Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity?
Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes, which is especially true in older women. Preference for a "Western diet" (WD), enriched with saturated fat, cholesterol, and sugars, may aggravate these conditions. In previous studies, decreased glucose tolerance, central and peripheral inflammation, dyslipidemia, emotional, cognitive, and social abnormalities were reported in WD-fed young female mice. We investigated the metabolic, molecular, and behavioral changes associated with a 3-week-long dietary regime of either the WD or control diet in 12-month-old female mice with three different Sert genotypes: homozygous (Slc6a4) gene knockout (Sert -/-: KO), heterozygous (Sert +/-: HET), or wild-type mice (Sert +/+: WT). In the WT-WD and KO-WD groups, but not in HET-WD-fed mice, most of changes induced by the WD paralleled those found in the younger mice, including brain overexpression of inflammatory marker Toll-like receptor 4 (Tlr4) and impaired hippocampus-dependent performance in the marble test. However, the 12-month-old female mice became obese. Control diet KO mice exhibited impaired hippocampal-dependent behaviors, increased brain expression of the serotonin receptors Htr2c and Htr1b, as well as increased Tlr4 and mitochondrial regulator, peroxisome proliferator-activated receptor gamma-coactivator-1a (Ppargc1a). Paradoxically, these, and other changes, were reversed in KO-WD mutants, suggesting a complex interplay between Sert deficiency and metabolic factors as well as potential compensatory molecular mechanisms that might be disrupted by the WD exposure. Most, but not all, of the changes in gene expression in the brain and liver of KO mice were not exhibited by the HET mice fed with either diet. Some of the WD-induced changes were similar in the KO-WD and HET-WD-fed mice, but the latter displayed a "rescued" phenotype in terms of diet-induced abnormalities in glucose tolerance, neuroinflammation, and hippocampus-dependent performance. Thus, complete versus partial Sert inactivation in aged mice results in distinct metabolic, molecular, and behavioral consequences in response to the WD. Our findings show that Sert +/- mice are resilient to certain environmental challenges and support the concept of heterosis as evolutionary adaptive mechanism.


Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines.
Exercise raises brain serotonin release and is postulated to cause fatigue in athletes; ingestion of branched-chain amino acids (BCAA), by competitively inhibiting tryptophan transport into brain, lowers brain tryptophan uptake and serotonin synthesis and release in rats, and reputedly in humans prevents exercise-induced increases in serotonin and fatigue. This latter effect in humans is disputed. But BCAA also competitively inhibit tyrosine uptake into brain, and thus catecholamine synthesis and release. Since increasing brain catecholamines enhances physical performance, BCAA ingestion could lower catecholamines, reduce performance and thus negate any serotonin-linked benefit. We therefore examined in rats whether BCAA would reduce both brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Sedentary and exercising rats received BCAA or vehicle orally; tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis rates were measured 1 h later in brain. BCAA reduced brain tryptophan and tyrosine concentrations, and serotonin and catecholamine synthesis. These reductions in tyrosine concentrations and catecholamine synthesis, but not tryptophan or serotonin synthesis, could be prevented by co-administering tyrosine with BCAA. Complete essential amino acid mixtures, used to maintain or build muscle mass, were also studied, and produced different effects on brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Since pharmacologically increasing brain catecholamine function improves physical performance, the finding that BCAA reduce catecholamine synthesis may explain why this treatment does not enhance physical performance in humans, despite reducing serotonin synthesis. If so, adding tyrosine to BCAA supplements might allow a positive action on performance to emerge.


Transformation of human granulosa cells with the E6 and E7 regions of human papillomavirus.
Ovarian granulosa cells are the primary site of estrogen and progesterone synthesis and play an essential role in the maturation of the developing ovum. Freshly isolated granulosa cells are often used to study the regulation of steroid and protein biosynthesis, but the small number of cells available for these cultures has proven inadequate for many detailed gene regulatory studies. The goal of this study was to develop human granulosa (HG) cell lines that maintain differentiated function. The E6 and E7 open reading frames of high risk strains of human papillomavirus have been used to produce immortalized cell lines. Primary cultures of human luteinized granulosa cells were infected with defective retroviruses containing the E6 and E7 regions of human papillomavirus 16 and with the neomycin phosphotransferase gene to confer G418 resistance. Three of eight clones that were isolated after selection in medium containing G418 were found to produce progesterone following treatment with forskolin or dibutyryl cAMP for 48 h. Forskolin caused these cells to retract in the characteristic rounding response, as described in primary HG cultures. One clone, HGL5, was used for a detailed characterization of differentiated function. HGL5 cells retained the ability to increase progesterone production and convert exogenously added androstenedione to estradiol in response to agonists of the protein kinase-A pathway (forskolin and dibutyryl cAMP), but were not responsive to FSH or LH treatment. A key enzyme in the production of estradiol, cytochrome P450 aromatase, has proven difficult to maintain in long term cultures of granulosa cells. For that reason, we examined the expression of aromatase in the transformed HGL5 clone by monitoring mRNA levels. Aromatase mRNA increased by 4- to 5-fold after forskolin treatment, as determined by Northern analysis. This human granulosa cell culture line maintains many of the functions of normal cells and should provide an important model to study the molecular events controlling granulosa cell differentiation and function.


The intelligibility of Lombard speech for non-native listeners.
Speech produced in the presence of noise--Lombard speech--is more intelligible in noise than speech produced in quiet, but the origin of this advantage is poorly understood. Some of the benefit appears to arise from auditory factors such as energetic masking release, but a role for linguistic enhancements similar to those exhibited in clear speech is possible. The current study examined the effect of Lombard speech in noise and in quiet for Spanish learners of English. Non-native listeners showed a substantial benefit of Lombard speech in noise, although not quite as large as that displayed by native listeners tested on the same task in an earlier study [Lu and Cooke (2008), J. Acoust. Soc. Am. 124, 3261-3275]. The difference between the two groups is unlikely to be due to energetic masking. However, Lombard speech was less intelligible in quiet for non-native listeners than normal speech. The relatively small difference in Lombard benefit in noise for native and non-native listeners, along with the absence of Lombard benefit in quiet, suggests that any contribution of linguistic enhancements in the Lombard benefit for natives is small.


A pretreatment nomogram for prediction of biochemical failure after primary cryoablation of the prostate.
To create a predictive nomogram for biochemical failure following primary whole-gland cryoablation of the prostate for localized prostate cancer (LPCa). We retrospectively analyzed 2,242 patients from the Cryo On-Line Database (COLD) who were treatment naive and had undergone primary whole gland cryoablation of the prostate for biopsy-confirmed LPCa. Kaplan-Meier (KM) curves estimating 5 year biochemical progression-free survival (bPFS) were generated. Multivariable Cox proportional hazards analysis (CoxPH) was performed in order to construct the nomogram. The nomogram was internally validated using the bootstrap technique. Overall, the KM estimated 5 year bPFS was 72.8%. Stratified by D'Amico risk, The KM estimated 5 year bPFS was 82.6%, 71.1%, and 57.8% for low-, intermediate-, and high-risk groups, respectively. Statistically significant predictors of biochemical outcomes from CoxPH analysis were pre-treatment prostate specific antigen (PTPSA) (P < 0.001), total prostate volume (P = 0.004), clinical stage (P = 0.034), and Gleason score (0.004). A nomogram for predicted 5 year biochemical progression free probability was constructed with a concordance index of 0.652. An online risk calculator was also generated. To the best of our knowledge, this is the first predictive nomogram for biochemical outcomes after primary whole gland cryoablation of the prostate using socio-demographic, pretreatment, clinical, and prostate biopsy data. Our nomogram and online risk calculator can guide both patients and urologists for shared decision making regarding definitive treatment options.


Effects of supplemental vitamin D and calcium on biomarkers of inflammation in colorectal adenoma patients: a randomized, controlled clinical trial.
Vitamin D and calcium affect several pathways involved in inflammation, tumor growth, and immune surveillance relevant to carcinogenesis. Also, epidemiologic evidence indicates that calcium and vitamin D may reduce risk for developing colorectal adenomas and cancer. To investigate the effects of calcium and vitamin D on biomarkers of inflammation in colorectal adenoma patients, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial (n = 92) of 2 g/d calcium and/or 800 IU/d vitamin D(3) supplementation versus placebo over 6 months. Plasma concentrations of proinflammatory markers [C-reactive protein (CRP), TNF-α, interleukin (IL)-6, IL-1β, and IL-8] and an anti-inflammatory marker (IL-10) were measured using ELISAs. After 6 months of treatment, in the vitamin D(3) supplementation group, CRP decreased 32% overall (P = 0.11), 37% in men (P = 0.05), and 41% among non-nonsteroidal anti-inflammatory drug (NSAID) users (P = 0.05) relative to placebo. In the vitamin D(3) supplementation group, TNF-α decreased 13%, IL-6 32%, IL-1β 50%, and IL-8 15%; in the calcium supplementation group, IL-6 decreased 37%, IL-8 11%, and IL-1β 27%. Although these changes were not statistically significant, a combined inflammatory markers z-score decreased 77% (P = 0.003) in the vitamin D(3) treatment group overall, 83% (P = 0.01) among men, and 48% among non-NSAID users (P = 0.01). There was no evidence of synergy between vitamin D(3) and calcium or effects on IL-10. These preliminary results are consistent with a pattern of reduction in tumor-promoting inflammation biomarkers with vitamin D(3) or calcium supplementation alone and support further investigation of vitamin D(3) as a chemopreventive agent against inflammation and colorectal neoplasms.


Variation in Bluetongue virus real-time reverse transcription polymerase chain reaction assay results in blood samples of sheep, cattle, and alpaca.
Bluetongue is a vector-borne viral disease that affects domestic and wild ruminants. The epidemiology of this disease has recently changed, with occurrence in new geographic areas. Various real-time quantitative reverse transcription polymerase chain reaction (real-time qRT-PCR) assays are used to detect Bluetongue virus (BTV); however, the impact of biologic differences between New World camelids and domestic ruminant samples on PCR efficiency, for which the BTV real-time qRT-PCR was initially validated are unknown. New world camelids are known to have important biologic differences in whole blood composition, including hemoglobin concentration, which can alter PCR performance. In the present study, sheep, cattle, and alpaca blood were spiked with BTV serotypes 10, 11, 13, and 17 and analyzed in 10-fold dilutions by real-time qRT-PCR to determine if species affected nucleic acid recovery and assay performance. A separate experiment was performed using spiked alpaca blood subsequently diluted in 10-fold series in sheep blood to assess the influence of alpaca blood on performance efficiency of the BTV real-time qRT-PCR assay. Results showed that BTV-specific nucleic acid detection from alpaca blood was consistently 1-2 logs lower than from sheep and cattle blood, and results were similar for each of the 4 BTV serotypes analyzed.


