoma (OR, 9.83; P=.012) were associated with likelihood of hospitalization in the last 30 days of life. A substantial minority of patients receiving CAR T-cell therapy experienced hospital readmission or ICU utilization in the first 3 months after CAR T-cell therapy, and most deceased recipients of CAR T-cell therapy received intensive EoL care. These findings underscore the need for interventions to optimize healthcare delivery and EoL care for this population.


Patterns and predictors of sexual activity among women in the Hormone Therapy trials of the Women's Health Initiative.
The aim of this study was to determine the patterns and predictors of sexual activity in the Hormone Therapy (HT) Trials of the Women's Health Initiative (WHI). Sexual activity questions were administered to 27,347 women ages 50 to 79 years at baseline and at year 1 and to a random 8.6% subsample at years 3 and 6. The associations with demographic and health characteristics were determined. Sexual activity at baseline was 60.7%, 44.9%, and 28.2% in the 50- to 59-, 60- to 69-, and 70- to 79-year-old age groups, respectively. Most of the participants were satisfied with their current sexual activity (63.2%). Of those dissatisfied, 57% preferred more sexual activity. Vaginal atrophy correlated with sexual inactivity at baseline (P < 0.001). The correlates associated with stopping sexual activity at year 1 included poor/fair self-rated health, lack of satisfaction with quality of life, depression, and loss of partner (P < 0.001). The strongest predictor of sexual activity at year 1 was sexual activity at baseline (odds ratio, 96.71; 95% CI, 81.90-114.20). A subset analysis of women adherent with HT or placebo at years 3 and 6 suggested that HT was associated with a higher percentage of participants reporting sexual activity (P = 0.01). Most women in the WHI HT Trials were satisfied with their sexual activity. Of those who were dissatisfied, the majority preferred more, rather than less, sexual activity. Vaginal atrophy at baseline correlated with sexual inactivity, and sexual activity at baseline was the strongest identified predictor of sexual activity at year 1. HT use was not predictive of ongoing sexual activity in the intent-to-treat analysis. This report further characterizes the participants in the WHI HT trials and reveals the complexity of factors related to the prevalence of sexual activity and satisfaction.


Reward fails to alter response bias in depression.
Several different models postulate that depression is associated with decreased approach-related behavior. Relatively little has been done to date to specifically investigate this issue. In the present study, a signal-detection analysis was used to examine the response biases of dysphoric and nondysphoric female undergraduates during 3 payoff conditions: neutral, reward, and punishment. As predicted, the dysphoric subjects had a smaller change in bias from the neutral to the reward condition compared with the nondysphoric group. The 2 groups did not differ during the neutral and punishment conditions. These findings are consistent with the hypothesis that the left frontal hypoactivation observed in depression reflects a deficit in approach-related behavior.


[Clinicopathologic characteristics of patients who underwent curative additional gastrectomy after endoscopic submucosal dissection for early gastric cancer or adenoma].
Endoscopic submucosal dissection (ESD) has been widely performed. However, procedure related-complications and the risk of tumor recurrence are limitations. We analyzed the clinicopathological characteristics of patients who underwent curative additional gastrectomy (gastrectomy) after ESD. The clinical characteristics of cases underwent gastrectomy after ESD were retrospectively analyzed. Between January 2002 and August 2010, 1,512 cases underwent ESD for early gastric cancer (n=511) or adenoma (n=1,001). Thirty-two cases (2.1%) underwent gastrectomy after ESD. Thirty cases (2.0%) were EGC and 2 cases (0.1%) were adenoma. Extended indication, larger tumor size and piecemeal resection were risk factors for gastrectomy after ESD. According to the causes of gastrectomy, 13 cases underwent gastrectomy due to complications (40.6%; bleeding in 9, perforation in 4), and 19 cases based on pathological results (incomplete resection in 13, lymphatic invasion in 6). In cases with incomplete resection, the rate of residual tumor and lymph node metastasis after gastrectomy was 69.2% (75% lateral margin, 60% deep and 75% both) and 7.7%, respectively. Three (50%) of the 6 cases with lymphatic invasion had lymph node metatstasis. The causes of gastrectomy after ESD were the procedure-related complications, the incomplete resection and lymphatic invasion. For complete and curative ESD, endoscopists should try to minimize complications and determine the depth of invasion accurately before ESD.


Serum concentrations and analgesic effects of liposome-encapsulated and standard butorphanol tartrate in parrots.
To compare serum concentrations of liposome-encapsulated butorphanol tartrate (LEBT) and standard butorphanol tartrate (STDBT) following SC and IM administration, respectively, and to evaluate analgesic effects of LEBT and STDBT after parenteral administration to Hispaniolan parrots. 11 adult Hispaniolan parrots. The ability of LEBT to prolong the duration of analgesia in an avian species was tested. Blood samples were collected at serial time points after SC administration of LEBT (10 mg/kg or 15 mg/kg) or IM administration of STDBT (5 mg/kg). Serum concentrations of butorphanol tartrate were determined by use of a commercial immunoassay that measured parent drug and metabolites. Analgesic efficacy was evaluated in parrots exposed to electrical and thermal stimuli. Foot withdrawal thresholds were recorded at baseline and at serial time points after LEBT (15 mg/kg), liposome vehicle, STDBT (2 mg/kg), or physiologic saline (0.9% NaCl) solution administration. LEBT had a prolonged in vivo release for up to 5 days. Negligible serum butorphanol and butorphanol metabolite concentrations were obtained at 24 hours after IM administration of STDBT. Analgesic efficacy of LEBT as measured by foot withdrawal threshold to noxious thermal and electrical stimuli persisted for 3 to 5 days following SC administration of LEBT. SC administration of LEBT provided analgesia and detectable serum butorphanol concentrations in Hispaniolan parrots for up to 5 days. The use of LEBT may allow for substantial improvement in long-term pain relief without subjecting birds to the stress of handling and multiple daily injections.


Accelerometer measured levels of moderate-to-vigorous intensity physical activity and sedentary time in children and adolescents with chronic disease: A systematic review and meta-analysis.
Moderate-to-vigorous physical activity (MVPA) and sedentary time (ST) are important for child and adolescent health. To examine habitual levels of accelerometer measured MVPA and ST in children and adolescents with chronic disease, and how these levels compare with healthy peers. Data sources: An extensive search was carried out in Medline, Cochrane library, EMBASE, SPORTDiscus and CINAHL from 2000-2017. Study selection: Studies with accelerometer-measured MVPA and/or ST (at least 3 days and 6 hours/day to provide estimates of habitual levels) in children 0-19 years of age with chronic diseases but without co-morbidities that would present major impediments to physical activity. In all cases patients were studied while well and clinically stable. Out of 1592 records, 25 studies were eligible, in four chronic disease categories: cardiovascular disease (7 studies), respiratory disease (7 studies), diabetes (8 studies), and malignancy (3 studies). Patient MVPA was generally below the recommended 60 min/day and ST generally high regardless of the disease condition. Comparison with healthy controls suggested no marked differences in MVPA between controls and patients with cardiovascular disease (1 study, n = 42) and type 1 diabetes (5 studies, n = 400; SMD -0.70, 95% CI -1.89 to 0.48, p = 0.25). In patients with respiratory disease, MVPA was lower in patients than controls (4 studies, n = 470; SMD -0.39, 95% CI -0.80, 0.02, p = 0.06). Meta-analysis indicated significantly lower MVPA in patients with malignancies than in the controls (2 studies, n = 90; SMD -2.2, 95% CI -4.08 to -0.26, p = 0.03). Time spent sedentary was significantly higher in patients in 4/10 studies compared with healthy control groups, significantly lower in 1 study, while 5 studies showed no significant group difference. MVPA in children/adolescents with chronic disease appear to be well below guideline recommendations, although comparable with activity levels of their healthy peers except for children with malignancies. Tailored and disease appropriate intervention strategies may be needed to increase MVPA and reduce ST in children and adolescents with chronic disease.


