Riding (High) into the danger zone: a review of potential differences in chemical exposures in fighter pilots resulting from high altitude and G-forces.
When in flight, pilots of high performance aircraft experience conditions unique to their profession. Training flights, performed as often as several times a week, can expose these pilots to altitudes in excess of 15 km (~50,000 ft, with a cabin pressurized to an altitude of ~20,000 ft), and the maneuvers performed in flight can exacerbate the G-forces felt by the pilot. While the pilots specifically train to withstand these extreme conditions, the physiologic stress could very likely lead to differences in the disposition of chemicals in the body, and consequently, dangerously high exposures. Unfortunately, very little is known about how the conditions experienced by fighter pilots affects chemical disposition. Areas covered: The purpose of this review is to present information about the effects of high altitude, G-forces, and other conditions experienced by fighter pilots on chemical disposition. Using this information, the expected changes in chemical exposure will be discussed, using isopropyl alcohol as an example. Expert opinion: There is a severe lack of information concerning the effects of the fighter pilot environment on the pharmacokinetics and pharmacodynamics of chemicals. Given the possibility of exposure prior to or during flight, it is important that these potential effects be investigated further.


Roles of flavonoids against coronavirus infection.
In terms of public health, the 21st century has been characterized by coronavirus pandemics: in 2002-03 the virus SARS-CoV caused SARS; in 2012 MERS-CoV emerged and in 2019 a new human betacoronavirus strain, called SARS-CoV-2, caused the unprecedented COVID-19 outbreak. During the course of the current epidemic, medical challenges to save lives and scientific research aimed to reveal the genetic evolution and the biochemistry of the vital cycle of the new pathogen could lead to new preventive and therapeutic strategies against SARS-CoV-2. Up to now, there is no cure for COVID-19 and waiting for an efficacious vaccine, the development of "savage" protocols, based on "old" anti-inflammatory and anti-viral drugs represents a valid and alternative therapeutic approach. As an alternative or additional therapeutic/preventive option, different in silico and in vitro studies demonstrated that small natural molecules, belonging to polyphenol family, can interfere with various stages of coronavirus entry and replication cycle. Here, we reviewed the capacity of well-known (e.g. quercetin, baicalin, luteolin, hesperetin, gallocatechin gallate, epigallocatechin gallate) and uncommon (e.g. scutellarein, amentoflavone, papyriflavonol A) flavonoids, secondary metabolites widely present in plant tissues with antioxidant and anti-microbial functions, to inhibit key proteins involved in coronavirus infective cycle, such as PLpro, 3CLpro, NTPase/helicase. Due to their pleiotropic activities and lack of systemic toxicity, flavonoids and their derivative may represent target compounds to be tested in future clinical trials to enrich the drug arsenal against coronavirus infections.


EBV-associated hepatic smooth muscle tumor of uncertain biologic behavior after heart transplantation in a pediatric patient: case report.
Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) is a rare neoplasm recognized in immunocompromised patients. There are less than 30 cases of EBV-SMT reported in pediatric population following solid organ transplantation. Herein, we report a case of an 8-year-old female who was incidentally noted to have multiple lesions in the liver 8 years after heart transplantation. The tumor was composed of a cellular proliferation of spindle-shaped cells with low mitotic activity. The diagnosis of EBV-SMT was confirmed by in situ hybridization for EBV-encoded small RNA (EBER) transcripts. Multiple additional lesions were detected by whole body positron emission tomography-computed tomography (PET-CT) scan 4 months after the initial finding of the hepatic lesions. Immunosuppression was switched to a mechanistic target of rapamycin (mTOR) inhibitor. We conclude that EBV-SMT should be included in the differential diagnoses in post-transplantation patients and further investigations should be performed to evaluate additional lesions.


Comparison of Drug Use Between Clinical Practice and Regulatory Approval: Results in Older Japanese Patients With Rheumatoid Arthritis, Diabetes, High Blood Pressure, or Depression.
In this study, differences in older patients between drug use as reported in clinical practice and in clinical trials for regulatory approval were examined. Electronic medical record (EMR) data such as patient background (age, sex), concomitant drugs, data on laboratory tests, and prescribed doses of drugs from outpatients with rheumatoid arthritis, diabetes, high blood pressure, or depression at Chiba University Hospital were obtained for the period from January 2003 to December 2012. These data were compared with data from relevant clinical trials for regulatory approval in order to examine differences in drug use. There were 5134 eligible patients. The prescribed doses of drugs were lower than the standard approved doses for depression and rheumatoid arthritis but were generally within the approved dose range for type 2 diabetes mellitus and hypertension. When comparing the characteristics of older patients taking tacrolimus, 5.6% to 17.0% of those would not be able to participate in clinical trials because of liver or renal abnormality, and the incidence rates of some adverse drug events (ADEs) differed significantly between clinical practice and clinical trials. Appropriate doses of drugs for older patients may differ from approved doses in certain diseases. Complex situations such as a lot of polypharmacy, comorbidity, and functional impairment in older patients in clinical practice make it difficult to evaluate safety based on data from clinical trials. In the future, utilization of a database created from the EMR of older patients should be considered for assessment of drug safety in older patients in clinical practice.


Anisotropy, in density and in distance, of the dispersal of yellow rust of wheat: experiments in large field plots and estimation.
ABSTRACT Long-distance dispersal of spores generally presents anisotropy. This anisotropy can appear in the mean number of spores deposited along a given direction (anisotropy in density) and in the mean distance that a spore travels in a given direction (anisotropy in distance). Specific experiments together with a statistical methodology are proposed to study this effect. The experiments are based on the use of a point source of a traceable inoculum and susceptible trap plots in large resistant field plots. The anisotropy is characterized by two functions: a directional density function and a mean distance function which are related with the anisotropies in density and distance, respectively. A nonparametric approach is developed to estimate these functions and to help in choosing a parametric model. Then, the parametric model is estimated. In two field experiments, migrations up to 175 and 225 m from the source were detected, with approximately 25% of the trap plots infected. Whatever the experiment, the two estimated anisotropies presented different shapes (i.e., the number of spores dispersed in a given direction was not proportional to the mean distance travelled by these spores).


Autoradiographic study of binding and internalization of follicle-stimulating hormone in the mouse testis minces in vitro.
The internalization of FSH-receptor complexes was demonstrated in mouse testis by means of light and electron microscopic autoradiography. Chopped testicular pieces were incubated with radioiodinated FSH (131I-NIADDK-rat FSH-I-4) for 10, 20, 60 and 180 min. After incubation the pieces were fixed with glutaraldehyde containing tannic acid, and embedded in Spurr's resin. Semithin and ultrathin sections were cut for light and electron microscopic autoradiography, respectively. In light microscopic autoradiographs, silver grains were preferentially localized over Sertoli cells, regardless of incubation time. Sixty to 70% of the total number of grains were located over Sertoli cells which account for only about 4% of the total cell population of the seminiferous tubules. The majority of these grains correspond to the specific FSH binding sites, because few grains remained after incubation with an excess amount of unlabeled FSH. In electron microscopic autoradiographs, the half-distance (HD) value for the 131I-labeled line source was about 216 nm in the present study. After 10 min of incubation, 56.6% of the total number of silver grains were located over the plasma membrane of Sertoli cells. In testicular pieces incubated for longer periods (20, 60 and 180 min), both the percentage and relative concentration of grains increased in the Golgi apparatus and lysosomes and decreased in the plasma membrane. These results suggest that [131I]iodo-FSH first binds to FSH receptors on the plasma membrane of Sertoli cells, then FSH-receptor complexes are internalized. The increase in the number of grains over the lysosomes following longer incubation, indicates that internalized [131I]iodo-FSH or FSH-receptor complexes are subjected to degradation.


Goezia spinulosa (Nematoda: Raphidascarididae), a pathogenic parasite of the arapaima Arapaima gigas (Osteichthyes).
The nematode Goezia spinulosa (Diesing, 1839) (Raphidascarididae) is redescribed based on specimens found in the stomach and intestine of the naturally infected arapaima Arapaima gigas (Schinz) from the Mexiana Island, Amazon River Delta, Brazil. Light and electron microscopy examinations revealed some previously unreported or inaccurately described morphological features in the species, such as the position of the excretory pore, phasmids in the male or the number (4) of postanal papillae. The morphology of G. spinulosa is compared with that of other four congeneric species parasitizing freshwater fishes in South America. This nematode seems to be one of the most pathogenic parasites of A. gigas in the Mexiana Island, which are responsible for a high mortality of cultured arapaima fingerlings. Apparently, the source of G. spinulosa infection for arapaima fingerlings cultured in tanks was the infected plankton collected in the localities inhabited by wild arapaimas. Therefore, control measures should include the sterilisation of the plankton before its use as food for fish. A rare infection of Eustrongylides sp. larvae (Dioctophymatidae) in arapaima fingerlings was also found (new host record); the larvae were inside swellings on the body surface.


Significance of group frequency distributions for group additivity.
The following hypothesis is proposed: When additivity is valid, the molecular frequency distribution (MFD) is a weighted sum of group frequency distributions (GFDs). On the basis of the transformation rules for distribution functions from statistical theory and the rigid-rotator harmonic oscillator approximation, it is shown analytically that the hypothesis leads to group additivity of vibrationally dependent thermochemical parameters. Graph theory has been used to find the structure of the matrices used to determine group additivity values, and the results show that, within the rigid-rotator harmonic oscillator approximation, additivity of the vibrational contributions leads to the experimentally observed group additivity of the total group contributions. Support for the hypothesis is obtained from ab initio and DFT frequency calculations of a total 182 different compounds from seven polymeric series. In agreement with the hypothesis, remarkable similarities of the MFDs are observed throughout each series. Molecular frequencies can be satisfactorily calculated from model calculations based on the hypothesis, and temperature dependent heat capacities for the monomeric units can be derived that are in agreement with experimental values.


