Clinically-approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia.
Cystic Fibrosis (CF) is a multi-organ progressive genetic disease caused by loss of functional cystic fibrosis transmembrane conductance regulator (CFTR) channel. Previously, we identified a significant dysfunction in CF cells and model mice of the transcription factor nuclear-factor-E2-related factor-2 (Nrf2), a major regulator of redox balance and inflammatory signaling. Here we report that approved F508del CFTR correctors VX809/VX661 recover diminished Nrf2 function and colocalization with CFTR in CF human primary bronchial epithelia by proximity ligation assay, immunoprecipitation, and immunofluorescence, concordant with CFTR correction. F508del CFTR correctors induced Nrf2 nuclear translocation, Nrf2-dependent luciferase activity, and transcriptional activation of target genes. Rescue of Nrf2 function by VX809/VX661 was dependent on significant correction of F508del and was blocked by inhibition of corrected channel function, or high-level shRNA knockdown of CFTR or F508del-CFTR. Mechanistically, F508del-CFTR modulation restored Nrf2 phosphorylation and its interaction with the coactivator CBP. Our findings demonstrate that sufficient modulation of F508del CFTR function corrects Nrf2 dysfunction in CF.


Multifractal signatures of infectious diseases.
Incidence of infection time-series data for the childhood diseases measles, chicken pox, rubella and whooping cough are described in the language of multifractals. We explore the potential of using the wavelet transform maximum modulus (WTMM) method to characterize the multiscale structure of the observed time series and of simulated data generated by the stochastic susceptible-exposed-infectious-recovered (SEIR) epidemic model. The singularity spectra of the observed time series suggest that each disease is characterized by a unique multifractal signature, which distinguishes that particular disease from the others. The wavelet scaling functions confirm that the time series of measles, rubella and whooping cough are clearly multifractal, while chicken pox has a more monofractal structure in time. The stochastic SEIR epidemic model is unable to reproduce the qualitative singularity structure of the reported incidence data: it is too smooth and does not appear to have a multifractal singularity structure. The precise reasons for the failure of the SEIR epidemic model to reproduce the correct multiscale structure of the reported incidence data remain unclear.


Central norepinephrine metabolism during alcohol intoxication in addicts and healthy volunteers.
The concentrations of the major norepinephrine metabolite, 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), in lumbar cerebrospinal fluid of alcoholic patients were markedly elevated during intoxication and successively declined during 1 and 3 weeks of abstinence. During intoxication the MOPEG concentration in cerebrospinal fluid showed a statistically significant correlation with the blood alcohol concentration. In healthy volunteers who received 80 grams of ethanol, the MOPEG concentration in cerebrospinal fluid increased significantly. Healthy subjects sampled during intoxication had significantly higher concentrations of MOPEG in the cerebrospinal fluid than did subjects sampled after the end of intoxication. The results indicate that alcohol administration markedly stimulates norepinephrine metabolism in the central nervous system in human subjects possibly by increasing unit impulse activity of central noradrenergic neurons.


GABAA and excitatory amino acid receptors in dorsomedial hypothalamus and heart rate in rats.
We have previously shown that microinjection of drugs that interfere with the function of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into the hypothalamus produces cardiorespiratory and behavioral changes resembling those seen in emotional stress. The purpose of this study was to determine whether excitatory amino acids (EAAs) can produce a cardiovascular response similar to that caused by the GABAA receptor antagonist bicuculline methiodide (BMI) when microinjected at the same hypothalamic site in urethan-anesthetized rats and to clarify the precise locus of action of these agents. N-methyl-D-aspartic acid (NMDA, 0.68-6.8 pmol/50 nl) and kainic acid (KA, 0.47-4.7 pmol/50 nl) produced dose-related increases in heart rate and blood pressure when injected at sites in the dorsomedial hypothalamus reactive to BMI (20 pmol/50 nl). Higher doses of NMDA (68 pmol), however, failed to elicit consistent increases in heart rate and blood pressure when injected at these same sites. The effects of NMDA were selectively blocked by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid, whereas the effects of KA were selectively blocked by the non-NMDA EAA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. These results demonstrate that 1) blockade of inhibitory amino acid receptors or stimulation of EAA receptors in the dorsomedial nucleus of the hypothalamus produces tachycardic and pressor responses in urethan-anesthetized rats and 2) use of high doses of EAAs may be an unreliable method of evoking local neuronal excitation in certain regions of the central nervous system.


Does Passive Sampling Accurately Reflect the Bee (Apoidea: Anthophila) Communities Pollinating Apple and Sour Cherry Orchards?
During bloom of spring orchard crops, bees are the primary providers of pollination service. Monitoring these insects for research projects is often done by timed observations or by direct aerial netting, but there has been increasing interest in blue vane traps as an efficient passive approach to collecting bees. Over multiple spring seasons in Michigan and Pennsylvania, orchards were monitored for wild bees using timed netting from crop flowers and blue vane traps. This revealed a distinctly different community of wild bees captured using the two methods, suggesting that blue vane traps can complement but cannot replace direct aerial netting. The bee community in blue vane traps was generally composed of nonpollinating species, which can be of interest for broader biodiversity studies. In particular, blue vane traps caught Eucera atriventris (Smith), Eucera hamata (Bradley), Bombus fervidus (F.), and Agapostemon virescens (F.) that were never collected from the orchard crop flowers during the study period. Captures of bee species in nets was generally stable across the 3 yr, whereas we observed significant declines in the abundance of Lasioglossum pilosum (Smith) and Eucera spp. trapped using blue vane traps during the project, suggesting local overtrapping of reproductive individuals. We conclude that blue vane traps are a useful tool for expanding insights into bee communities within orchard crop systems, but they should be used with great caution to avoid local extirpation of these important insects.


Folate and methotrexate polyglutamate tissue levels in rhesus monkeys following chronic low-dose methotrexate.
Methotrexate (MTX), a mainstay in the treatment of acute lymphoblastic leukemia, is associated with both hepatic and neurologic toxicity. Like a folate, MTX is metabolized to polyglutamated derivatives (MTXGlun) with long intracellular half-lives. These metabolites may contribute to MTX toxicity through a direct effect on cellular metabolism or indirectly through a perturbation of folate homeostasis. To better define the effects of chronic MTX treatment, tissue levels of MTX, MTXGlun, and folate were measured in three monkeys treated with weekly intramuscular MTX for 1 year. Greater than 80% of the total tissue MTX found was in the form of polyglutamated derivatives. Most of these derivatives were MTXGlu3-5 but Glu6-7 were easily detectable. Total tissue folates were measured in liver, kidney, brain and testis with MTX treated animals having a 90% loss of total folate in brain tissue. This is of special interest since inborn errors of folate metabolism are often associated with severe neurologic abnormalities.


Failure of interventions to maintain mitochondrial function in ischemic myocardium.
The purpose of this study was to investigate whether pyruvate (2.5 mmol/kg), the combination of glucose (3.9 mmol/kg) and insulin (0.13 unit/kg) with potassium (9.27 meq/kg), or sodium dichloroacetate (120 mg/kg) infused for 15 minutes before and 20 minutes after ligation of the left anterior descending coronary arterv in anesthetized dogs restricted the depression in mitochondrial respiratory function induced by ischemia. Myocardial blood flow after ligation in the three groups was o.2 ml/min per gram or less in ischemic subendocardium and was similar to that in saline-infused controls that had also undergone coronary artery ligation. The depressions induced in mitochondrial respiratory control index and state 3 respiration by ischemia in the subendocardium and subepicardium of the three treatment groups, when compared with corresponding nonischemic tissue, were not significantly improved from the control values. It was concluded that these three interventions fail to preserve mitochondrial respiration in ischemic myocardium.


Plasminogen activator inhibitor-1 in the aqueous humor of patients with and without glaucoma.
To determine the levels of plasminogen activator inhibitor-1 (PAI-1) and total protein in the aqueous humor of patients with glaucoma vs those without glaucoma. A total of 125 aqueous humor samples (50-150 microL each) were collected at 3 institutions from patients with glaucoma and a control group of patients with cataract. Fifteen samples were excluded, and the levels of PAI-1 antigen were determined by enzyme-linked immunosorbent assay in 110 samples (36 glaucoma and 74 control). Total protein levels were determined by the Bradford method in 81 samples (28 glaucoma and 53 control), in which the aqueous humor collected was sufficient. Statistical analysis of the results was conducted using the Mann-Whitney U test. The correlation between PAI-1 and protein levels was calculated using the Spearman rank correlation coefficient. The mean +/- SD PAI-1 levels detected in aqueous humor samples of the control and glaucoma groups were 0.44 +/- 0.61 and 1.45 +/- 1.91 ng/mL, respectively. The mean +/- SD levels of total protein were 64.91 +/- 89.75 and 86.64 +/- 44.16 microg/mL, respectively. For both parameters, the difference between the 2 groups was significant (P< .001). The correlation between PAI-1 and total protein levels was moderate in the glaucoma group (r = 0.43; P = .01) and low in the control group (r = 0.23; P = .04). The glaucoma group showed in the aqueous humor a 3.3-fold increase in the mean level of PAI-1 compared with the control group, whereas the increase in total protein level was only 1.3-fold. These data are consistent with the possibility that intraocularly produced PAI-1 may contribute to glaucoma pathogenesis. Reducing the production or activity of PAI-1 in the eye could constitute a new target for the design of drugs to treat glaucoma.


Center-based prevalence of anxiety and depression in women of the northern areas of Pakistan.
To estimate the prevalence of anxiety and depression in women of the Northern areas. A cross-sectional center-based study was conducted at Singal Medical Center (SMC), Gilgit, in the Northern Areas of Pakistan, using the Hospital Anxiety and Depression Scale (HADS). One hundred and twenty women, between the ages of 16 and 60, attended the SMC over a two month period and were included in the study. Using HADS, it was found that 50% of the women had anxiety and/or depression; 25% suffered only from anxiety, 8% from depression and 17% had features of both. This study supports the previous studies of stress in remote areas and also contradicts the belief that people who live in the remote rural areas lead stress-free lives or have low rates of psychiatric morbidity (JPMA 50:138, 2000).