Dietary Patterns and 10-year (2002-2012) Incidence of Type 2 Diabetes: Results from the ATTICA Cohort Study.
To identify dietary patterns among apparently healthy individuals and to determine their long-term effect on diabetes incidence. During 2001-2002, a random sample of 3,042 men and women (18-89 years old), living in greater Athens, was randomly selected to participate in the study. During 2011-2012, the 10-year follow-up was performed in 2,583 participants (15% drop-out rate). After excluding participants with diabetes at baseline and those for whom no information on diabetes status was available at follow-up, the working sample consisted of 1,485 participants. Dietary habits were assessed by means of a validated semi-quantitative, food frequency questionnaire. Factor analysis was performed to extract dietary patterns from 18 food groups. Diabetes diagnosis at follow-up was made in 191 participants, yielding an incidence rate of 12.9%. Six factors (i.e. dietary patterns) were identified that explained 54% of the variation in consumption. After adjusting for major confounders, and stratification by age-group, logistic regression revealed that the most healthful pattern consisted of the consumption of fruits, vegetables, legumes, bread, rusk, and pasta which reduced the 10-year diabetes risk by 40%, among participants aged 45-55 years. The association reached marginal statistical significance (95% CI: 0.34, 1.07), while no significant association was observed for the other age-groups. When the analysis was additionally adjusted for carbohydrate percentage, statistical significance was lost completely, suggesting a possibly mediating effect of this macronutrient. The results confirm the potentially protective effect of a plant-based dietary pattern in the primary prevention of diabetes, in particular among middle-aged people. Carbohydrate content may be a specific factor in this relationship; other micronutrients found in plant-based food groups may also play a role.


Metabolic and cardiovascular outcomes of bariatric surgery.
Bariatric surgery is an effective therapy for morbid obesity that also improves weight-related metabolic parameters and reduces morbidity and mortality. The purpose of this review is to consolidate our current understanding of metabolic, macrovascular and microvascular benefits of bariatric surgery and to provide an update. Early resolution of insulin resistance and type 2 diabetes mellitus (T2DM) varies by type of bariatric surgery and appears to be mediated by changes in secretion of gut hormones, metabolism of bile acids, expression of glucose transporters and the gut microbiome. Dyslipidaemia, atherosclerosis, microvascular complications of obesity and diabetes, systemic and tissue-level inflammation show evidence of regression and hypertension improves significantly after bariatric surgery. Bariatric surgery leads to improvements in obesity-related metabolic comorbidities such as dyslipidaemia, HDL functionality, hypertension, T2DM, insulin resistance and inflammation. It slows the atherosclerotic process and reduces cardiovascular and all-cause mortality. Recent data have demonstrated regression of the microvascular complications of obesity and diabetes including the regeneration of small nerve fibres. The magnitude of change in short-term metabolic effects depends on the surgical procedure whilst longer term effects are related to the amount of sustained excess weight loss.


Force-pCa relation and troponin T isoforms of rabbit myocardium.
We have previously reported the existence of at least four troponin T isoforms in rabbit ventricular muscle and described the changes in their distribution with development. In this report we test whether the proportions of the troponin T isoforms are related to the sensitivity of the myofilaments to calcium. We measured the force-pCa relations in 12 detergent-skinned ventricular strands of cardiac muscle from newborn (2-5-day-old) rabbits. We determined from each strand the amount of each troponin T isoform relative to the total amount of troponin T by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and densitometric scans of Western blots probed with a cardiac-specific troponin T monoclonal antibody, MAb 13-11. To assess the presence of different relative amounts of cardiac and slow skeletal troponin I among the strands, we determined the amount of cardiac troponin I relative to tropomyosin. We determined the Hill coefficient and the pCa for half-maximal force, pCa50, for each strand. pCa50 was related directly to the relative amount of troponin T2 (pslope = 0.037). Our results do not indicate a relation between the Hill coefficient and troponin T2. We also did not find a relation between pCa50 and the cardiac troponin I/tropomyosin ratio, which suggests that the correlation between pCa50 and troponin T2 was not a result of changes in the relative amounts of cardiac and slow skeletal muscle troponin I. Our findings indicate that a relation exists between the force-pCa characteristics of rabbit myocardium and the troponin T isoforms that it expresses, suggesting a role for troponin T in modulating the sensitivity of cardiac myofilaments to calcium.


Irreversible cell-cycle transitions are due to systems-level feedback.
The irreversibility of cell-cycle transitions is commonly thought to derive from the irreversible degradation of certain regulatory proteins. We argue that irreversible transitions in the cell cycle (or in any other molecular control system) cannot be attributed to a single molecule or reaction, but that they derive from feedback signals in reaction networks. This systems-level view of irreversibility is supported by many experimental observations.


Deep Sequencing of RNA from Blood and Oral Swab Samples Reveals the Presence of Nucleic Acid from a Number of Pathogens in Patients with Acute Ebola Virus Disease and Is Consistent with Bacterial Translocation across the Gut.
In this study, samples from the 2013-2016 West African Ebola virus outbreak from patients in Guinea with Ebola virus disease (EVD) were analyzed to discover and classify what other pathogens were present. Throat swabs were taken from deceased EVD patients, and peripheral blood samples were analyzed that had been taken from patients when they presented at the treatment center with acute illness. High-throughput RNA sequencing (RNA-seq) and bioinformatics were used to identify the potential microorganisms. This approach confirmed Ebola virus (EBOV) in all samples from patients diagnosed as acute positive for the virus by quantitative reverse transcription-PCR in deployed field laboratories. Nucleic acid mapping to Plasmodium was also used on the patient samples, confirming results obtained with an antigen-based rapid diagnostic test (RDT) conducted in the field laboratories. The data suggested that a high Plasmodium load, as determined by sequence read depth, was associated with mortality and influenced the host response, whereas a lower parasite load did not appear to affect outcome. The identifications of selected bacteria from throat swabs via RNA-seq were confirmed by culture. The data indicated that the potential pathogens identified in the blood samples were associated with translocation from the gut, suggesting the presence of bacteremia, which transcriptome data suggested may induce or aggravate the acute-phase response observed during EVD. Transcripts mapping to different viruses were also identified, including those indicative of lytic infections. The development of high-resolution analysis of samples from patients with EVD will help inform care pathways and the most appropriate general antimicrobial therapy to be used in a resource-poor setting. IMPORTANCE Our results highlight the identification of an array of pathogens in the blood of patients with Ebola virus disease (EVD). This has not been done before, and the data have important implications for the treatment of patients with EVD, particularly considering antibiotic stewardship. We show that EVD patients who were also infected with Plasmodium, particularly at higher loads, had more adverse outcomes than patients with lower levels of Plasmodium. However, the presence of Plasmodium did not influence the innate immune response, and it is likely that the presence of EBOV dominated this response. Several viruses other than EBOV were identified, and bacteria associated with sepsis were also identified. These findings were indicative of bacterial translocation across the gut during the acute phase of EVD.


Modeling the synergy of cofilin and Arp2/3 in lamellipodial protrusive activity.
Rapid polymerization of actin filament barbed ends generates protrusive forces at the cell edge, leading to cell migration. Two important regulators of free barbed ends, cofilin and Arp2/3, have been shown to work in synergy (net effect greater than additive). To explore this synergy, we model the dynamics of F-actin at the leading edge, motivated by data from EGF-stimulated mammary carcinoma cells. We study how synergy depends on the localized rates and relative timing of cofilin and Arp2/3 activation at the cell edge. The model incorporates diffusion of cofilin, membrane protrusion, F-actin capping, aging, and severing by cofilin and branch nucleation by Arp2/3 (but not G-actin recycling). In a well-mixed system, cofilin and Arp2/3 can each generate a large pulse of barbed ends on their own, but have little synergy; high synergy occurs only at low activation rates, when few barbed ends are produced. In the full spatially distributed model, both synergy and barbed-end production are significant over a range of activation rates. Furthermore, barbed-end production is greatest when Arp2/3 activation is delayed relative to cofilin. Our model supports a direct role for cofilin-mediated actin polymerization in stimulated cell migration, including chemotaxis and cancer invasion.