Improving Utilization of Maximal Oxygen Uptake and Work Economy in Recreational Cross-Country Skiers With High-Intensity Double-Poling Intervals.
To investigate the effect of a double-poling (DP) high-intensity aerobic interval-training (HIT) intervention performed without increasing total HIT volume. This means that regular HIT training (eg, running) was replaced by HIT DP. The aim was to explore whether this intervention could improve peak oxygen uptake in DP, the fractional utilization of maximal oxygen uptake (VO2max) in DP, oxygen cost of DP, maximal aerobic speed, and a 3-km DP time trial. Nine non-specially-DP-trained cross-country skiers (intervention group) and 9 national-level cross-country skiers (control group) were recruited. All participants were tested for VO2max in running, peak oxygen uptake in DP, oxygen cost of DP, and time-trial performance before and after a 6-wk, 3-times-per-week HIT DP intervention. The intervention group omitted all regular HIT with HIT in DP, leaving the total weekly amount of HIT unchanged. Seven participants in each group completed the study. VO2max in running remained unchanged in both groups, whereas peak oxygen uptake in DP improved by 7.1% (P = .005) in the intervention group. The fractional utilization of VO2max in DP thus increased by 7.3% (P = .019), oxygen cost of DP by 9.2% (P = .047), maximal aerobic speed by 16.5% (P = .009), and time trial by 19.5% (P = .004) in the intervention group but remained unchanged in the control group. The results indicate that a 6-wk HIT DP intervention could be an effective model to improve DP-specific capacities, with maintenance of VO2max in running.


Now you hear it: a predictive coding model for understanding rhythmic incongruity.
Rhythmic incongruity in the form of syncopation is a prominent feature of many contemporary musical styles. Syncopations afford incongruity between rhythmic patterns and the meter, giving rise to mental models of differently accented isochronous beats. Syncopations occur either in isolation or as part of rhythmic patterns, so-called grooves. On the basis of the predictive coding framework, we discuss how brain processing of rhythm can be seen as a special case of predictive coding. We present a simple, yet powerful model for how the brain processes rhythmic incongruity: the model for predictive coding of rhythmic incongruity. Our model proposes that a given rhythm's syncopation and its metrical uncertainty (precision) is at the heart of how the brain models rhythm and meter based on priors, predictions, and prediction error. Our minimal model can explain prominent features of brain processing of syncopation: why isolated syncopations lead to stronger prediction error in the brains of musicians, as evidenced by larger event-related potentials to rhythmic incongruity, and why we all experience a stronger urge to move to grooves with a medium level of syncopation compared with low and high levels of syncopation.


Restoration with implants in patients with recessive dystrophic epidermolysis bullosa and patient satisfaction with the implant-supported superstructure.
The use of endosseous implants in the prosthetic restoration of edentulous patients with recessive dystrophic epidermolysis bullosa (RDEB) may provide improved outcomes when compared with traditional prosthetic methods. The aim of this study was to evaluate the feasibility of placing endosseous implants in patients with RDEB and to compare the treatment outcomes of fixed and removable implant-supported restorations in the edentulous maxilla or mandible with the main emphasis on patient response. Six patients with RDEB were treated with implants. All patients were completely edentulous in either the maxilla or mandible and had marked oral involvement, with alterations in the soft and hard tissues in all cases. Three patients were treated with fixed, screw-retained implant-supported prostheses, and 3 were treated with removable implant-supported prostheses. Six months after prosthetic restoration, patients were given a questionnaire to assess their psychologic well-being and satisfaction with the implant-supported restoration marked on a visual analog scale. A total of 38 dental implants (21 maxillary, 17 mandibular) were placed in 6 patients. The implant success rate was 97.9%. The average follow-up from implant placement was 5.5 years (range, 1 to 9). The fixed and removable implant-supported prostheses were associated with improvements in comfort and retention, function, esthetics and appearance, taste, speech, and self-esteem. The level of satisfaction was slightly higher in patients with a fixed prosthesis. These findings suggest that endosseous implants can be successfully placed and provide support for prostheses in patients with RDEB. Patients with fixed prostheses and overdentures were satisfied with their implant-supported prostheses in the edentulous maxilla and mandible.


'In a dark place, we find ourselves': light intensity in critical care units.
Intensive care units provide specialised care for critically ill patients around the clock. However, intensive care unit patients have disrupted circadian rhythms. Furthermore, disrupted circadian rhythms are associated with worse outcome. As light is the most powerful 're-setter' of circadian rhythm, we measured light intensity on intensive care unit. Light intensity was low compared to daylight during the 'day'; frequent bright light interruptions occurred over 'night'. These findings are predicted to disrupt circadian rhythms and impair entrainment to external time. Bright lighting during daytime and black out masks at night might help maintain biological rhythms in critically ill patients and improve clinical outcomes.


ISOLATION OF A NON-PHAGE-LIKE LYTIC VIRUS INFECTING AUREOCOCCUS ANOPHAGEFFERENS(1).
We have been working to characterize viruses that infect the HAB-forming pelagophyte Aureococcus anophagefferens Hargraves et Sieburth. Field samples were collected during brown-tide events in 2002 and tested for the presence of lytic agents. Here, we describe a recently isolated, lytic virus-like particle (VLP) that is morphologically similar to particles observed in thin sections of infected A. anophagefferens cells from natural samples. TEM and SEM have revealed VLPs consistent with the morphological characteristics of previously described Phycodnaviridae. Large icosahedral particles (∼140 nm) of similar shape and morphology dominate cell lysates and are accompanied by smaller phage-like particles and heterotrophic prokaryotes that appear to be incurable from our cultures. To determine which of these particles interacts with the Aureococcus cells, we preserved cultures during the early stage of infection so that SEM could be used to visualize those particles that attach to the surface of naïve cultures. SEM revealed that 63% of the large icosahedral-shaped particles attached to A. anophagefferens cells after only 30 min of exposure, while no significant frequency of attachment to the alga was observed for the phage-like particles. The results of these observations are in contrast to previous studies, where phage-like particles were reported to infect cells. When considered in conjunction with field observations, the results suggest that this newly isolated virus represents the dominant virus-morphotype associated with bloom collapse and termination.


APOE genotype, lipids, and coronary heart disease risk: a prospective population study.
The risk of coronary heart disease (CHD) may be related to genetic mutations in the production of apolipoprotein E via alterations to the metabolism of CHD-related blood lipids such as low-density lipoprotein cholesterol and triglycerides. The relationship between APOE genotype (*E3/*E3, *E3/*E4, *E2/*E3, *E4/*E4, *E2/*E4, and *E2/*E2) and fatal and nonfatal CHD was examined among 10 035 men and 12 134 women, aged 440 to 79 years, from the Norfolk, England, arm of the European Prospective Into Nutrition and Cancer Study (1993-2007). During an average of 11 years of follow-up, 2712 CHD events were documented. The hazard ratio for CHD was 0.88 (95% confidence interval, 0.77-0.99) for *E2 carriers (*E2/*E2 and *E2/*E3) and 1.09 (1.00-1.19) for *E4 carriers (*E3/*E4 and *E4/*E4) compared with homozygous *E3/*E3 individuals after age and sex adjustment. Similar values were obtained when systolic blood pressure, body mass index, diabetes mellitus, alcohol intake, physical activity, and smoking were added to the model. After additional adjustment for baseline levels of the ratio of low- to high-density lipoprotein cholesterol, the hazard ratios (and 95% confidence intervals) for *E2 and *E4 carriers were 0.97 (0.85-1.10) and 1.06 (0.97-1.15), respectively, when compared with *E3 homozygotes. No interactions by sex, smoking status, or age groups were observed. In the largest prospective cohort study to date, CHD risk was not associated with APOE genotype after controlling for a variety of cardiovascular risk factors, particularly the ratio of low- to high-density lipoprotein cholesterol.


Regulatory cascade controls virulence in Vibrio cholerae.
Expression of more than 17 virulence genes in Vibrio cholerae is under the coordinate control of the ToxR protein. ToxR is a transmembrane protein that binds to and activates the promoter of the operon encoding cholera toxin. As yet, the ability of ToxR to activate directly other genes in this regulon has not been demonstrated. We have cloned a gene called toxT from V. cholerae 569B; the toxT gene product, like ToxR, can activate the ctx promoter in Escherichia coli. In addition, expression of other genes identified as members of the ToxR regulon (tcpA, tcpI, aldA, and tagA) can be activated in E. coli by the toxT gene product but not by ToxR. When expressed from a constitutive promoter, the toxT gene product partially suppresses the ToxR- phenotype of a toxR deletion mutant of V. cholerae. The level of toxT mRNA is greatly reduced in a toxR mutant of V. cholerae. In addition, growth conditions under which the ToxR regulon is not expressed also repress the synthesis of toxT mRNA. These results suggest that ToxR controls transcription of toxT, whose product in turn is directly responsible for activation of several virulence genes under ToxR control.