Pregnancy: An Underutilized Window of Opportunity to Improve Long-term Maternal and Infant Health-An Appeal for Continuous Family Care and Interdisciplinary Communication.
Physiologic adaptations during pregnancy unmask a woman's predisposition to diseases. Complications are increasingly predicted by first-trimester algorithms, amplify a pre-existing maternal phenotype and accelerate risks for chronic diseases in the offspring up to adulthood (Barker hypothesis). Recent evidence suggests that vice versa, pregnancy diseases also indicate maternal and even grandparent's risks for chronic diseases (reverse Barker hypothesis). Pub-Med and Embase were reviewed for Mesh terms "fetal programming" and "pregnancy complications combined with maternal disease" until January 2017. Studies linking pregnancy complications to future cardiovascular, metabolic, and thrombotic risks for mother and offspring were reviewed. Women with a history of miscarriage, fetal growth restriction, preeclampsia, preterm delivery, obesity, excessive gestational weight gain, gestational diabetes, subfertility, and thrombophilia more frequently demonstrate with echocardiographic abnormalities, higher fasting insulin, deviating lipids or clotting factors and show defective endothelial function. Thrombophilia hints to thrombotic risks in later life. Pregnancy abnormalities correlate with future cardiovascular and metabolic complications and earlier mortality. Conversely, women with a normal pregnancy have lower rates of subsequent diseases than the general female population creating the term: "Pregnancy as a window for future health." Although the placenta works as a gatekeeper, many pregnancy complications may lead to sickness and earlier death in later life when the child becomes an adult. The epigenetic mechanisms and the mismatch between pre- and postnatal life have created the term "fetal origin of adult disease." Up to now, the impact of cardiovascular, metabolic, or thrombotic risk profiles has been investigated separately for mother and child. In this manuscript, we strive to illustrate the consequences for both, fetus and mother within a cohesive perspective and thus try to demonstrate the complex interrelationship of genetics and epigenetics for long-term health of societies and future generations. Maternal-fetal medicine specialists should have a key role in the prevention of non-communicable diseases by implementing a framework for patient consultation and interdisciplinary networks. Health-care providers and policy makers should increasingly invest in a stratified primary prevention and follow-up to reduce the increasing number of manifest cardiovascular and metabolic diseases and to prevent waste of health-care resources.


Levels of iron, vitamin B12, folic acid and their binding proteins during pregnancy.
One hundred pregnant women, not anemic and not receiving iron or vitamin supplements, were chosen at random among the three trimesters of pregnancy to determine the incidence of unexpected iron, plasma folate and/or cobalamin deficiency, and the significance of fluctuating levels of their respective binding proteins. Pregnant females had a nonsignificant fall in serum iron and a fourfold decline in serum ferritin in the 3rd trimester compared with 1st trimester values. There was a steady decrease in plasma cobalamin and cobalophilin levels in every trimester but no difference in transcobalamin II values. Unsaturated cobalamin (UBBC) and unsaturated transcobalamin binding capacity (UTCBC) were lower in the 1st trimester fully recovering afterwards. Plasma folate levels were not lower, although there was a steady reduction in total and unsaturated folate binding capacity throughout pregnancy.


Nominal and functional task difficulty in skill acquisition: Effects on performance in two tests of transfer.
The influence of nominal and functional task difficulty during the acquisition of a motor skill was examined in two tests of transfer of learning. The task involved a ballistic, target-directed, finger action. Nominal task difficulty was defined as the distance of the target from the home position. Functional task difficulty was created by manipulating the progression of target distances during practice. Based on the challenge point framework (Guadagnoli & Lee, 2004), we predicted that practice with a set of targets farther away from the performer would benefit from less functional task difficulty, while practice with a closer set of targets would benefit from more functional task difficulty. In single-task transfer tests, learners who practiced using the high nominal task difficulty targets benefitted in terms of persistence of performance over time. In dual-task transfer tests, groups with an intermediate combined (nominal and functional) task difficulty performed with greater persistence over time on tests of transfer than those who practiced with the highest or lowest combined difficulty. Together these findings suggest that the influences of nominal and functional task difficulty during acquisition are weighted differentially depending upon the transfer test context. The challenge point framework does not accurately capture this complex relationship in its current form.


Investigating the motivational behavior of pupils during outdoor science teaching within self-determination theory.
This paper presents data from a mixed-method pilot study (n = 84) searching into learning psychological aspects of an outdoor science teaching program. We use data from qualitative explorations into the pupils' learning motivation during field observation, a group interview, and open questionnaires, in order to understand quantitative measures from the Self-Determination Index (SDI), and the Practical Orientation (PO) of the program. Our data suggest that lower self-regulated pupils in "normal" science classes show a significantly higher self-regulated learning motivational behavior in the outdoor educational setting (p < 10(-4)), and that the outdoor-teaching has generally been perceived as more practical than teaching at the normal school context (p < 10(-4)), irrespective of gender or school culture. We are going to provide in-depth analyses of all quantitative findings with our qualitative data and thus explain the findings logically, with respect to the direction of the statistical interpretation, and substantially, with respect to the meaning of the discoveries. We conclude that outdoor programming appears to be a suitable tool to trigger interest in science in youngsters, especially for less motivated pupils.


The Apoptotic Effect of Ursolic Acid on SK-Hep-1 Cells is Regulated by the PI3K/Akt, p38 and JNK MAPK Signaling Pathways.
Ursolic acid (UA) is a pentacyclic triterpene acid that is present in a wide variety of medicinal herbs and edible plants. This study investigated the effect of UA on apoptosis and proliferation of hepatocellular carcinoma SK-Hep-1 cells. After treatment of SK-Hep-1 cells with different concentrations of UA, we observed that cell viability was reduced in a dose- and time-dependent manner. Furthermore, there was a dose-dependent increase in the percentage of cells in the sub-G1 and G2/M phases, with cells treated with 60 μM showing the highest percentages of cells in those phases. UA-induced chromatin condensation of nuclei was observed by using DAPI staining. The western blot results revealed that exposure to UA was associated with decreased expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, Bcl-2, and TCTP and increased expression of apoptosis-related proteins TNF-α, Fas, FADD, Bax, cleaved caspase-3, caspase-8, caspase-9, and PARP. Immunocytochemistry staining showed that treatment with UA resulted in increased expression of caspase-3. Moreover, exposure to UA resulted in the inhibition of the PI3K/Akt and p38 MAPK signaling pathways. These findings suggest that UA inhibits the proliferation of SK-Hep-1 cells and induces apoptosis.


Hidden patterns of codon usage bias across kingdoms.
The genetic code is necessarily degenerate with 64 possible nucleotide triplets being translated into 20 amino acids. Eighteen out of the 20 amino acids are encoded by multiple synonymous codons. While synonymous codons are clearly equivalent in terms of the information they carry, it is now well established that they are used in a biased fashion. There is currently no consensus as to the origin of this bias. Drawing on ideas from stochastic thermodynamics we derive from first principles a mathematical model describing the statistics of codon usage bias. We show that the model accurately describes the distribution of codon usage bias of genomes in the fungal and bacterial kingdoms. Based on it, we derive a new computational measure of codon usage bias-the distance D capturing two aspects of codon usage bias: (i) differences in the genome-wide frequency of codons and (ii) apparent non-random distributions of codons across mRNAs. By means of large scale computational analysis of over 900 species across two kingdoms of life, we demonstrate that our measure provides novel biological insights. Specifically, we show that while codon usage bias is clearly based on heritable traits and closely related species show similar degrees of bias, there is considerable variation in the magnitude of D within taxonomic classes suggesting that the contribution of sequence-level selection to codon bias varies substantially within relatively confined taxonomic groups. Interestingly, commonly used model organisms are near the median for values of D for their taxonomic class, suggesting that they may not be good representative models for species with more extreme D, which comprise organisms of medical and agricultural interest. We also demonstrate that amino acid specific patterns of codon usage are themselves quite variable between branches of the tree of life, and that some of this variability correlates with organismal tRNA content.


Novel Vision Monitoring Method Based on Multi Light Points for Space-Time Analysis of Overhead Contact Line Displacements.
The article presents an innovative vision monitoring method of overhead contact line (OCL) displacement, which utilizes a set of LED light points installed along it. A light point is an, LED fed from a battery. Displacements of the LED points, recorded by a camera, are interpreted as a change of OCL shape in time and space. The vision system comprises a camera, properly situated with respect to the OCL, which is capable of capturing a dozen light points in its field of view. The monitoring system can be scaled by increasing the number of LED points and video cameras; thus, this method can be used for monitoring the motion of other large-size objects (e.g., several hundred meters). The applied method has made it possible to obtain the following novel results: vibration damping in a contact wire is nonlinear by nature and its intensity depends on the wire vibration amplitude; the natural frequency of contact wire vibration varies, and it is a function of vibration amplitude; the natural frequency of contact wire vibration also depends on the wire temperature. The proposed method can be used to monitor the uplift of contact and messenger wires in laboratory conditions, or for experimental OCL testing, as well as for verifying simulation models of OCL.


Relationship between low bone mineral density and varus deformity in postmenopausal women with knee osteoarthritis.
To assess the relationship between bone mineral density (BMD) and varus deformity arising from bone structural changes caused by knee osteoarthritis (OA) in postmenopausal women. This cross-sectional study involved 135 consecutive postmenopausal female patients who had varus knee OA and a Kellgren-Lawrence grade > or = 2. Knee radiographs were obtained with the patient standing on one leg, and subjects were classified into 3 tertile groups according to femorotibial angle, which was taken as a measure of varus knee OA severity. We also measured the 3 subangles that make up the femorotibial angle, and focused on the varus inclination of the tibial plateau. BMD was measured in the lumbar spine, femoral neck, and medial and lateral tibial condyles using dual-energy X-ray absorptiometry. Differences between femorotibial angle tertile groups were assessed, and associations between femorotibial sub-angles and BMD values at various points were evaluated. After adjustment for age and body mass index, there was no significant association between the varus inclination of the tibial plateau and lumbar spine BMD. A weak but statistically significant negative correlation existed between varus inclination of the tibial plateau and BMD at the ipsilateral proximal femur and lateral tibial condyle. Varus inclination of the tibial plateau was significantly more severe in the femorotibial angle tertile 3 group, and in patients with lower BMD in the ipsilateral lower limb. Varus knee OA may result not only from cartilage loss but also from structural changes of the bone.