Sonoluminescent tomography of strongly scattering media.
A novel optical imaging technique called sonoluminescent tomography was developed for cross-sectional imaging of strongly scattering media noninvasively. Sonoluminescence, which was generated internally in the medium by cw ultrasound, was used to produce a two-dimensional image of an object embedded in a scattering medium by means of raster scanning the medium. The image had a high contrast and good spatial resolution. The spatial resolution was limited by the focal-spot size of the ultrasound, and one could improve the resolution by tightening the focus. This inexpensive imaging technique has potential applications in medicine and other fields related to scattering media.


Automated signal quality assessment of mobile phone-recorded heart sound signals.
Mobile phones, due to their audio processing capabilities, have the potential to facilitate the diagnosis of heart disease through automated auscultation. However, such a platform is likely to be used by non-experts, and hence, it is essential that such a device is able to automatically differentiate poor quality from diagnostically useful recordings since non-experts are more likely to make poor-quality recordings. This paper investigates the automated signal quality assessment of heart sound recordings performed using both mobile phone-based and commercial medical-grade electronic stethoscopes. The recordings, each 60 s long, were taken from 151 random adult individuals with varying diagnoses referred to a cardiac clinic and were professionally annotated by five experts. A mean voting procedure was used to compute a final quality label for each recording. Nine signal quality indices were defined and calculated for each recording. A logistic regression model for classifying binary quality was then trained and tested. The inter-rater agreement level for the stethoscope and mobile phone recordings was measured using Conger's kappa for multiclass sets and found to be 0.24 and 0.54, respectively. One-third of all the mobile phone-recorded phonocardiogram (PCG) signals were found to be of sufficient quality for analysis. The classifier was able to distinguish good- and poor-quality mobile phone recordings with 82.2% accuracy, and those made with the electronic stethoscope with an accuracy of 86.5%. We conclude that our classification approach provides a mechanism for substantially improving auscultation recordings by non-experts. This work is the first systematic evaluation of a PCG signal quality classification algorithm (using a separate test dataset) and assessment of the quality of PCG recordings captured by non-experts, using both a medical-grade digital stethoscope and a mobile phone.


CerealsDB-new tools for the analysis of the wheat genome: update 2020.
CerealsDB (www.cerealsdb.uk.net) is an online repository of mainly hexaploid wheat (Triticum aestivum) single nucleotide polymorphisms (SNPs) and genotyping data. The CerealsDB website has been designed to enable wheat breeders and scientists to select the appropriate markers for research breeding tasks, such as marker-assisted selection. We report a large update of genotyping information for over 6000 wheat accessions and describe new webtools for exploring and visualizing the data. We also describe a new database of quantitative trait loci that links phenotypic traits to CerealsDB SNP markers and allelic scores for each of those markers. CerealsDB is an open-access website that hosts information on wheat SNPs considered useful for both plant breeders and research scientists. The latest CerealsDB database is available at https://www.cerealsdb.uk.net/cerealgenomics/CerealsDB/indexNEW.php.


Effects of the Nd:YAG 1320-nm laser on skin rejuvenation: clinical and histological correlations.
The neodymium:yttrium-aluminum-garnet (Nd:YAG) laser is a popular non-ablative treatment used for skin rejuvenation. The purpose of this prospective study was to evaluate the clinical effects, coupled with a quantitative assessment, of the histological changes in response to Nd:YAG 1320-nm laser treatment of periocular wrinkles. Six volunteers with Fitzpatrick skin types III and IV and Glogau class I-II wrinkles were subjected to 3 months of Nd:YAG 1320-nm treatment in the periocular area (six sessions at 2-week intervals). Volunteers were photographed, and skin biopsies were obtained at baseline as well as 3 and 6 months after the start of treatments. Quantitative evaluation of total elastin, newly synthesized tropoelastin, collagen types I, III and VII, and newly synthesized collagen was performed using a computerized morphometric analysis. A noticeable clinical and histological improvement was observed after Nd:YAG 1320-nm treatment. Collagen types I, III and VII, as well as newly synthesized collagen, together with tropoelastin showed a statistically significant increase in response to treatment, while the mean level of total elastin was significantly decreased after treatment. Our data suggest that Nd:YAG 1320 nm is an effective treatment for skin rejuvenation as it stimulates the repair processes, and reverses the clinical, as well as the histopathological, signs of skin aging.


Silicon in beer and brewing.
It has been claimed that beer is one of the richest sources of silicon in the diet; however, little is known of the relationship between silicon content and beer style and the manner in which beer is produced. The purpose of this study was to measure silicon in a diversity of beers and ascertain the grist selection and brewing factors that impact the level of silicon obtained in beer. Commercial beers ranged from 6.4 to 56.5 mg L(-1) in silicon. Products derived from a grist of barley tended to contain more silicon than did those from a wheat-based grist, likely because of the high levels of silica in the retained husk layer of barley. Hops contain substantially more silicon than does grain, but quantitatively hops make a much smaller contribution than malt to the production of beer and therefore relatively less silicon in beer derives from them. During brewing the vast majority of the silicon remains with the spent grains; however, aggressive treatment during wort production in the brewhouse leads to increased extraction of silicon into wort and much of this survives into beer. It is confirmed that beer is a very rich source of silicon.


[Neonatal thrombosis of the jugular veins: long-term repercussions on cerebral development (two cases)].
Bilateral obstruction of the internal jugular veins is rare in the neonatal period and no long-term follow-up has been reported yet. We report two cases. The first developped an extensive thrombosis of superior veina cava related to a central veinous line, the second an unilateral thrombosis of the transverse-sigmoid sinus associated to a constitutional hypoplasia of the contralateral jugular vein. In the latter case, no cause or risk factor was noticeable, except for a forceps delivery. In both cases the clinical course was dominated by the development of a prominent collateral network of cervico-facial veins and by a progressive macrocrania. According to MRImaging, the latter was not related to a dilation of CSF spaces, but to a macro-encephaly, either by inflation of the vascular veinous compartment inside the parenchyma or by genuine brain's overgrowth. Long-term follow-up showed a grossly normal course, both from the neurological and the scholar point of view. However, slight neuropsychological anomalies were noticed, bringing some shade on the prognosis.


Competitive bulk liquid membrane transport and solvent extraction of some metal ions using RC(S)NHP(X)(OiPr)(2) (X = O, S) as ionophores. Formation of the polynuclear complex of [Ag(N[triple bond]C-NP(S)(OiPr)(2))](n).
Competitive transport experiments involving metal ions from an aqueous source phase through a chloroform membrane into an aqueous receiving phase have been carried out using a series of N-(thio)phosphorylated (thio)amide and thiourea ligands as the ionophore present in the organic phase. The source phase contained equimolar concentrations of Co(II), Ni(II), Cu(II), Zn(II), Ag(I), Cd(II) and Pb(II) with the source and receiving phases being buffered at a number of different pHs. Solvent extraction properties of the ligands towards the same metal cations under the same experimental conditions as for the transport were also studied. All ligands demonstrated 100% extraction of Ag(I). Reaction of AgNO(3) with the potassium salt of the N-thiophosphorylated thiourea NH(2)C(S)NHP(S)(OiPr)(2) gave a new supramolecular Ag(I) complex, [AgZ](n) (Z = {N[triple bond]C-NP(S)(OiPr)(2)}(-)) that contains both tri- and tetracoordinated Ag(I). The novel polynuclear Ag(I) complex [AgZ](n) described and structurally characterized by single crystal X-ray diffraction has no precedent.


Ultrasound assessment of asymmetric hypertrophy of the rectus abdominis muscle and prevalence of associated injury in professional tennis players.
To assess rectus abdominis (RA) thickness and injury prevalence using ultrasound in a group of professional tennis players. Observations with regard to muscle fiber repair is described. We likewise studied the potential link between RA volume asymmetry and the risk of muscle strain. The degree of asymmetry between the different RA slices was assessed using ultrasound in 61 professional tennis players. The history of RA injury in these tennis players was likewise studied, taking into account the following factors: dominant vs non-dominant arm, history of RA strains, duration thereof and number of recurrences. Ultrasound examination was performed with an 8- to 12-MHz linear multi-frequency transducer. Ultrasound revealed the presence of fibrous scar tissue in the RA muscle in 18 cases (29.5%). In all instances, the lesion was located in the RA on the side of the nondominant arm. In 16 of the cases, the lesion was infra-umbilical and L2 was affected in two cases. The mean maximum width of the fibrous repair tissue was 9 mm (range 5-16). The mean distance between the umbilicus and the scar was 5.8 cm (range 2.9-11.4). Statistical study of the ultrasound measurements obtained for the different slices revealed statistically significant differences between the different depths and according to arm dominance. In the series studied, the prevalence of RA muscle lesion in professional tennis players was 29.5%. Asymmetric hypertrophy of the RA muscle appears to constitute a risk factor for suffering an injury in this location.