A rare coronary artery anomaly: duplication of right coronary artery with separate ostium on 64-row multidetector computed tomography.
Coronary artery anomalies are rare, and their incidence varies from 0.6% to 1.3%. Conventional angiography is a commonly used modality for the assessment of coronary artery anomalies, but it may not identify and define the anatomy of anomalous arteries due to the complexity of the course and three-dimensional orientation of the arteries. We present a rare case of duplicated right coronary artery (RCA) with separate ostium on 64-row multidetector computed tomography (MDCT). MDCT is better than conventional angiography in cases where selective catheterisation of either a single artery or ostium during catheter angiography has resulted in missing an important vessel. So far, 13 cases of duplicated RCA have been reported in the literature, and the features on MDCT were described only in three cases.


A spatially resolved network spike in model neuronal cultures reveals nucleation centers, circular traveling waves and drifting spiral waves.
We show that in model neuronal cultures, where the probability of interneuronal connection formation decreases exponentially with increasing distance between the neurons, there exists a small number of spatial nucleation centers of a network spike, from where the synchronous spiking activity starts propagating in the network typically in the form of circular traveling waves. The number of nucleation centers and their spatial locations are unique and unchanged for a given realization of neuronal network but are different for different networks. In contrast, if the probability of interneuronal connection formation is independent of the distance between neurons, then the nucleation centers do not arise and the synchronization of spiking activity during a network spike occurs spatially uniform throughout the network. Therefore one can conclude that spatial proximity of connections between neurons is important for the formation of nucleation centers. It is also shown that fluctuations of the spatial density of neurons at their random homogeneous distribution typical for the experiments in vitro do not determine the locations of the nucleation centers. The simulation results are qualitatively consistent with the experimental observations.


The effect of iron availability on transcription of the Neisseria meningitidis fHbp gene varies among clonal complexes.
Factor H binding protein (fHbp) is a major antigenic component of novel vaccines designed to protect against meningococcal disease. Prediction of the potential coverage of these vaccines is difficult, as fHbp is antigenically variable and levels of expression differ among isolates. Transcriptional regulation of the fHbp gene is poorly understood, although evidence suggests that oxygen availability is involved. In this study iron accessibility was found to affect fHbp transcription. However, regulation differed among meningococcal clonal complexes (ccs). For the majority of isolates, increased iron concentrations upregulated transcription. This effect was enhanced by the presence of a 181 bp insertion element upstream of fHbp, associated with isolates belonging to cc4 and cc5. Conversely, meningococci belonging to cc32 showed iron-repressed control of fHbp, as regulation was dominated by cotranscription with the iron-repressed upstream gene cbbA. These results highlight the complexity of fHbp regulation and demonstrate that control of transcription can vary among genetic lineages.


Seroprevalences of Toxoplasma gondii and Neospora caninum in pet rabbits in Japan.
The potential contamination of Toxoplasma gondii and Neospora caninum oocysts in the human environment is a concern from the public health viewpoint. However, estimation of their seroprevalences in humans cannot be performed in a manner that distinguishes between oocysts and tissue cysts as a source of infection. Rabbits are considered popular pet animals in Japan that can acquire natural infections by the aforementioned parasites only through the ingestion of oocysts. Therefore, this study was conducted to estimate the seroprevalences of T. gondii and N. caninum in pet rabbits in Japan as an indicator of the possible oocyst contamination in the environment surrounding human beings. Serum samples of 337 rabbits were examined by different serological methods. Enzyme-linked immunosorbent assays were performed to measure the titer of IgG and IgM antibodies. Samples revealed to be seropositive by ELISA were further analyzed by a latex agglutination test, Western blotting and an indirect immunofluorescence assay. The rates of seropositivity for T. gondii were 0.89% (3/337) and 0.29% (1/337) in IgG and IgM ELISA, respectively. SAG1 and SAG2 were detected as major antigens by the positive rabbit sera in Western blotting associated with strong staining observed by IFA in T. gondii tachyzoites. Regarding N. caninum, none of the serum samples showed a specific reaction in both Western blotting and the IFA. The results of this study indicate low seroprevalences of toxoplasmosis and neosporosis in pet rabbits in Japan, suggesting low oocyst contamination in the human environment.


Delineation and diagnostic criteria of Oral-Facial-Digital Syndrome type VI.
Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.


Changes produced by external radiation in parameters influencing intestinal permeability and microparticle uptake in vitro.
To determine the interaction between X-irradiation and in vitro intestinal microparticle uptake through Caco-2 epithelial cells. Caco-2 cells were cultured on 3 microm porous membranes for 21 days, X-irradiated with 2 Gy or sham-irradiated, then incubated for 5 or 30 min and exposed apically for 30 min to 2 microm latex microparticles. Measurements included cell dimensions, from confocal microscope 'optical slices'; transepithelial resistance (TER) for tight junction (TJ) permeability; particle aggregation; and particle numbers on (adsorbed), in (intraepithelial) and through (submembranous) the epithelium. Irradiation alone reduced TJ permeability more than sham-treatment, more so 5 min than 30 min after treatment. Irradiated epithelia were more permeable to particles than the equivalent sham-irradiated or previously untreated (particle only) groups: the latter two were similar. Irradiation altered adsorbed particle numbers and increased submembranous counts: particle uptake correlated best with cell height. 2 Gy X-irradiation increased particle uptake and translocation through the epithelium. This correlated well with the TJ opening seen after particle exposure in irradiated samples and changes in cell morphology. New data on cell dimensions underlined the similarity in particle uptake between this in vitro epithelium and that in an in vivo model, highlighting the translational significance of the work.


Combined MRI and ³¹P-MRS investigations of the ACTA1(H40Y) mouse model of nemaline myopathy show impaired muscle function and altered energy metabolism.
Nemaline myopathy (NM) is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. Mutations in the skeletal muscle α-actin gene (ACTA1) account for ∼25% of all NM cases and are the most frequent cause of severe forms of NM. So far, the mechanisms underlying muscle weakness in NM patients remain unclear. Additionally, recent Magnetic Resonance Imaging (MRI) studies reported a progressive fatty infiltration of skeletal muscle with a specific muscle involvement in patients with ACTA1 mutations. We investigated strictly noninvasively the gastrocnemius muscle function of a mouse model carrying a mutation in the ACTA1 gene (H40Y). Skeletal muscle anatomy (hindlimb muscles and fat volumes) and energy metabolism were studied using MRI and (31)Phosphorus magnetic resonance spectroscopy. Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (from 1-150 Hz) and a fatigue protocol (80 stimuli at 40 Hz). H40Y mice showed a reduction of both absolute (-40%) and specific (-25%) maximal force production as compared to controls. Interestingly, muscle weakness was associated with an improved resistance to fatigue (+40%) and an increased energy cost. On the contrary, the force frequency relationship was not modified in H40Y mice and the extent of fatty infiltration was minor and not different from the WT group. We concluded that the H40Y mouse model does not reproduce human MRI findings but shows a severe muscle weakness which might be related to an alteration of intrinsic muscular properties. The increased energy cost in H40Y mice might be related to either an impaired mitochondrial function or an alteration at the cross-bridges level. Overall, we provided a unique set of anatomic, metabolic and functional biomarkers that might be relevant for monitoring the progression of NM disease but also for assessing the efficacy of potential therapeutic interventions at a preclinical level.


Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure.
Although past reports have identified a variety of prognostic factors in patients with severe chronic heart failure, previous studies have not evaluated the interaction of prognostic variables and drug treatment. We analyzed the association of 30 clinical, hemodynamic, and biochemical variables with survival in 203 consecutive patients with severe heart failure; all variables were assessed just before initiation of treatment with a variety of vasodilator drugs, and all patients were subsequently followed for 6 to 94 months. By regression analysis, pretreatment serum sodium concentration was the most powerful predictor of cardiovascular mortality, with hyponatremic patients having a substantially shorter median survival than did patients with a normal serum sodium concentration (164 vs 373 days, p = .006). The unfavorable prognosis for hyponatremic patients appeared to be related to the marked elevation of plasma renin activity that we noted in these individuals (10.0 +/- 2.0 ng/ml/hr), since hyponatremic patients fared significantly better when treated with angiotensin converting-enzyme inhibitors than when treated with vasodilator drugs that did not interfere with angiotensin II biosynthesis (median survival 232 vs 108 days, p = .003). In contrast, there was no selective benefit of converting-enzyme inhibition on the survival of patients with a normal serum sodium concentration, in whom plasma renin activity was low (1.9 +/- 0.3 ng/ml/hr). This interaction between serum sodium concentration, drug treatment, and long-term outcome suggests that the renin-angiotensin system may exert a deleterious effect on the survival of some patients with chronic heart failure, which can be antagonized by converting enzyme inhibition, and provides a clinical counterpart for the similar prognostic role that has been postulated for angiotensin II in experimental preparations of heart failure.


The Tripartite Influence model of body image and eating disturbance: a covariance structure modeling investigation testing the mediational role of appearance comparison.
Recent theoretical approaches to the etiology of eating disorders and body image disturbances have begun to focus on multifactorial models. In the current study, the Tripartite Influence model was examined in a large sample of college females (ages 18-22). This model proposes that three primary core sources of influence--parents, peers and media--contribute to the development of body image and eating disturbances. Additionally, the model suggests that at least two factors mediate the relationship between influences and disturbance-appearance comparison and internalization of media information. In this study, appearance comparison was examined as a mediational link between peer, family and media influence variables and the outcome disturbance measures of eating dysfunction and body image dissatisfaction. Covariance structure modeling (CSM) was used to test the proposed pathways. The results indicated that appearance comparison mediated the effects of family and media influences on body dissatisfaction, which in turn influenced restrictive and bulimic behaviors. In addition, peer influences had a direct influence on restriction. Perfectionism was hypothesized to relate to body dissatisfaction, but was in fact found to influence appearance comparison. The findings were limited by the necessity of several modifications to the originally proposed models, yet offer replication and extension of previous work with appearance comparison and support for further testing of the Tripartite Influence model.


The Dogfish Scyliorhinus canicula: A Reference in Jawed Vertebrates.
INTRODUCTIONDue to their large size and long generation times, chondrichthyans have been largely ignored by geneticists. However, their key phylogenetic position makes them ideal subjects to study the molecular bases of the important morphological and physiological innovations that characterize jawed vertebrates. Such analyses are crucial to understanding the origin of the complex genetic mechanisms unraveled in osteichthyans. The small spotted dogfish Scyliorhinus canicula, a representative of the largest order of extant sharks, presents a number of advantages in this context. Due to its relatively small size among sharks, its abundance, and easy maintenance, the dogfish has been an important model in comparative anatomy and physiology for more than a century. Recently, revived interest has occurred with the development of large-scale transcriptomic and genomic resources, together with the establishment of facilities allowing massive egg and embryo production. These new tools open the way to molecular analyses of the elaborate physiological and sensory systems used by sharks. They also make it possible to take advantage of unique characteristics of these species, such as organ zonation, in analyses of cell proliferation and differentiation. Finally, they offer important perspectives to evolutionary developmental biology that will provide a better understanding of the origin and diversifications of jawed vertebrates. The dogfish whole-genome sequence, which may shortly become accessible, should establish this species as an essential shark reference, complementary to other chondrichthyan models. These analyses are likely to reveal an organism of an underestimated complexity, far from the primitive prototypical gnathostome anticipated in gradistic views.


Interdigitating dendritic cell sarcoma. A report of four cases and review of the literature.
To better define the clinical and pathologic features of interdigitating dendritic cell sarcoma (IDCS), we report 4 cases, including the first reported in the tonsil. There were 2 male and 2 female patients (mean age, 70 years). Sites of tumor included 1 case each in the right cervical lymph node, left axillary lymph node, right tonsil, and right inguinal lymph node. Histologically, all showed diffuse effacement of the lymphoid tissue by pleomorphic round to spindled cells with convoluted nuclei and abundant eosinophilic cytoplasm. All were immunoreactive for S-100, CD68, lysozyme, and vimentin. CD45 was positive in 3 cases and CD1a in 1 case. Fascin was positive in 3 cases. Other immunostains, including CD3, CD20, CD21, CD30, actin, cytokeratin, and HMB-45, were negative. Ultrastructurally, the tumor cells were elongated and showed indented nuclei, variable numbers of lysosomes, and interdigitating cytoplasmic processes. Follow-up was available for all cases. One patient died of widespread disease 2 months after diagnosis. One was alive with metastatic lung disease at 12 months. Two patients were disease free at 5 and 9 months.


Revision of the sixgill sawsharks, genus Pliotrema (Chondrichthyes, Pristiophoriformes), with descriptions of two new species and a redescription of P. warreni Regan.
Recent sampling efforts in Madagascar and Zanzibar, as well as examinations of six-gilled sawsharks in several museum collections provided evidence for a complex of species within Pliotrema warreni Regan. The present manuscript contains a redescription of P. warreni involving the syntypes and additional material, as well as formal descriptions of two new species of Pliotrema Regan. All specimens of both new species were found in the western Indian Ocean. Individuals of the first new species, hereafter referred to as P. kajae sp. nov., were identified originating from Madagascar and the Mascarene Ridge. Specimens of the second new species, hereafter referred to as P. annae sp. nov., were only found off Zanzibar. Pliotrema kajae sp. nov. appears to inhabit upper insular slopes and submarine ridges at depths of 214-320 m, P. annae sp. nov. so far is only known from shallow waters (20-35 m). Both new species differ from P. warreni in a number of characteristics including the known distribution range and fresh coloration. Taxonomical differences include barbels that are situated approximately half way from rostral tip to mouth, with prebarbel length equidistant from barbel origin to symphysis of the upper jaw in P. kajae sp. nov. and P. annae sp. nov. (vs. about two thirds way from rostral tip to mouth, with prebarbel length about twice the distance from barbel origin to symphysis of upper jaw in P. warreni) and rostra that are clearly and slightly constricted between barbel origin and nostrils, respectively (vs. rostrum not constricted). Pliotrema kajae sp. nov. differs from P. annae sp. nov. in a longer snout, more numerous large lateral rostral teeth and upper jaw tooth rows, jaw teeth with (vs. without) sharp basal folds, and coloration, particularly pale to light brown (vs. medium to dark brown) dorsal coloration with (vs. without) two indistinct yellowish stripes. A revised diagnosis of Pliotrema and a key to the species are provided.


On the role of phase separation in the biogenesis of membraneless compartments.
Molecular mechanistic biology has ushered us into the world of life's building blocks, revealing their interactions in macromolecular complexes and inspiring strategies for detailed functional interrogations. The biogenesis of membraneless cellular compartments, functional mesoscale subcellular locales devoid of strong internal order and delimiting membranes, is among mechanistic biology's most demanding current challenges. A developing paradigm, biomolecular phase separation, emphasizes solvation of the building blocks through low-affinity, weakly adhesive unspecific interactions as the driver of biogenesis of membraneless compartments. Here, I discuss the molecular underpinnings of the phase separation paradigm and demonstrate that validating its assumptions is much more challenging than hitherto appreciated. I also discuss that highly specific interactions, rather than unspecific ones, appear to be the main driver of biogenesis of subcellular compartments, while phase separation may be harnessed locally in selected instances to generate material properties tailored for specific functions, as exemplified by nucleocytoplasmic transport.