Saliva as a medium for investigating intra- and interindividual differences in sex hormone levels in premenopausal women.
Repeated measurement of ovarian steroids in saliva could provide an advantage in studies estimating long-term sex steroid exposure in premenopausal women, by reducing the measurement error associated with collection of serum or urine samples. We previously reported on characteristics of ultrasensitive RIAs adapted for extraction-free measurement of estradiol (E2) and progesterone (PG) in saliva. The purpose of the present study was to evaluate the consistency of E2 and PG levels in saliva in the same women across menstrual cycles, and to compare this with the variation observed between women. We also evaluated the effect of altering the number of consecutive daily samples considered and the method for locating a particular cycle day in relation to ovulation (day 0). Study participants included 12 healthy women who provided daily saliva samples for two consecutive, ovulatory menstrual cycles. A single midluteal serum sample was collected 7-8 days after detection of a luteinizing hormone (LH) peak in urine. We plotted individual cycle profiles and computed intraclass correlation coefficients (ICC) for various definitions of peak and cumulative daily hormone level. For peak PG, determined as the maximal running 3-day mean, ICC was 0.68. For cumulative PG, based on 8 consecutive cycle days (+2 to +9), ICCs were 0.72-0.76 when reverse dating LH peak or rise in salivary PG determined day 0. For E2, ICCs ranged from 0.74 to 0.79 by various dating methods for the 5 preovulatory days (-4-0), and from 0.85 to 0.92 for the 15 days about the center of the cycle (-6 to +8). With exclusion of just the first 5 days of the cycle, the ICC for E2 was 0.91. For both E2 and PG, selection of 5 or 7 days for the estimation of the midluteal mean level provided separation of within and between subject variance that was comparable with a LH-timed serum sample. These results indicate that daily saliva samples can be combined to clarify the interindividual differences in E2 and PG levels in premenopausal women, and that these interindividual differences may be greater than previously imagined.


The aging hippocampus: interactions between exercise, depression, and BDNF.
Late adulthood is associated with increased hippocampal atrophy and dysfunction. Although there are multiple paths by which hippocampal deterioration occurs in late life, the authors discuss the evidence that a single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene and age-related changes in BDNF protein or receptor expression contribute to hippocampal atrophy. The authors conclude that few studies have tested whether BDNF mediates age-related hippocampal atrophy and memory impairment. However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. Importantly, the most consistent associations between BDNF and hippocampal dysfunction have emerged from research on BDNF protein expression in rodents and serum and plasma concentrations of BDNF in humans. Current research suggests that the BDNF val66met polymorphism may be only weakly associated with hippocampal atrophy in late adulthood. These conclusions are interpreted in relation to age-related memory impairment and preventions for hippocampal atrophy.


The problem of home choice in skyline-based homing.
Navigation in cluttered environments is an important challenge for animals and robots alike and has been the subject of many studies trying to explain and mimic animal navigational abilities. However, the question of selecting an appropriate home location has, so far, received only little attention. This is surprising, since the choice of a home location might greatly influence an animal's navigation performance. To address the question of home choice in cluttered environments, a systematic analysis of homing trajectories was performed by computer simulations using a skyline-based local homing method. Our analysis reveals that homing performance strongly depends on the location of the home in the environment. Furthermore, it appears that by assessing homing success in the immediate vicinity of the home, an animal might be able to predict its overall success in returning to it from within a much larger area.


Activation of contraction in cardiac muscle.
This paper begins with consideration of a qualitative model of excitation-contraction coupling in cardiac muscle which is based to a large extent on experimental work carried out on isolated preparations of cardiac muscle by Earl Wood during sabbatical years in Europe in 1966-67 and 1972-73. It goes on to consider newer evidence about excitation-contraction coupling that has been obtained from studies of "skinned" fiber preparations (that is, muscles in which the cell membranes have been disrupted or are absent) and from studied of isolated preparations in which the photoprotein aequorin was used to monitor changes in sarcoplasmic Ca2+ concentration. The results obtained from these two kinds of study are then combined in a qualitative way to illustrate current ideas about the mode of action of inotropic interventions and to provide possible explanations of the Frank-Starling effect as it appears in isolated preparations of cardiac muscle.


Sonar equations for planetary exploration.
The set of formulations commonly known as "the sonar equations" have for many decades been used to quantify the performance of sonar systems in terms of their ability to detect and localize objects submerged in seawater. The efficacy of the sonar equations, with individual terms evaluated in decibels, is well established in Earth's oceans. The sonar equations have been used in the past for missions to other planets and moons in the solar system, for which they are shown to be less suitable. While it would be preferable to undertake high-fidelity acoustical calculations to support planning, execution, and interpretation of acoustic data from planetary probes, to avoid possible errors for planned missions to such extraterrestrial bodies in future, doing so requires awareness of the pitfalls pointed out in this paper. There is a need to reexamine the assumptions, practices, and calibrations that work well for Earth to ensure that the sonar equations can be accurately applied in combination with the decibel to extraterrestrial scenarios. Examples are given for icy oceans such as exist on Europa and Ganymede, Titan's hydrocarbon lakes, and for the gaseous atmospheres of (for example) Jupiter and Venus.


Increased prevalence of celiac disease among pediatric patients with irritable bowel syndrome: a 6-year prospective cohort study.
Recurrent abdominal pain is a prevalent health issue in childhood. Clinical criteria (ie, the Rome criteria) have been established to aid diagnosis. Studies of adults have shown an increased prevalence of celiac disease among patients with irritable bowel syndrome (IBS); few data are available with regard to children. To assess the prevalence of celiac disease among children with abdominal pain-related functional gastrointestinal disorders classified according to the Rome criteria. Six-year (2006-2012) prospective cohort study conducted in a tertiary referral center for the diagnosis and follow-up of gastrointestinal disorders in southern Italy (ie, Bari, Italy). A total of 992 children (42.8% male; median age, 6.8 years) consecutively referred for recurrent abdominal pain by their primary care physicians without previous investigation were evaluated. Patients were classified according to Rome III criteria as having IBS, functional dyspepsia, functional abdominal pain, or abdominal migraine. Prevalence of celiac disease in each category of abdominal pain-related functional gastrointestinal disorder. Concentrations of IgA, IgA antitissue transglutaminase, and endomysial antibodies were measured, and a duodenal biopsy was performed in case of antibody positivity. A total of 992 children were evaluated: 270 were classified as having IBS, 201 as having functional dyspepsia, and 311 as having functional abdominal pain, and 210 children were excluded from the study because they had an organic disorder or some other functional gastrointestinal disorder (not related to abdominal pain). Serologic testing was performed for all 782 children included in the study, and 15 patients tested positive for celiac disease (12 of 270 patients with IBS [4.4%], 2 of 201 patients with functional dyspepsia [1%], and 1 of 311 patients with functional abdominal pain [0.3%]). Children presenting with IBS have a 4 times higher risk of having celiac disease than children without IBS (odds ratio, 4.19 [95% CI, 2.03-8.49]; P < .001). The prevalence of celiac disease among children with IBS is 4 times higher than among the general pediatric population. Rome III classification of abdominal pain-related functional gastrointestinal disorders might help to select children who deserve screening for celiac disease.


Structure of the prolyl-acyl carrier protein oxidase involved in the biosynthesis of the cyanotoxin anatoxin-a.
Anatoxin-a and homoanatoxin-a are two potent cyanobacterial neurotoxins biosynthesized from L-proline by a short pathway involving polyketide synthases. Proline is first loaded onto AnaD, an acyl carrier protein, and prolyl-AnaD is then oxidized to 1-pyrroline-5-carboxyl-AnaD by a flavoprotein, AnaB. Three polyketide synthases then transform this imine into anatoxin-a or homoanatoxin-a. AnaB was crystallized in its holo form and its three-dimensional structure was determined by X-ray diffraction at 2.8 Å resolution. AnaB is a homotetramer and its fold is very similar to that of the acyl-CoA dehydrogenases (ACADs). The active-site base of AnaB, Glu244, superimposed very well with that of human isovaleryl-CoA dehydrogenase, confirming previous site-directed mutagenesis experiments and mechanistic proposals. The substrate-binding site of AnaB is small and is likely to be fitted for the pyrrolidine ring of proline. However, in contrast to ACADs, which use an electron-transport protein, AnaB uses molecular oxygen as the electron acceptor, as in acyl-CoA oxidases. Calculation of the solvent-accessible surface area around the FAD in AnaB and in several homologues showed that it is significantly larger in AnaB than in its homologues. A protonated histidine near the FAD in AnaB is likely to participate in oxygen activation. Furthermore, an array of water molecules detected in the AnaB structure suggests a possible path for molecular oxygen towards FAD. This is consistent with AnaB being an oxidase rather than a dehydrogenase. The structure of AnaB is the first to be described for a prolyl-ACP oxidase and it will contribute to defining the structural basis responsible for oxygen reactivity in flavoenzymes.