Phylogenetic background and habitat drive the genetic diversification of Escherichia coli.
Escherichia coli is mostly a commensal of birds and mammals, including humans, where it can act as an opportunistic pathogen. It is also found in water and sediments. We investigated the phylogeny, genetic diversification, and habitat-association of 1,294 isolates representative of the phylogenetic diversity of more than 5,000 isolates from the Australian continent. Since many previous studies focused on clinical isolates, we investigated mostly other isolates originating from humans, poultry, wild animals and water. These strains represent the species genetic diversity and reveal widespread associations between phylogroups and isolation sources. The analysis of strains from the same sequence types revealed very rapid change of gene repertoires in the very early stages of divergence, driven by the acquisition of many different types of mobile genetic elements. These elements also lead to rapid variations in genome size, even if few of their genes rise to high frequency in the species. Variations in genome size are associated with phylogroup and isolation sources, but the latter determine the number of MGEs, a marker of recent transfer, suggesting that gene flow reinforces the association of certain genetic backgrounds with specific habitats. After a while, the divergence of gene repertoires becomes linear with phylogenetic distance, presumably reflecting the continuous turnover of mobile element and the occasional acquisition of adaptive genes. Surprisingly, the phylogroups with smallest genomes have the highest rates of gene repertoire diversification and fewer but more diverse mobile genetic elements. This suggests that smaller genomes are associated with higher, not lower, turnover of genetic information. Many of these genomes are from freshwater isolates and have peculiar traits, including a specific capsule, suggesting adaptation to this environment. Altogether, these data contribute to explain why epidemiological clones tend to emerge from specific phylogenetic groups in the presence of pervasive horizontal gene transfer across the species.


Anomalous Decay of Nanomechanical Modes Going Through Nonlinear Resonance.
Because of the small size of nanomechanical systems, their vibrations become nonlinear already for small amplitudes. Many nontrivial aspects of the vibration dynamics arise from the coexistence of several nonlinearly coupled modes. We show that such coupling can lead to anomalous decay of the modes where they go through nonlinear resonance, so that their amplitude-dependent frequencies become commensurate. We demonstrate the possibility of a strongly nonmonotonic dependence of the decay rate on the amplitude if one of the modes serves as a thermal reservoir for another mode. Where the decay of both modes is slow compared to the rate of resonant energy exchange, the decay is accompanied by amplitude oscillations. Depending on the initial conditions, with increasing time it can display an extremely sharp or a comparatively smooth crossover between different regimes. The results provide insight into recent experimental results by several groups and suggest new ways of characterizing and controlling nanomechanical systems.


Passive smoking and heart disease. Epidemiology, physiology, and biochemistry.
The evidence that ETS increases risk of death from heart disease is similar to that which existed in 1986 when the US Surgeon General concluded that ETS caused lung cancer in healthy nonsmokers. There are 10 epidemiological studies, conducted in a variety of locations, that reflect about a 30% increase in risk of death from ischemic heart disease or myocardial infarction among nonsmokers living with smokers. The larger studies also demonstrate a significant dose-response effect, with greater exposure to ETS associated with greater risk of death from heart disease. These epidemiological studies are complemented by a variety of physiological and biochemical data that show that ETS adversely affects platelet function and damages arterial endothelium in a way that increases the risk of heart disease. Moreover, ETS, in realistic exposures, also exerts significant adverse effects on exercise capability of both healthy people and those with heart disease by reducing the body's ability to deliver and utilize oxygen. In animal experiments, ETS also depresses cellular respiration at the level of mitochondria. The polycyclic aromatic hydrocarbons in ETS also accelerate, and may initiate, the development of atherosclerotic plaque. Of note, the cardiovascular effects of ETS appear to be different in nonsmokers and smokers. Nonsmokers appear to be more sensitive to ETS than do smokers, perhaps because some of the affected physiological systems are sensitive to low doses of the compounds in ETS, then saturate, and also perhaps because of physiological adaptions smokers undergo as a result of long-term exposure to the toxins in cigarette smoke. In any event, these findings indicate that, for cardiovascular disease, it is incorrect to compute "cigarette equivalents" for passive exposure to ETS and then to extrapolate the effects of this exposure on nonsmokers from the effects of direct smoking on smokers. These results suggest that heart disease is an important consequence of exposure to ETS. The combination of epidemiological studies with demonstration of physiological changes with exposure to ETS, together with biochemical evidence that elements of ETS have significant adverse effects on the cardiovascular system, leads to the conclusion that ETS causes heart disease. This increase in risk translates into about 10 times as many deaths from ETS-induced heart disease as lung cancer; these deaths contribute greatly to the estimated 53,000 deaths annually from passive smoking. This toll makes passive smoking the third leading preventable cause of death in the United States today, behind active smoking and alcohol.


[Current status of acute pancreatitis in Korea].
The annual incidence of acute pancreatitis (AP) per 100,00 people has increased from 15.6 in 1995 to 19.4 in 2000. Gender distribution revealed male predominance in patients aged between 30 and 60. AP has diverse etiologies. Alcohol consumption and gallstones were the main contribution factors. Due to advanced diagnostic equipments and techniques, the percentage of AP owing to miscellaneous and idiopathic causes has decreased significantly. The mortality rate of AP was 3% in 1980s, 4.4% in the early 1990s, and 2.1% in the late 1990s in Korea. During the late 1990s, the mortality rate has decreased even though the percentage of severe form has increased. This may be partly due to recent advances in medical management. Currently, there is no specific treatment capable of preventing complications of AP. Therefore, it is important to identify patients with severe AP using multiple clinical criteria, CT scans, and laboratory criteria. Close surveillance is necessary for patients with severe AP in order to identify and treat potential complications such as hemorrhage, shock, multiorgan failure as well as infection. Despite our thorough work-up using advanced diagnostic techniques, about one-fifth of the patients remain "idiopathic". As our understanding of AP improves and more advanced endoscopic and imaging techniques become available, this number will continue to decline.


Burden of Chemotherapy-Induced Febrile Neutropenia Hospitalizations in US Clinical Practice, by Use and Patterns of Prophylaxis with Colony-Stimulating Factor.
Evidence suggests that many cancer chemotherapy patients who are candidates for colony-stimulating factor (CSF) prophylaxis do not receive it or receive it inconsistent with guidelines, and that such patients have a higher risk of febrile neutropenia hospitalization (FNH). Little is known about the number and consequences of FNH by use/patterns of CSF prophylaxis in US clinical practice. A retrospective cohort design and private healthcare claims data were employed. Study population comprised adults who received a chemotherapy course with a high-risk regimen, or an intermediate-risk regimen (if ≥1 FN risk factor present), for non-metastatic breast cancer or non-Hodgkin's lymphoma (NHL); each chemotherapy cycle within the course and each FNH episode within the cycles were identified. Consequences included mortality, inpatient days, and costs (US$2013) during FNH. Use (yes/no) and patterns (agent, administration day/duration) of CSF prophylaxis were evaluated within cycles in which FNH episodes occurred. Among all FNH episodes (n=6,355; 109 episodes per 1,000 patients), 41.3% (95% CI: 40.1-42.5) occurred among patients who did not receive CSF prophylaxis in that cycle, and 8.8% (8.1-9.5) occurred among those who received CSF prophylaxis on the same day as chemotherapy. Among FNH episodes occurring in patients who received daily CSF agents (2% of CSF use), 56.1% (44.1-68.0) received prophylaxis <7 days during the cycle. Results for FNH consequences were comparable. In this retrospective evaluation, one-half of FNH episodes, outcomes, and costs among cancer chemotherapy patients who were candidates for CSF prophylaxis occurred in those who either did not receive it or received it inconsistent with guidelines.


Older persons' experiences of depressive ill-health and family support.
The aim of this study was to explore experiences of the meaning of family support among older persons with depressive ill-health. Data were collected from twenty-nine participants through semistructured interviews and analysed using interpretative hermeneutic and reflective methodology. The findings revealed a main theme, hovering between feelings of belongingness and aloneness in relationships with family members, based on two themes: a sense of being worthy and a sense of being unworthy. Experiences of support and lack of support from family members were not opposites but connected in internal relationships and can be pictured as a movement on a continuum of ambiguity. Family support promotes the emotional needs of older persons with depressive ill-health to be confirmed. The family plays a vital role, not always by direct assistance, but indirectly by supporting the older person's own "guiding principles" for managing her/his situation. The feelings of aloneness as well as shame and guilt at poor or absent family responsiveness should be adequately addressed. Innovative nursing care can lead to improvement by focusing on acquiescence to the older person's life situation.


An Evaluation of Cucurbits for Susceptibility to Cucurbitaceous and Solanaceous Phytophthora capsici isolates.
Cucumber (Cucumis sativus) and squash (Cucurbita spp.) production in Michigan is limited by the oomycete pathogen Phytophthora capsici. Cucumber, summer squash, and winter squash fruit were evaluated for susceptibility to five isolates of P. capsici. Detached fruit were inoculated with a 5-mm-diameter culture plug of mycelia and sporangia and were incubated in a laboratory or greenhouse. Lesion and pathogen growth diameters were measured and pathogen growth density was visually assessed. All P. capsici isolates incited rot, with significant differences found among fruit type and pathogen isolate. Straightneck squash (Cucurbita pepo), slicing cucumber, and butternut squash (C. moschata) exhibited more severe symptoms than the other fruit tested. Summer and winter squash seedlings were evaluated in greenhouse experiments, in which P. capsici-infested millet seed (approximately 1 g) were placed on the surface of soilless potting media. Disease severity was visually assessed every 2 days for 14 days post inoculation. Crop type, pathogen isolate, or the crop type-pathogen isolate interaction term were significant for symptom appearance and area under the disease progress curve values. Differences in susceptibility of butternut squash and zucchini cultivars were observed following inoculation with solanaceous isolate 13351. Results from this study can refine management programs for Phytophthora rot.


Rapid Screening of Musa Species for Resistance to Black Leaf Streak Using In Vitro Plantlets in Tubes and Detached Leaves.
This study investigated the utility of inoculation of in vitro plantlets in tubes and detached leaves as reliable and rapid assays for screening Musa genotypes against Mycosphaerella fijiensis, the causal agent of black leaf streak. In the first part of the study, three types of inocula were evaluated to determine suitability for in vitro inoculation. Inoculation of in vitro plantlets with mycelial fragments resulted in significantly (P < 0.05) higher levels of disease severity and faster rates of disease progress compared with inoculations using conidial suspensions. In the detached leaf assay, amending agar medium with plant hormones significantly (P < 0.0001) aided retention of green leaf color. Leaf pieces on medium containing gibberellic acid at 5 mg/liter had about 5% chlorosis at 52 days after plating. When in vitro plantlets in tubes and detached leaves of 10 Musa genotypes with different levels of disease resistance were inoculated with M. fijiensis, there were significant (P < 0.05) differences among genotypes in leaf area infected, incubation time, and symptom evolution time. For incubation time and leaf area infected, cultivars responded depending on their level of disease resistance, with resistant genotypes Calcutta-4 and PITA-17 having significantly (P = 0.001) longer incubation times and lower infected leaf areas compared with the susceptible cultivar Agbagba and moderately resistant cultivar FHIA-23. A similar pattern in cultivar response was observed for symptom evolution time. Leaf area infected was not significantly (P = 0.2817 for two-tailed t test) different when assessed using the two assays, and infected leaf areas in both assays were strongly correlated (r = 0.88, n = 48, P < 0.0001). Although incubation times were significantly (P = 0.0062 for two-tailed t test) different between the two assays, values from the two assays were strongly correlated (r = 0.69, n = 48, P < 0.0001). These results show that these two assays are rapid and space-effective, and can reliably be used for screening Musa genotypes for resistance to black leaf streak.