Decision aids for people facing health treatment or screening decisions.
Decision aids are interventions that support patients by making their decisions explicit, providing information about options and associated benefits/harms, and helping clarify congruence between decisions and personal values. To assess the effects of decision aids in people facing treatment or screening decisions. Updated search (2012 to April 2015) in CENTRAL; MEDLINE; Embase; PsycINFO; and grey literature; includes CINAHL to September 2008. We included published randomized controlled trials comparing decision aids to usual care and/or alternative interventions. For this update, we excluded studies comparing detailed versus simple decision aids. Two reviewers independently screened citations for inclusion, extracted data, and assessed risk of bias. Primary outcomes, based on the International Patient Decision Aid Standards (IPDAS), were attributes related to the choice made and the decision-making process.Secondary outcomes were behavioural, health, and health system effects.We pooled results using mean differences (MDs) and risk ratios (RRs), applying a random-effects model. We conducted a subgroup analysis of studies that used the patient decision aid to prepare for the consultation and of those that used it in the consultation. We used GRADE to assess the strength of the evidence. We included 105 studies involving 31,043 participants. This update added 18 studies and removed 28 previously included studies comparing detailed versus simple decision aids. During the 'Risk of bias' assessment, we rated two items (selective reporting and blinding of participants/personnel) as mostly unclear due to inadequate reporting. Twelve of 105 studies were at high risk of bias.With regard to the attributes of the choice made, decision aids increased participants' knowledge (MD 13.27/100; 95% confidence interval (CI) 11.32 to 15.23; 52 studies; N = 13,316; high-quality evidence), accuracy of risk perceptions (RR 2.10; 95% CI 1.66 to 2.66; 17 studies; N = 5096; moderate-quality evidence), and congruency between informed values and care choices (RR 2.06; 95% CI 1.46 to 2.91; 10 studies; N = 4626; low-quality evidence) compared to usual care.Regarding attributes related to the decision-making process and compared to usual care, decision aids decreased decisional conflict related to feeling uninformed (MD -9.28/100; 95% CI -12.20 to -6.36; 27 studies; N = 5707; high-quality evidence), indecision about personal values (MD -8.81/100; 95% CI -11.99 to -5.63; 23 studies; N = 5068; high-quality evidence), and the proportion of people who were passive in decision making (RR 0.68; 95% CI 0.55 to 0.83; 16 studies; N = 3180; moderate-quality evidence).Decision aids reduced the proportion of undecided participants and appeared to have a positive effect on patient-clinician communication. Moreover, those exposed to a decision aid were either equally or more satisfied with their decision, the decision-making process, and/or the preparation for decision making compared to usual care.Decision aids also reduced the number of people choosing major elective invasive surgery in favour of more conservative options (RR 0.86; 95% CI 0.75 to 1.00; 18 studies; N = 3844), but this reduction reached statistical significance only after removing the study on prophylactic mastectomy for breast cancer gene carriers (RR 0.84; 95% CI 0.73 to 0.97; 17 studies; N = 3108). Compared to usual care, decision aids reduced the number of people choosing prostate-specific antigen screening (RR 0.88; 95% CI 0.80 to 0.98; 10 studies; N = 3996) and increased those choosing to start new medications for diabetes (RR 1.65; 95% CI 1.06 to 2.56; 4 studies; N = 447). For other testing and screening choices, mostly there were no differences between decision aids and usual care.The median effect of decision aids on length of consultation was 2.6 minutes longer (24 versus 21; 7.5% increase). The costs of the decision aid group were lower in two studies and similar to usual care in four studies. People receiving decision aids do not appear to differ from those receiving usual care in terms of anxiety, general health outcomes, and condition-specific health outcomes. Studies did not report adverse events associated with the use of decision aids.In subgroup analysis, we compared results for decision aids used in preparation for the consultation versus during the consultation, finding similar improvements in pooled analysis for knowledge and accurate risk perception. For other outcomes, we could not conduct formal subgroup analyses because there were too few studies in each subgroup. Compared to usual care across a wide variety of decision contexts, people exposed to decision aids feel more knowledgeable, better informed, and clearer about their values, and they probably have a more active role in decision making and more accurate risk perceptions. There is growing evidence that decision aids may improve values-congruent choices. There are no adverse effects on health outcomes or satisfaction. New for this updated is evidence indicating improved knowledge and accurate risk perceptions when decision aids are used either within or in preparation for the consultation. Further research is needed on the effects on adherence with the chosen option, cost-effectiveness, and use with lower literacy populations.


The oldest known primate skeleton and early haplorhine evolution.
Reconstructing the earliest phases of primate evolution has been impeded by gaps in the fossil record, so that disagreements persist regarding the palaeobiology and phylogenetic relationships of the earliest primates. Here we report the discovery of a nearly complete and partly articulated skeleton of a primitive haplorhine primate from the early Eocene of China, about 55 million years ago, the oldest fossil primate of this quality ever recovered. Coupled with detailed morphological examination using propagation phase contrast X-ray synchrotron microtomography, our phylogenetic analysis based on total available evidence indicates that this fossil is the most basal known member of the tarsiiform clade. In addition to providing further support for an early dichotomy between the strepsirrhine and haplorhine clades, this new primate further constrains the age of divergence between tarsiiforms and anthropoids. It also strengthens the hypothesis that the earliest primates were probably diurnal, arboreal and primarily insectivorous mammals the size of modern pygmy mouse lemurs.


The Dissociation Rate of Acetylacetonate Ligands Governs the Size of Ferrimagnetic Zinc Ferrite Nanocubes.
Magnetic nanoparticles are critical to a broad range of applications from medical diagnostics and therapeutics to biotechnological processes and single-molecule manipulation. To advance these applications, facile and robust routes to synthesize highly magnetic nanoparticles over a wide size range are needed. Here, we demonstrate that changing the degassing temperature of thermal decomposition of metal acetylacetonate precursors from 90 to 25 °C tunes the size of ferrimagnetic ZnxFe3-xO4 nanocubes from 25 to 100 nm, respectively. We show that degassing at 90 °C nearly entirely removes acetylacetone ligands from the reaction, which results in an early formation of monomers and a reaction-controlled growth following LaMer's model toward small nanocubes. In contrast, degassing at 25 °C only partially dissociates acetylacetone ligands from the metal center and triggers a delayed formation of monomers, which leads to intermediate assembled structures made of tiny irregular crystallites and an eventual formation of large nanocubes via a diffusion-controlled growth mechanism. Using complementary techniques, we determine the substitution fraction x of Zn2+ to be in the range of 0.35-0.37. Our method reduces the complexity of the thermal decomposition method by narrowing the synthesis parameter space to a single physical parameter and enables fabrication of highly magnetic and uniform zinc ferrite nanocubes over a broad size range. The resulting particles are promising for a range of applications from magnetic fluid hyperthermia to actuation of macromolecules.


Whole and refined grains change behavior and reduce brain derived neurotrophic factor and neurotrophin-3 in rats.
In most of the world, wheat is one of the main staple foods, and is also widely used in livestock feed. In the current study, we investigated the effects of wheat grain consumption on the rat behavior and neurogenesis markers. Thirty male rats were divided into three equal groups (n = 10). Group 1 was the control group fed with chow diet (Carbohydrates 63%, fat 13% and protein 24%), the Group 2 rats were fed with whole grains and the Group 3 rats were fed with refined grains. After 12 weeks, we measured the hippocampal and prefrontal cortical brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), 5-hydroxytryptamine, dopamine, norepinephrine, malondialdehyde (MDA) and reduced glutathione (GSH) levels. Also, we evaluated the rat behavior by forced swimming test (FST) and elevated plus maze (EPM) test. Additionally, we measured serum level of glucose, lipid profile, insulin and cortisol. Weight gain at the end of the study was measured in each group. The rats on a diet of whole and refined grains had low BDNF, NT-3, norepinephrine, dopamine and serotonin significantly (p < .01) in both the hippocampus and prefrontal cortex as compared to control rats. Moreover, the MDA increased significantly with significant reduction in GSH versus the control rats. Moreover, in response to grain consumption, the performance in FST showed a significant (p < .01) shortage in the latency of the attempts to escape as well as a significant prolongation (p < .01) in behavioral immobility as compared to control rats with significant (p < .05) prolongation in time spent in closed arm in EPM. An exclusive diet of either whole or refined grain in a rat model induced anxiety and depressive behaviors and negatively affected the BDNF and NT-3 and modulated the level of the neurotransmitters with significant shift in their behavior. PRACTICAL APPLICATIONS: Grains are considered the major caloric source all over the world that may predispose to the development of chronic diseases. In this research, we evaluated the role of grains in modulating the rate of production of neurogenic factors in rats.


In-chain neutral hydrocarbon loss from crocin apocarotenoid ester glycosides and the crocetin aglycon (Crocus sativus L.) by ESI-MS(n) (n=2, 3).
The stigmas of Crocus sativus L. have been used as spice and colorant agent (i.e. saffron) for more than 4000 years. For an updated structural investigation of the aglycon present in the glycosylated crocetin apocarotenoids (i.e. crocins), seven representative derivatives ranging from one up to five glucosyl-residues with a maximum number of three monosaccharides per glycosylation site (glucose, gentiobiose, gentiotriose and neapolitanose) were isolated and purified by high-performance liquid chromatography. The compounds selected for further mass spectrometric investigation include glucosyl-, bis-glucosyl-, gentiobiosyl-, gentiobiosyl-glucosyl-, bis-gentiobiosyl-, gentiobiosyl-gentiotriosyl- and gentiobiosyl-neapolitanosyl-crocetin. Electrospray ionization in combination with low-energy collision-induced dissociation/tandem mass spectrometry of sodiated crocin precursor ions utilizing either a 3D-ion trap (MS(n) , n = 2, 3) or a QqTOF instrument, with the latter providing accurate mass determination with an accuracy of ±1-3 ppm or better at a resolution of 10,000 (full width at half maximum), was used. Major fragmentation pathways included loss of either one or two carbohydrate substituents leading to the sodiated aglycon without interglycosidic bond cleavage during in MS(2) -experiments. All sodiated precursor ions and major product ions were accompanied by a loss of 92 Da, which was elucidated as C7 H8 -loss from the aglycon by skeletal rearrangement via an eight-membered transition state as previously described for intact C40-carotenoids.