Microfluidic amplification as a tool for massive parallel sequencing of the familial hypercholesterolemia genes.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder that affects cholesterol metabolism and is an important risk factor for heart disease. Three different genes were causally linked to this disorder: LDLR (low density lipoprotein receptor), APOB [apolipoprotein B (including Ag(x) antigen)], and PCSK9 (proprotein convertase subtilisin/kexin type 9). We evaluated a new amplicon preparation tool for resequencing these genes on next generation sequencing (NGS) platforms. For the 3 genes, 38 primer pairs were designed and loaded on the Fluidigm Access Array, a microfluidic array in which a PCR was performed. We amplified 144 DNA samples (73 positive controls and 71 patient samples) and performed 3 sequencing runs on a GS FLX Titanium system from Roche 454, using pyrosequencing. Data were analyzed with the SeqNext module of the Sequence Pilot software. From the 38 amplicons, 37 were amplified successfully, without any further optimization. Sequencing resulted in a mean coverage of the individual amplicons of 71-fold, 74-fold, and 117-fold for the 3 runs, respectively. In the positive controls, all known mutations were identified. In 29% of the patient samples, a pathogenic point mutation or small deletion/insertion was found. Large rearrangements were not detectable with NGS, but were picked up by multiplex ligation-dependent probe amplification. Combining a microfluidic amplification system with massive parallel sequencing is an effective method for mutation scanning in FH patients, which can be implemented in diagnostics. For data analysis, we propose a minimum variant frequency threshold of 20% and a minimum coverage of 25-fold.


Feeding ecology of Coryphaenoides rupestris from the mid-Atlantic Ridge.
The Macrourid fish roundnose grenadier, Coryphaenoides rupestris, is one of the most common benthopelagic fishes on the northern mid-Atlantic Ridge. The ecology of the species is comparatively well studied in continental slope waters of the North Atlantic, but not on the mid-Atlantic Ridge, which is a central mid-ocean area of its distribution. In total, 166 specimens from the RV G.O. Sars cruise in July 2004 were examined. The diet mainly comprised cephalopods, pelagic shrimps and fish. Pelagic and benthopelagic copepods were the most numerous prey, but did not contribute much on a weight basis. Cephalopods were by far the most important prey of the small grenadiers, while shrimps and fish became increasingly significant with increasing size. Previous studies from other areas have also found pelagic prey to be important, but in contrast to this study, cephalopods were generally of less importance. The study was an element of more wide-ranging food-web studies of the mid-Atlantic Ridge macro- and megafauna communities within the international MAR-ECO project.


Consensus formation on adaptive networks.
The structure of a network can significantly influence the properties of the dynamical processes that take place on them. While many studies have been paid to this influence, much less attention has been devoted to the interplay and feedback mechanisms between dynamical processes and network topology on adaptive networks. Adaptive rewiring of links can happen in real life systems such as acquaintance networks, where people are more likely to maintain a social connection if their views and values are similar. In our study, we consider different variants of a model for consensus formation. Our investigations reveal that the adaptation of the network topology fosters cluster formation by enhancing communication between agents of similar opinion, although it also promotes the division of these clusters. The temporal behavior is also strongly affected by adaptivity: while, on static networks, it is influenced by percolation properties, on adaptive networks, both the early and late time evolutions of the system are determined by the rewiring process. The investigation of a variant of the model reveals that the scenarios of transitions between consensus and polarized states are more robust on adaptive networks.


Nicotine differentially activates inhibitory and excitatory neurons in the dorsal spinal cord.
Nicotinic agonists have well-documented antinociceptive properties when administered subcutaneously or intrathecally in mice. However, secondary mild to toxic effects are observed at analgesic doses, as a consequence of the activation of the large family of differentially expressed nicotinic receptors (nAChRs). In order to elucidate the action of nicotinic agonists on spinal local circuits, we have investigated the expression and function of nAChRs in functionally identified neurons of neonate mice spinal cord. Molecular markers, amplified at the single-cell level by RT-PCR, distinguished two neuronal populations in the dorsal horn of the spinal cord: GABAergic/glycinergic inhibitory interneurons, and calbindin (CA) or NK1 receptor (NK1-R) expressing, excitatory interneurons and projection neurons. The nicotinic response to acetylcholine of single cells was examined, as well as the pattern of expression of nAChR subunit transcripts in the same neuron. Beside the most expressed subunits alpha4, beta2 and alpha7, the alpha2 subunit transcript was found in 19% of neurons, suggesting that agonists targeting alpha2* nAChRs may have specific actions at a spinal level without major supra-spinal effects. Both inhibitory and excitatory neurons responded to nicotinic stimulation, however, the nAChRs involved were markedly different. Whereas GABA/glycine interneurons preferentially expressed alpha4alpha6beta2* nAChRs, alpha3beta2alpha7* nAChRs were preferentially expressed by CA or NK1-R expressing neurons. Recorded neurons were also classified by firing pattern, for comparison to results from single-cell RT-PCR studies. Altogether, our results identify distinct sites of action of nicotinic agonists in circuits of the dorsal horn, and lead us closer to an understanding of mechanisms of nicotinic spinal analgesia.


Quantitative determination of atenolol in dried blood spot samples by LC-HRMS: a potential method for assessing medication adherence.
The use of blood spot collection cards was investigated as a means of obtaining small volume samples for the quantification of therapeutic drugs for assessing medication adherence. A liquid chromatography-high resolution TOF mass spectrometry (LC-HRMS) method, based on the measurement at the accurate mass to charge ratio of the target analyte, was used to ensure specificity for atenolol in the dried blood spot (DBS) samples. A working method was developed and validated. For the preparation of DBS samples whole blood spiked with analyte was used to produce 30 μl blood spots on specimen collection cards. A 5mm disc was cut from the dried blood spot and extracted using methanol:water (60:40, v/v) containing the internal standard, atenolol-d(7). Extracts were vortexed, sonicated and then centrifuged. Gradient chromatographic elution was achieved using an Ascentis Express C18 100mm×2.1mm column and a mobile phase flow rate of 0.2 ml/min and the column oven temperature at 30 °C. MS detection was carried out in electrospray positive ion mode for target ions at accurate mass m/z 267.1703 for atenolol and 274.2143 for the IS. Drug extraction efficiency from spiked blood spots was demonstrated to be 96±5% and the drug was stable in DBS for at least 10 weeks. The developed LC-HRMS method was linear within the tested calibration range of 25-1500 ng/ml and validation showed the accuracy (relative error) and precision (coefficient of variation) values were within the pre-defined limits of ≤ 5% at all concentrations with a limit of quantification of 25 ng/ml. Factors with potential to affect drug quantification measurements such as the matrix effects, volume of blood applied onto the collection card and effect of different sampling cards were investigated. The developed LC-HRMS method was applied to blood spots on sampling card taken from adult healthy volunteers previously administered a 50mg atenolol tablet and a DBS concentration-time profile was obtained for atenolol. Requiring only a micro volume (30 μl) blood sample for analysis, the developed DBS based assay has the potential to assess patient adherence to atenolol.


Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway.
Sulforaphane, a naturally occurring isothiocyanate present in cruciferous vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of sulforaphane at physiological concentrations remain unclear. Here, we report that a sulforaphane concentration as low as 0.5 μM significantly inhibited tumor necrosis factor-α (TNF-α)-induced adhesion of monocytes to human umbilical vein endothelial cells, a key event in the pathogenesis of atherosclerosis both in static and under flow conditions. Such physiological concentrations of sulforaphane also significantly suppressed TNF-α-induced production of monocyte chemotactic protein-1 and adhesion molecules including soluble vascular adhesion molecule-1 and soluble E-selectin, key mediators in the regulation of enhanced endothelial cell-monocyte interaction. Furthermore, sulforaphane inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, Inhibitor of NF-κB alpha (IκBα) degradation and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that sulforaphane can inhibit inflammation by suppressing NF-κB signaling. In an animal study, sulforaphane (300 ppm) in a mouse diet significantly abolished TNF-α-increased ex vivo monocyte adhesion and circulating adhesion molecules and chemokines in C57BL/6 mice. Histology showed that sulforaphane treatment significantly prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers' delicate organization, as shown by Verhoeff-van Gieson staining. Immunohistochemistry studies showed that sulforaphane treatment also reduced vascular adhesion molecule-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, sulforaphane at physiological concentrations protects against TNF-α-induced vascular endothelial inflammation, in both in vitro and in vivo models. This anti-inflammatory effect of sulforaphane may be, at least in part, associated with interfering with the NF-κB pathway.


Clinical Profile and Comorbidities Associated with Rheumatoid Arthritis Patients in Sudair, Saudi Arabia.
Rheumatoid arthritis (RA) is a chronic, debilitating condition that has a significant effect on the lives of patients, their families, and society at large. The aim is to determine the clinical profile and any comorbidities associated with RA patients in the Sudair region of Saudi Arabia. Sixty patients were included in this cross-sectional observational study, both newly or already diagnosed with RA, fulfilling the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for RA. They were followed up in the rheumatology clinic in King Khalid Majmaah Hospital in the Majmaah province from January 2017 to December 2020. The subjects' mean age was 47.87 ± 11.55 years, 52 female and 8 male (female-to-male ratio 6.5:1). About 23.3% of patients with RA had positive family history. The main comorbidities and associated diseases were hypertension (18.3%) and hypothyroidism (15%). The most frequently involved joints were the wrist, metacarpophalangeal, proximal interphalangeal, elbow, and knee joints. Subjects were positive in 66.7% for rheumatoid factor and 78.3% for anti-cyclic citrullinated peptide. Both markers were positive in 60% of the patients. Approximately one-quarter of the studied group had a family history of RA. Hypertension followed by hypothyroidism was the most common comorbidities reported in our study.


[Study on p53, mdm-2 and p21WAF1 protein expression in ER-positive and ER-negative human breast cancer cell lines and its relation to biological features].
To study p53, mdm-2 and p21WAF1 protein expression levels in ER-positive and ER-negative human breast cancer cell lines and their relations to biological features. Using cell culture, DNA stable transfection and immunohistochemical methods, the protein expression levels of p53, mdm-2 and WAF1 genes in ER-positive expressing wtp53 MCF-7 cells, ER-negative expressing mtp53 MDA-MB-231 cells and ER-transfected MDA-MB-231 cells were determined, and then, their relation to biological features were compared. (1) The function and expression of p53 protein of MCF-7 and MDA-MB-231 cells were obviously different. The expression levels of mdm-2 and p21WAF1 proteins in MCF-7 cells were higher than those of MDA-MB-231 cells (P < 0.05), The biological features of the former were more favorable than those of the latter. (2) The ER-transfected MDA-MB-231 cells showed lower expression of mtp53 and higher expression of mdm-2 protein (P < 0.05), but no significant difference from that of p21WAF1 protein (P > 0.05). Meanwhile, biological features leading to favorable prognosis were manifested. The ER status of breast cancer cell lines is related to the expression level of p53 and mdm-2 proteins and the biological features.


Serological screening for celiac disease in children with systemic lupus erythematosus.
The aim of the present study was to investigate the frequency of celiac disease (CD) in patients with juvenile systemic lupus erythematosus (JSLE) and the potential association of JSLE and CD. This was a cross-sectional study performed from October 2015 to October 2017. A total of 50 patients with JSLE were included in the study. The levels of total IgA and tissue transglutaminase (tTG) IgA antibody were measured in all patients. Subjects with increased tTG were further evaluated for anti-endomysial antibodies (EMAs). Gastroduodenoscopy and intestinal biopsy were performed in those with increased EMA levels to confirm the diagnosis of CD. The study included 44 (88.0%) female and 6 (12.0%) male patients. Of the 50 patients, 30 (60.0%) received corticosteroids, and only 4 (8.0%) received no therapy at the time of the study. Only 3 (6.0%) patients were positive for tTG IgA. Patients with positive tTG IgA were then tested for EMA IgA antibodies, and none of them had a positive result. We did not find CD in children with systemic lupus erythematosus. Studies with more patients with JSLE are needed to conclude a more precise result.


Demographically Corrected Normative Standards for the Spanish Language Version of the NIH Toolbox Cognition Battery.
Hispanics are the fastest growing ethnicity in the United States, yet there are limited well-validated neuropsychological tools in Spanish, and an even greater paucity of normative standards representing this population. The Spanish NIH Toolbox Cognition Battery (NIHTB-CB) is a novel neurocognitive screener; however, the original norms were developed combining Spanish- and English-versions of the battery. We developed normative standards for the Spanish NIHTB-CB, fully adjusting for demographic variables and based entirely on a Spanish-speaking sample. A total of 408 Spanish-speaking neurologically healthy adults (ages 18-85 years) and 496 children (ages 3-7 years) completed the NIH Toolbox norming project. We developed three types of scores: uncorrected based on the entire Spanish-speaking cohort, age-corrected, and fully demographically corrected (age, education, sex) scores for each of the seven NIHTB-CB tests and three composites (Fluid, Crystallized, Total Composites). Corrected scores were developed using polynomial regression models. Demographic factors demonstrated medium-to-large effects on uncorrected NIHTB-CB scores in a pattern that differed from that observed on the English NIHTB-CB. For example, in Spanish-speaking adults, education was more strongly associated with Fluid scores, but showed the strongest association with Crystallized scores among English-speaking adults. Demographic factors were no longer associated with fully corrected scores. The original norms were not successful in eliminating demographic effects, overestimating children's performances, and underestimating adults' performances on the Spanish NIHTB-CB. The disparate pattern of demographic associations on the Spanish versus English NIHTB-CB supports the need for distinct normative standards developed separately for each population. Fully adjusted scores presented here will aid in more accurately characterizing acquired brain dysfunction among U.S. Spanish-speakers.


Developing a telepresence robot for interpersonal communication with the elderly in a home environment.
"Telepresence" is an interesting field that includes virtual reality implementations with human-system interfaces, communication technologies, and robotics. This paper describes the development of a telepresence robot called Telepresence Robot for Interpersonal Communication (TRIC) for the purpose of interpersonal communication with the elderly in a home environment. The main aim behind TRIC's development is to allow elderly populations to remain in their home environments, while loved ones and caregivers are able to maintain a higher level of communication and monitoring than via traditional methods. TRIC aims to be a low-cost, lightweight robot, which can be easily implemented in the home environment. Under this goal, decisions on the design elements included are discussed. In particular, the implementation of key autonomous behaviors in TRIC to increase the user's capability of projection of self and operation of the telepresence robot, in addition to increasing the interactive capability of the participant as a dialogist are emphasized. The technical development and integration of the modules in TRIC, as well as human factors considerations are then described. Preliminary functional tests show that new users were able to effectively navigate TRIC and easily locate visual targets. Finally the future developments of TRIC, especially the possibility of using TRIC for home tele-health monitoring and tele-homecare visits are discussed.