Human telomeric RNA G-quadruplex response to point mutation in the G-quartets.
Many putative G-quadruplex forming sequences have been predicted to exist in the human genome and transcriptome. As these sequences are subject to point mutations or SNPs (single nucleotide polymorphisms) during the course of evolution, we attempt to understand impact of these mutations in context of RNA G-quadruplex formation using human telomeric RNA (TERRA) as a model sequence. Our studies suggest that G-quadruplex stability is sensitive to substitution of the guanines comprising G-quartets. While central G-quartet plays a crucial role in maintaining the DNA G-quadruplex stability as evident in literature, there is equal importance of three G-quartets in the stability of RNA quadruplex structure. The work here highlights the alterations in the G-quartet are detrimental to the integrity of overall RNA G-quadruplex structure. Furthermore, TmPyP4 molecules are shown to exhibit similar binding behavior toward telomeric RNA G-quadruplex harboring base substitutions employing CD titrations and isothermal titration calorimetry; well indicating that mutation does not influence TmPyP4 recognition ability as it affects the stability of RNA G-quadruplex. Thus, our study implicates that mutation in G-quartets causes destabilization of RNA G-quadruplex without affecting its trans factor binding ability.


The mass flow and proposed management of bisphenol A in selected Norwegian waste streams.
Current initiatives for waste-handling in a circular economy favor prevention and recycling over incineration or landfilling. However, the impact of such a transition on environmental emissions of contaminants like bisphenol A (BPA) during waste-handling is not fully understood. To address this, a material flow analysis (MFA) was constructed for selected waste categories in Norway, for which the amount recycled is expected to increase in the future; glass, vehicle, electronic, plastic and combustible waste. Combined, 92tons/y of BPA are disposed of via these waste categories in Norway, with 98.5% associated with plastic and electronic waste. During the model year 2011, the MFA showed that BPA in these waste categories was destroyed through incineration (60%), exported for recycling into new products (35%), stored in landfills (4%) or released into the environment (1%). Landfilling led to the greatest environmental emissions (up to 13% of landfilled BPA), and incinerating the smallest (0.001% of incinerated BPA). From modelling different waste management scenarios, the most effective way to reduce BPA emissions are to incinerate BPA-containing waste and avoid landfilling it. A comparison of environmental and human BPA concentrations with CoZMoMAN exposure model estimations suggested that waste emissions are an insignificant regional source. Nevertheless, from monitoring studies, landfill emissions can be a substantial local source of BPA. Regarding the transition to a circular economy, it is clear that disposing of less BPA-containing waste and less landfilling would lead to lower environmental emissions, but several uncertainties remain regarding emissions of BPA during recycling, particularly for paper and plastics. Future research should focus on the fate of BPA, as well as BPA alternatives, in emerging reuse and recycling processes, as part of the transition to a circular economy.


Long-Term Exposure to Air Pollution, Road Traffic Noise, and Heart Failure Incidence: The Danish Nurse Cohort.
Background We examined the association of long-term exposure to air pollution and road traffic noise with incident heart failure (HF). Methods And Results Using data on female nurses from the Danish Nurse Cohort (aged >44 years), we investigated associations between 3-year mean exposures to air pollution and road traffic noise and incident HF using Cox regression models, adjusting for relevant confounders. Incidence of HF was defined as the first hospital contact (inpatient, outpatient, or emergency) between cohort baseline (1993 or 1999) and December 31, 2014, based on the Danish National Patient Register. Annual mean levels of particulate matter with a diameter <2.5 µm since 1990 and NO2 and road traffic noise since 1970 were estimated at participants' residences. Of the 22 189 nurses, 484 developed HF. We detected associations with all 3 pollutants, with hazard ratios (HRs) of 1.17 (95% CI, 1.01-1.36), 1.10 (95% CI, 0.99-1.22), and 1.12 (95% CI, 0.99-1.26) per increase of 5.1 µg/m3 in particulate matter with a diameter <2.5 µm, 8.6 µg/m3 in NO2, and 9.3 dB in road traffic noise, respectively. We observed an enhanced risk of HF incidence for those exposed to high levels of the 3 pollutants; however, the effect modification of coexposure was not statistically significant. Former smokers and nurses with hypertension showed the strongest associations with particulate matter with a diameter <2.5 µm (Peffect modification<0.05). Conclusions We found that long-term exposures to air pollution and road traffic noise were independently associated with HF.


Systemic delivery of selective EP1 and EP3 receptor antagonists attenuates pentylenetetrazole-induced seizures in mice.
Neuroinflammation plays a major role in brain excitability and may contribute to the development of epilepsy. Prostaglandin E2 (PGE2) is a direct mediator of inflammatory responses and, through EP receptors, plays an important role in neuronal excitability. Pharmacological evidence supports that centrally-administered EP1 and EP3 receptor antagonists reduced acutely evoked seizures in rats. Translation of these findings would benefit from evidence of efficacy with a more clinically relevant route of delivery and validation in another species. In the current study we investigated whether the systemic administration of EP1 and EP3 agonists and antagonists modulate pentylenetetrazole (PTZ)-induced seizures in mice. In addition, it was examined whether these compounds alter Na+, K+-ATPase activity, an enzyme responsible for the homeostatic ionic equilibrium and, consequently, for the resting membrane potential in neurons. While the systemic administration of EP1 and EP3 antagonists (ONO-8713 and ONO-AE3-240, respectively) attenuated, the respective agonists (ONO-DI-004 and ONO-AE-248) potentiated PTZ-induced seizures (all compounds injected at the dose of 10 µg/kg, s.c., 30 min before PTZ challenge). Co-administration of either EP1 or EP3 agonist with the respective antagonists nullified the anticonvulsant effects of EP1/3 receptor blockade. In addition, EP1 and EP3 agonists exacerbated PTZ-induced decrease of Na+, K+-ATPase activity in both cerebral cortex and hippocampus, whereas, EP1 and EP3 antagonists prevented PTZ-induced decrease of Na+, K+-ATPase activity in both structures. Our findings support and extend evidence that EP1 and EP3 receptors may be novel targets for the development of anticonvulsant drugs.


Infection of human B lymphocytes with MMR vaccine induces IgE class switching.
Circulating immunoglobulin E (IgE) is one of the characteristics of human allergic diseases including allergic asthma. We recently showed that infection of human B cells with rhinovirus or measles virus could lead to the initial steps of IgE class switching. Since many viral vaccines are live viruses, we speculated that live virus vaccines may also induce IgE class switching in human B cells. To examine this possibility, we selected the commonly used live attenuated measles mumps rubella (MMR) vaccine. Here, we show that infection of a human IgM(+) B cell line with MMR resulted in the expression of germline epsilon transcript. In addition, infection of freshly prepared human PBLs with this vaccine resulted in the expression of mature IgE mRNA transcript. Our data suggest that a potential side effect of vaccination with live attenuated viruses may be an increase in the expression of IgE.


Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking.
In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by inhibition of glutamate or dopamine transmission in nucleus accumbens shell, or inactivation of ventral medial prefrontal cortex (mPFC). Here, we used an anatomical asymmetrical disconnection procedure to demonstrate that an interaction between glutamatergic projections from ventral mPFC to accumbens shell and local dopamine D(1) postsynaptic receptors contributes to context-induced reinstatement of heroin seeking. We also combined the marker of neuronal activity, Fos, with the retrograde tracer Fluoro-Gold to assess activation in this pathway during context-induced reinstatement. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a nondrug-associated context in the presence of the discrete cue. Rats were then tested in the heroin- or extinction-associated contexts under extinction conditions. Injections of muscimol + baclofen into ventral mPFC in one hemisphere and D(1)-family receptor antagonist SCH 23390 into the contralateral or ipsilateral accumbens shell decreased context-induced reinstatement. Unilateral injections of muscimol + baclofen into ventral mPFC or SCH 23390 into the accumbens shell had no effect. Context-induced reinstatement was associated with increased Fos expression in ventral mPFC neurons, including those projecting to accumbens shell, with higher double-labeling in the ipsilateral projection than in the contralateral projection. Our results demonstrate that activation of glutamatergic projections from ventral mPFC to accumbens shell, previously implicated in inhibition of cocaine relapse, promotes heroin relapse.


Increased plasma adrenaline concentrations in benign essential hypertension.
Plasma adrenaline, noradrenaline, and dopamine concentrations and plasma renin activity were measured in the supine position and after standing for 10 minutes in 14 patients with sustained benign essential hypertension and in five patients with labile hypertension. Results were compared with values obtained in 11 normotensive control subjects. In controls plasma noradrenaline concentrations increased with age, while plasma adrenaline values tended to decrease with age. No significant difference in mean plasma noradrenaline was found between hypertensive and control subjects, but plasma noradrenaline seemed slightly increased in a proportion of hypertensive patients aged less than 50. Plasma adrenaline was considerably raised in both supine and standing positions in eight patients with sustained hypertension and in two with labile hypertension. Dopamine concentrations and plasma renin activity were similar in all groups studied. The finding of significantly raised plasma adrenaline concentrations in a large proportion of hypertensive patients supports the hypothesis that the activity of the sympathetic nervous system is increased in essential hypertension. Measurement of plasma adrenaline seems to be a more sensitive index of this activity than that of plasma noradrenaline.


