The use of screening episodes linked to CIN3 and invasive cancer registrations to study outcomes from the NHS Cervical Screening Programme.
The use of screening episodes linked to CIN3 and invasive cancer registrations to study outcomes from the NHS Cervical Screening ProgrammeObjective: To examine how NHS cervical screening data can be collected and analysed in order to evaluate women's screening histories as episodes rather than as individual smears. Analysis of routine cervical screening data grouped into screening episodes for a cohort of women regarding episodes starting in a given year. NHS Cervical Screening Programme. Data from four Health Authorities (now eight Primary Care Trusts) from the NHS Cervical Screening Programme with primary smears (first in an episode) taken between 1 April 1999 and 31 March 2000. Cytology information obtained from the call/recall ('Exeter') computer system was linked to cervical intraepithelial neoplasia (CIN) 3 and invasive cancer outcome information obtained from cancer registries. Screening histories were divided into episodes, each starting with a primary smear that was followed up to episode closure or, for episodes still open followed for an average 4.25 years, from the primary smear. The episode was divided into two parts (up to referral to colposcopy and following the referral). The outcomes of the episodes are described including referral rate to colposcopy and CIN3 and invasive cancer rates by factors such as age. Episode histories and rates of referral to colposcopy, CIN3 and invasive cancer. There were 176 923 episodes from 176 319 women (1.003 episodes per woman) followed up to March 2004, the date at which the first phase of information accrual ceased. Of these episodes, 172 100 (97.3%) were closed either by a negative smear referring the woman back to routine recall or by default (defined as no smear recorded within 21 months following a smear requiring an action of repeat or refer to colposcopy). The remaining 4823 (2.7%) of episodes were still open, of which in 3121 (1.8%) the woman had been referred to colposcopy and in 1702 (1.0%) no referral decision had been made. Referral rates to colposcopy varied by age from 5.7% in women aged 20-24 years down to 0.9% in women aged 60-64 years. The overall efficiency of screening was highest for woman aged about 30 years, with a CIN3 detection rate of eight per 1000 women and a positive predictive value (for CIN3 or worse) of referral to colposcopy of 21%. The study has shown that routinely collected NHS cervical screening data can be combined to give information on complete episodes, allowing important performance measures to be studied. We suggest that in future information in the NHS screening system should be structured to facilitate such analysis and to allow cytology and histology information to be readily linked.


Thin-film vertical-type AlGaInP LEDs fabricated by epitaxial lift-off process via the patterned design of Cu substrate.
In this study, the thin-film vertical-type AlGaInP LEDs on Cu substrates were fabricated. By performing the epitaxial lift-off (ELO) process, the LED device can be transferred from GaAs to Cu substrate. Then the GaAs substrate was separated and the ELO-LED was completed. To overcome the drawback of crack formation in the epilayer during the ELO process, various patterned Cu substrates were designed. Moreover, the finite element method was used to simulate the stress distribution in the LED sample during the ELO process. From the simulation results, an optimum structure of patterned Cu substrate was obtained since its maximum stress can be confined to the chip edges and the stress was decreased significantly during the ELO process, resulting in an apparent reduction of crack generation after separating the GaAs substrate. This optimum patterned Cu substrate was employed for the fabrication of ELO-LED. In addition, the chemical etching process was also used to etch the GaAs substrate, and this device transferred to Cu substrate was denoted as CE-LED. Based on the measurements of device performances, the forward voltages (@350 mA) of the CE-LED and ELO-LED were measured to be 2.20 and 2.29 V, while the output powers (@350 mA) of these two devices were 49.9 and 48.2 mW, respectively. Furthermore, the surface temperatures (@350 mA) of these two samples were 46.9-48.3 and 45.2-47.0 °C, respectively. Obviously, the device characteristics of the ELO-LED are very similar to those of the CE-LED. It confirms that the design of patterned Cu substrate is very helpful to obtain the thin-film vertical-type AlGaInP LEDs. Additionally, via the ELO process, the separated GaAs substrate can be reused for production cost down.


Changes in cell morphology and carnitine acetyltransferase activity in Candida albicans following growth on lipids and serum and after in vivo incubation in mice.
Candida albicans C316, maintained in the yeast form, showed a proliferation of peroxisomes when grown on triolein or serum as sole carbon source but these structures were absent from glucose-grown cells. Peroxisomes were also apparent in C. albicans obtained after injection into mice and recovery from intraperitoneal washings and kidneys; they may therefore be useful markers to assess a potential in vivo response in cells that are growing in vitro. Transcell-wall structures also occurred in C. albicans grown on triolein or serum, and in cells cultured in vivo, but were not seen in cells grown on glucose. These structures consisted of electron-dense fibrillar material penetrating through the cell wall from the plasmalemma side and protruded out to the exterior of the cell. Endoplasmic reticulum, located at the periphery of the cell, was found to be in close proximity with these cell wall structures. Carnitine acetyltransferase (CAT; EC 220.127.116.11), the key enzyme for the translocation of acetyl units between intracellular compartments, was present in low activities in glucose-grown cells; its activity was increased some 100-fold in triolein-grown cells but only 4-fold in serum-grown cells. It was not possible to assess this activity in the in vivo-cultured cells. Two separate CAT proteins, partially purifed from isolated microchondria and peroxisomes, respectively, were identified, with different specificities and kinetic properties.