Fast switching, high contrast and high resolution liquid crystal device for virtual reality display.
Virtual reality-head mounted displays require a display with high resolution over 2000 ppi, super-fast response time and high contrast ratio for realizing super image quality at near-eyes. Several liquid crystal devices utilizing fringe-field switching (FFS) mode, having response times less than of half of conventional FFS mode, were proposed for this purpose. However, its contrast ratio is still less than 2000:1 because of intrinsic electro-optic characteristics of homogenous alignment mode and also realizing high resolution like 2000 ppi has some difficulty because twist deformation of liquid crystals can easily affect liquid crystal orientation near pixels. In this paper, we propose a vertically aligned liquid crystal device in which bend deformation occurs in a confined area by an oblique electric field, exhibiting 4 times faster decay response time than that of conventional FFS mode, higher contrast ratio over 5000:1, and pixel pitch less than 4 μm. The proposed liquid crystal device has a strong potential to be the main display for high-resolution virtual reality over 2000 ppi.


In vitro and in vivo safety evaluation of the bacteriocin producer Streptococcus macedonicus ACA-DC 198.
Streptococcus macedonicus ACA-DC 198, a bacteriocin producer isolated from Greek Kasseri cheese, was used in a series of in vitro and in vivo experiments in order to evaluate its pathogenic potential. The strain was examined in vitro for haemolytic activity, antibiotic resistance and presence of pathogenicity genes encountered in Streptococcus pyogenes. Subsequently, the strain was orally administered to mice (8.9 log cfu daily), continuously over a period of 12 weeks, in order to ascertain the effects of its long term consumption on animal health and gastric inflammation. S. macedonicus ACA-DC 198 was found to be non-haemolytic and sensitive to ampicillin, chloramphenicol, ciprofloxacin, erythromycin, streptomycin, tetracycline, and vancomycin, with the only resistance observed against kanamycin. PCR amplification and DNA-DNA hybridization did not reveal the presence of any of the S.pyogenes pathogenicity genes examined, namely emm, scpA, hasA, speB, smez2, speJ, sagAB, hylA, ska, speF, speG, slo, hylP2 and mga. In the mouse study, no detrimental effects were observed in the behaviour, general well being, weight gain and water consumption of the animals receiving S. macedonicus ACA-DC 198. Histologic analysis showed no evidence of inflammation in the stomach of the animals receiving S. macedonicus ACA-DC 198, while faecal microbiological analysis revealed that the strain retained its viability passing through the mouse gastrointestinal tract. Finally, no evidence of translocation to the liver, spleen and mesenteric lymph nodes was observed. In conclusion, none of the examined virulence determinants were detected in S. macedonicus ACA-DC 198 and its long term, high dosage oral administration did not appear to induce any pathogenic effect in mice.


Blind Image Inpainting with Mixture Noise Using ℓ 0 and Total Regularization.
The blind image inpainting problem need to be handle when faced with a large number of images, especially medical images in medical health. For the proposed nonconvex sparse optimization model, a proximal based alternating direction method of multipliers (PADMM) method is designed to solve the problem. Firstly, ℓ 0 sparse regularization is imposed to the binary mask since the missing pixels are sparse in our experiments. Secondly, the total variation term is utilized to describe the underlying clean image. Finally, ℓ 2 regularization of the fidelity term is used to solve the given blind inpainting problem. Experiments show that this method has better performance than traditional method, and could deal with the blind image inpainting problem.


Breast pain.
Breast pain may be cyclical (worse before a period) or non-cyclical, originating from the breast or the chest wall, and occurs at some time in 70% of women. Cyclical breast pain resolves spontaneously in 20% to 30% of women, but tends to recur in 60% of women. Non-cyclical pain responds poorly to treatment but tends to resolve spontaneously in half of women. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for breast pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, bromocriptine, combined oral contraceptive pill, danazol, diuretics, evening primrose oil, gestrinone, gonadorelin analogues, hormone replacement therapy (HRT), lisuride, low-fat diet, progestogens, pyridoxine, tamoxifen, tibolone, topical or oral non-steroidal anti-inflammatory drugs (NSAIDs), toremifene, and vitamin E.


Annexin A5-functionalized bimodal nanoparticles for MRI and fluorescence imaging of atherosclerotic plaques.
Apoptosis and macrophage burden are believed to correlate with atherosclerotic plaque vulnerability and are therefore considered important diagnostic and therapeutic targets for atherosclerosis. These cell types are characterized by the exposure of phosphatidylserine (PS) at their surface. In the present study, we developed and applied a small micellar fluorescent annexin A5-functionalized nanoparticle for noninvasive magnetic resonance imaging (MRI) of PS exposing cells in atherosclerotic lesions. Annexin A5-mediated target-specificity was confirmed with ellipsometry and in vitro binding to apoptotic Jurkat cells. In vivo T(1)-weighted MRI of the abdominal aorta in atherosclerotic ApoE(-/-) mice revealed enhanced uptake of the annexin A5-micelles as compared to control-micelles, which was corroborated with ex vivo near-infrared fluorescence images of excised whole aortas. Confocal laser scanning microscopy (CLSM) demonstrated that the targeted agent was associated with macrophages and apoptotic cells, whereas the nonspecific control agent showed no clear uptake by such cells. In conclusion, the annexin A5-conjugated bimodal micelles displayed potential for noninvasive assessment of cell types that are considered to significantly contribute to plaque instability and therefore may be of great value in the assessment of atherosclerotic lesion phenotype.


Identification of genes affecting lipid content using transposon mutagenesis in Saccharomyces cerevisiae.
Genes involved in lipid accumulation were identified in Saccharomyces cerevisiae using transposon insertion mutagenesis. Five ORFs, such as SNF2, IRA2, PRE9, PHO90, and SPT21 were found from the analysis of the insertion sites in transposon insertion mutants with higher lipid content. Since these ORFs are not directly involved in storage lipid biosynthesis, we speculate that they are involved in carbon fluxes into storage lipids in response to nutrient conditions. Lipid analysis of disruptants of these ORFs indicated that the Deltasnf2, and Deltaira2 disruptants had significantly higher lipid content. Cultivation in a nitrogen-limited medium increased the lipid content in all disruptants, among which the Deltapre9 disruptant was the most sensitive to nitrogen limitation. We then focused on the Deltasnf2 disruptant due to its higher lipid content and its function as a regulator of phospholipid synthesis. Lipid class analysis indicated that triacylglycerol and free fatty acids contributed to the increase in total lipids of the Deltasnf2 disruptant. The addition of exogenous fatty acids was not so effective at increasing the lipid content in the Deltasnf2 disruptant as it was in the wild type. It should be noticed that exogenous free linoleic acid was much higher in the Deltasnf2 disruptant than in the wild type, as in the case of endogenous free fatty acids. In addition, the incorporation of exogenous fatty acids into cells increased in the disruptant, suggesting that fatty acid transporters were regulated by SNF2. The results suggest that metabolic fluxes into storage lipids, which are activated in the Deltasnf2 disruptant, is repressed by the incorporation of exogenous fatty acids. They provide new insight into the biosynthesis of storage lipids in yeast.


Characterization of the retinal proteome during rod photoreceptor genesis.
The process of rod photoreceptor genesis, cell fate determination and differentiation is complex and multi-factorial. Previous studies have defined a model of photoreceptor differentiation that relies on intrinsic changes within the presumptive photoreceptor cells as well as changes in surrounding tissue that are extrinsic to the cell. We have used a proteomics approach to identify proteins that are dynamically expressed in the mouse retina during rod genesis and differentiation. A series of six developmental ages from E13 to P5 were used to define changes in retinal protein expression during rod photoreceptor genesis and early differentiation. Retinal proteins were separated by isoelectric focus point and molecular weight. Gels were analyzed for changes in protein spot intensity across developmental time. Protein spots that peaked in expression at E17, P0 and P5 were picked from gels for identification. There were 239 spots that were picked for identification based on their dynamic expression during the developmental period of maximal rod photoreceptor genesis and differentiation. Of the 239 spots, 60 of them were reliably identified and represented a single protein. Ten proteins were represented by multiple spots, suggesting they were post-translationally modified. Of the 42 unique dynamically expressed proteins identified, 16 had been previously reported to be associated with the developing retina. Our results represent the first proteomics study of the developing mouse retina that includes prenatal development. We identified 26 dynamically expressed proteins in the developing mouse retina whose expression had not been previously associated with retinal development.


Histopathologic evaluation of the inflammatory factors and stromal cells in the endometriosis lesions: A case-control study.
Endometriosis is a multifaceted gynecological disorder defined as a benign estrogen-dependent chronic inflammatory process in which endometrial glands and stroma-like tissues are located outside the uterine cavity. It affects around 2-10% of all women during their reproductive years. This study aimed to evaluate the traffic of mesenchymal stem cells and inflammatory factors toward the lesions. Ten samples of normal endometrium and eutopic endometrium were studied as a control group and 10 ectopic samples were considered as a case group. Hematoxylin and eosin staining was used to evaluate stromal cells and inflammatory cells. Immunohistochemical staining was performed to show the presence of proliferating cell nuclear antigen in the lesions. The cells were digested and cultured in the laboratory to study cell proliferation. The number of cells and vessels were counted with Image J software, and data analysis was performed with Prism software. Data analysis showed that the number of stromal cells and vessels in ectopic tissue were significantly higher than the control group (p < 0.001). Also, the number of inflammatory cells, including neutrophils, monocytes, lymphocytes, and macrophages, in the ectopic group was much higher than in the control group (p < 0.005). By expanding the number of blood vessels, blood flow increases, and cell migration to tissues is facilitated. The accumulation of inflammatory cells, especially macrophages, stimulates the growth of stem cells and helps implant cells by creating an inflammatory process.


Photoinduced arylation of chloroarenes in flow: synthesis of unsymmetrical biaryls.
A photoflow method is presented for a radical-based coupling of unactivated arenes and aryl chlorides. The process proceeded smoothly at ambient temperature under metal-free conditions. Of note is that the reaction conditions are fine-tuned for chloroarenes with different electronic properties. While the reactivity profile of aryl chlorides is generally known to be inferior to those of the corresponding iodides and bromides, we demonstrate that the title protocol is efficient in converting readily available and inexpensive chloroarenes into unsymmetrical biaryl products.