Limited-information goodness-of-fit testing of diagnostic classification item response models.
Despite the growing popularity of diagnostic classification models (e.g., Rupp et al., 2010, Diagnostic measurement: theory, methods, and applications, Guilford Press, New York, NY) in educational and psychological measurement, methods for testing their absolute goodness of fit to real data remain relatively underdeveloped. For tests of reasonable length and for realistic sample size, full-information test statistics such as Pearson's X2 and the likelihood ratio statistic G2 suffer from sparseness in the underlying contingency table from which they are computed. Recently, limited-information fit statistics such as Maydeu-Olivares and Joe's (2006, Psychometrika, 71, 713) M2 have been found to be quite useful in testing the overall goodness of fit of item response theory models. In this study, we applied Maydeu-Olivares and Joe's (2006, Psychometrika, 71, 713) M2 statistic to diagnostic classification models. Through a series of simulation studies, we found that M2 is well calibrated across a wide range of diagnostic model structures and was sensitive to certain misspecifications of the item model (e.g., fitting disjunctive models to data generated according to a conjunctive model), errors in the Q-matrix (adding or omitting paths, omitting a latent variable), and violations of local item independence due to unmodelled testlet effects. On the other hand, M2 was largely insensitive to misspecifications in the distribution of higher-order latent dimensions and to the specification of an extraneous attribute. To complement the analyses of the overall model goodness of fit using M2 , we investigated the utility of the Chen and Thissen (1997, J. Educ. Behav. Stat., 22, 265) local dependence statistic XLD2 for characterizing sources of misfit, an important aspect of model appraisal often overlooked in favour of overall statements. The XLD2 statistic was found to be slightly conservative (with Type I error rates consistently below the nominal level) but still useful in pinpointing the sources of misfit. Patterns of local dependence arising due to specific model misspecifications are illustrated. Finally, we used the M2 and XLD2 statistics to evaluate a diagnostic model fit to data from the Trends in Mathematics and Science Study, drawing upon analyses previously conducted by Lee et al., (2011, IJT, 11, 144).


Exploring transcriptomic diversity in muscle revealed that cellular signaling pathways mainly differentiate five Western porcine breeds.
Among transcriptomic studies, those comparing species or populations can increase our understanding of the impact of the evolutionary forces on the differentiation of populations. A particular situation is the one of short evolution time with breeds of a domesticated species that underwent strong selective pressures. In this study, the gene expression diversity across five pig breeds has been explored in muscle. Samples came from: 24 Duroc, 33 Landrace, 41 Large White dam line, 10 Large White sire line and 39 Piétrain. From these animals, 147 muscle samples obtained at slaughter were analyzed using the porcine Agilent 44 K v1 microarray. A total of 12,358 genes were identified as expressed in muscle after normalization and 1,703 genes were declared differential for at least one breed (FDR < 0.001). The functional analysis highlighted that gene expression diversity is mainly linked to cellular signaling pathways such as the PI3K (phosphoinositide 3-kinase) pathway. The PI3K pathway is known to be involved in the control of development of the skeletal muscle mass by affecting extracellular matrix - receptor interactions, regulation of actin cytoskeleton pathways and some metabolic functions. This study also highlighted 228 spots (171 unique genes) that differentiate the breeds from each other. A common subgroup of 15 genes selected by three statistical methods was able to differentiate Duroc, Large White and Piétrain breeds. This study on transcriptomic differentiation across Western pig breeds highlighted a global picture: mainly signaling pathways were affected. This result is consistent with the selection objective of increasing muscle mass. These transcriptional changes may indicate selection pressure or simply breed differences which may be driven by human selection. Further work aiming at comparing genetic and transcriptomic diversities would further increase our understanding of the consequences of human impact on livestock species.


A Comparison Study of Classifier Algorithms for Cross-Person Physical Activity Recognition.
Physical activity is widely known to be one of the key elements of a healthy life. The many benefits of physical activity described in the medical literature include weight loss and reductions in the risk factors for chronic diseases. With the recent advances in wearable devices, such as smartwatches or physical activity wristbands, motion tracking sensors are becoming pervasive, which has led to an impressive growth in the amount of physical activity data available and an increasing interest in recognizing which specific activity a user is performing. Moreover, big data and machine learning are now cross-fertilizing each other in an approach called "deep learning", which consists of massive artificial neural networks able to detect complicated patterns from enormous amounts of input data to learn classification models. This work compares various state-of-the-art classification techniques for automatic cross-person activity recognition under different scenarios that vary widely in how much information is available for analysis. We have incorporated deep learning by using Google's TensorFlow framework. The data used in this study were acquired from PAMAP2 (Physical Activity Monitoring in the Ageing Population), a publicly available dataset containing physical activity data. To perform cross-person prediction, we used the leave-one-subject-out (LOSO) cross-validation technique. When working with large training sets, the best classifiers obtain very high average accuracies (e.g., 96% using extra randomized trees). However, when the data volume is drastically reduced (where available data are only 0.001% of the continuous data), deep neural networks performed the best, achieving 60% in overall prediction accuracy. We found that even when working with only approximately 22.67% of the full dataset, we can statistically obtain the same results as when working with the full dataset. This finding enables the design of more energy-efficient devices and facilitates cold starts and big data processing of physical activity records.


Geographic inequities in liver allograft supply and demand: does it affect patient outcomes?
Significant geographic inequities mar the distribution of liver allografts for transplantation. We analyzed the effect of geographic inequities on patient outcomes. During our study period (January 1 through December 31, 2010), 11,244 adult candidates were listed for liver transplantation: 5,285 adult liver allografts became available, and 5,471 adult recipients underwent transplantation. We obtained population data from the 2010 United States Census. To determine the effect of regional supply and demand disparities on patient outcomes, we performed linear regression and multivariate Cox regression analyses. Our proposed disparity metric, the ratio of listed candidates to liver allografts available varied from 1.3 (region 11) to 3.4 (region 1). When that ratio was used as the explanatory variable, the R(2) values for outcome measures were as follows: 1-year waitlist mortality, 0.23 and 1-year posttransplant survival, 0.27. According to our multivariate analysis, the ratio of listed candidates to liver allografts available had a significant effect on waitlist survival (hazards ratio, 1.21; 95% confidence interval, 1.04-1.40) but was not a significant risk factor for posttransplant survival. We found significant differences in liver allograft supply and demand--but these differences had only a modest effect on patient outcomes. Redistricting and allocation-sharing schemes should seek to equalize regional supply and demand rather than attempting to equalize patient outcomes.


Natural history of vancomycin-resistant enterococcal colonization in liver and kidney transplant recipients.
At Mayo Medical Center (Rochester, MN), surveillance rectal (and other-site) cultures have been routinely collected from liver transplant recipients as part of a selective bowel decontamination program. Beginning in 1995, vancomycin-resistant enterococcus (VRE) colonization and infection were identified in Mayo Clinic liver and kidney transplant patients through our surveillance cultures. The purpose of this study is to describe the natural history of VRE colonization in this patient population. Fifty-two patients with VRE colonization (predominantly with a single vanB clone) were identified from September 1995 through December 1997. Five hundred ninety cultures were reviewed for this study (mean, 11.3 cultures/patient). The median time from initial VRE colonization to the last surveillance culture obtained was 306 days (range, 1 to 1,393 days). VRE infection was documented in 6 patients (11.3%). Eighteen patients (35%) met the criteria for clearance of VRE colonization, defined as VRE-negative rectal culture results on at least 3 consecutive occasions greater than 1 week apart. However, VRE was detected on subsequent surveillance cultures from 2 of these patients (11% relapse rate). Of the remaining 34 patients, 16 remained colonized with VRE and 18 did not meet the definition for clearance of VRE colonization because of incomplete follow-up. This study documents that VRE colonization usually persists for months to years in liver and kidney transplant patients.


Mechanically dependent changes in action potentials recorded from the intact frog ventricle.
The wall of the ventricle contracts inhomogeneously during an isovolumic beat of an isolated, intact frog ventricle. Some epicardial segments actually lengthen while the pressure is rising. Almost simultaneously, the early repolarization phase of the monophasic action potential recorded from such a segment is accelerated, compared to the same phase for an isotonic beat in which the segment shortens. Segment lengthening during the isovolumic beat also may be seen during the late repolarization phase when, in contract to the above, it produces an afterdepolarization. These electrical changes disappear when isotonic contraction is restored. Corroborative findings were obtained from microelectrode and insulated gap recordings from isolated frog ventricular strip. Both electrical changes can be seen clearly when the segment is lengthened by intraventricular injections of Ringer's solution. There also is a short transition period toward the end of the action potential plateau when lengthening produces neither depolarization nor repolarization. The accelerated repolarization is manifest as a shortening of the Q-T interval in the ventricular electrogram. In all experimental preparations, the afterdepolarizations reached threshold for a propagated action potential. This mechanism may explain the generation of extrasystoles in myocardial ischemia.


Current position of phenobarbital in epilepsy and its future.
This article reviews the current position of phenobarbital using articles published since 2000 and speculates on its likely future contribution to epilepsy care. Over the last decade there have been no major double-blind randomized placebo-controlled or comparative trials with phenobarbital. Previous studies have suggested that phenobarbital is as effective in monotherapy as phenytoin and carbamazepine. Several observational studies undertaken in developing countries over the last decade have confirmed its efficacy and safety for the common epilepsies. This was particularly so in the substantial demonstration project undertaken in rural China under the auspices of the World Health Organization in partnership with the International League Against Epilepsy and International Bureau for Epilepsy. Phenobarbital is still widely used for neonatal and childhood seizures and for drug-resistant convulsive and nonconvulsive status epilepticus. Recent data have confirmed in a prospective cohort of women taking phenobarbital as monotherapy that the drug can be associated with a range of congenital defects in exposed infants. Much effort has gone into exploring the apparent contradiction of higher withdrawal rates due to cognitive and behavioral side effects in studies undertaken in developed countries but not in those sited in the developing world. A raft of data over the last 10 years, including a systematic review, showed no important differences between the tolerability of phenobarbital compared to that with other antiepileptic drugs. Finally, cognitive test scores and mood ratings in 136 people with epilepsy receiving phenobarbital for a year were similar to those in 137 age-, sex-, and education-matched controls in a number of Chinese villages. Indeed, there were some cognitive gains in the patients possibly due to improved seizure control. Phenobarbital is still the most cost-effective pharmacologic treatment for epilepsy. All these data predict a healthy future for phenobarbital, particularly in helping to close the treatment gap in low- and middle-income countries during its second century of clinical use.