Biolistic transformation of a procaryote, Bacillus megaterium.
We present a simple and rapid method for introducing exogenous DNA into a bacterium, Bacillus megaterium, utilizing the recently developed biolistic process. A suspension of B. megaterium was spread onto the surface of nonselective medium. Plasmid pUB110 DNA, which contains a gene that confers kanamycin resistance, was precipitated onto tungsten particles. Using a biolistic propulsion system, the coated particles were accelerated at high velocities into the B. megaterium recipient cells. Selection was done by use of an agar overlay containing 50 micrograms of kanamycin per ml. Antibiotic-resistant transformants were recovered from the medium interface after 72 h of incubation, and the recipient strain was shown to contain the delivered plasmid by agarose gel electrophoresis of isolated plasmid DNA. All strains of B. megaterium tested were successfully transformed by this method, although transformation efficiency varied among strains. Physical variables of the biolistic process and biological variables associated with the target cells were optimized, yielding greater than 10(4) transformants per treated plate. This is the first report of the biolistic transformation of a procaryote.


Combining quantitative and qualitative breast density measures to assess breast cancer risk.
Accurately identifying women with dense breasts (Breast Imaging Reporting and Data System [BI-RADS] heterogeneously or extremely dense) who are at high breast cancer risk will facilitate discussions of supplemental imaging and primary prevention. We examined the independent contribution of dense breast volume and BI-RADS breast density to predict invasive breast cancer and whether dense breast volume combined with Breast Cancer Surveillance Consortium (BCSC) risk model factors (age, race/ethnicity, family history of breast cancer, history of breast biopsy, and BI-RADS breast density) improves identifying women with dense breasts at high breast cancer risk. We conducted a case-control study of 1720 women with invasive cancer and 3686 control subjects. We calculated ORs and 95% CIs for the effect of BI-RADS breast density and Volpara™ automated dense breast volume on invasive cancer risk, adjusting for other BCSC risk model factors plus body mass index (BMI), and we compared C-statistics between models. We calculated BCSC 5-year breast cancer risk, incorporating the adjusted ORs associated with dense breast volume. Compared with women with BI-RADS scattered fibroglandular densities and second-quartile dense breast volume, women with BI-RADS extremely dense breasts and third- or fourth-quartile dense breast volume (75% of women with extremely dense breasts) had high breast cancer risk (OR 2.87, 95% CI 1.84-4.47, and OR 2.56, 95% CI 1.87-3.52, respectively), whereas women with extremely dense breasts and first- or second-quartile dense breast volume were not at significantly increased breast cancer risk (OR 1.53, 95% CI 0.75-3.09, and OR 1.50, 95% CI 0.82-2.73, respectively). Adding continuous dense breast volume to a model with BCSC risk model factors and BMI increased discriminatory accuracy compared with a model with only BCSC risk model factors (C-statistic 0.639, 95% CI 0.623-0.654, vs. C-statistic 0.614, 95% CI 0.598-0.630, respectively; P < 0.001). Women with dense breasts and fourth-quartile dense breast volume had a BCSC 5-year risk of 2.5%, whereas women with dense breasts and first-quartile dense breast volume had a 5-year risk ≤ 1.8%. Risk models with automated dense breast volume combined with BI-RADS breast density may better identify women with dense breasts at high breast cancer risk than risk models with either measure alone.


An association study between catechol-O-methyl transferase gene polymorphism and methamphetamine psychotic disorder.
A series of methamphetamine psychosis reveals two kinds of clinical courses of methamphetamine psychosis: transient type and prolonged type. Furthermore, paranoid psychosis sometimes recurs without methamphetamine reuse, referred to as spontaneous relapse. Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of these psychiatric states. Catechol-O-methyl transferase appears to play a unique role in regulating synaptic dopaminergic activity. This study aimed to investigate whether a functional polymorphism of the catechol-O-methyl transferase gene would be involved in the development of these psychiatric states. We examined the functional polymorphism of val 158 met (catechol-O-methyl transferase) in 143 patients with methamphetamine psychosis and 200 healthy controls in Japan. The patients were divided into subgroups by several characteristic clinical features. We found a significant difference in the catechol-O-methyl transferase allele frequency between patients with spontaneous relapse and the controls (P=0.018, odds ratio=1.67). Odds ratio implied that the patients with spontaneous relapse had a nearly 1.7-fold higher rate of the low activity alleles (met) than the controls. Our results indicate that the met allele frequency of the catechol-O-methyl transferase is associated with patients who experienced methamphetamine psychosis and spontaneous relapse, suggesting that patients with a met allele appear to be at increased risk of an adverse response to methamphetamine.


Increased SBPase activity improves photosynthesis and grain yield in wheat grown in greenhouse conditions.
To meet the growing demand for food, substantial improvements in yields are needed. This is particularly the case for wheat, where global yield has stagnated in recent years. Increasing photosynthesis has been identified as a primary target to achieve yield improvements. To increase leaf photosynthesis in wheat, the level of the Calvin-Benson cycle enzyme sedoheptulose-1,7-biphosphatase (SBPase) has been increased through transformation and expression of a Brachypodium distachyon SBPase gene construct. Transgenic lines with increased SBPase protein levels and activity were grown under greenhouse conditions and showed enhanced leaf photosynthesis and increased total biomass and dry seed yield. This showed the potential of improving yield potential by increasing leaf photosynthesis in a crop species such as wheat. The results are discussed with regard to future strategies for further improvement of photosynthesis in wheat.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'.


Surface localization of Helicobacter pylori urease and a heat shock protein homolog requires bacterial autolysis.
Helicobacter pylori is a gram-negative bacterium which causes chronic gastritis and is associated with peptic ulcer disease, gastric carcinoma, and gastric lymphoma. The bacterium is characterized by potent urease activity, thought to be located on the outer membrane, which is essential for survival at low pH. The purpose of the present study was to investigate mechanisms whereby urease and HspB, a GroEL homolog, become surface associated in vitro. Urease, HspB, and catalase were located almost exclusively within the cytoplasm in fresh log-phase cultures assessed by cryo- immunoelectron microscopy. In contrast, significant amounts of surface-associated antigen were observed in older or subcultured preparations concomitantly with the appearance of significant amounts of extracellular antigen, amorphous debris, and membrane fragments. By use of a variety of biochemical methods, a significant fraction of urease and HspB was associated with the outer membrane in subcultured preparations of H. pylori. Taken together, these results strongly suggest that H. pylori cells undergo spontaneous autolysis during culture and that urease and HspB become surface associated only concomitant with bacterial autolysis. By comparing enzyme sensitivity to flurofamide (a potent, poorly diffusible urease inhibitor) in whole cells with that in deliberately lysed cells, we show that both extracellular and intracellular urease molecules are active enzymatically. Autolysis of H. pylori is an important phenomenon to recognize since it likely exerts significant effects on the behavior of H. pylori. Furthermore, the surface properties of H. pylori must be unique in promoting adsorption of cytoplasmic proteins.


Myths and realities of continuous dopaminergic stimulation.
Motor fluctuations and dyskinesia in later stages of Parkinson's disease (PD) are caused by pharmacokinetic as well as pharmacodynamic factors, intermittent dopaminergic stimulation being one of the most important. In the healthy brain, dopamine neurons in the substantia nigra pars compacta fire tonically at a steady rate of about 4 cycles/second. In later stages of PD, steady firing is replaced by pulsatile stimulation which causes molecular and physiologic changes in the basal ganglia. Continuous dopaminergic stimulation has been shown to dramatically improve motor fluctuations and dyskinesia by modifications of oral treatment (dopamine agonists, smaller, more frequent levodopa doses, controlled-release formulation of levodopa, addition of agents that slow down the catabolism of dopamine, such as inhibitors of catechol-O-methyl transferase and monoamine oxidase), transdermal delivery (rotigotine), infusion therapies (intravenous levodopa, subcutaneous application of apomorphine and lisuride, duodenal infusion of levodopa) and deep brain stimulation of the subthalamic nucleus.