A qualitative evaluation of medication management services in six Minnesota health systems.
The initiation, establishment, and sustainability of medication management programs in six Minnesota health systems are described. Six Minnesota health systems with well-established medication management programs were invited to participate in this study: Essentia Health, Fairview Health Services, HealthPartners, Hennepin County Medical Center, Mayo Clinic, and Park Nicollet Health Services. Qualitative methods were employed by conducting group interviews with key staff from each institution who were influential in the development of medication management services within their organization. Kotter's theory of eight steps for leading organizational change served as the framework for the question guide. The interviews were audio recorded, transcribed, and analyzed for recurring and emergent themes. A total of 13 distinct themes were associated with the successful integration of medication management services across the six healthcare systems. Identified themes clustered within three stages of Kotter's model for leading organizational change: creating a climate for change, engaging and enabling the whole organization, and implementing and sustaining change. The 13 themes included (1) external influences, (2) pharmacists as an untapped resource, (3) principles and professionalism, (4) organizational culture, (5) momentum champions, (6) collaborative relationships, (7) service promotion, (8) team-based care, (9) implementation strategies, (10) overcoming challenges, (11) supportive care model process, (12) measuring and reporting results, and (13) sustainability strategies. A qualitative survey of six health systems that successfully implemented medication management services in ambulatory care clinics revealed that a supportive culture and team-based collaborative care are among the themes identified as necessary for service sustainability.


Cognitive and Behavioral Predictors of Quit Attempts and Biochemically-Validated Abstinence During Pregnancy.
Initiating a quit attempt and achieving abstinence are distinct behaviors that have distinct correlates in general smokers. Studies predicting prenatal smoking have not addressed this. Pregnant smokers (N = 207), recruited to a cessation intervention trial, were used as an observational cohort. Women completed measures at baseline and 12-week follow-up (mid-late pregnancy). Outcomes were having made at least one quit attempt since baseline, and cotinine-validated 7-day abstinence at follow-up in attempters. Baseline predictors included demographics (age, deprivation, partner's smoking), smoking behaviors (nicotine dependence, quit attempt history, previous prenatal smoking), and smoking beliefs (self-efficacy, determination, intention to quit, nonsmoker identity, social support, pregnancy-outcome beliefs). For each outcome, variables reaching p < .1 in logistic regression analyses were entered into a multivariate model controlling for trial arm. A complete case analysis was undertaken, with missing data assumptions tested in sensitivity analyses. One hundred seventy-five women (85%) completed follow-up. Intention and determination to quit (p < .001), self-efficacy, nonsmoker identity, and not having previously smoked in pregnancy (p < .05) were univariate predictors of making a quit attempt, with stronger intention to quit the only independent predictor (multivariate odds ratio [OR] = 2.41, 95% confidence interval [CI] 1.19-4.87). Only nicotine dependence predicted validated abstinence among those who made a quit attempt (multivariate OR = 0.25, 95% CI 0.10-0.60). Initiating a quit attempt and achieving abstinence during pregnancy were found to have different correlates. For women yet to make a quit attempt in their pregnancy, smoking beliefs may be important intervention targets, but once they are engaged in quitting, nicotine dependence appears of prime importance. This study suggests that cognitive, particularly motivational, variables predict whether pregnant smokers will make a quit attempt, but they do not predict successful abstinence in those who attempt to quit, where nicotine dependence dominates. Interventions should facilitate quit attempts by targeting motivational variables among pregnant women who continue to smoke, but should focus on managing withdrawal once a woman initiates a quit attempt.


Characterizing Flame Retardant Applications and Potential Human Exposure in Backpacking Tents.
Flame retardant (FR) chemicals are applied to products to meet flammability standards; however, exposure to some additive FRs has been shown to be associated with adverse health effects. Previous research on FR exposure has primarily focused on chemicals applied to furniture and electronics; however, camping tents sold in the United States, which often meet flammability standard CPAI-84, remain largely unstudied in regards to their chemical treatments. In this study, FRs from five brands of CPAI-84-compliant, two-person backpacking tents were measured and potential exposure was assessed. Dermal and inhalation exposure levels were assessed by collecting hand wipes from 20 volunteers before and after tent setup and by using active air samplers placed inside assembled tents, respectively. Organophosphate flame retardants (OPFRs) were the most commonly detected FR in the tent materials and included triphenyl phosphate (TPHP), tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tris(2-chloroethyl)phosphate (TCEP). Levels of OPFRS measured on hand wipes were significantly higher post-tent setup compared to pre setup, and in the case of TDCIPP, levels were 29 times higher post setup. OPFRs were also detected at measurable concentrations in the air inside of treated tents. Significant, positive correlations were found between FR levels in treated textiles and measures of dermal and inhalation exposure. These results demonstrate that dermal exposure to FRs occurs from handling camping tents and that inhalation exposure will likely occur while inside a tent.


Surface functional group modification induced partial Fermi level pinning and ohmic contact at borophene-MoS2 interfaces.
Large Schottky barrier at the electric contact interface drastically hinders the performance of two-dimensional (2D) semiconductor devices, because of which it is crucial to develop better methods to achieve the ohmic contact. Recently, a new field effect transistor (FET) device was constructed by the popular 2D channel material MoS2 and an electrode material borophene was detected theoretically, but the large Schottky barrier still existed. Hence, we used surface functional groups modification on the borophene surface to regulate this Schottky barrier, based on ab initio electronic structure calculations and quantum transport simulations. Our study shows that this method makes it possible to obtain tunable metal work functions in a wide range, and the ohmic contact can still be realized. Although van der Waals (vdW) contacts were observed at all the interfaces between the 2D borophene-based metals and the monolayer MoS2, the Fermi level pinning (FLP) effect was still obvious, and existed in our proposed system with the ohmic contact. Moreover, we also discuss the origin of the FLP with varying degrees. It was found that the interface dipole and metal-induced gap states (MIGS) would be responsible for the FLP of vertical and lateral directions, respectively. More precisely, we find that the size of MIGS is dependent on the relative orientation between the functional group and metal-MoS2 interface. This work not only suggests that surface functional group modification is effective in forming ohmic contact with MoS2, but also holds some implication in the fundamental research on metal-semiconductor contacts with the vdW type.


Reprint of Neutrophil cell surface receptors and their intracellular signal transduction pathways.
Neutrophils play a critical role in the host defense against bacterial and fungal infections, but their inappropriate activation also contributes to tissue damage during autoimmune and inflammatory diseases. Neutrophils express a large number of cell surface receptors for the recognition of pathogen invasion and the inflammatory environment. Those include G-protein-coupled chemokine and chemoattractant receptors, Fc-receptors, adhesion receptors such as selectins/selectin ligands and integrins, various cytokine receptors, as well as innate immune receptors such as Toll-like receptors and C-type lectins. The various cell surface receptors trigger very diverse signal transduction pathways including activation of heterotrimeric and monomeric G-proteins, receptor-induced and store-operated Ca(2+) signals, protein and lipid kinases, adapter proteins and cytoskeletal rearrangement. Here we provide an overview of the receptors involved in neutrophil activation and the intracellular signal transduction processes they trigger. This knowledge is crucial for understanding how neutrophils participate in antimicrobial host defense and inflammatory tissue damage and may also point to possible future targets of the pharmacological therapy of neutrophil-mediated autoimmune or inflammatory diseases.


Estimating the number of sexual events per generation in a facultatively sexual haploid population.
In populations of facultatively sexual organisms, the proportion of sexually produced offspring contributed to each generation is a critical determinant of their evolutionary potential. However, estimating this parameter in natural populations has proved difficult. Here we develop a population genetic model for estimating the number of sexual events occurring per generation for facultatively sexual haploids possessing a biallelic mating-type locus (e.g., Chlamydomonas, ascomycete fungi). Our model treats the population as two subpopulations possessing opposite mating-type alleles, which exchange genes only when a sexual event takes place. Where mating types are equally abundant, we show that, for a neutral genetic marker, genetic differentiation between mating-type subpopulations is a simple function of the effective population size, the frequency of sexual reproduction, and the recombination fraction between the genetic marker and the mating-type locus. We employ simulations to examine the effects of linkage of markers to the mating-type locus, inequality of mating-type frequencies, mutation rate, and selection on this relationship. Finally, we apply our model to estimate the number of sexual reproduction events per generation in populations of four species of facultatively sexual ascomycete fungi, which have been jointly scored for mating type and a range of polymorphic molecular markers. Relative estimates are in line with expectations based on the known reproductive biology of these species.


Self-supported single crystalline H2Ti8O17 nanoarrays as integrated three-dimensional anodes for lithium-ion microbatteries.
Well-ordered, one-dimensional H2Ti2O5, H2Ti8O17, TiO2-B, and anatase TiO2/TiO2-B nanowire arrays were innovatively designed and directly grown on current collectors as high performance three dimensional (3D) anodes for binder and carbon free lithium ion batteries (LIBs). The prepared thin nanowires exhibited a single crystalline phase with highly uniform morphologies, diameters ranging from 70-80 nm, and lengths of around 15 μm. Specifically, reversible Li insertion and extraction reactions around 1.6-1.8 V with initial intercalation capacities of 326 and 271 mA h g(-1) at a cycling rate of 0.1 C (where 1 C = 335 mA g(-1)) were observed for H2Ti8O17 and TiO2-B nanowire arrays, respectively. Among the four compounds investigated, the H2Ti8O17 nanowire electrode demonstrated optimal cycling stability, delivering a high specific discharge capacity of 157.8 mA h g(-1) with a coulombic efficiency of 100%, even after the 500th cycle at a current rate of 1 C. Furthermore, the H2Ti8O17 nanowire electrode displayed superior rate performance with rechargeable discharge capacities of 127.2, 111.4, 87.2, and 73.5 mA h g(-1) at 5 C, 10 C, 20 C, and 30 C, respectively. These results present the potential opportunity for the development of high-performance LIBs based on nanostructured Ti-based anode materials in terms of high stability and high rate capability.