Reflections on a complex intervention targeting healthy eating in young children.
In this article, the author offers her experiences of conducting a public health nursing intervention based on the use of the Medical Research Council framework for complex interventions. This article provides examples aimed at helping and inspiring others who might be interested in conducting a complex intervention study. The intervention focused on counseling about food and feeding practices provided by public health nurses in a sample of child health centers in Norway 2015-2018. Aspects of food and nutrition are central to public health nurses' counseling at the child health center, and they experience challenges when counseling on these themes. This article offers an approach to handling the complexity of public health nursing interventions on counseling among families. The topics presented on planning and performing an intervention and the related challenges might have relevance for public health nursing in several countries.


Comparison of Etomidate, Benzocaine, and MS222 Anesthesia with and without Subsequent Flunixin Meglumine Analgesia in African Clawed Frogs (Xenopus laevis).
Often few alternative anesthetics for exotic species are available, due to the small numbers of these animals used in research. In this study, we evaluated the depth and duration of anesthesia in Xenopus laevis after their immersion in 3 doses of etomidate (15, 22.5, and 30 mg/L) and in 3 doses of benzocaine (0.1%, 0.5%, and 1%) compared with the 'gold standard,' tricaine methanesulfonate (MS222; 2 g/L). We then chose an optimal dose for each alternative anesthetic according to induction time, duration of surgical plane, and time to complete recovery. The optimal etomidate and benzocaine doses (22.5 mg/L and 0.1%, respectively) as well as the MS222 dose were then used to achieve a surgical plane of anesthesia, with the addition of flunixin meglumine (25 or 50 mg/kg) administered in the dorsal lymph sac at the completion of mock oocyte harvest. Efficacy of the analgesic was assessed at 1, 3, 6, and 24 h postoperatively by using acetic acid testing (AAT). Histology of the liver, kidney, and tissues surrounding the dorsal lymph sac was performed at day 3, 14, and 28 in each group of animals. Mild to moderate myocyte degeneration and necrosis were present in tissues surrounding the dorsal lymph sac at both flunixin meglumine doses after etomidate and benzocaine anesthesia. In addition, the 50-mg/kg dose of flunixin meglumine resulted in the death of 5 of the 12 frogs within 24 h, despite an otherwise uneventful anesthetic recovery. In conclusion, benzocaine and etomidate offer alternative anesthetic regimens, according to typical requirements for an anesthetic event. Flunixin meglumine at the 25-mg/kg dose provided analgesic relief at the latest time point during etomidate dosage and at all time points during benzocaine dosage, but further characterization is warranted regarding long-term or repeated analgesic administration.


High-resolution x-ray structure and functional analysis of the murine norovirus 1 capsid protein protruding domain.
Murine noroviruses (MNV) are closely related to the human noroviruses (HuNoV), which cause the majority of nonbacterial gastroenteritis. Unlike HuNoV, MNV grow in culture and in a small-animal model that represents a tractable model to study norovirus biology. To begin a detailed investigation of molecular events that occur during norovirus binding to cells, the crystallographic structure of the murine norovirus 1 (MNV-1) capsid protein protruding (P) domain has been determined. Crystallization of the bacterially expressed protein yielded two different crystal forms (Protein Data Bank identifiers [PDB ID], 3LQ6 and 3LQE). Comparison of the structures indicated a large degree of structural mobility in loops on the surface of the P2 subdomain. Specifically, the A'-B' and E'-F' loops were found in open and closed conformations. These regions of high mobility include the known escape mutation site for the neutralizing antibody A6.2 and an attenuation mutation site, which arose after serial passaging in culture and led to a loss in lethality in STAT1(-/-) mice, respectively. Modeling of a Fab fragment and crystal structures of the P dimer into the cryoelectron microscopy three-dimensional (3D) image reconstruction of the A6.2/MNV-1 complex indicated that the closed conformation is most likely bound to the Fab fragment and that the antibody contact is localized to the A'-B' and E'-F' loops. Therefore, we hypothesize that these loop regions and the flexibility of the P domains play important roles during MNV-1 binding to the cell surface.


Factors Moderating the Association Between Cannabis Use and Psychosis Risk: A Systematic Review.
Increasing evidence indicates a relationship between cannabis use and psychosis risk. Specific factors, such as determinants of cannabis use or the genetic profile of cannabis users, appear to moderate this association. The present systematic review presents a detailed and up-to-date literature overview on factors that influence the relationship between cannabis use and psychosis risk. A systematic search was performed according to the PRISMA guidelines in MEDLINE and Embase, and 56 studies were included. The results show that, in particular, frequent cannabis use, especially daily use, and the consumption of high-potency cannabis are associated with a higher risk of developing psychosis. Moreover, several genotypes moderate the impact of cannabis use on psychosis risk, particularly those involved in the dopamine function, such as AKT1. Finally, cannabis use is associated with an earlier psychosis onset and increased risk of transition in individuals at a clinical high risk of psychosis. These findings indicate that changing cannabis use behavior could be a harm reduction strategy employed to lower the risk of developing psychosis. Future research should aim to further develop specific biomarkers and genetic profiles for psychosis, thereby contributing to the identification of individuals at the highest risk of developing a psychotic disorder.


Integration of microfluidics into the synthetic biology design flow.
One goal of synthetic biology is to design and build genetic circuits in living cells for a range of applications. Major challenges in these efforts include increasing the scalability and robustness of engineered biological systems and streamlining and automating the synthetic biology workflow of specification-design-assembly-verification. We present here a summary of the advances in microfluidic technology, particularly microfluidic large scale integration, that can be used to address the challenges facing each step of the synthetic biology workflow. Microfluidic technologies allow precise control over the flow of biological content within microscale devices, and thus may provide more reliable and scalable construction of synthetic biological systems. The integration of microfluidics and synthetic biology has the capability to produce rapid prototyping platforms for characterization of genetic devices, testing of biotherapeutics, and development of biosensors.


Can markets give us the health system we want?
The purpose of this article is to reconsider the foundations of health economics as applied to the study of competition. It shows that conclusions concerning the purported desirability of competitive markets are based on a number of assumptions--many of which have heretofore been ignored--that typically are not fulfilled in the health care area. Once this is recognized market mechanisms no longer necessarily provide the best way to improve social welfare. The article is divided into two parts: competition and demand. Each of these sections presents and then critiques key assumptions of the conventional economic model, and then provides a number of health applications. It concludes that by not considering the validity of these assumptions in health care applications, researchers and policy analysts will bind themselves to policy options that may be most effective in improving social welfare.


Alcohol distribution reforms and school proximity to liquor sales outlets in New Brunswick.
The purpose of this project was to evaluate how changes to the sale of alcohol in New Brunswick would be distributed across urban and rural communities, and low- and high-income neighbourhoods. The study objectives were to 1) estimate the population living close to alcohol outlets before and after liquor distribution reforms, 2) identify communities or regions that would be more or less affected, and 3) determine whether expanding access to alcohol products would reduce school proximity to retailers. Data from Statistics Canada, Desktop Mapping Technologies Inc. (DMTI), and geocoded publicly available information were spatially linked and analyzed using descriptive statistics. The populations living within 499 m, 500-999 m and 1-5 km of an outlet were estimated, and the distances from schools to stores were examined by geographic characteristics and neighbourhood socio-economic status. Permitting the sale of alcohol in all grocery stores throughout the province would increase the number of liquor outlets from 153 to 282 and would increase the population residing within 499 m of an outlet by 97.49%, from 19 886 to 39 273 residents. The sale of alcohol in grocery stores would result in an additional 35 liquor sales outlets being located within 499 m of schools. Low-income neighbourhoods would have the highest number and proportion of stores within 499 m of schools. The findings of this study demonstrate the importance of considering social, economic and health inequities in the context of alcohol policy reforms that will disproportionately affect low-income neighbourhoods and youth living within these areas.


High prevalence of stroke symptoms among persons without a diagnosis of stroke or transient ischemic attack in a general population: the REasons for Geographic And Racial Differences in Stroke (REGARDS) study.
A substantial portion of the general population has clinically silent stroke on brain imaging. These lesions may cause symptoms. This study assessed the prevalence of stroke symptoms in a stroke- and transient ischemic attack (TIA)-free population and the association of symptoms with risk factors indexed by the Framingham Stroke Risk Score. We performed a cross-sectional analysis from a randomly sampled national cohort enrolled from January 25, 2003, through November 30, 2005, with oversampling from the southeastern stroke belt and African American populations. The main outcome measure was stroke symptoms assessed by validated questionnaire. The study included 18 462 (41% African American; 51% female; mean age, 65.8 years) participants who reported no stroke or TIA. The prevalence of stroke symptoms was 5.8% for sudden painless hemibody weakness, 8.5% for sudden hemibody numbness, 4.6% for sudden painless loss of vision in one or both eyes, 3.1% for sudden hemifield visual loss, 2.7% for sudden inability to understand speech, and 3.8% for sudden inability of linguistic expression. The prevalence of 1 or more symptoms was 17.8%. Relative to the first quartile of the Framingham Stroke Risk Score, the adjusted odds ratio for 1 or more stroke symptoms increased from 1.0 (95% confidence interval [CI], 0.90-1.2) in the second quartile to 1.2 (95% CI, 1.1-1.5) and 1.5 (95% CI, 1.3-1.6) in successive quartiles. Symptoms were more prevalent among African American compared with white participants and among those with lower income, lower educational level, and fair to poor perceived health status. The general population without prior diagnosed stroke or TIA has a high prevalence of stroke symptoms. The relationship between symptoms and risk factors suggests that some symptomatic individuals may have had clinically undetected cerebrovascular events and may benefit from aggressive stroke prophylaxis.