Microfluidics-based digital quantitative PCR for single-cell small RNA quantification.
Quantitative analyses of small RNAs at the single-cell level have been challenging because of limited sensitivity and specificity of conventional real-time quantitative PCR methods. A digital quantitative PCR (dqPCR) method for miRNA quantification has been developed, but it requires the use of proprietary stem-loop primers and only applies to miRNA quantification. Here, we report a microfluidics-based dqPCR (mdqPCR) method, which takes advantage of the Fluidigm BioMark HD system for both template partition and the subsequent high-throughput dqPCR. Our mdqPCR method demonstrated excellent sensitivity and reproducibility suitable for quantitative analyses of not only miRNAs but also all other small RNA species at the single-cell level. Using this method, we discovered that each sperm has a unique miRNA profile.


A Bayesian approach for suppression of limited angular sampling artifacts in single particle 3D reconstruction.
In the single particle reconstruction, the initial 3D structure often suffers from the limited angular sampling artifact. Selecting 2D class averages of particle images generally improves the accuracy and efficiency of the reference-free 3D angle estimation, but causes an insufficient angular sampling to fill the information of the target object in the 3D frequency space. Similarly, the initial 3D structure by the random-conical tilt reconstruction has the well-known "missing cone" artifact. Here, we attempted to solve the limited angular sampling problem by sequentially applying maximum a posteriori estimate with expectation maximization algorithm (sMAP-EM). Using both simulated and experimental cryo-electron microscope images, the sMAP-EM was compared to the direct Fourier method on the basis of reconstruction error and resolution. To establish selection criteria of the final regularization weight for the sMAP-EM, the effects of noise level and sampling sparseness on the reconstructions were examined with evenly distributed sampling simulations. The frequency information filled in the missing cone of the conical tilt sampling simulations was assessed by developing new quantitative measurements. All the results of visual and numerical evaluations showed the sMAP-EM performed better than the direct Fourier method, regardless of the sampling method, noise level, and sampling sparseness. Furthermore, the frequency domain analysis demonstrated that the sMAP-EM can fill the meaningful information in the unmeasured angular space without detailed a priori knowledge of the objects. The current research demonstrated that the sMAP-EM has a high potential to facilitate the determination of 3D protein structures at near atomic-resolution.


Curcumin: a new paradigm and therapeutic opportunity for the treatment of osteoarthritis: curcumin for osteoarthritis management.
The management of osteoarthritis represents a real challenge. This complex and multi-factorial disease evolves over decades and requires not only the alleviation of symptoms, i.e. pain and joint function but also the preservation of articular structure without side effects. Nutraceuticals are good candidates for the management of OA due to their safety profile and potential efficacy. However, they are not part of the treatment guidelines and published recommendations. Curcumin is the yellow pigment isolated from the rhizomes of Curcuma longa, commonly known as turmeric. Curcumin is a highly pleiotropic molecule with an excellent safety profile. Strong molecular evidence has been published for its potency to target multiple inflammatory diseases. However, naturally occurring curcumin cannot achieve its optimum therapeutic outcomes due to its low solubility and poor bioavailability. Nevertheless, curcumin presents great potential for treating OA and has been categorized as having preclinical evidence of efficacy. This review aimed at gathering most of the available information to document the potential efficacy of curcumin based on the results obtained in in vitro models of cartilage and osteoarthritis and in other diseases.


Developing and validating a conceptual model of recurring problems in teaching clinic.
Recurrent problems in medical teaching clinic are common and difficult to address because of complex interpersonal dynamics. To minimize this difficulty, we developed a conceptual model that simplifies problems and identifies the root cause of tension between groups in clinic. We used recursive analysis and modeling of the data from a larger multi-site, multi-method study of problems in teaching clinic. The first dataset from this study consisted of problem lists generated and prioritized by knowledgeable insiders from each site. The second dataset was a cultural consensus analysis independently performed at each site. The final model was checked for face validity and construct validity (using model predictions versus prior data and convergent/discriminant analysis). The study was performed in five Veterans Affairs teaching clinics in the U.S. Our final model, the Perception of Care Map, is a pentagram with five critical perspectives of the clinic visit. These five perspectives are structured care, educational care, relationship-based care, algorithmic care and efficient care. Each group emphasizes one or more of these perspectives, and group locations on the conceptual map explain the observed tensions between groups. Validity of the model is high. The Perception of Care Map may be a useful adjunct for understanding and addressing recurrent problems in teaching clinic.