In vivo resistance of lipolysis to epinephrine. A new feature of childhood onset obesity.
A decreased mobilization of triglycerides may contribute to fat accumulation in adipocytes, leading to obesity. However, this hypothesis remains to be proven. In this study, epinephrine-induced lipid mobilization was investigated in vivo in nine markedly obese children (160+/-5% ideal body weight) aged 12.1+/-0.1 yr during the dynamic phase of fat deposition, compared with six age-matched nonobese children. As an in vivo index of lipolysis, we measured glycerol flux using a nonradioactive tracer dilution approach, and plasma free fatty acid concentrations. In the basal state, the obese children had a 30% lower rate of glycerol release per unit fat mass than the lean children. To study the regulation of lipolysis, epinephrine was infused stepwise at fixed doses of 0.75 and then 1. 50 microg/min in both groups. In lean children, glycerol flux and plasma free fatty acid increased to an average of 249-246% of basal values, respectively, in response to a mean plasma epinephrine of 396+/-41 pg/ml. The corresponding increase was only 55-72% in the obese children, although their mean plasma epinephrine reached 606+/-68 pg/ml. All obese and nonobese children, except an Arg64Trp heterozygote, were homozygotes for Trp at position 64 of their beta3-adrenoreceptor. The resistance of lipolysis to epinephrine showed no relationship with the Arg64 polymorphism of the beta3-adrenoreceptor gene. In summary, in vivo lipolysis, which mostly reflects the mobilization of lipid stores from subcutaneous adipose tissue, shows a decreased sensitivity to epinephrine in childhood onset obesity. Since our study was carried out in obese children during the dynamic phase of fat accumulation, the observed resistance to catecholamines might possibly be causative rather than the result of obesity.


Archaic human remains from Hualongdong, China, and Middle Pleistocene human continuity and variation.
Middle to Late Pleistocene human evolution in East Asia has remained controversial regarding the extent of morphological continuity through archaic humans and to modern humans. Newly found ∼300,000-y-old human remains from Hualongdong (HLD), China, including a largely complete skull (HLD 6), share East Asian Middle Pleistocene (MPl) human traits of a low vault with a frontal keel (but no parietal sagittal keel or angular torus), a low and wide nasal aperture, a pronounced supraorbital torus (especially medially), a nonlevel nasal floor, and small or absent third molars. It lacks a malar incisure but has a large superior medial pterygoid tubercle. HLD 6 also exhibits a relatively flat superior face, a more vertical mandibular symphysis, a pronounced mental trigone, and simple occlusal morphology, foreshadowing modern human morphology. The HLD human fossils thus variably resemble other later MPl East Asian remains, but add to the overall variation in the sample. Their configurations, with those of other Middle and early Late Pleistocene East Asian remains, support archaic human regional continuity and provide a background to the subsequent archaic-to-modern human transition in the region.


Effects of exercises on biophoton emission of the wrist.
Using two photomultiplier tubes (PMT), we measured the biophoton emission of the left and right wrists simultaneously. The subjects performed hand-grip exercises with both hands, during the measurements. We found a slow increase of the emission rates during the exercises, rising in average from 51.6 cps (counts per second) to 72.3 cps and an immediate decrease after the ending of the exercises. Simultaneous measurement of the skin temperature near the wrist using a thermocouple showed steady increase of temperature even after the ending of the exercises. Thus we demonstrated manifestly that the biophoton has no correlation with body temperature changes. We proposed a hypothesis to account the increase of the biophoton due to muscular activity. The oxygen used by the respiratory chain is the main source of reactive oxygen species (ROS) and therefore must be one of the biophoton sources. To flesh out this hypothesis we compared our data to heart beat rates and oxygen consumption values measured while doing the same type of exercises.


A qualitative exploration of the dynamics of guilt experience in family cancer caregivers.
Caregiving for cancer patients can cause stress among family caregivers. Caregiving stress is also associated with guilt as they cannot provide adequate care for cancer patients. However, guilt among family caregivers of cancer patients is poorly understood. This qualitative study aimed to explore the dynamics of guilt feelings in families that care for cancer patients. This study involved 45 family caregivers of cancer patients. Thematic data analysis was conducted. There were six themes emerging. Caregiving can be challenging, guilt and blame, guilt due to lack of self-capacity, guilt for neglecting others, no guilt at all, and discussion of guilt and blame as a caregiver. This study offers insight into social workers regarding the challenges and experiences faced by family caregivers of cancer patients. Appropriate health interventions and support should be provided to family caregivers of cancer patients to improve their well-being.


Visual attention circuitry in schizophrenia investigated with oddball event-related functional magnetic resonance imaging.
Schizophrenia patients have problems directing attention. Sustained attention requires ensuring that brain resources are focused on a selected target (top-down task) while ignoring irrelevant distractors (bottom-up interference). Whether patients have too little ability to focus or too much interference from distraction has not been clarified. The oddball paradigm embeds infrequent targets and distractors into the stimulus train, and schizophrenia deficits have been linked to diminished responses to both. Cerebral activity underlying abnormal attention can be examined with event-related functional magnetic resonance imaging. A visual oddball task was presented to 22 patients with schizophrenia and 28 comparison subjects. Statistical probability maps reflecting blood-oxygenation-level-dependent changes were generated for infrequent targets and novel distractors relative to frequent standard stimuli. Activation was related to performance and symptoms. Activation specific to targets and distractors was associated with faster performance. For targets, patients had diminished activation in superior temporal and frontal gyri, cingulate, thalamus, and basal ganglia. They had increased activation in right insula, mid-frontal gyrus, posterior cingulate, and left inferior parietal lobule. For distractors, patients showed less activation in occipital regions and left inferior parietal lobule but increased activation in parietal-occipital, right mid-frontal, and left inferior frontal gyri. Abnormal activation correlated with positive and negative symptoms. Abnormal activation in schizophrenia in response to attentional demands reflects both insufficient recruitment of brain systems required for target detection and overcommitment of resources for processing irrelevant distractors. Schizophrenia patients appear to have an inability both to focus on targets and ignore distraction.


Infrared study of the hydroxyl bands in clinoamphiboles.
Sharp single peaks in the fundamental and first-overtone bands of the O-H stretching vibration in pure Mg(2)+ and Fe(2)+ amphiboles split into a maximum of four sharp peaks, corresponding to hydroxyl groups linked to 3 Fe, 2 Fe + Mg, 2 Mg + Fe, and 3 Mg, in mixed Fe(2)+-Mg(2)+ amphiboles. Within any one solid-solution series, the frequencies of these peaks can be correlated with the electronegativity of ions in the M(l) and M(3) positions, and differences between series can be correlated with the size of ions in the M(4) position. The O-H vector lies approximately normal to z in the (010) plane. The distribution of Fe(2)+ and Mg(2)+ ions between the (M(1),M(3)) and (M(2)M(4)) positions in the cummingtonite-grunerite series, and between the (M(1),M(3)) and M(2) positions in the tremolite-ferroactinolite series, has also been estimated.


Surgeon factors but not hospital factors associated with length of stay after colorectal surgery - A population based study.
Length of stay (LOS) after colorectal surgery (CRS) is a significant driver of healthcare utilization and adverse patient outcomes. To date, there is little high-quality evidence in the literature examining how individual surgeon and hospital factors independently impact LOS. We aimed to identify and quantify the independent impact of surgeon and hospital factors on LOS after CRS. A retrospective population-based cohort study was conducted using validated health administrative databases, encompassing all patients from the province of Ontario, Canada. All patients from 121 hospitals in Ontario who underwent elective CRS between 2008 and 2019 in Ontario were included, and factors pertaining to these patients and their treating surgeon and hospital were assessed. A negative binomial regression model was used to assess the independent effect of surgeon and hospital factors on LOS, accounting for a comprehensive collection of determinants of LOS. To minimize unmeasured confounding, the analysis was repeated in a subgroup comprising patients undergoing lower-complexity CRS without postoperative complications. A total of 90,517 CRS patients were analysed. Independent of patient and procedural factors, low surgeon volume (lowest volume quartile) was associated with a 20% increase in LOS (95% CI: 12-29, p < 0.0001) compared to high surgeon volume (highest volume quartile). In the 22,639 patients undergoing uncomplicated lower-complexity surgeries, a 43% longer LOS was seen in the lowest volume surgeon quartile (95% CI: 26-61, p < 0.0001). In both models, more years-in-practice was associated with a small increase in LOS (RR 1.02, 95% CI: 1.02-1.03, p < 0.0001). Hospital factors were not significantly associated with increased LOS. Surgeon factors, including low surgeon volume and increasing years-in-practice, were strongly and independently associated with longer LOS, whereas hospital factors did not have an independent impact. This suggests that LOS is driven primarily by surgeon-mediated care processes and may provide actionable targets for provider-level interventions to reduce LOS after CRS.


Controlling highly pathogenic avian influenza outbreaks: An epidemiological and economic model analysis.
Outbreaks of highly pathogenic avian influenza (HPAI) can cause large losses for the poultry sector and for animal disease controlling authorities, as well as risks for animal and human welfare. In the current simulation approach epidemiological and economic models are combined to compare different strategies to control highly pathogenic avian influenza in Dutch poultry flocks. Evaluated control strategies are the minimum EU strategy (i.e., culling of infected flocks, transport regulations, tracing and screening of contact flocks, establishment of protection and surveillance zones), and additional control strategies comprising pre-emptive culling of all susceptible poultry flocks in an area around infected flocks (1 km, 3 km and 10 km) and emergency vaccination of all flocks except broilers around infected flocks (3 km). Simulation results indicate that the EU strategy is not sufficient to eradicate an epidemic in high density poultry areas. From an epidemiological point of view, this strategy is the least effective, while pre-emptive culling in 10 km radius is the most effective of the studied strategies. But these two strategies incur the highest costs due to long duration (EU strategy) and large-scale culling (pre-emptive culling in 10 km radius). Other analysed pre-emptive culling strategies (i.e., in 1 km and 3 km radius) are more effective than the analysed emergency vaccination strategy (in 3 km radius) in terms of duration and size of the epidemics, despite the assumed optimistic vaccination capacity of 20 farms per day. However, the total costs of these strategies differ only marginally. Extending the capacity for culling substantially reduces the duration, size and costs of the epidemic. This study demonstrates the strength of combining epidemiological and economic model analysis to gain insight in a range of consequences and thus to serve as a decision support tool in the control of HPAI epidemics.