Cathepsin E is a marker of gastric differentiation and signet-ring cell carcinoma of stomach: a novel suggestion on gastric tumorigenesis.
Gastric cancer (GC) presents various histological features, though the mechanism underlying its diversity is seldom elucidated. It is mainly classified into well differentiated tubular adenocarcinoma (tub1), moderately differentiated tubular adenocarcinoma (tub2), poorly differentiated adenocarcinoma (por), signet-ring cell carcinoma (sig), mucinous adenocarcinoma (muc), and papillary adenocarcinoma (pap). By screening, we found cathepsin E (CTSE) expresses universally in sig-type, occasionally in por-type, and rarely in tub1/tub2-type GC cell lines. In surgically-resected specimens, CTSE was immunostained in 50/51 sig-type (98.0%), 3/10 tub1-type (30.0%), 7/18 tub2-type (38.9%), 15/26 por-type (57.7%), 4/10 pap-type (40.0%), and 0/3 muc-type (0.0%) GC. In endoscopically-resected specimens, 6/7 sig-type (85.7%), 7/52 tub1-type (13.7%), 5/12 tub2-type (41.7%), 2/7 pap-type (28.6%) GC and 0/6 adenoma (0.0%) expressed CTSE. For non-malignant tissues, CTSE is universally expressed in normal fundic, pyloric, and cardiac glands of stomach, but hardly in other digestive organs. In the precancerous intestinal metaplasia of stomach, CTSE is mostly observed in mixed gastric-and-intestinal type and deficient in solely-intestinal type. CTSE expression is positively correlated with gastric marker MUC5AC (p<0.0001) and negatively correlated with intestinal marker MUC2 (p = 0.0019). For sig-type GC, in both tumors and background mucosa, expression of MUC5AC and CTSE is high whereas that of MUC2 is low, indicating that sig-type GC reflects the features of background mucosa. For gastric adenoma and tub1/tub2-type GC, more undifferentiated tumors tend to show higher expression of CTSE with MUC5AC and lower expression of MUC2 in tumors, but they tend to present lower expression of CTSE, MUC5AC and MUC2 in background mucosa. These suggest that more malignant gastric adenocarcinoma with stronger gastric and weaker intestinal properties tend to arise from background mucosa with decreased both gastric and intestinal features. In conclusion, CTSE is a marker of both gastric differentiation and signet-ring cell carcinoma, which should shed light on the mechanism of gastric tumorigenesis.


A study of acute respiratory disease in the community of Port Chalmers. I. Illnesses within a group of selected families and the relative incidence of respiratory pathogens in the whole community.
A study of respiratory diseases in the semi-isolated community of Port Chamlers, New Zealand, began in April 1973. The intensive surveillance of a selected group fo 26 families involved the weekly reporting of illness, the collection of specimens for virus, Group A streptococci and Mycoplasma pneumoniae isolation and the collection of sera at 6-month intervals. A total of 956 illnesses were reported during 32 months. The median number of illnesses per year were: infants 4.4, children 2.5, female adults 2.4 and male adults 2.0. Of all these illnesses, 57% were upper respiratory, 31% were lower respiratory and 9% were enteric. The severity of these illnesses was not greater than would be expected in open communities. Surveillance by pathogen isolation only of the whole community through the patients in the general practice was carried out concurrently. A total of 640 nasopharyngeal swab specimens were collected from which 161 viruses, 47 Group A streptococci and 2 M. pneumoniae were isolated. The overall isolation rate was 33%. The similarities between the epidemiological patterns of respiratory disease in the open community and the isolated community are discussed.


The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1.
CD8(+) T-cell responses are an essential antiviral host defense in persistent viral infections, and their sustained effectiveness is thought to be critically dependent on CD4(+) T-helper cells. To determine the relationship between HIV-1-induced CD4(+) T-cell depletion and hepatitis C virus (HCV)-specific CD8(+) T-cell responses during viral persistence, we studied 103 persons positive for HCV, 74 coinfected with HIV-1. CD8(+) T-cell responses to the entire HCV polyprotein were determined by using an interferon-gamma enzyme-linked immunospot (ELISpot) assay. Although HIV-1 infection by itself was not associated with a diminished HCV-specific response, HIV-1-associated CD4(+) depletion was associated with significantly lower HCV-specific CD8(+) T cells (R = 0.48, P < .0001). In contrast, declining CD4(+) counts over the same range were not associated with diminished Epstein-Barr virus (EBV)- (R = 0.19, P = .31) or HIV-1-specific (R = -0.13, P = .60) CD8(+) T-cell responses in persons infected with all viruses. These data indicate that frequencies of circulating HCV-specific CD8(+) T-cell responses are sensitive to absolute CD4(+) T-cell counts and provide a possible explanation for the accelerated HCV disease course in persons coinfected with HIV-1 and HCV.


Altered DNA base excision repair profile in brain tissue and blood in Alzheimer's disease.
Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia globally. AD is associated with increased oxidative stress, resulting from imbalance in production and clearance of reactive oxygen species (ROS). ROS can damage DNA and other macromolecules, leading to genome instability and disrupted cellular functions. Base excision repair (BER) plays a major role in repairing oxidative DNA lesions. Here, we compared the expression of BER components APE1, OGG1, PARP1 and Polβ in blood and postmortem brain tissue from patients with AD, mild cognitive impairment (MCI) and healthy controls (HC). BER mRNA levels were correlated to clinical signs and cerebrospinal fluid biomarkers for AD. Notably, the expression of BER genes was higher in brain tissue than in blood samples. Polβ mRNA and protein levels were significantly higher in the cerebellum than in the other brain regions, more so in AD patients than in HC. Blood mRNA levels of OGG1 was low and PARP1 high in MCI and AD. These findings reflect the oxidative stress-generating energy-consumption in the brain and the importance of BER in repairing these damage events. The data suggest that alteration in BER gene expression is an event preceding AD. The results link DNA repair in brain and blood to the etiology of AD at the molecular level and can potentially serve in establishing novel biomarkers, particularly in the AD prodromal phase.


A high-confidence human plasma proteome reference set with estimated concentrations in PeptideAtlas.
Human blood plasma can be obtained relatively noninvasively and contains proteins from most, if not all, tissues of the body. Therefore, an extensive, quantitative catalog of plasma proteins is an important starting point for the discovery of disease biomarkers. In 2005, we showed that different proteomics measurements using different sample preparation and analysis techniques identify significantly different sets of proteins, and that a comprehensive plasma proteome can be compiled only by combining data from many different experiments. Applying advanced computational methods developed for the analysis and integration of very large and diverse data sets generated by tandem MS measurements of tryptic peptides, we have now compiled a high-confidence human plasma proteome reference set with well over twice the identified proteins of previous high-confidence sets. It includes a hierarchy of protein identifications at different levels of redundancy following a clearly defined scheme, which we propose as a standard that can be applied to any proteomics data set to facilitate cross-proteome analyses. Further, to aid in development of blood-based diagnostics using techniques such as selected reaction monitoring, we provide a rough estimate of protein concentrations using spectral counting. We identified 20,433 distinct peptides, from which we inferred a highly nonredundant set of 1929 protein sequences at a false discovery rate of 1%. We have made this resource available via PeptideAtlas, a large, multiorganism, publicly accessible compendium of peptides identified in tandem MS experiments conducted by laboratories around the world.


From treatment to prevention: the interplay between HIV/AIDS treatment availability and HIV/AIDS prevention programming in Khayelitsha, South Africa.
There is a paucity of research that illustrates the interplay between HIV/AIDS treatment and prevention programs. We describe the central role that public access to antiretroviral (ARV) medication has played in the development and efficacy of HIV/AIDS prevention programming in Khayelitsha, a resource-poor township in the Western Cape of South Africa. We document the range of preventive interventions and services available in Khayelitsha since the early 1990s and explore the impact of ARV availability on prevention efforts and disease stigma on the basis of extensive indepth interviews, supplemented by data collection. The information gathered suggests that the introduction of the mother-to-child-transmission (MTCT) prevention programs in 1999 and the three HIV treatment clinics run by Doctors Without Borders/Médecins Sans Frontières (MSF) in 2000 were turning points in the region's response to the HIV/AIDS epidemic. These programs have provided incentives for HIV testing, galvanized HIV/AIDS educators to reach populations most at risk, and decreased the HIV incidence rates in Khayeltisha compared to other areas in the Western Cape. Lessons learned in Khayelitsha about the value of treatment availability in facilitating prevention efforts can inform the development of comprehensive approaches to HIV/AIDS in other resource-poor areas.


Lavender and the nervous system.
Lavender is traditionally alleged to have a variety of therapeutic and curative properties, ranging from inducing relaxation to treating parasitic infections, burns, insect bites, and spasm. There is growing evidence suggesting that lavender oil may be an effective medicament in treatment of several neurological disorders. Several animal and human investigations suggest anxiolytic, mood stabilizer, sedative, analgesic, and anticonvulsive and neuroprotective properties for lavender. These studies raised the possibility of revival of lavender therapeutic efficacy in neurological disorders. In this paper, a survey on current experimental and clinical state of knowledge about the effect of lavender on the nervous system is given.


Sample preparation methods for femtosecond electron diffraction experiments.
Exploring the dynamics of Charge density wave system 1T-TaS2 via femtosecond electron diffraction demonstrated the power of this technique for studying ultrafast structural phenomena in strongly correlated electron materials [1]. The results revealed first direct information on the order parameter dynamics of Charge Density Waves as well as on their photo-induced phase transition. A prerequisite to perform such experiments on modern quantum materials is the availability of laterally large (~100 μm) and sufficiently thin (<100 nm) single crystalline samples. Different approaches to reach these specifications have been tried out and their effect on sample integrity has been investigated. Finally, using an ultra-microtome, we were able to prepare 30 nm free standing single crystalline films of 1T-TaS2 with lateral dimensions of 200 μm × 200 μm. We have characterized these films with different techniques for their stoichiometric and crystalline integrity, ensuring no measurable alternation of sample properties. The application of this sample thinning technique is expected to find its use in further structural dynamics studies, as well as in optical time-resolved studies where homogeneous excitation profile and/or data in transmission geometry may be required.


Selective-releasing-affected lubricant mechanism of a self-assembled MoS2/Mo-S-C nanoperiod multilayer film sliding in diverse atmospheres.
A self-assembled MoS2/Mo-S-C multilayer film prepared by r.f. co-sputtering of MoS2 and graphite targets was tribotested in diverse sliding atmospheres, and the lubricant mechanism and its correlations to the selective releasing behavior of non-lubricant component were analyzed in detail. Based on the analysis of composition and structural transformation of transferred materials by Raman and HRTEM characterizations, selective releasing behavior according to the sliding atmospheres were found to be particularly apparent in vacuum and dry inert atmospheres. Under these conditions, a-C in graphitic form was selectively released outwards from the topmost surfaces of contacts, leaving MoS2 layers finely reordered in (002) orientation playing a lubricant role. Composition and structural transformation were observed not only on the topmost surface of wear track but also on the underlying layer at a thickness of tens of nanometers. Moreover, it was found that the selective releasing of a-C initiated from the center of contacts with higher pressure, and then developed toward the edges, resulting in a gradual change in the composition and microstructure of the transferred materials from the well-aligned MoS2 layers in the center to the graphitic a-C dominant composites at the edges. The short running-in periods and low-friction performance in all the tribotests suggested that the initial preference of MoS2-riched sublayers in (002) orientation may facilitate the formation of shearless tribofilms and therefore provide a feasible way of structural tailoring in the MoS2-based lubricant films for an improved triboactive response.