Pharmaceutical Care in NICUs in Australia and Poland: Attitudes and Perspectives of Doctors and Nurses.
A multidisciplinary and collaborative team network is essential in ensuring positive health outcomes for critically ill neonatal patients. The objective of this study was to investigate the perceptions of neonatal intensive care unit (NICU) doctors and nurses in Australia and Poland toward pharmaceutical care services in the NICU. A cross-sectional, anonymous, electronic-based survey was distributed between January and April 2017 among a sample of NICU doctors, nurses, and midwives. A total of 77 participants from Australia and 93 from Poland completed the survey. Overall, from the perspectives of medical and nursing staff, it is apparent that clinical pharmacy practice on the NICU is more established in Australia than in Poland. Only 8.6% of Polish participants reported that a pharmacist worked directly on the NICU in comparison with 87% of Australian participants (P < .001). The main roles performed by pharmacists in Polish NICUs related to the provision of medicines, whereas Australian pharmacists were highly involved in all aspects of pharmacotherapy, particularly in the clinical and education domains. Future efforts should focus on how practice is structured in each country and what support can be implemented from educational, cultural, and legislative levels to enable better pharmacist integration into the NICU therapeutic team.


One-dimensional metal oxide-carbon hybrid nanostructures for electrochemical energy storage.
Numerous metal oxides (MOs) have been considered as promising electrode materials for electrochemical energy storage devices, including lithium-ion batteries (LIBs) and electrochemical capacitors (ECs), because of their outstanding features such as high capacity/capacitance, low cost, as well as environmental friendliness. However, one major challenge for MO-based electrodes is the poor cycling stability derived from the large volume variation and intense mechanic strain, which are inevitably generated during repeated charge/discharge processes. Nanostructure engineering has proven to be one of the most effective strategies to improve the electrochemical performance of MO-based electrode materials. Among various nanostructures, one-dimensional (1D) metal oxide-carbon hybrid nanostructures might offer some solution for the challenging issues involved in bulk MO-based electrode materials for energy storage devices. Herein, we give an overview of the rational design, synthesis strategies and electrochemical properties of such 1D MO-carbon structures and highlight some of the latest advances in this niche area. It starts with a brief introduction to the development of nanostructured MO-based electrodes. We will then focus on the advanced synthesis and improved electrochemical performance of 1D MO-carbon nanostructures with different configurations, including MO-carbon composite nanowires, core-shell nanowires and hierarchical nanostructures. Lastly, we give some perspective on the current challenges and possible future research directions in this area.


Dimensionality of stress experiences: Factorial structure of the Perceived Stress Questionnaire (PSQ) in a population-based Swedish sample.
We investigated the factorial structure of the Perceived Stress Questionnaire (PSQ-recent; Levenstein, Prantera, Varvo et al., 1993) in a large (N = 1516; 35-95 years) population-based Swedish sample (Nilsson, Adolfsson, Bäckman et al., 2004; Nilsson, Bäckman, Erngrund et al., 1997). Exploratory principal components analysis (PCA) was conducted on a first, randomly drawn subsample (n = 506). Next, the model based on the PCA was tested in a second sample (n = 505). Finally, a third sample (n = 505) was used to cross-validate the model. Five components were extracted in the PCA (eigenvalue > 1) and labeled "Demands," "Worries/Tension," "Lack of joy," "Conflict," and "Fatigue," respectively. Twenty-one out of the 30 original PSQ items were retained in a confirmatory factor analysis (CFA) model that included the five (first-order) factors and, additionally, a general (second-order) stress factor, not considered in prior models. The model showed reasonable goodness of fit [χ(2)(184) = 511.2, p < 0.001; CFI = 0.904; RMSEA = 0.059; and SRMR = 0.063]. Multigroup confirmatory factor analyses supported the validity of the established model. The results are discussed in relation to prior investigations of the factorial structure of the PSQ.


Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner.
Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2-/-Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2-/-Fancd2-/- HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging.


Loss of cellular K+ mimics ribotoxic stress. Inhibition of protein synthesis and activation of the stress kinases SEK1/MKK4, stress-activated protein kinase/c-Jun NH2-terminal kinase 1, and p38/HOG1 by palytoxin.
The tumor promoter palytoxin has been found to activate the stress-activated protein kinase/c-Jun NH2-terminal kinase 1 (SAPK/JNK1), and it also potentiates, as demonstrated here, the p38/HOG1 mitogen-activated protein kinase and the upstream activator of SAPK/JNK1, SEK1/MKK4. In search of possible mechanisms for both the cytotoxicity and the activation of stress kinases by palytoxin, we found that palytoxin is a potent inhibitor of cellular protein synthesis. The inhibition of translation by palytoxin does not result from its direct binding to the translational apparatus. We have previously demonstrated that ribotoxic stressors (Iordanov, M. S., Pribnow, D., Magun, J. L., Dinh, T.-H., Pearson, J. A., Chen, S. L.-Y., and Magun, B. E. (1997) Mol. Cell. Biol. 17, 3373-3381) signal the activation of SAPK/JNK1 by binding to or covalently modifying 28 S rRNA in ribosomes that are active at the time of exposure to the stressor. Palytoxin acted as a ribotoxic stressor, inasmuch as it required actively translating ribosomes at the time of exposure to activate SAPK/JNK1. Palytoxin has been shown to augment ion fluxes by binding to the Na+/K+-ATPase in the plasma membrane of cells. To determine whether altered fluxes of either Na+ or K+ could be responsible for the effects of palytoxin on translation and on activation of SAPK/JNK1, cells were exposed to palytoxin in modified culture medium in which a major portion of the Na+ was replaced by either K+ or by choline+. The substitution of Na+ by K+ strongly inhibited the ability of palytoxin both to inhibit protein translation and to activate SAPK/JNK1, whereas the substitution of Na+ by choline+ did not. These results suggest that palytoxin-induced efflux of cellular K+ mimics ribotoxic stress by provoking both translational inhibition and activation of protein kinases associated with cellular defense against stress.


Understanding how consumers categorise nutritional labels: a consumer derived typology for front-of-pack nutrition labelling.
Significant ongoing debate exists amongst stakeholders as to the best front-of-pack labelling approach and emerging evidence suggests that the plethora of schemes may cause confusion for the consumer. To gain a better understanding of the relevant psychological phenomena and consumer perspectives surrounding FoP labelling schemes and their optimal development a Multiple Sort Procedure study involving free sorting of a range of nutritional labels presented on cards was performed in four countries (n=60). The underlying structure of the qualitative data generated was explored using Multiple Scalogram Analysis. Elicitation of categorisations from consumers has the potential to provide a very important perspective in this arena and results demonstrated that the amount of information contained within a nutrition label has high salience for consumers, as does the health utility of the label although a dichotomy exists in the affective evaluation of the labels containing varying degrees of information aggregation. Classification of exiting front-of-pack labelling systems on a proposed dimension of 'directiveness' leads to a better understanding of why some schemes may be more effective than others in particular situations or for particular consumers. Based on this research an enhanced hypothetical front-of-pack labelling scheme which combines both directive and non-directive elements is proposed.


Diagnosis of a primary pericardial mesothelioma by the combination of conventional echocardiography and contrast echocardiography.
Primary malignancies arising from the pericardium are rare, even more unusual for primary pericardial mesothelioma. The diagnosis is difficult and has no standard treatment. We herein present a case of a 65-year-old woman with primary pericardial mesothelioma associated with dyspnoea and palpitations. Transthoracic conventional echocardiography revealed mild pericardial effusion and a hypo-echogenic mass in the pericardium. Contrast echocardiography showed that the mass was hyper-enhanced with a radial enhancement pattern. The patient underwent open chest exploration and was diagnosed by pathological examination. She had no further treatment and died 2 years later. In conclusion, the combination of conventional echocardiography and contrast echocardiography plays a significant role in diagnosing primary pericardial mesothelioma. Comprehensive evaluation and accurately preoperative diagnosis are important to exclude certain tumours that do not require surgery.