Genetic variation in aggregation behaviour and interacting phenotypes in Drosophila.
Aggregation behaviour is the tendency for animals to group together, which may have important consequences on individual fitness. We used a combination of experimental and simulation approaches to study how genetic variation and social environment interact to influence aggregation dynamics in Drosophila To do this, we used two different natural lines of Drosophila that arise from a polymorphism in the foraging gene (rovers and sitters). We placed groups of flies in a heated arena. Flies could freely move towards one of two small, cooler refuge areas. In groups of the same strain, sitters had a greater tendency to aggregate. The observed behavioural variation was based on only two parameters: the probability of entering a refuge and the likelihood of choosing a refuge based on the number of individuals present. We then directly addressed how different strains interact by mixing rovers and sitters within a group. Aggregation behaviour of each line was strongly affected by the presence of the other strain, without changing the decision rules used by each. Individuals obeying local rules shaped complex group dynamics via a constant feedback loop between the individual and the group. This study could help to identify the circumstances under which particular group compositions may improve individual fitness through underlying aggregation mechanisms under specific environmental conditions.


Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men.
In animals, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma agonists down-regulate 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARgamma agonists reduce ACTH secretion from corticotrope cells. Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11beta-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARgamma agonists. Three randomized placebo-controlled crossover studies were conducted at a clinical research facility. Healthy men and patients with type 2 diabetes participated. INTERVENTIONS, OUTCOME MEASURES, AND RESULTS: In nine healthy men, 7 d of PPARalpha agonist (fenofibrate) or PPARgamma agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration, or tracer kinetics during 9,11,12,12-[(2)H](4)-cortisol infusion, although rosiglitazone marginally reduced cortisol generation in sc adipose tissue measured by in vivo microdialysis. In 12 healthy men, 4-5 wk of rosiglitazone increased insulin sensitivity during insulin infusion but did not change 11beta-HSD1 mRNA or activity in sc adipose tissue, and insulin sensitization was unaffected by glucocorticoid blockade with a combination of metyrapone and RU38486. In 12 men with type 2 diabetes 12 wk of rosiglitazone reduced arteriovenous cortisone extraction across abdominal sc adipose tissue and reduced 11beta-HSD1 mRNA in sc adipose tissue but increased plasma cortisol concentrations. Neither PPARalpha nor PPARgamma agonists down-regulate 11beta-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitizing effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11beta-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, e.g. mediated by changes in body fat.


Validation of a sensitive PCR assay for the detection of Chelonid fibropapilloma-associated herpesvirus in latent turtle infections.
The Chelonid fibropapilloma-associated herpesvirus (CFPHV) is hypothesized to be the causative agent of fibropapillomatosis, a neoplastic disease in sea turtles, given its consistent detection by PCR in fibropapilloma tumours. CFPHV has also been detected recently by PCR in tissue samples from clinically healthy (non exhibiting fibropapilloma tumours) turtles, thus representing presumably latent infections of the pathogen. Given that template copy numbers of viruses in latent infections can be very low, extremely sensitive PCR assays are needed to optimize detection efficiency. In this study, efficiency of several PCR assays designed for CFPHV detection is explored and compared to a method published previously. The results show that adoption of a triplet set of singleplex PCR assays outperforms other methods, with an approximately 3-fold increase in detection success in comparison to the standard assay. Thus, a new assay for the detection of CFPHV DNA markers is presented, and adoption of its methodology is recommended in future CFPHV screens among sea turtles.


The relationship between dietary total antioxidant capacity, clinical parameters, and oxidative stress in fibromyalgia syndrome: A novel point of view.
This study aims to reveal the relationship between serum total antioxidant status (TAS), clinical parameters, and nutrition (dietary total antioxidant capacity [TAC]) in patients with fibromyalgia. This cross-sectional study was conducted with a total of 60 female participants (mean age: 44.7±9.7 years; range, 18 to 50 years) at Gaziler Physical Medicine and Rehabilitation Hospital between July 2020 and February 2021. Thirty female patients with fibromyalgia were compared with 30 age-, sex-, and body mass index-matched healthy individuals. The short-form McGill Pain Questionnaire, Fibromyalgia Impact Questionnaire (FIQ), and Pittsburg Sleep Quality Index were used. Total antioxidant status, total oxidant status (TOS), and oxidative stress index (OSI) were measured. Dietary TAC was calculated using the ferric reducing ability of plasma according to a food frequency questionnaire. Total antioxidant status showed no significant difference between groups (p=0.080). Total oxidant status and OSI were significantly higher in the patient group (p<0.001 and p=0.005, respectively). The mean dietary TAC was 16.5±6.5 in the patient group and 17.2±6.2 in the control group, and it was similar between groups (p=0.492). Pittsburg Sleep Quality Index global score was significantly higher in the patient group than in the control group (p<0.001). Dietary TAC showed a moderate positive correlation with serum TAS in both groups (r=0.373, p=0.042 for the patient group, and r=0.380, p=0.038 for the control group). In the patient group, TOS and OSI showed a moderate positive correlation with FIQ total scores (r=0.420, p=0.021 and r=0.450, p=0.013, respectively). The mean polyunsaturated fatty acid and omega-6 intake of the patient group was significantly lower than the control group (p=0.025 for both). Dietary antioxidant intake from vegetables (p=0.025), legumes/nuts (p=0.049), and meat (p<0.001) was significantly lower, whereas dietary antioxidant intake from cereal and potatoes was significantly higher in the patient group compared to the control group (p=0.028). The results indicate that oxidative stress can be reduced by increasing dietary antioxidant intake in fibromyalgia.


The Immunogenicity and Safety of CYD-Tetravalent Dengue Vaccine (CYD-TDV) in Children and Adolescents: A Systematic Review.
to assess the immunogenicity and safety of CYD-tetravalent dengue vaccine (CYD-TDV) in children. comprehensive literature searches were conducted on various databases. Randomized-controlled trials on children with CYD-TDV as intervention were selected based on inclusion and exclusion criteria. Data extracted from selected trials included safety of vaccine and immunogenicity in terms of Geometric Mean Titres (GMT) of antibodies. six clinical trials were selected based on preset criteria. GMT values were obtained using 50% Plaque Reduction Neutralization Test (PRNT) and safety was semi-quantitatively assessed based on adverse effects. Additional data processing was done to obtain a better understanding on the trends among the studies. The results showed that the groups vaccinated with CYD-TDV showed higher immunogenicity against dengue virus antigens than the control groups. Safety results were satisfactory in all trials, and most severe side effects were unrelated to the vaccine. CYD-TDV is both effective and safe for patients in endemic regions. This gives promise for further development and large-scale research on this vaccine to assess its efficacy in decreasing dengue prevalence, and its pervasive implementation in endemic countries, such as Indonesia.


Formation of a novel colored product during the Maillard reaction of D-glucose.
Reactions between reducing sugars and proteins or amino acids (Maillard reaction) lead to the formation of yellow to brown products (melanoidins) that are important for food preparation and processing, such as baking, roasting, or malt production. Thus far, the structures of the melanoidins have not been elucidated, although some structural insights have been gained from model reactions. In this study, D-glucose was heated with an amine and two colored compounds were detected by HPLC/UV--vis. After purification, the main product was identified as [(4aS,6R,7S,8R,8aR)-4,4a,6,7,8,8a-hexahydro-7,8-dihydroxy-6-hydroxymethyl-1,4-dipropyl-1H-pyrano[2,3-b]pyrazine-2-yl]-1-hydroxy-3-buten-2-one (1a). For the minor compound (2a), some spectral data were obtained, but the structure was not fully characterized. 1a and 2a are the main colored compounds when the reaction is performed in alcoholic solution or on a cellulose surface. Thus, it was concluded that products with an analogous structure are important for the color formation of foodstuffs with low water activity.


Rapid spread of a bacterial symbiont in an invasive whitefly is driven by fitness benefits and female bias.
Maternally inherited bacterial symbionts of arthropods are common, yet symbiont invasions of host populations have rarely been observed. Here, we show that Rickettsia sp. nr. bellii swept into a population of an invasive agricultural pest, the sweet potato whitefly, Bemisia tabaci, in just 6 years. Compared with uninfected whiteflies, Rickettsia-infected whiteflies produced more offspring, had higher survival to adulthood, developed faster, and produced a higher proportion of daughters. The symbiont thus functions as both mutualist and reproductive manipulator. The observed increased performance and sex-ratio bias of infected whiteflies are sufficient to explain the spread of Rickettsia across the southwestern United States. Symbiont invasions such as this represent a sudden evolutionary shift for the host, with potentially large impacts on its ecology and invasiveness.


Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection.
The intravitreal injection of steroids may be potentially useful in the treatment of endophthalmitis and other ocular inflammatory diseases. The retinal toxicity and intraocular turnover of aqueous solutions of dexamethasone sodium phosphate in doses ranging from 440 to 4000 micrograms were evaluated in the rabbit; evaluation was also performed for a 0.1-mL injection of a commercially available preparation (dexamethasone phosphate [Decadron] injection, 4 mg/mL). After the 440-micrograms dose, a transient increase in staining of the Müller cells was observed, which normalized after 2 days. Progressively higher doses resulted in an increasing spectrum of disorganization in Müller and other retinal cells. The half-life of the intravitreally injected drug was 3.48 hours. These findings suggest a primary interference in Müller cell function, possibly through dexamethasone-induced alterations in retinal glutamate or glucose metabolism.