Relationship Between Plasma Concentrations and Clinical Effects of Cariprazine in Patients With Schizophrenia or Bipolar Mania.
Population pharmacokinetic/pharmacodynamic modeling (via NONMEM) was used to describe longitudinal exposure-response relationships for total cariprazine (sum of cariprazine and its major active metabolites) in 2,558 patients with schizophrenia or bipolar mania. Drug exposure metrics were explored for potential relationships with efficacy and safety end points. Total cariprazine exposures were significantly related to reductions in Positive and Negative Syndrome Scale (PANSS) or Young Mania Rating Scale (YMRS) total scores in schizophrenia or bipolar mania, respectively, via a maximum effect (Emax )-type relationship. Typical steady-state plasma concentrations after 3 and 4.5 mg/day were associated with 50% of maximum typical reductions in PANSS and YMRS total scores, respectively. Time-weighted cariprazine exposures had significant relationships with the probability of common adverse events (AEs). Dose increase was associated with increased efficacy but was also associated with an increase in AEs. Results of these pharmacokinetic/pharmacodynamic analyses support that the recommended dose range (1.5-6 mg/day for schizophrenia and 3-6 mg/day for bipolar mania) provides an appropriate benefit-risk balance between cariprazine efficacy and safety.


Pyrochlore lattice, self-assembly and photonic band gap optimizations.
Non-spherical colloidal building blocks introduce new design principles for self-assembly, making it possible to realize optical structures that could not be assembled previously. With this added complexity, the phase space expands enormously so that computer simulation becomes a valuable tool to design and assemble structures with useful optical properties. We recently demonstrated that tetrahedral clusters and spheres, interacting through a DNA-mediated short-range attractive interaction, self-assemble into a superlattice of interpenetrating diamond and pyrochlore sublattices, but only if the clusters consist of partially overlapping spheres. Here we show how the domain of crystallization can be extended by implementing a longer range potential and consider how the resultant structures affect the photonic band gaps of the underlying pyrochlore sublattice. We show that with the proper design, using clusters of overlapping spheres lead to larger photonic band gaps that open up at lower optical contrast.


The role of postnatal x-ray pelvimetry after caesarean section in the management of subsequent delivery.
The purpose of this study was to investigate the influence of postnatal x-ray pelvimetry after caesarean section on the management of the subsequent pregnancy. The case records of 331 women delivered by casearean section in their first pregnancy were reviewed. By standard radiological criteria, the pelvis was considered to be inadequate in 248 (75%) of them and adequate in 83 (25%). Of the women with a radiologically inadequate pelvis, 172 underwent an elective caesarean section. Seventy-six were allowed vaginal delivery: 51 of these women delivered vaginally and 25 required an emergency caesarean section. Of the women with a radiologically adequate pelvis, 61 achieved a vaginal delivery and 22 were delivered by caesarean section. All of the three cases of uterine rupture occurred in women with a radiologically adequate pelvis. This study suggests that x-ray pelvimetry is not a good predictor of the outcome of a trial of vaginal delivery. We conclude that the practice of routine postnatal pelvimetry should be abandoned.


The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression.
Beta-catenin plays a pivotal role in the transcriptional activation of Wnt-responsive genes by binding to TCF/LEF transcription factors. Although it has been suggested that the COOH-terminal region of beta-catenin functions as an activation domain, the mechanisms of activation remain unclear. To screen for potential transcriptional coactivators that bind to the COOH-terminal region of beta-catenin, we used a novel yeast two-hybrid system, the Ras recruitment system (RRS) that detects protein-protein interactions at the inner surface of the plasma membrane. Using this system, we isolated the CREB-binding protein (CBP). Armadillo (Arm) repeat 10 to the COOH terminus of beta-catenin is involved in binding to CBP, whereas beta-catenin interacts directly with the CREB-binding domain of CBP. Beta-catenin synergizes with CBP to stimulate the activity of a synthetic reporter in vivo. Conversely, beta-catenin-dependent transcriptional activation is repressed by E1A, an antagonist of CBP function, but not by an E1A mutant that does not bind to CBP. The activation of Wnt target genes such as siamois and Xnr3 in Xenopus embryos is also sensitive to E1A. These findings suggest that CBP provides a link between beta-catenin and the transcriptional machinery, and possibly mediates the oncogenic function of beta-catenin.