Effect of Including Alcohol and Cannabis Content in a Sexual Risk-Reduction Intervention on the Incidence of Sexually Transmitted Infections in Adolescents: A Cluster Randomized Clinical Trial.
Adolescents in the juvenile justice system are at high risk for sexually transmitted infections (STIs). Concurrent use of alcohol and cannabis increase this risk. To determine whether a theory-based sexual risk-reduction intervention that included alcohol- and cannabis-focused content resulted in greater reductions in STIs than an intervention that included alcohol-related content only and an intervention that did not include substance use content. Cluster randomized clinical trial with 3 conditions. Between July 1, 2010, and December 10, 2014, adolescents living at a juvenile detention facility in the southwestern United States were tested and treated for STI before randomization and again 12 months after the intervention. Data analyses were conducted in July and August 2017. Eligibility criteria included (1) being aged 14 to 18 years, (2) able to speak English, (3) having a remaining detention term of less than 1 month, and (4) signing a release granting access to STI results if tested at intake. Six hundred ninety-three adolescents were assessed for eligibility. Of these, 460 completed baseline assessments and were randomized to 1 of 3 intervention conditions. Data analysis was by intent-to-treat. There were 3 intervention conditions: sexual risk reduction intervention (SRRI); SRRI plus alcohol content (SRRI + ETOH); and SRRI + ETOH plus cannabis content (SRRI + ETOH + THC). Interventions were conducted in same-sex groups by trained clinicians and included video presentations with discussion, group activities, and active feedback by participants, consistent with the principles of motivational enhancement therapy. Although not the outcome on which the study was originally powered, the main outcome variable presented herein is STI incidence (Chlamydia trachomatis and/or Neisseria gonorrhoeae) 12 months after the intervention. Of the 460 participants randomized, mean (SD) age was 15.8 (1.1) years, 347 participants (75.4%) were male, and 57.0% were of Hispanic ethnicity. Among the participants, 143 were randomized to SSRI, 155 to SRRI + ETOH, and 162 to SRRI + ETOH + THC. Attrition at 12-month follow-up was 99 (21.5%) for the STI outcome variable. Participants in the SRRI + ETOH + THC intervention had lower incidence of STI at follow-up (3.9%) than those in either the SRRI (12.4%; odds ratio, 0.29; 95% CI, 0.10-0.84) or the SRRI + ETOH (10.2%; odds ratio, 0.36; 95% CI, 0.12-1.05) interventions. An intervention delivered in a motivational enhancement therapy format that includes theory-based sexual risk reduction combined with alcohol- and cannabis-focused elements is effective at reducing STI incidence among justice-involved adolescents. This 1-session manualized intervention can be delivered in the context of short-term detention and is easily disseminated to juvenile justice agencies. clinicaltrials.gov Identifier: NCT01170260.


Effect of music on depression levels and physiological responses in community-based older adults.
Many people over the age of 65 do not regard depression as a treatable mental disorder and find it difficult to express themselves verbally. Listening to music can facilitate the non-verbal expression of emotion and allow people's inner feelings to be expressed without being threatened. The aim of this study was to determine the effect of music on depression levels in elderly people. A randomized controlled study was conducted with 47 elderly people (23 using music and 24 controls) who completed the study after being recruited in Hong Kong. Blood pressure, heart rate (HR), respiratory rate (RR), and depression level variables were collected. In the music group, there were statistically-significant decreases in depression scores (P < 0.001) and blood pressure (P = 0.001), HR (P < 0.001), and RR (P < 0.001) after 1 month. The implication is that nurses may utilize music as an effective nursing intervention for patients with depressive symptoms in the community setting.


Attention and suppression affect tactile perception in reach-to-grasp movements.
Reaching with the hand is characterized by a decrease in sensitivity to tactile stimuli presented to the moving hand. Here, we investigated whether tactile suppression can be canceled by attentional orienting. In a first experiment, participants performed a dual-task involving a goal-directed movement paired with the speeded detection of a tactile pulse. The pulse was either delivered to the moving or stationary hand, during movement preparation, execution, or the post-movement phase. Furthermore, stimulation was delivered with equal probability to either hand, or with a higher probability to either the moving or resting hand. The results highlighted faster RTs under conditions of higher probability of stimulation delivery to both moving and resting hands, thus indicating an attentional effect. For the motor preparation period, RTs were faster only at the resting hand under conditions where tactile stimulation was more likely to be delivered there. In a second experiment, a non-speeded perceptual task was used as a secondary task and tactile discrimination thresholds were recorded. Tactile stimulation was delivered concomitantly at both index fingers either in the movement preparation period (both before and after the selection of the movement effector had taken place), in the motor execution period, or, in a control condition, in the time-window of motor execution, but the movement of the hand was restrained. In the preparation period, tactile thresholds were comparable for the two timings of stimulation delivery; i.e., before and after the selection of the movement effector had taken place. These results therefore suggest that shortly prior to, and during, the execution of goal-directed movements, a combined facilitatory and inhibitory influence acts on tactile perception.


Tenascin-C splice variant adhesive/anti-adhesive effects on chondrosarcoma cell attachment to fibronectin.
Tenascin-C is an oligomeric glycoprotein of the extracellular matrix that has been found to have both adhesive and anti-adhesive properties for cells. Recent elucidation of the two major TNC splice variants (320 kDa and 220 kDa) has shed light on the possibility of varying functions of the molecule based on its splicing pattern. Tenascin-C is prominently expressed in embryogenesis and in pathologic conditions such as tumorogenesis and wound healing. Fibronectin is a prominent adhesive molecule of the extracellular matrix that is often co-localized with tenascin-C in these processes. We studied the chondrosarcoma cell line JJ012 with enzyme-linked immunoabsorbance assays, cell attachment assays and antibody-blocking assays to determine the adhesive/anti-adhesive properties of the two major tenascin-C splice variants with respect to fibronectin and their effect on chondrosarcoma cell attachment. We found that the small tenascin-C splice variant (220 kDa) binds to fibronectin, whereas the large tenascin-C splice variant (320 kDa) does not. In addition, the small tenascin-C splice variant was found to decrease adhesion for cells when bound to fibronectin, but contributed to adhesion when bound to plastic in fibronectin-coated wells. Antibody blocking experiments confirmed that both the small tenascin-C splice variant and fibronectin contribute to cell adhesion when bound to plastic. The large tenascin-C splice variant did not promote specific cell attachment. We hypothesize that the biologic activity of tenascin-C is dependent on the tissue-specific splicing pattern. The smaller tenascin-C isoform likely plays a structural and adhesive role, whereas the larger isoform, preferentially expressed in malignant tissue, likely plays a role in cell egress and metastasis.


A new species of Pachycara Zugmayer, 1911 (Teleostei: Zoarcidae) from deep-sea chemosynthetic environments in the Caribbean Sea.
The 28th species of the eelpout genus Pachycara Zugmayer, 1911, is described from specimens collected from an active hydrothermal vent field at a depth of about 2300 m at the Mid-Cayman Spreading Centre of the Caribbean Sea. A tentatively identified early juvenile is recorded at a methane seep at a depth of 1049 m near Tobago. The new species is distinguished from its congeners mainly by its few pectoral fin rays, low vertebral counts, single, mediolateral branch of the lateral line system and presence of scales on the nape and cheeks.


Adapting quality of life instruments.
Due to the international nature of many clinical studies and trials it is often necessary to produce several language versions of specific measures. While it is generally acknowledged that it is necessary to produce versions that are conceptually equivalent, the best method of achieving this is more controversial. It is commonly stated that there is a gold-standard method, which involves forward and backward translation. However, no evidence has been presented to support this view. This paper argues that the "gold-standard" method is difficult to support and describes an alternative method involving dual translation panels that has been used in the production of all adaptations of needs-based quality of life instruments.


The Deinococcus radiodurans DR1245 protein, a DdrB partner homologous to YbjN proteins and reminiscent of type III secretion system chaperones.
The bacterium Deinococcus radiodurans exhibits an extreme resistance to ionizing radiation. A small subset of Deinococcus genus-specific genes were shown to be up-regulated upon exposure to ionizing radiation and to play a role in genome reconstitution. These genes include an SSB-like protein called DdrB. Here, we identified a novel protein encoded by the dr1245 gene as an interacting partner of DdrB. A strain devoid of the DR1245 protein is impaired in growth, exhibiting a generation time approximately threefold that of the wild type strain while radioresistance is not affected. We determined the three-dimensional structure of DR1245, revealing a relationship with type III secretion system chaperones and YbjN family proteins. Thus, DR1245 may display some chaperone activity towards DdrB and possibly other substrates.


Dosing interval between mifepristone and misoprostol in second and third trimester termination.
To compare several strategies for second trimester labor induction for termination of pregnancy (TOP) using misoprostol and mifepristone and to determine which one is more effective in accelerating the time to delivery. This was a retrospective study in which pregnancies that underwent second and third trimester TOP due to fetal anomalies between 2007 and 2017 were classified into a group that received misoprostol alone, a group that received mifepristone followed by misoprostol on the same day, one where misoprostol was given 1 day after mifepristone and one where the medications were administered 2 days apart. The primary outcome measure was the induction to delivery interval. 481 pregnancies fulfilled the inclusion criteria. In 140 cases, mifepristone was not administered. 341 women received mifepristone prior to induction, which was administered on the day of induction in 85 cases, and 1 or 2 days prior to induction in 140 and 19 cases. Median time interval between first induction and delivery was 15.0 (IQR 10.0-24.1) h in case no mifepristone was given and 13.2 (9.7-18.2) h if mifepristone was given on the same day and 9.3 (6.6-14.9) and 10.5 (7.2-22.3) h, if mifepristone was given 1 or 2 days prior to induction. After 24 h, the proportion of terminated pregnancies in each of the four groups was 75.0, 83.5, 93.2 and 78.9%. A 1 day interval between mifepristone and misoprostol is more effective in second and third trimester TOP compared to other strategies in terms of reducing the induction to abortion interval.