Biological Treatment of Cyanide by Using Klebsiella pneumoniae Species.
In this study, optimization conditions for cyanide biodegradation by Klebsiella pneumoniae strain were determined to be 25 °C, pH=7 and 150 rpm at the concentration of 0.5 mM potassium cyanide in the medium. Additionally, it was found that K. pneumoniae strain is not only able to degrade potassium cyanide, but also to degrade potassium hexacyanoferrate(II) trihydrate and sodium ferrocyanide decahydrate with the efficiencies of 85 and 87.5%, respectively. Furthermore, this strain degraded potassium cyanide in the presence of different ions such as magnesium, nickel, cobalt, iron, chromium, arsenic and zinc, in variable concentrations (0.1, 0.25 and 0.5 mM) and as a result the amount of the bacteria in the biodegradation media decreased with the increase of ion concentration. Lastly, it was also observed that sterile crude extract of K. pneumoniae strain degraded potassium cyanide on the fifth day of incubation. Based on these results, it is concluded that both culture and sterile crude extract of K. pnemoniae will be used in cyanide removal from different wastes.


Antioxidant intervention blunts renal injury in experimental renovascular disease.
Atherosclerotic renovascular disease (RVD) amplifies damage in a stenotic kidney by inducing pro-inflammatory mechanisms and disrupting tissue remodeling. Oxidative stress is increased in RVD, but its direct contribution to renal injury has not been fully established. The authors hypothesized that chronic antioxidant intervention in RVD would improve renal function and attenuate tissue injury. Single-kidney hemodynamics and function at baseline and during vasoactive challenge were quantified using electron-beam computed tomography in pigs after 12 wk of experimental RVD (simulated by concurrent hypercholesterolemia and renal artery stenosis, n = 7), RVD daily supplemented with antioxidant vitamins C (1 g), and E (100 IU/kg) (RVD+Vitamins, n = 7), or controls (normal, n = 7). Renal tissue was studied ex vivo using Western blot analysis and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate (GFR) were similarly decreased in the stenotic kidney of both RVD groups. RBF and GFR response to acetylcholine was blunted in RVD, but significantly improved in RVD+Vitamins (P < 0.05 versus RVD). RVD+Vitamins also showed increased renal expression of endothelial nitric oxide synthase (eNOS) and decreased expression of NAD(P)H-oxidase, nitrotyrosine, inducible-NOS, and NF-kappaB, suggesting decreased superoxide abundance and inflammation. Furthermore, decreased expression of pro-fibrotic factors in RVD+Vitamins was accompanied by augmented expression of extracellular (matrix metalloproteinase-2) and intracellular (ubiquitin) protein degradation systems, resulting in significantly attenuated glomerulosclerosis and renal fibrosis. In conclusion, chronic antioxidant intervention in early experimental RVD improved renal functional responses, enhanced tissue remodeling, and decreased structural injury. This study supports critical pathogenic contribution of increased oxidative stress to renal injury and scarring in RVD and suggests a role for antioxidant strategies in preserving the atherosclerotic and ischemic kidney.


Short RNAs repress translation after initiation in mammalian cells.
MicroRNAs (miRNAs) are predicted to regulate 30% of mammalian protein-encoding genes by interactions with their 3' untranslated regions (UTRs). We use partially complementary siRNAs to investigate the mechanism by which miRNAs mediate translational repression in human cells. Repressed mRNAs are associated with polyribosomes that are engaged in translation elongation, as shown by puromycin sensitivity. The inhibition appears to be postinitiation because translation driven by the cap-independent processes of HCV IRES and CrPV IRES is repressed by short RNAs. Further, metabolic labeling suggests that silencing occurs before completion of the nascent polypeptide chain. In addition, silencing by short RNAs causes a decrease in translational readthrough at a stop codon, and ribosomes on repressed mRNAs dissociate more rapidly after a block of initiation of translation than those on control mRNAs. These results suggest that repression by short RNAs, and thus probably miRNAs, is primarily due to ribosome drop off during elongation of translation.


The Internet-Based Conversational Engagement Clinical Trial (I-CONECT) in Socially Isolated Adults 75+ Years Old: Randomized Controlled Trial Protocol and COVID-19 Related Study Modifications.
Background: Increasing social interactions through communication technologies could offer a cost-effective prevention approach that slows cognitive decline and delays the onset of Alzheimer's disease. This paper describes the protocol of an active project named "Internet-based conversational engagement clinical trial (I-CONECT)" (ClinicalTrials.gov: NCT02871921). The COVID-19 pandemic related protocol modifications are also addressed in the current paper. Methods: I-CONECT is a multi-site, assessor-blind, randomized controlled behavioral intervention trial (RCT). We aim to randomize 320 socially isolated adults 75+ years old [160 Caucasian and 160 African American participants, 50:50 split between those with normal cognition and mild cognitive impairment (MCI)] recruited from the community to either the video chat intervention group or the control group (1:1 allocation). Those in the video chat group receive a computer and Internet service for the duration of the study, which they use to video chat with study staff for 30 min/day 4×/week for 6 months (high dose), and then 2×/week for an additional 6 months (maintenance dose). Both video chat and control groups have a brief (about 10 min) telephone check-in with study staff once per week. The primary outcome is the change in global cognitive function measured by Montreal Cognitive Assessment (MoCA) from baseline to 6 months. Secondary outcomes include changes in cognition in memory and executive function domains, emotional well-being measured by NIH Toolbox emotional battery, and daily functional abilities assessed with the Revised Observed Tasks of Daily Living (OTDL-R). Eligible participants have MRIs at baseline and 6 months. Participants contribute saliva for genetic testing (optional consent), and all video chats, weekly check-in calls and neuropsychological assessment sessions are recorded for speech and language analysis. The pandemic halted research activities and resulted in protocol modifications, including replacing in-person assessment with remote assessment, remote deployment of study equipment, and revised targeted sample size. Discussion: This trial provides user-friendly hardware for the conversational-based intervention that can be easily provided at participants' homes. The trial aspires to use age and culture-specific conversational materials and a related platform developed in this trial for enhancing cognitive reserve and improving cognitive function.


A universal measure of chaotropicity and kosmotropicity.
Diverse parameters, including chaotropicity, can limit the function of cellular systems and thereby determine the extent of Earth's biosphere. Whereas parameters such as temperature, hydrophobicity, pressure, pH, Hofmeister effects, and water activity can be quantified via standard scales of measurement, the chao-/kosmotropic activities of environmentally ubiquitous substances have no widely accepted, universal scale. We developed an assay to determine and quantify chao-/kosmotropicity for 97 chemically diverse substances that can be universally applied to all solutes. This scale is numerically continuous for the solutes assayed (from +361 kJ kg(-1) mol(-1) for chaotropes to -659 kJ kg(-1) mol(-1) for kosmotropes) but there are key points that delineate (i) chaotropic from kosmotropic substances (i.e. chaotropes ≥ +4; kosmotropes ≤ -4 kJ kg(-1) mol(-1) ); and (ii) chaotropic solutes that are readily water-soluble (log P < 1.9) from hydrophobic substances that exert their chaotropic activity, by proxy, from within the hydrophobic domains of macromolecular systems (log P > 1.9). Examples of chao-/kosmotropicity values are, for chaotropes: phenol +143, CaCl(2) +92.2, MgCl(2) +54.0, butanol +37.4, guanidine hydrochloride +31.9, urea +16.6, glycerol [> 6.5 M] +6.34, ethanol +5.93, fructose +4.56; for kosmotropes: proline -5.76, sucrose -6.92, dimethylsulphoxide (DMSO) -9.72, mannitol -6.69, trehalose -10.6, NaCl -11.0, glycine -14.2, ammonium sulfate -66.9, polyethylene glycol- (PEG-)1000 -126; and for relatively neutral solutes: methanol, +3.12, ethylene glycol +1.66, glucose +1.19, glycerol [< 5 M] +1.06, maltose -1.43 (kJ kg(-1) mol(-1)). The data obtained correlate with solute interactions with, and structure-function changes in, enzymes and membranes. We discuss the implications for diverse fields including microbial ecology, biotechnology and astrobiology.


Nucleolin participates in DNA double-strand break-induced damage response through MDC1-dependent pathway.
H2AX is an important factor for chromatin remodeling to facilitate accumulation of DNA damage-related proteins at DNA double-strand break (DSB) sites. In order to further understand the role of H2AX in the DNA damage response (DDR), we attempted to identify H2AX-interacting proteins by proteomics analysis. As a result, we identified nucleolin as one of candidates. Here, we show a novel role of a major nucleolar protein, nucleolin, in DDR. Nucleolin interacted with γ-H2AX and accumulated to laser micro-irradiated DSB damage sites. Chromatin Immunoprecipitation assay also displayed the accumulation of nucleolin around DSB sites. Nucleolin-depleted cells exhibited repression of both ATM-dependent phosphorylation following exposure to γ-ray and subsequent cell cycle checkpoint activation. Furthermore, nucleolin-knockdown reduced HR and NHEJ activity and showed decrease in IR-induced chromatin accumulation of HR/NHEJ factors, agreeing with the delayed kinetics of γ-H2AX focus. Moreover, nucleolin-knockdown decreased MDC1-related events such as focus formation of 53 BP1, RNF168, phosphorylated ATM, and H2A ubiquitination. Nucleolin also showed FACT-like activity for DSB damage-induced histone eviction from chromatin. Taken together, nucleolin could promote both ATM-dependent cell cycle checkpoint and DSB repair by functioning in an MDC1-related pathway through its FACT-like function.


Management of axilla in breast cancer - The saga continues.
Prospective trials investigating the accuracy of SLNB for cN0 (primary surgical therapy) and cN1 patients (neoadjuvant chemotherapy) have not utilized likelihood ratios (LR) to assess the impact of false negative SLNB. This review evaluates the evidence on accuracy of SLNB using STARD and QUADAS-2 (revised) criteria for patients undergoing primary surgical therapy and primary chemotherapy. It utilizes the: (i) Reported rates for pre-test probabilities of node positive disease from Surveillance, Epidemiology, and End Results (SEER) database for the cN0 patients (primary surgical therapy) for each T stage; calculates the negative LR from cumulative evidence; and uses the Bayesian nomogram to compute the post-test probability of missing the metastatic axillary node based on negative SLNB. (ii) Reported rates of complete axillary response in ACOSOG-Z1071 trial for cN1 patients to calculate the pre-test probabilities of residual nodal disease for each biological tumor sub-type; calculates the negative LR from ACOSOG-Z1071, and SENTINA trial data; and uses the Bayesian nomogram to compute the post-test probability of missing the residual metastatic axillary node based on negative SLNB. For cN0 disease, the odds of missing axillary disease based on negative SLNB for each T stage are: T1a = 0.7%; T1b = 1.5%; T1c = 3%; T2 = 7%; T3 = 18%. For cN1 disease, the odds of missing residual axillary disease based on negative SLNB for each biological subtype are: HER2neu+ = 8%; Triple negative = 15%; ER+/PR+/HER2neu- = 45%. Negative LR is more accurate and superior to false negative rate for determining the clinical utility of SLNB by taking into account the changing pre-test probability of disease.