Magnetic seizure therapy improves mood in refractory major depression.
This report describes the successful treatment of a patient suffering from an episode of drug-resistant major depression using magnetic seizure therapy (MST). The patient suffered from recurrent major depression since adolescence. MST is a novel brain stimulation method using transcranial magnetic stimulation at convulsive parameters in order to induce therapeutic seizures under general anesthesia in the same setting used for electroconvulsive therapy (ECT). The first use of therapeutic magnetic seizure induction in a psychiatric patient took place at the University Hospital in Bern, Switzerland, in May 2000. Results of a recent randomized, within-subject, double-masked trial comparing ECT and MST in 10 patients indicate that MST appears to have less subjective and objective side effects, is associated with faster recovery of orientation, and is superior to ECT on measures of attention, retrograde amnesia, and category fluency. ECT has an unparalleled and well-documented efficacy in severe depression but is associated with cognitive side effects. MST is currently under study in several centers with respect to its antidepressant efficacy. We report here on the treatment of a patient with refractory major depression (DSM IV-R), who underwent a series of 12 sessions of MST in an inpatient setting. Baseline Hamilton Depression Rating Scale (HRSD-21) of 33 and Beck Depression Inventory (BDI) of 40 decreased to 6 and 11 respectively, 1 week after completion of the MST trial. Measures of cognitive functions support the hypothesis that MST is associated with a less severe profile of cognitive side effects. [(99m)Tc]-HMPAO SPECT studies (baseline and 4 days after the completion of the MST trial) point to a raise of blood flow at baseline in the left fronto-parietal region and the brainstem. Our preliminary data support the prospect of antidepressant efficacy of MST and point to a benign cognitive side-effect profile in a patient suffering from severe treatment-resistant major depression.


Lycopene stability during food processing.
Accumulating epidemiological evidence continues to show that lycopene, found in tomatoes, grapefruits and watermelons, is associated with a reduced risk of developing certain chronic diseases and cancers. With respect to lycopene in tomato products, the effect of thermal processing on its stability has not yet been rigorously addressed. This paper assesses the effect of several different heat treatments on lycopene's isomeric distribution in a variety of tomato products, as well as in organic solvent mixtures containing all-trans lycopene. Experimental results indicate that in contrast to beta-carotene, lycopene remained relatively resistant to heat-induced geometrical conversion during typical food processing of tomatoes and related products. The presence of fat, the change in percentage of solids, and the severity of heat treatment were not contributing factors in the formation of lycopene isomers in tomato products, except at extreme conditions not regularly employed in the food industry or during food preparation. However, lycopene in organic solvent isomerized readily as a function of time even in the absence of light and the presence of antioxidants. These findings suggest that while lycopene is stable in the tomato matrix, sample handling techniques should be carefully evaluated to minimize the formation of lycopene cis isomers in organic solutions.


Concentrations of oestradiol and oestrone in plasma, uterus and other tissues of fetal guinea-pigs: their relationship to uptake and specific binding of [3H]oestradiol.
The concentrations of unconjugated oestradiol-17 beta and oestrone have been measured by radioimmunoassay in the plasma of fetal, newborn and immature guinea-pigs. In fetal plasma, the values of oestradiol ranged from 15 to 50 pg/ml with no significant variations with gestational age except for an abrupt increase at the very end of gestation (148 pg/ml). Low concentrations of oestradiol were also found postnatally (from not detectable to 31 pg/ml) as well as in maternal plasma (22 pg/ml). The values of oestrone were consistently higher in all plasma regardless of age (43--164 pg/ml). Oestrogen concentrations were also determined in the fetal uterus, lung, kidney and brain and were found to be as much as 60 times higher (per g tissue) than in plasma, especially in the fetal uterus which contained four to five times more than the other tissues. These data correlated well with a 20--90 times greater uptake of [3H]oestradiol by the fetal uterus compared with the other tissues after in-vivo administration of [3H]oestradiol to the fetuses. The selective retention of oestradiol was probably due to the presence of specific oestradiol binding in these fetal tissues, particularly in the uterus whose binding was 60--120 times higher than in the other fetal tissues. Thus, the levels of oestrogen in the circulation of fetal guinea-pigs are low, but the fetal uterus is capable of maintaining a higher concentration which may be important physiologically since oestradiol has been shown to evoke a biological response in the fetal guinea-pig uterus.