Mokken scale analysis of mental health and well-being questionnaire item responses: a non-parametric IRT method in empirical research for applied health researchers.
Mokken scaling techniques are a useful tool for researchers who wish to construct unidimensional tests or use questionnaires that comprise multiple binary or polytomous items. The stochastic cumulative scaling model offered by this approach is ideally suited when the intention is to score an underlying latent trait by simple addition of the item response values. In our experience, the Mokken model appears to be less well-known than for example the (related) Rasch model, but is seeing increasing use in contemporary clinical research and public health. Mokken's method is a generalisation of Guttman scaling that can assist in the determination of the dimensionality of tests or scales, and enables consideration of reliability, without reliance on Cronbach's alpha. This paper provides a practical guide to the application and interpretation of this non-parametric item response theory method in empirical research with health and well-being questionnaires. Scalability of data from 1) a cross-sectional health survey (the Scottish Health Education Population Survey) and 2) a general population birth cohort study (the National Child Development Study) illustrate the method and modeling steps for dichotomous and polytomous items respectively. The questionnaire data analyzed comprise responses to the 12 item General Health Questionnaire, under the binary recoding recommended for screening applications, and the ordinal/polytomous responses to the Warwick-Edinburgh Mental Well-being Scale. After an initial analysis example in which we select items by phrasing (six positive versus six negatively worded items) we show that all items from the 12-item General Health Questionnaire (GHQ-12)--when binary scored--were scalable according to the double monotonicity model, in two short scales comprising six items each (Bech's "well-being" and "distress" clinical scales). An illustration of ordinal item analysis confirmed that all 14 positively worded items of the Warwick-Edinburgh Mental Well-being Scale (WEMWBS) met criteria for the monotone homogeneity model but four items violated double monotonicity with respect to a single underlying dimension.Software availability and commands used to specify unidimensionality and reliability analysis and graphical displays for diagnosing monotone homogeneity and double monotonicity are discussed, with an emphasis on current implementations in freeware.


Imaging Findings and Clinicopathological Correlation of Breast Cancer in Women under 40 Years Old.
The aim of this study was to evaluate the clinical, imaging and histopathological features of breast cancer in patients aged under 40 years of age. The relationship between radiological characteristics and histopathological features was also investigated. The study included 131 patients aged under 40 years, diagnosed pathologically with breast cancer. A retrospective evaluation was made of the imaging and clinicopathological findings and the relationship between pathological and imaging findings was investigated. Most of the cancers were detected from clinical symptoms, especially a palpable mass (76.3%). The most common histological type of tumor was invasive ductal carcinoma and 64.8% of the tumors were high grade tumors. The predominant features were irregular borders (92.4%), microlobulated-angulated contours (43.5%), hypo-homogeneous internal echogenicity (80.9%) on ultrasonography, and the presence of a mass (41.2%) and suspicious microcalcifications (40.2%) on mammography. Magnetic resonance imaging commonly showed mass enhancement (66.7%) with type 2 or 3 dynamic curve (92.6%). High-grade tumors were associated with posterior acoustic enhancement (p: 0.03) while low-grade tumors presented with spiculated margins more than high grade tumors (p: 0.04). Breast cancer in women aged under 40 years usually presents with a self-detected palpable mass and can show different imaging findings according to the histological grade. Ultrasonography is the main modality for the diagnosis of breast cancer in young women, but mammography and magnetic resonance imaging can help in both diagnosis and evaluation of the extent of disease.


Characterization of antigens on human lymphocytes coded by messenger RNA translated in vitro.
Translation and immunoprecipitation were used to identify messenger RNAs (mRNAs) coding for surface antigens expressed on human lymphoblastoid cells. The mRNAs were extracted from several human lymphoid cell lines as well as from fibroblastoid lines. These mRNAs were translated in vitro, and the translation products were reacted with xenoantisera raised against the antigens on human lymphoid cells. Products immunoprecipitated by these antisera were analysed by electrophoresis and fluorography. Four antisera immunoprecipitated a polypeptide with a mol. wt (MW) of approximately 32,000 (p32) from translations programmed with mRNA extracted from all the cell lines. Two antisera immunoprecipitated, in addition to p32, another polypeptide with a MW of approximately 25,000 (p25) only from translations programmed with RNA from lymphoid cell lines. p25 mRNA in the different lymphoid cell lines fell into three basic abundance classes as determined by in vitro translation and immunoprecipitation. Cells from two Burkitt's lymphomas (Raji and Daudi) did not express detectable p25 mRNA. Two T-lymphoblastoid lines (Molt-4 and 1301) contained five- to 10-fold less p25 mRNA than the B-lymphoid cell lines (Victor, RPMI-8866, RPMI-6410, RPMI-8226 and RPMI-1788). Both p32 and p25 were expressed on the cell surface inasmuch as lymphoblastoid cells adsorbed antibodies to both polypeptides. Human fibroblast, Raji or Daudi cells adsorbed anti-p32 antibodies from the antiserum but not anti-p25. Quantitative absorptions of the antiserum with T- or B-lymphoblastoid cells was used to determine the relative amounts of p32 and p25 expressed on the cell surface. B-lymphoblastoid cells were found to express two- to five-fold more p25 on the cell surface then T-lymphoblastoid cells. p25 does not represent an immunoglobulin light-chain precursor inasmuch as a 1000-fold excess of unlabeled human Ig did not compete with p25 translated in vitro for binding by its respective antibody.


Investigation of the dynamics of aqueous proline solutions using neutron scattering and molecular dynamics simulations.
We applied quasielastic neutron scattering (QENS) techniques to samples with two different contrasts (deuterated solute/hydrogenated solvent and the opposite label) to selectively study the component dynamics of proline/water solutions. Results on diluted and concentrated solutions (31 and 6 water molecules/proline molecule, respectively) were analyzed in terms of the susceptibility and considering a recently proposed model for water dynamics [Arbe et al., Phys. Rev. Lett., 2016, 117, 185501] which includes vibrations and the convolution of localized motions and diffusion. We found that proline molecules not only reduce the average diffusion coefficient of water but also extend the time/frequency range of the crossover region ('cage') between the vibrations and purely diffusive behavior. For the high proline concentration we also found experimental evidence of water heterogeneous dynamics and a distribution of diffusion coefficients. Complementary molecular dynamics simulations show that water molecules start to perform rotational diffusion when they escape the cage regime but before the purely diffusive behavior is established. The rotational diffusion regime is also retarded by the presence of proline molecules. On the other hand, a strong coupling between proline and water diffusive dynamics which persists with decreasing temperature is directly observed using QENS. Not only are the temperature dependences of the diffusion coefficients of both components the same, but their absolute values also approach each other with increasing proline concentration. We compared our results with those reported using other techniques, in particular using dielectric spectroscopy (DS). A simple approach based on molecular hydrodynamics and a molecular treatment of DS allows rationalizing the a priori puzzling inconsistency between QENS and dielectric results regarding the dynamic coupling of the two components. The interpretation proposed is based on general grounds and therefore should be applicable to other biomolecular solutions.


Double-pulse technique for optical emission spectroscopy of ablation plasmas of samples in liquids.
Sharp atomic and ionic line spectra of excimer-laser-induced ablation plasmas of samples in liquids were observed. A new double-pulse technique employing quartz fibers facilitates spectral analysis of samples in liquids in which spectral lines normally are strongly broadened and quenched. The first pulse generates a cavitation bubble on the sample surface, which provides a gaseous environment for optical emission spectroscopy on the ablation plasma induced by a second pulse fired into the bubble.


Asteroid (101955) Bennu's weak boulders and thermally anomalous equator.
Thermal inertia and surface roughness are proxies for the physical characteristics of planetary surfaces. Global maps of these two properties distinguish the boulder population on near-Earth asteroid (NEA) (101955) Bennu into two types that differ in strength, and both have lower thermal inertia than expected for boulders and meteorites. Neither has strongly temperature-dependent thermal properties. The weaker boulder type probably would not survive atmospheric entry and thus may not be represented in the meteorite collection. The maps also show a high-thermal inertia band at Bennu's equator, which might be explained by processes such as compaction or strength sorting during mass movement, but these explanations are not wholly consistent with other data. Our findings imply that other C-complex NEAs likely have boulders similar to those on Bennu rather than finer-particulate regoliths. A tentative correlation between albedo and thermal inertia of C-complex NEAs may be due to relative abundances of boulder types.


Lone mothers, social exclusion and depression.
In this paper, data from the British National Survey of Psychiatric Morbidity are used to assess depressive disorders and markers of social disadvantage in women bringing up children on their own. The household component of the British National Surveys of Psychiatric Morbidity was based on a stratified random sample of > 10000 subjects. This paper reports on 5281 women interviewed in person. Psychiatric symptoms and ICD-10 diagnoses were established by lay interviewers using the CIS-R. Results are presented in terms of depressive episode and mixed anxiety/depressive disorder. Housing tenure and access to a car were used as proxy measures of material status. The life event rate in the 6 months before interview was used to indicate overall exposure to stress, and subjects were asked in detail about perceived social support. Information was collected about various other sociodemographic attributes. Lone mothers were compared with supported mothers and with women not involved in care of children under 16. Lone mothers had prevalence rates of depressive episode of 7%, about three times higher than any other group. The milder condition, mixed anxiety/depression, was also increased in frequency. These increased rates of depressive conditions were no longer apparent after controlling for measures of social disadvantage, stress and isolation. Lone mothers are increasing in numbers as marital stability declines. Their high rates of material disadvantage and of depressive disorder may have considerable implications for psychiatric and social policy.