Rapid and label-free identification of single leukemia cells from blood in a high-density microfluidic trapping array by fluorescence lifetime imaging microscopy.
The rapid screening and isolation of single leukemia cells from blood has become critical for early leukemia detection and tumor heterogeneity interrogation. However, due to the size overlap between leukemia cells and the more abundant white blood cells (WBCs), the isolation and identification of leukemia cells individually from peripheral blood is extremely challenging and often requires immunolabeling or cytogenetic assays. Here we present a rapid and label-free single leukemia cell identification platform that combines: (1) high-throughput size-based separation of hemocytes via a single-cell trapping array, and (2) leukemia cell identification through phasor approach and fluorescence lifetime imaging microscopy (phasor-FLIM), to quantify changes between free/bound nicotinamide adenine dinucleotide (NADH) as an indirect measurement of metabolic alteration in living cells. The microfluidic trapping array designed with 1600 highly-packed addressable single-cell traps can simultaneously filter out red blood cells (RBCs) and trap WBCs/leukemia cells, and is compatible with low-magnification imaging and fast-speed fluorescence screening. The trapped single leukemia cells, e.g., THP-1, Jurkat and K562 cells, are distinguished from WBCs in the phasor-FLIM lifetime map, as they exhibit significant shift towards shorter fluorescence lifetime and a higher ratio of free/bound NADH compared to WBCs, because of their glycolysis-dominant metabolism for rapid proliferation. Based on a multiparametric scheme comparing the eight parameter-spectra of the phasor-FLIM signatures, spiked leukemia cells are quantitatively distinguished from normal WBCs with an area-under-the-curve (AUC) value of 1.00. Different leukemia cell lines are also quantitatively distinguished from each other with AUC values higher than 0.95, demonstrating high sensitivity and specificity for single cell analysis. The presented platform is the first to enable high-density size-based single-cell trapping simultaneously with RBC filtering and rapid label-free individual-leukemia-cell screening through non-invasive metabolic imaging. Compared to conventional biomolecular diagnostics techniques, phasor-FLIM based single-cell screening is label-free, cell-friendly, robust, and has the potential to screen blood in clinical volumes through parallelization.


5S RNA synthesized by Escherichia coli in presence of chloramphenicol: different 5'-terminal sequences.
Escherichia coli cells, grown in the presence of chloramphenicol, synthesize a low molecular weight RNA (CM-5S RNA) not bound to ribosomes which is similar to ribosomal 5S RNA. Oligonucleotide patterns derived from ribonuclease digests of 5S RNA and of CM-5S RNA are indistinguishable except that the 5'-terminal oligonucleotides differ. Whereas the nucleotide sequence of the 5'-terminus of normal 5S RNA is (p)U(p)G-, there are three alternate sequences of the 5'-terminus of CM-5S RNA: (p)U(p)U(p)G-, (p)U(p)U(p)U(p)G-, and (p)A(p)U(p)U(p)U(p)G-.


Reversible self-assembly of patchy particles into monodisperse icosahedral clusters.
We systematically study the design of simple patchy sphere models that reversibly self-assemble into monodisperse icosahedral clusters. We find that the optimal patch width is a compromise between structural specificity (the patches must be narrow enough to energetically select the desired clusters) and kinetic accessibility (they must be sufficiently wide to avoid kinetic traps). Similarly, for good yields the temperature must be low enough for the clusters to be thermodynamically stable, but the clusters must also have enough thermal energy to allow incorrectly formed bonds to be broken. Ordered clusters can form through a number of different dynamic pathways, including direct nucleation and indirect pathways involving large disordered intermediates. The latter pathway is related to a reentrant liquid-to-gas transition that occurs for intermediate patch widths upon lowering the temperature. We also find that the assembly process is robust to inaccurate patch placement up to a certain threshold and that it is possible to replace the five discrete patches with a single ring patch with no significant loss in yield.


The potential of circulating extracellular small RNAs (smexRNA) in veterinary diagnostics-Identifying biomarker signatures by multivariate data analysis.
Worldwide growth and performance-enhancing substances are used in cattle husbandry to increase productivity. In certain countries however e.g., in the EU, these practices are forbidden to prevent the consumers from potential health risks of substance residues in food. To maximize economic profit, 'black sheep' among farmers might circumvent the detection methods used in routine controls, which highlights the need for an innovative and reliable detection method. Transcriptomics is a promising new approach in the discovery of veterinary medicine biomarkers and also a missing puzzle piece, as up to date, metabolomics and proteomics are paramount. Due to increased stability and easy sampling, circulating extracellular small RNAs (smexRNAs) in bovine plasma were small RNA-sequenced and their potential to serve as biomarker candidates was evaluated using multivariate data analysis tools. After running the data evaluation pipeline, the proportion of miRNAs (microRNAs) and piRNAs (PIWI-interacting small non-coding RNAs) on the total sequenced reads was calculated. Additionally, top 10 signatures were compared which revealed that the readcount data sets were highly affected by the most abundant miRNA and piRNA profiles. To evaluate the discriminative power of multivariate data analyses to identify animals after veterinary drug application on the basis of smexRNAs, OPLS-DA was performed. In summary, the quality of miRNA models using all mapped reads for both treatment groups (animals treated with steroid hormones or the β-agonist clenbuterol) is predominant to those generated with combined data sets or piRNAs alone. Using multivariate projection methodologies like OPLS-DA have proven the best potential to generate discriminative miRNA models, supported by small RNA-Seq data. Based on the presented comparative OPLS-DA, miRNAs are the favorable smexRNA biomarker candidates in the research field of veterinary drug abuse.


Root waving and skewing: unexpectedly in micro-g.
Gravity has major effects on both the form and overall length of root growth. Numerous papers have documented these effects (over 300 publications in the last 5 years), the most well-studied being gravitropism, which is a growth re-orientation directed by gravity toward the earth's center. Less studied effects of gravity are undulations due to the regular periodic change in the direction root tips grow, called waving, and the slanted angle of growth roots exhibit when they are growing along a nearly-vertical surface, called skewing. Although diverse studies have led to the conclusion that a gravity stimulus is needed for plant roots to show waving and skewing, the novel results just published by Paul et al. (2012) reveal that this conclusion is not correct. In studies carried out in microgravity on the International Space Station, the authors used a new imaging system to collect digital photographs of plants every six hours during 15 days of spaceflight. The imaging system allowed them to observe how roots grew when their orientation was directed not by gravity but by overhead LED lights, which roots grew away from because they are negatively phototropic. Surprisingly, the authors observed both skewing and waving in spaceflight plants, thus demonstrating that both growth phenomena were gravity independent. Touch responses and differential auxin transport would be common features of root waving and skewing at 1-g and micro-g, and the novel results of Paul et al. will focus the attention of cell and molecular biologists more on these features as they try to decipher the signaling pathways that regulate root skewing and waving.


Competitive reactions of organophosphorus radicals on coke surfaces.
The efficacy of organophosphorus radicals as anticoking agents was subjected to a computational study in which a representative set of radicals derived from industrially relevant organophosphorus additives was used to explore competitive reaction pathways on the graphene-like coke surface formed during thermal cracking. The aim was to investigate the nature of the competing reactions of different organophosphorus radicals on coke surfaces, and elucidate their mode of attack and inhibiting effect on the forming coke layer by use of contemporary computational methods. Density functional calculations on benzene and a larger polyaromatic hydrocarbon, namely, ovalene, showed that organophosphorus radicals have a high propensity to add to the periphery of the coke surface, inhibiting methyl radical induced hydrogen abstraction, which is known to be a key step in coke growth. Low addition barriers reported for a phosphatidyl radical suggest competitive aptitude against coke formation. Moreover, organophosphorus additives bearing aromatic substituents, which were shown to interact with the coke surface through dispersive π-π stacking interactions, are suggested to play a nontrivial role in hindering further stacking among coke surfaces. This may be the underlying rationale behind experimental observation of softer coke in the presence of organophosphorus radicals. The ultimate goal is to provide information that will be useful in building single-event microkinetic models. This study presents pertinent information on potential reactions that could be taken up in these models.


Energy efficiency of mobile soft robots.
The performance of mobile soft robots is usually characterized by their locomotion/velocity efficiency, whereas the energy efficiency is a more intrinsic and fundamental criterion for the performance evaluation of independent or integrated soft robots. In this work, a general framework is established to evaluate the energy efficiency of mobile soft robots by considering the efficiency of the energy source, actuator and locomotion, and some insights for improving the efficiency of soft robotic systems are presented. Proposed as the ratio of the desired locomotion kinetic energy to the input mechanical energy, the energy efficiency of locomotion is found to play a critical role in determining the overall energy efficiency of soft robots. Four key factors related to the locomotion energy efficiency are identified, that is, the locomotion modes, material properties, geometric sizes, and actuation states. It is found that the energy efficiency of most mobile soft robots reported in the literature is surprisingly low (mostly below 0.1%), due to the inefficient mechanical energy that essentially does not contribute to the desired locomotion. A comparison of the locomotion energy efficiency for several representative locomotion modes in the literature is presented, showing a descending ranking as: jumping ≫ fish-like swimming > snake-like slithering > rolling > rising/turning over > inchworm-like inching > quadruped gait > earthworm-like squirming. Besides, considering the same locomotion mode, soft robots with lower stiffness, higher density and larger size tend to have higher locomotion energy efficiency. Moreover, a periodic pulse actuation instead of a continuous actuation mode may significantly reduce the input mechanical energy, thus improving the locomotion energy efficiency, especially when the pulse actuation matches the resonant states of the soft robots. The results presented herein indicate a large and necessary space for improving the locomotion energy efficiency, which is of practical significance for the future development and application of soft robots.