A practical guide to environmental association analysis in landscape genomics.
Landscape genomics is an emerging research field that aims to identify the environmental factors that shape adaptive genetic variation and the gene variants that drive local adaptation. Its development has been facilitated by next-generation sequencing, which allows for screening thousands to millions of single nucleotide polymorphisms in many individuals and populations at reasonable costs. In parallel, data sets describing environmental factors have greatly improved and increasingly become publicly accessible. Accordingly, numerous analytical methods for environmental association studies have been developed. Environmental association analysis identifies genetic variants associated with particular environmental factors and has the potential to uncover adaptive patterns that are not discovered by traditional tests for the detection of outlier loci based on population genetic differentiation. We review methods for conducting environmental association analysis including categorical tests, logistic regressions, matrix correlations, general linear models and mixed effects models. We discuss the advantages and disadvantages of different approaches, provide a list of dedicated software packages and their specific properties, and stress the importance of incorporating neutral genetic structure in the analysis. We also touch on additional important aspects such as sampling design, environmental data preparation, pooled and reduced-representation sequencing, candidate-gene approaches, linearity of allele-environment associations and the combination of environmental association analyses with traditional outlier detection tests. We conclude by summarizing expected future directions in the field, such as the extension of statistical approaches, environmental association analysis for ecological gene annotation, and the need for replication and post hoc validation studies.


Sensitivity analyses of cables to suspen-dome structural system.
The construction of the cables is a key step for erecting suspen-dome structures. In practical engineering, it is difficult to ensure that the designed pre-stresses of cables have been exactly introduced into the structures in the site; so it is necessary to evaluate the influence of the variation of the pre-stresses on the structural behavior. In the present work, an orthogonal design method was employed to investigate the pre-stressed cables' sensitivity to the suspen-dome system. The investigation was concentrated on a Kiewitt suspen-dome. Parametric studies were carried out to study the sensitivity of the structure's static behavior, dynamic behavior, and buckling loads when the pre-stresses in the cables varied. The investigation indicated that suspen-dome structures are sensitive to the pre-stresses in all cables; and that the sensitivity depended on the location of the cables and the kind of structural behavior. Useful suggestions are given at the end of the paper.


Cross-talk between the signal pathways for pathogen-induced systemic acquired resistance and grazing-induced insect resistance.
Reducing phenylpropanoid biosynthesis in transgenic tobacco compromises systemic acquired resistance (SAR) to tobacco mosaic virus, while increasing phenylpropanoid biosynthesis enhances SAR. Surprisingly, transgenic tobacco plants compromised in SAR exhibit more effective grazing-induced systemic resistance to larvae of Heliothis virescens, whereas induced insect resistance is compromised in transgenic plants with elevated phenylpropanoid levels. Levels of the phenylpropanoid-derived signal salicylic acid are directly correlated with overall phenylpropanoid biosynthesis in this series of transgenic plants. Moreover, while pathogen-induced SAR is almost completely compromised in salicylic acid-deficient plants expressing the bacterial nahG salicylate hydroxylase gene, these plants show enhanced grazing-induced insect resistance compared to wild-type. Hence, suppression of grazing-induced insect resistance is mediated at least in part by salicylic acid and likely reflects salicylic acid inhibition of the synthesis and action of the wound signal jasmonic acid. We propose that the dual functions of salicylic acid contribute to a signal poise which constrains constitutive expression of disease and insect resistance mechanisms, and reciprocally switches their selective activation.


The effect of cleft lip and palate, and the timing of lip repair on mother-infant interactions and infant development.
Children with cleft lip and palate are at risk for psychological problems. Difficulties in mother-child interactions may be relevant, and could be affected by the timing of lip repair. We assessed cognitive development, behaviour problems, and attachment in 94 infants with cleft lip (with and without cleft palate) and 96 non-affected control infants at 18 months; mother-infant interactions were assessed at two, six and 12 months. Index infants received either 'early', neonatal, lip repair, or 'late' repair (3-4 months). Index infants did not differ from controls on measures of behaviour problems or attachment, regardless of timing of lip repair; however, infants having late lip repair performed worse on the Bayley Scales of Mental Development; the cognitive development of early repair infants was not impaired. Difficulties in early mother-infant interactions mediated the effects of late lip repair on infant cognitive outcome. Early interaction difficulties between mothers and infants having late repair of cleft lip are associated with poor cognitive functioning at 18 months. Interventions to facilitate mother-infant interactions prior to surgical lip repair should be explored.


A review of arsenic exposure and lung cancer.
As a well-established human carcinogen, arsenic has increased the risk of lung cancer over the past decades. Wide exposure to arsenic in the environment has attracted the attention of scientists. Its carcinogenicity at early life stages has been observed in certain animal studies already, yet current evidence is insufficient to extrapolate this to humans. Although the mechanisms of lung cancer induced by arsenic remain unclear, most of them are related to the biotransformation of arsenic, which would further provide target sites for precaution and therapy. This review comprehensively summarizes current studies associated to arsenic exposure and lung cancer and the mechanism of its carcinogenesis in lung cancer in three sections, namely, epidemiological studies, experimental studies, and mechanistic studies. In addition, prevention and treatment strategies as well as directions for future studies are discussed.