Molecular characterization of the Clostridium difficile toxin A gene.
The gene encoding the toxin A protein of Clostridium difficile (strain VPI 10463) was cloned and sequenced. The coding region of 8,133 base pairs had a mol% G + C of 26.9 and encodes 2,710 amino acids. The deduced polypeptide has a molecular mass of ca. 308 kilodaltons. Nearly a third of the gene, at the 3' end, consists of 38 repeating sequences. The repeating units were grouped into two classes, I and II, on the basis of length and the low levels of DNA sequence similarities between them. There were seven class I repeating units, each containing 90 nucleotides, and 31 class II units, which, with two exceptions, were either 60 or 63 nucleotides in length. On the basis of DNA sequence similarities, the class II repeating units were further segregated into subclasses: 7 class IIA, 13 class IIB, 5 class IIC, and 6 class IID. The dipeptide tyrosine-phenylalanine was found in all 38 repeating units, and other amino acid sequences were unique to a specific class or subclass. This region of the protein has epitopes for the monoclonal antibody PCG-4 and includes the binding region for the Gal alpha 1-3Gal beta 1-4GlcNAc carbohydrate receptor. Located 1,350 base pairs upstream from the toxin A translation start site is the 3' end of the toxin B gene. Between the two toxin genes is a small open reading frame, which encodes a deduced polypeptide of ca. 16 or 19 kilodaltons. The role of this open reading frame is unknown.


Precipitation of abstinence in nordiazepam- and diazepam-dependent dogs.
Dogs were made dependent on p.o. administered diazepam (24 or 36 mg/kg/day) or nordiazepam (18 mg/kg/day). Flumazenil (2, 6 or 18 mg/kg) administered p.o. once a week according to a Latin Square design precipitated abstinence in both groups of dogs. Abstinence was evaluated using a Nordiazepam Precipitated Abstinence Scale (NPAS) of various signs of abstinence and by counting seizure episodes. Flumazenil caused dose-related increases in the NPAS scores of both diazepam- and nordiazepam-dependent dogs; the slopes of the two dose-response lines were not different. Both groups of dogs also had both clonic and tonic-clonic seizures after flumazenil administration. CGS-8216 (2, 6 or 18 mg/kg) administered p.o. did not cause a dose-related elevation in NPAS scores for either group of dogs but clonic and tonic-clonic seizures were seen. Thus, flumazenil precipitates the benzodiazepine abstinence syndrome, as evidenced by tremors, tachypnea and other signs, including seizures, whereas CGS-8216 may have some selectivity in precipitating seizures without other signs of abstinence.


A meta-analysis on heart rate variability biofeedback and depressive symptoms.
Heart rate variability biofeedback (HRVB) has been used for a number of years to treat depressive symptoms, a common mental health issue, which is often comorbid with other psychopathological and medical conditions. The aim of the present meta-analysis is to test whether and to what extent HRVB is effective in reducing depressive symptoms in adult patients. We conducted a literature search on Pubmed, ProQuest, Ovid PsycInfo, and Embase up to October 2020, and identified 721 studies. Fourteen studies were included in the meta-analysis. Three meta-regressions were also performed to further test whether publication year, the questionnaire used to assess depressive symptoms, or the interval of time between T0 and T1 moderated the effect of HRVB. Overall, we analysed 14 RCTs with a total of 794 participants. The random effect analysis yielded a medium mean effect size g = 0.38 [95% CI = 0.16, 0.60; 95% PI = - 0.19, 0.96], z = 3.44, p = 0.0006. The total heterogeneity was significant, QT = 23.49, p = 0.03, I2 = 45%, which suggested a moderate variance among the included studies. The year of publication (χ2(1) = 4.08, p = 0.04) and the questionnaire used to assess symptoms (χ2(4) = 12.65, p = 0.01) significantly moderated the effect of the interventions and reduced heterogeneity. Overall, results showed that HRVB improves depressive symptoms in several psychophysiological conditions in adult samples and should be considered as a valid technique to increase psychological well-being.


Workshops of the Sixth International Brain-Computer Interface Meeting: brain-computer interfaces past, present, and future.
The Sixth International Brain-Computer Interface (BCI) Meeting was held 30 May-3 June 2016 at the Asilomar Conference Grounds, Pacific Grove, California, USA. The conference included 28 workshops covering topics in BCI and brain-machine interface research. Topics included BCI for specific populations or applications, advancing BCI research through use of specific signals or technological advances, and translational and commercial issues to bring both implanted and non-invasive BCIs to market. BCI research is growing and expanding in the breadth of its applications, the depth of knowledge it can produce, and the practical benefit it can provide both for those with physical impairments and the general public. Here we provide summaries of each workshop, illustrating the breadth and depth of BCI research and highlighting important issues and calls for action to support future research and development.


Gastroenteropancreatic neuroendocrine tumours.
Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.


Somatostatin Interneurons Control a Key Component of Mismatch Negativity in Mouse Visual Cortex.
Patients with schizophrenia have deficient sensory processing, undermining how they perceive and relate to a changing environment. This impairment can be captured by the reduced mismatch negativity (MMN) index, an electroencephalographic biomarker of psychosis. The biological factors contributing to MMN are unclear, though mouse research, in which genetic and optical methods could be applied, has given some insight. Using fast two-photon calcium imaging and multielectrode recordings in awake mice, we find that visual cortical circuits display adapted (decreased) responses to repeated stimuli and amplified responses to a deviant stimulus, the key component of human MMN. Moreover, pharmacogenetic silencing of somatostatin-containing interneurons specifically eliminated this amplification, along with its associated theta/alpha-band response, leaving stimulus-specific adaption and related gamma-band modulations intact. Our results validate a mouse model of MMN and suggest that abnormalities in somatostatin-containing interneurons cause sensory deficits underlying MMN and schizophrenia.


Estimating coverage of a women's group intervention among a population of pregnant women in rural Bangladesh.
Reducing maternal and child mortality requires focused attention on better access, utilisation and coverage of good quality health services and interventions aimed at improving maternal and newborn health among target populations, in particular, pregnant women. Intervention coverage in resource and data poor settings is rarely documented. This paper describes four different methods, and their underlying assumptions, to estimate coverage of a community mobilisation women's group intervention for maternal and newborn health among a population of pregnant women in rural Bangladesh. Primary and secondary data sources were used to estimate the intervention's coverage among pregnant women. Four methods were used: (1) direct measurement of a proxy indicator using intervention survey data; (2) direct measurement among intervention participants and modelled extrapolation based on routine longitudinal surveillance of births; (3) direct measurement among participants and modelled extrapolation based on cross-sectional measurements and national data; and (4) direct measurement among participants and modelled extrapolation based on published national data. The estimated women's group intervention's coverage among pregnant women ranged from 30% to 34%, depending on method used. Differences likely reflect differing assumptions and methodological biases of the various methods. In the absence of complete and timely population data, choice of coverage estimation method must be based on the strengths and limitations of available methods, capacity and resources for measurement and the ultimate end user needs. Each of the methods presented and discussed here is likely to provide a useful understanding of intervention coverage at a single point in time and Methods 1 and 2 may also provide more reliable estimates of coverage trends.


Dermatoglyphics of the Ogoni of Nigeria and its historiographic implications.
The dermal ridges on the surfaces of the palms and the fingers form dermatoglyphic patterns which are phylogenetically stable traits useful for evaluating interpopulation affinities and distinctiveness. In this study, these traits were investigated according to traditional methods among the Ogoni people of the Niger Delta region of Southern Nigeria, considering the uncertainties surrounding the people's historiography and the paucity of morphologic studies on the tribe. The evidences of finger whorl pattern frequencies, Total Ridge Count and palmar A-B ridge count indicate the close dermatoglyphic resemblance of the Ogoni to tribal populations of southern Ghana. These findings have implications as to the likely provenance of the Ogoni people, providing support to the traditionally view among the people that their ancestors are migrants from some tribe in southern Ghana, West Africa.


Arctic lake physical processes and regimes with implications for winter water availability and management in the National Petroleum Reserve Alaska.
Lakes are dominant landforms in the National Petroleum Reserve Alaska (NPRA) as well as important social and ecological resources. Of recent importance is the management of these freshwater ecosystems because lakes deeper than maximum ice thickness provide an important and often sole source of liquid water for aquatic biota, villages, and industry during winter. To better understand seasonal and annual hydrodynamics in the context of lake morphometry, we analyzed lakes in two adjacent areas where winter water use is expected to increase in the near future because of industrial expansion. Landsat Thematic Mapper and Enhanced Thematic Mapper Plus imagery acquired between 1985 and 2007 were analyzed and compared with climate data to understand interannual variability. Measured changes in lake area extent varied by 0.6% and were significantly correlated to total precipitation in the preceding 12 months (p < 0.05). Using this relation, the modeled lake area extent from 1985 to 2007 showed no long-term trends. In addition, high-resolution aerial photography, bathymetric surveys, water-level monitoring, and lake-ice thickness measurements and growth models were used to better understand seasonal hydrodynamics, surface area-to-volume relations, winter water availability, and more permanent changes related to geomorphic change. Together, these results describe how lakes vary seasonally and annually in two critical areas of the NPRA and provide simple models to help better predict variation in lake-water supply. Our findings suggest that both overestimation and underestimation of actual available winter water volume may occur regularly, and this understanding may help better inform management strategies as future resource use expands in the NPRA.


Incidence of heterotopic bone formation after major hip surgery.
Heterotopic bone formation is a well-established complication of major hip surgery, but traditional reviews of the published literature may have underestimated its frequency. A systematic overview of all the relevant studies was performed to determine reliably the incidence of any heterotopic bone formation and the incidence of each Brooker equivalent grade. Separate estimates were made for patients with total hip replacement and patients with acetabular fracture repair. A computer-based search identified 218 studies with data on the incidence of heterotopic bone formation after either hip replacement or acetabular fracture repair. These studies included data from an estimated 59 121 operated hips among patients that received total hip replacement and an estimated 998 hips among patients that underwent acetabular fracture repair. In these studies, the incidence of any heterotopic bone formation was 43% after total hip replacement and 51% after acetabular fracture repair. The incidence of severe heterotopic bone formation was 9% and 19%, respectively. These results suggest that heterotopic bone formation occurs more frequently after total hip replacement than is generally believed. It is possible that heterotopic bone formation is a more important cause of postoperative disability than has previously been recognized and that effective prophylactic regimens might improve outcome in substantial numbers of patients.