Rotation of the sun.
Dicke has interpreted his recent measurement of the sun's oblateness as implying a fast (1.8-day period) rotation of the solar radiative interior. We find that differentially rotating solar models, such as the one proposed by Dicke, are unstable. The rate of turbulent diffusion in the unstable regions of these models is so rapid that it appears to preclude a fast spinning solar interior. As a corollary of the stability analysis, we conclude that the loss of a significant fraction of a star's angular momentum must be accomnpanied by the mixing of material below its convective zone. Such mixing inevitably leads to the depletion of lithium in the star's photosphere.


[The effect of UV radiation on Trevira threads].
The UV sensitivity of trevira threads, which are used as material of loops in intraocular lenses, was examined under different conditions. Severe changes of the thread surface were induced by direct UV radiation without absorbing media. The in vitro alterations of the surface were smaller. The in vivo changes were unimportant and not clearly distinguishable from biological changes. Nevertheless, it is advisable for people using intraocular lenses to provide with short-wavelength filtration devices, such as absorptive spectacles.


[Thyroid status and clinical features of osteoarthrosis in the region of goiter endemia].
The study of osteoarthrosis (OA) course in the region of goiter endemia regarding thyroid status. The examination of 62 females with OA included enzyme immunoassay of blood TTH, T4, T3 and ultrasound investigation of the thyroid. OA patients were found to have subnormal levels of thyroid hormones and low thyroid index. Blood TTH rose with thyroid size. Joint changes were also directly related to thyroid size. Alterations in the thyroid status influence the course of degenerative-dystrophic process in the joints.


The role of the uplift of the Qinghai-Tibetan Plateau for the evolution of Tibetan biotas.
Biodiversity is unevenly distributed on Earth and hotspots of biodiversity are often associated with areas that have undergone orogenic activity during recent geological history (i.e. tens of millions of years). Understanding the underlying processes that have driven the accumulation of species in some areas and not in others may help guide prioritization in conservation and may facilitate forecasts on ecosystem services under future climate conditions. Consequently, the study of the origin and evolution of biodiversity in mountain systems has motivated growing scientific interest. Despite an increasing number of studies, the origin and evolution of diversity hotspots associated with the Qinghai-Tibetan Plateau (QTP) remains poorly understood. We review literature related to the diversification of organisms linked to the uplift of the QTP. To promote hypothesis-based research, we provide a geological and palaeoclimatic scenario for the region of the QTP and argue that further studies would benefit from providing a complete set of complementary analyses (molecular dating, biogeographic, and diversification rates analyses) to test for a link between organismic diversification and past geological and climatic changes in this region. In general, we found that the contribution of biological interchange between the QTP and other hotspots of biodiversity has not been sufficiently studied to date. Finally, we suggest that the biological consequences of the uplift of the QTP would be best understood using a meta-analysis approach, encompassing studies on a variety of organisms (plants and animals) from diverse habitats (forests, meadows, rivers), and thermal belts (montane, subalpine, alpine, nival). Since the species diversity in the QTP region is better documented for some organismic groups than for others, we suggest that baseline taxonomic work should be promoted.


Precision Control of CRISPR-Cas9 Using Small Molecules and Light.
The CRISPR (clustered regularly interspaced short palindromic repeat)-Cas system is an adaptive immune system of bacteria that has furnished several RNA-guided DNA endonucleases (e.g., Cas9) that are revolutionizing the field of genome engineering. Cas9 is being used to effect genomic alterations as well as in gene drives, where a particular trait may be propagated through a targeted species population over several generations. The ease of targeting catalytically impaired Cas9 to any genomic loci has led to development of technologies for base editing, chromatin imaging and modeling, epigenetic editing, and gene regulation. Unsurprisingly, Cas9 is being developed for numerous applications in biotechnology and biomedical research and as a gene therapy agent for multiple pathologies. There is a need for precise control of Cas9 activity over several dimensions, including those of dose, time, and space in these applications. Such precision controls, which are required of therapeutic agents, are particularly important for Cas9 as off-target effects, chromosomal translocations, immunogenic response, genotoxicity, and embryonic mosaicism are observed at elevated levels and with prolonged activity of Cas9. Here, we provide a perspective on advances in the precision control of Cas9 over aforementioned dimensions using external stimuli (e.g., small molecules or light) for controlled activation, inhibition, or degradation of Cas9.


Rondeau Seminars amalgamated mid-sagittal (lateral) cephalometric analysis.
The author presents a comprehensive International Association for Orthodontics--Rondeau Seminars Amalgamated Mid-sagittal (Lateral) Cephalometric Analysis. Norms on the Cephalometric Data Sheet are age and gender specific for the Caucasian population and the postings are color coded for visual attraction. If the patient is ofa different ethnic group, the Norms should be adjusted accordingly. This Cephalometric Analysis is comprised often Sections, in alphabetical order and twenty nine Factors. The author expanded Rondeau Seminars Cephalometric Analysis by only six Factors, thus fulfilling the requirement for the case presentation for the Fellow of the IAO and the Diplomate ofthe IBO.


Huge photoresistance in transparent and conductive indium titanium oxide films prepared by electron beam-physical vapor deposition.
Transparent and conductive indium titanium oxide (ITiO) films have been obtained by electron beam physical vapour deposition with Ti content from 5 at % up to 28 at %. X-ray absorption spectroscopy techniques have been used to identify the local environment of Ti ions. Even at the lowest concentrations Ti is not incorporated into the In2O3 structure but forms clusters of a Ti-In mixed oxide that present a distorted rutile TiO2 short-range order. The optical transmittance of the annealed samples reaches 95 % and no significant variation of the gap energy (around 3.7 eV) is observed with Ti content. The electronic conductivity under light irradiation is studied evidencing a huge photo-resistance in the samples with Ti content above 22 at % reaching more than two orders of magnitude for the 26 at % Ti under illumination with few μW/cm(2) at 365 nm. Hall and conductivity results are analyzed using a model that takes into account both electron and hole carriers as well as the conductivity enhancement by carrier photogeneration. The electron carrier density decreases with Ti content while its mobility increases up to values of 1000 cm(2)/(V s). Oxygen annealed ITiO films obtained by this technique with Ti content below 10 at % have properties adequate as transparent semiconductors and those with Ti content higher than 22 at % have exceptional photoresistive properties relevant for numerous applications.


Neurological Complications during Treatment of Middle East Respiratory Syndrome.
Middle East respiratory syndrome (MERS) has a high mortality rate and pandemic potential. However, the neurological manifestations of MERS have rarely been reported since it first emerged in 2012. We evaluated four patients with laboratory-confirmed MERS coronavirus (CoV) infections who showed neurological complications during MERS treatment. These 4 patients were from a cohort of 23 patients who were treated at a single designated hospital during the 2015 outbreak in the Republic of Korea. The clinical presentations, laboratory findings, and prognoses are described. Four of the 23 admitted MERS patients reported neurological symptoms during or after MERS-CoV treatment. The potential diagnoses in these four cases included Bickerstaff's encephalitis overlapping with Guillain-Barré syndrome, intensive-care-unit-acquired weakness, or other toxic or infectious neuropathies. Neurological complications did not appear concomitantly with respiratory symptoms, instead being delayed by 2-3 weeks. Neuromuscular complications are not rare during MERS treatment, and they may have previously been underdiagnosed. Understanding the neurological manifestations is important in an infectious disease such as MERS, because these symptoms are rarely evaluated thoroughly during treatment, and they may interfere with the prognosis or require treatment modification.


Real-time simulation of contact and cutting of heterogeneous soft-tissues.
This paper presents a numerical method for interactive (real-time) simulations, which considerably improves the accuracy of the response of heterogeneous soft-tissue models undergoing contact, cutting and other topological changes. We provide an integrated methodology able to deal both with the ill-conditioning issues associated with material heterogeneities, contact boundary conditions which are one of the main sources of inaccuracies, and cutting which is one of the most challenging issues in interactive simulations. Our approach is based on an implicit time integration of a non-linear finite element model. To enable real-time computations, we propose a new preconditioning technique, based on an asynchronous update at low frequency. The preconditioner is not only used to improve the computation of the deformation of the tissues, but also to simulate the contact response of homogeneous and heterogeneous bodies with the same accuracy. We also address the problem of cutting the heterogeneous structures and propose a method to update the preconditioner according to the topological modifications. Finally, we apply our approach to three challenging demonstrators: (i) a simulation of cataract surgery (ii) a simulation of laparoscopic hepatectomy (iii) a brain tumor surgery.


Effect of sourdough addition and storage time on in vitro starch digestibility and estimated glycemic index of tef bread.
The effect of sourdough amount and storage time on starch digestibility and estimated glycemic index (eGI) of tef bread was investigated. The rapidly digestible starch (RDS), slowly digestible starch (SDS) and resistant starch (RS) of 0-30% sourdough fresh tef breads ranged from 49 to 58, 16 to 29 and 20 to 26 g/100 g starch, respectively. Storage of tef breads up to 5 days decreased the RDS by more than 2-fold while SDS and RS increased by 2 and 3 fold, respectively. The eGI for fresh and stored breads ranged from 39 to 89. Addition of sourdough increased the eGI of fresh breads while no uniform pattern was seen in the stored breads. As the storage time increased, all the breads showed a decrease in eGI. In vivo study is necessary to further investigate the effect of sourdough on GI of tef bread.


On the origin of the controversial electrostatic field effect in superconductors.
Superconducting quantum devices offer numerous applications, from electrical metrology and magnetic sensing to energy-efficient high-end computing and advanced quantum information processing. The key elements of quantum circuits are (single and double) Josephson junctions controllable either by electric current or magnetic field. The voltage control, commonly used in semiconductor-based devices via the electrostatic field effect, would be far more versatile and practical. Hence, the field effect recently reported in superconducting devices may revolutionise the whole field of superconductor electronics provided it is confirmed. Here we show that the suppression of the critical current attributed to the field effect, can be explained by quasiparticle excitations in the constriction of superconducting devices. Our results demonstrate that a miniscule leakage current between the gate and the constriction of devices perfectly follows the Fowler-Nordheim model of electron field emission from a metal electrode and injects quasiparticles with energies sufficient to weaken or even suppress superconductivity.