Disordered Eating Behaviours and Eating Disorders in Women in Australia with and without Polycystic Ovary Syndrome: A Cross-Sectional Study.
Psychological co-morbidities common in polycystic ovary syndrome (PCOS) may contribute to disordered eating and subsequent weight gain. This cross-sectional study aimed to determine the prevalence of disordered eating and a range of eating disorders and demographic risk factors associated with these behaviours within an Australian group of women with and without PCOS. Data from 899 women with (n = 501) and without (n = 398) PCOS were analysed as possibly indicative of disordered eating or eating disorders using the Eating Disorder Examination Questionnaire (EDE-Q) and The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria. Disordered eating (p = 0.012) but not eating disorders (p = 0.076) were more prevalent in women with PCOS compared to controls. Increased body mass index (BMI) [Odds Ratio (OR): 1.03; 95%; Confidence Interval (CI): 1.01, 1.05, p = 0.012] and older age [OR: 1.05; 95%CI: 1.02, 1.08, p = 0.002] but not PCOS diagnosis [OR: 1.43; 95%CI: 0.96, 2.13 p = 0.078] increased the odds of disordered eating. Increased BMI [OR: 1.04; 95%CI: 1.02, 1.06, p < 0.001] and younger age [OR: -0.95; 95%CI: 0.93-0.95, p < 0.001] but not PCOS diagnosis [OR: 1.38; 95%CI: 0.97, 1.95, p = 0.076] increased the odds of an eating disorder. Clinicians are recommended to screen all women with PCOS for possible disordered eating behaviours, with particular attention to women with elevated BMI.


[Cardiovascular disease in pediatric patients under chronic peritoneal dialysis].
Peritoneal dialysis (PD) is the most common renal replacement therapy used in pediatric patients with end stage renal disease. This population has a mortality rate 1,000 times greater compare to pediatric population, mainly due to cardiovascular causes. To characterize pediatric patients on chronic PD in relation to dialysis and cardiovascular outcome. Cross sectional study. Patients in stable PD according to DOQI criteria were selected. Epidemiological, dialytic, biochemical and cardiovascular variables were registered. Left Ventricular Mass Index (LVMI) was calculated by height/age (g/m2.7). Left Ventricular Hypertrophy (LVH) was diagnosed with > 38.6 g/m2.7, severe LVH > 51 g/m2.7. Data were analyzed using STATA 11.0. continuous variables using ANOVA test and categorical variables were analyzed using χ2 test or Fisher's exact test. 21 patients, 11 males. Mean age 9.2 ± 3.52 years. The most frequent diagnosis was renal dysplasia (52%). Residual and Peritoneal KtV were 0.8 and 1.9 respectively. Fifty-two percent of patients showed LVH, 91% in severe range. A significant relationship between ultrafiltration/m2 and systolic blood pressure was depicted. Also a significant relationship between left ventricular mass index and hemoglobin (p < 0.05) was founded. The majority of the population showed left ventricular hypertrophy -particularly severe LVH-, which confirms an increased CV risk in this population. Blood pressure and loss of ultrafiltration were founded to be correlated to LVH.


UNC93B1 facilitates the localization and signaling of TLR5M in Epinephelus coioides.
Toll-like receptor 5 (TLR5), serving as a sensor of bacterial flagellin, mediates the innate immune response to actively engage in the host's immune processes against pathogen invasion. However, the mechanism underlying TLR5-mediated immune response in fish remains unclear. Despite the presumed cell surface expression of TLR5 member form TLR5M, its trafficking dynamics remain elusive. Here, we have identified Epinephelus coioides TLR5M as a crucial mediator of Vibrio flagellin-induced cytokine expression in grouper cells. EcTLR5M facilitated the activation of NF-κB signaling pathway in response to flagellin stimulation and exerted a modest influence on the mitogen-activated protein kinase (MAPK)-extracellular regulated kinase (ERK) signaling. The trafficking chaperone Unc-93 homolog B1 (EcUNC93B1) participated in EcTLR5M-mediated NF-κB signaling activation and downstream cytokine expression. In addition, EcUNC93B1 combined with EcTLR5M to mediate its exit from the endoplasmic reticulum, and also affected its post-translational maturation. Collectively, these findings first discovered that EcTLR5M mediated the flagellin-induced cytokine expression primarily by regulating the NF-κB signaling pathway, and EcUNC93B1 mediated EcTLR5M function through regulating its trafficking and post-translational maturation. This research expanded the understanding of fish innate immunity and provided a novel concept for the advancement of anti-vibrio immunity technology.