Radioprotection of plasmid and cellular DNA and Swiss mice by silibinin.
The radioprotective effect of a non-toxic bioactive component in plant milk thistle, silibinin against genotoxicity induced by gamma-irradiation was investigated in vivo/in vitro. Under in vitro conditions of irradiation, silibinin protected plasmid pBR322 DNA against gamma-radiation-induced strand breaks in a concentration dependent manner (0-200microM). Under cellular conditions of radiation exposure (3Gy), silibinin offered protection to lymphocyte DNA as evidenced from reduction in DNA damage and micronuclei formation, which showed correlation to the extent of intracellular reactive oxygen species reduction. Our extended animal studies suggest that oral administration of silibinin (70mg/kg for 3 days) to mice prior to whole-body gamma-exposure (7.5Gy) resulted in significant protection to radiation-induced mortality and DNA damage in blood leukocytes. However, silibinin treatment after irradiation was not as effective as pre-administration. In conclusion, present study indicated that silibinin has a strong potential to prevent radiation-induced DNA damage under both in vitro and in vivo.


A new method to compute K-mer frequencies and its application to annotate large repetitive plant genomes.
The challenges of accurate gene prediction and enumeration are further aggravated in large genomes that contain highly repetitive transposable elements (TEs). Yet TEs play a substantial role in genome evolution and are themselves an important subject of study. Repeat annotation, based on counting occurrences of k-mers, has been previously used to distinguish TEs from low-copy genic regions; but currently available software solutions are impractical due to high memory requirements or specialization for specific user-tasks. Here we introduce the Tallymer software, a flexible and memory-efficient collection of programs for k-mer counting and indexing of large sequence sets. Unlike previous methods, Tallymer is based on enhanced suffix arrays. This gives a much larger flexibility concerning the choice of the k-mer size. Tallymer can process large data sizes of several billion bases. We used it in a variety of applications to study the genomes of maize and other plant species. In particular, Tallymer was used to index a set of whole genome shotgun sequences from maize (B73) (total size 109 bp.). We analyzed k-mer frequencies for a wide range of k. At this low genome coverage ( approximately 0.45x) highly repetitive 20-mers constituted 44% of the genome but represented only 1% of all possible k-mers. Similar low-complexity was seen in the repeat fractions of sorghum and rice. When applying our method to other maize data sets, High-C0t derived sequences showed the greatest enrichment for low-copy sequences. Among annotated TEs, the most highly repetitive were of the Ty3/gypsy class of retrotransposons, followed by the Ty1/copia class, and DNA transposons. Among expressed sequence tags (EST), a notable fraction contained high-copy k-mers, suggesting that transposons are still active in maize. Retrotransposons in Mo17 and McC cultivars were readily detected using the B73 20-mer frequency index, indicating their conservation despite extensive rearrangement across cultivars. Among one hundred annotated bacterial artificial chromosomes (BACs), k-mer frequency could be used to detect transposon-encoded genes with 92% sensitivity, compared to 96% using alignment-based repeat masking, while both methods showed 92% specificity. The Tallymer software was effective in a variety of applications to aid genome annotation in maize, despite limitations imposed by the relatively low coverage of sequence available. For more information on the software, see http://www.zbh.uni-hamburg.de/Tallymer.


All-digital ring-wedge detector applied to fingerprint recognition.
An all-digital ring-wedge detector system is presented that simulates the analog multielement array commonly used in coherent optoelectronic processors. The system is applicable with either hard-copy or digital imagery. Using neural-network software, we demonstrate high accuracy for the recognition of fingerprints, including both orientation and wide-scale size-independent sortings by using ring-only and wedge-only input neurons, respectively. Also, the system is applied on windowed subregions of fingerprint imagery, providing a feature set that summarizes localized information about spatial-frequency content and edge-angle correlations. Examples are presented in which this localized spatial-frequency information is used to produce local ridge-orientation maps and to detect regions of poor print quality. In summary, both direct-image data and spatial-transform data are found to be important.


Population-based, case-control study of blood C-peptide level and breast cancer risk.
Insulin resistance has been suggested to be associated with an increased risk of breast cancer. Insulin sensitivity can be measured using blood C-peptide, a marker of insulin secretion. It is thus conceivable that blood C-peptide levels may be associated with breast cancer risk. To evaluate this hypothesis, we analyzed data from a subset (143 case-control pairs matched by age and status of menopause) of women who participated in the Shanghai Breast Cancer Study, a population-based, case-control study conducted in Shanghai during 1996-1998. Fasting blood samples were collected from study subjects to measure C-peptide levels. For cancer patients, the samples were collected before any cancer therapy. Conditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals related to C-peptide levels. Breast cancer risk was increased with increasing levels of C-peptide (trend test, P = 0.01), with an odds ratio of 2.7 (95% confidence interval = 1.2-5.9) observed for the highest compared with the lowest tertile of C-peptide concentration after adjusting for body mass index and age at the first live birth. The risk was not altered after fully adjusting for other traditional risk factors for breast cancer. This positive association was observed in both pre and postmenopausal women and regardless of the levels of waist-to-hip ratio or body mass index. The results from this study were consistent with the insulin-resistance hypothesis for breast cancer and suggest that increased levels of C-peptide may contribute to the development of breast cancer.


Isolation of intrinsically active (MEK-independent) variants of the ERK family of mitogen-activated protein (MAP) kinases.
MAPKs are key components of cell signaling pathways with a unique activation mechanism: i.e. dual phosphorylation of neighboring threonine and tyrosine residues. The ERK enzymes form a subfamily of MAPKs involved in proliferation, differentiation, development, learning, and memory. The exact role of each Erk molecule in these processes is not clear. An efficient strategy for addressing this question is to activate individually each molecule, for example, by expressing intrinsically active variants of them. However, such molecules were not produced so far. Here, we report on the isolation, via a specifically designed genetic screen, of six variants (each carries a point mutation) of the yeast MAPK Mpk1/Erk that are active, independent of upstream phosphorylation. One of the activating mutations, R68S, occurred in a residue conserved in the mammalian Erk1 (Arg-84) and Erk2 (Arg-65) and in the Drosophila ERK Rolled (Arg-80). Replacing this conserved Arg with Ser rendered these MAPKs intrinsically active to very high levels when tested in vitro as recombinant proteins. Combination of the Arg to Ser mutation with the sevenmaker mutation (producing Erk2(R65S+D319N) and Rolled(R80S+D334N)) resulted in even higher activity (45 and 70%, respectively, in reference to fully active dually phosphorylated Erk2 or Rolled). Erk2(R65S) and Erk2(R65S+D319N) were found to be spontaneously active also when expressed in human HEK293 cells. We further revealed the mechanism of action of the mutants and show that it involves acquisition of autophosphorylation activity. Thus, a first generation of Erk molecules that are spontaneously active in vitro and in vivo has been obtained.


Genomic evidence that resource-based trade-offs limit host-range expansion in a seed beetle.
Trade-offs have often been invoked to explain the evolution of ecological specialization. Phytophagous insects have been especially well studied, but there has been little evidence that resource-based trade-offs contribute to the evolution of host specialization in this group. Here, we combine experimental evolution and partial genome resequencing of replicate seed beetle selection lines to test the trade-off hypothesis and measure the repeatability of evolution. Bayesian estimates of selection coefficients suggest that rapid adaptation to a poor host (lentil) was mediated by standing genetic variation at multiple genetic loci and involved many of the same variants in replicate lines. Sublines that were then switched back to the ancestral host (mung bean) showed a more gradual and variable (less repeatable) loss of adaptation to lentil. We were able to obtain estimates of variance effective population sizes from genome-wide differences in allele frequencies within and between lines. These estimates were relatively large, which suggests that the contribution of genetic drift to the loss of adaptation following reversion was small. Instead, we find that some alleles that were favored on lentil were selected against during reversion on mung bean, consistent with the genetic trade-off hypothesis.


Complex RNA folding kinetics revealed by single-molecule FRET and hidden Markov models.
We have developed a hidden Markov model and optimization procedure for photon-based single-molecule FRET data, which takes into account the trace-dependent background intensities. This analysis technique reveals an unprecedented amount of detail in the folding kinetics of the Diels-Alderase ribozyme. We find a multitude of extended (low-FRET) and compact (high-FRET) states. Five states were consistently and independently identified in two FRET constructs and at three Mg(2+) concentrations. Structures generally tend to become more compact upon addition of Mg(2+). Some compact structures are observed to significantly depend on Mg(2+) concentration, suggesting a tertiary fold stabilized by Mg(2+) ions. One compact structure was observed to be Mg(2+)-independent, consistent with stabilization by tertiary Watson-Crick base pairing found in the folded Diels-Alderase structure. A hierarchy of time scales was discovered, including dynamics of 10 ms or faster, likely due to tertiary structure fluctuations, and slow dynamics on the seconds time scale, presumably associated with significant changes in secondary structure. The folding pathways proceed through a series of intermediate secondary structures. There exist both compact pathways and more complex ones, which display tertiary unfolding, then secondary refolding, and, subsequently, again tertiary refolding.


X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization.
The ability to parse tumors into subsets based on biomarker expression has many clinical applications; however, there is no global way to visualize the best cut-points for creating such divisions. We have developed a graphical method, the X-tile plot that illustrates the presence of substantial tumor subpopulations and shows the robustness of the relationship between a biomarker and outcome by construction of a two dimensional projection of every possible subpopulation. We validate X-tile plots by examining the expression of several established prognostic markers (human epidermal growth factor receptor-2, estrogen receptor, p53 expression, patient age, tumor size, and node number) in cohorts of breast cancer patients and show how X-tile plots of each marker predict population subsets rooted in the known biology of their expression.