Fundamentals of soft robot locomotion.
Soft robotics and its related technologies enable robot abilities in several robotics domains including, but not exclusively related to, manipulation, manufacturing, human-robot interaction and locomotion. Although field applications have emerged for soft manipulation and human-robot interaction, mobile soft robots appear to remain in the research stage, involving the somehow conflictual goals of having a deformable body and exerting forces on the environment to achieve locomotion. This paper aims to provide a reference guide for researchers approaching mobile soft robotics, to describe the underlying principles of soft robot locomotion with its pros and cons, and to envisage applications and further developments for mobile soft robotics.


Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization.
Phosphatidylinositol bisphosphate (PIP2) directly regulates functions as diverse as the organization of the cytoskeleton, vesicular transport and ion channel activity. It is not known, however, whether dynamic changes in PIP2 levels have a regulatory role of physiological importance in such functions. Here, we show in both native cardiac cells and heterologous expression systems that receptor-regulated PIP2 hydrolysis results in desensitization of a GTP-binding protein-stimulated potassium current. Two receptor-regulated pathways in the plasma membrane cross-talk at the level of these channels to modulate potassium currents. One pathway signals through the betagamma subunits of G proteins, which bind directly to the channel. Gbetagamma subunits stabilize interactions with PIP2 and lead to persistent channel activation. The second pathway activates phospholipase C (PLC) which hydrolyses PIP2 and limits Gbetagamma-stimulated activity. Our results provide evidence that PIP2 itself is a receptor-regulated second messenger, downregulation of which accounts for a new form of desensitization.


Spirituality and hearing voices: considering the relation.
For millennia, some people have heard voices that others cannot hear. These have been variously understood as medical, psychological and spiritual phenomena. In this article we consider the specific role of spirituality in voice-hearing in two ways. First, we examine how spirituality may help or hinder people who hear voices. Benefits are suggested to include offering an alternative meaning to the experience which can give more control and comfort, enabling the development of specific coping strategies, increasing social support, and encouraging forgiveness. Potential drawbacks are noted to include increased distress and reduced control resulting from placing frightening or coercive constructions on voices, social isolation, the development of dysfunctional beliefs, and missed/delayed opportunities for successful mental health interventions. After examining problems surrounding classifying voices as either spiritual or psychotic, we move beyond an essentialist position to examine how such a classification is likely to be fluid, and how a given voice may move between these designations. We also highlight tensions between modernist and postmodernist approaches to voice-hearing.


Approximate Causal Abstraction.
Scientific models describe natural phenomena at different levels of abstraction. Abstract descriptions can provide the basis for interventions on the system and explanation of observed phenomena at a level of granularity that is coarser than the most fundamental account of the system. Beckers and Halpern (2019), building on work of Rubenstein et al. (2017), developed an account of abstraction for causal models that is exact. Here we extend this account to the more realistic case where an abstract causal model offers only an approximation of the underlying system. We show how the resulting account handles the discrepancy that can arise between low- and high-level causal models of the same system, and in the process provide an account of how one causal model approximates another, a topic of independent interest. Finally, we extend the account of approximate abstractions to probabilistic causal models, indicating how and where uncertainty can enter into an approximate abstraction.


Tremor stability index: a new tool for differential diagnosis in tremor syndromes.
See Vidailhet et al. (doi:10.1093/brain/awx140) for a scientific commentary on this article. Misdiagnosis among tremor syndromes is common, and can impact on both clinical care and research. To date no validated neurophysiological technique is available that has proven to have good classification performance, and the diagnostic gold standard is the clinical evaluation made by a movement disorders expert. We present a robust new neurophysiological measure, the tremor stability index, which can discriminate Parkinson's disease tremor and essential tremor with high diagnostic accuracy. The tremor stability index is derived from kinematic measurements of tremulous activity. It was assessed in a test cohort comprising 16 rest tremor recordings in tremor-dominant Parkinson's disease and 20 postural tremor recordings in essential tremor, and validated on a second, independent cohort comprising a further 55 tremulous Parkinson's disease and essential tremor recordings. Clinical diagnosis was used as gold standard. One hundred seconds of tremor recording were selected for analysis in each patient. The classification accuracy of the new index was assessed by binary logistic regression and by receiver operating characteristic analysis. The diagnostic performance was examined by calculating the sensitivity, specificity, accuracy, likelihood ratio positive, likelihood ratio negative, area under the receiver operating characteristic curve, and by cross-validation. Tremor stability index with a cut-off of 1.05 gave good classification performance for Parkinson's disease tremor and essential tremor, in both test and validation datasets. Tremor stability index maximum sensitivity, specificity and accuracy were 95%, 95% and 92%, respectively. Receiver operating characteristic analysis showed an area under the curve of 0.916 (95% confidence interval 0.797–1.000) for the test dataset and a value of 0.855 (95% confidence interval 0.754–0.957) for the validation dataset. Classification accuracy proved independent of recording device and posture. The tremor stability index can aid in the differential diagnosis of the two most common tremor types. It has a high diagnostic accuracy, can be derived from short, cheap, widely available and non-invasive tremor recordings, and is independent of operator or postural context in its interpretation.


A Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux.
Endogenous circadian rhythms are thought to modulate responses to external factors, but mechanisms that confer time-of-day differences in organismal responses to environmental insults/therapeutic treatments are poorly understood. Using a xenobiotic, we find that permeability of the Drosophila "blood"-brain barrier (BBB) is higher at night. The permeability rhythm is driven by circadian regulation of efflux and depends on a molecular clock in the perineurial glia of the BBB, although efflux transporters are restricted to subperineurial glia (SPG). We show that transmission of circadian signals across the layers requires cyclically expressed gap junctions. Specifically, during nighttime, gap junctions reduce intracellular magnesium ([Mg2+]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti-epileptic phenytoin is more effective at treating a Drosophila seizure model. These findings identify a novel mechanism of circadian regulation and have therapeutic implications for drugs targeted to the central nervous system.


Incorporating groundwater-surface water interaction into river management models.
Accurate representation of groundwater-surface water interactions is critical to modeling low river flows in the semi-arid southwestern United States. Although a number of groundwater-surface water models exist, they are seldom integrated with river operation/management models. A link between the object-oriented river and reservoir operations model, RiverWare, and the groundwater model, MODFLOW, was developed to incorporate groundwater-surface water interaction processes, such as river seepage/gains, riparian evapotranspiration, and irrigation return flows, into a rule-based water allocations model. An explicit approach is used in which the two models run in tandem, exchanging data once in each computational time step. Because the MODFLOW grid is typically at a finer resolution than RiverWare objects, the linked model employs spatial interpolation and summation for compatible communication of exchanged variables. The performance of the linked model is illustrated through two applications in the Middle Rio Grande Basin in New Mexico where overappropriation impacts endangered species habitats. In one application, the linked model results are compared with historical data; the other illustrates use of the linked model for determining management strategies needed to attain an in-stream flow target. The flows predicted by the linked model at gauge locations are reasonably accurate except during a few very low flow periods when discrepancies may be attributable to stream gaging uncertainties or inaccurate documentation of diversions. The linked model accounted for complex diversions, releases, groundwater pumpage, irrigation return flows, and seepage between the groundwater system and canals/drains to achieve a schedule of releases that satisfied the in-stream target flow.


Tailoring the multistability of origami-inspired, buckled magnetic structures via compression and creasing.
Origami-inspired multistable structures are gaining increasing interest because of their potential applications in fields ranging from deployable structures to reconfigurable microelectronics. The multistability of such structures is critical for their applications but is challenging to manipulate due to the highly nonlinear deformations and complex configurations of the structures. Here, a comprehensive experimental and computational study is reported to tailor the multistable states of origami-inspired, buckled ferromagnetic structures and their reconfiguration paths. Using ribbon structures as an example, a design phase diagram is constructed as a function of the crease number and compressive strain. As the crease number increases from 0 to 7, the number of distinct stable states first increases and then decreases. The multistability is also shown to be actively tuned by varying the strain from 0% to 40%. Furthermore, analyzing energy barriers for reconfiguration among the stable states reveals dynamic changes in reconfiguration paths with increasing strains. Guided by studies above, diverse examples are designed and demonstrated, from programmable structure arrays to a soft robot. These studies lay out the foundation for the rational design of functional, multistable structures.


l-Dopa in dystonia: A modern perspective.
"Every child exhibiting dystonia merits an l-dopa trial, lest the potentially treatable condition of dopa-responsive dystonia (DRD) is missed" has been a commonly cited and highly conserved adage in movement disorders literature stemming from the 1980s. We here provide a historical perspective on this statement, discuss the current diagnostic and therapeutic applications of l-dopa in everyday neurologic practice, contrast these with its approved indications, and finish with our view on both a diagnostic and therapeutic trial in children and adults with dystonia. In light of the relatively low prevalence of DRDs, the large interindividual variation in the required l-dopa dose, the uncertainty about an adequate trial duration, the substantial advances in knowledge on etiology and pathophysiology of these disorders, and the availability of various state-of-the-art diagnostic tests, we think that a diagnostic l-dopa trial as a first step in the approach of early-onset dystonia (≤25 years) is outdated. Rather, in high-resource countries, we suggest to use l-dopa after biochemical corroboration of a defect in dopamine biosynthesis, in genetically confirmed DRD, or if nigrostriatal degeneration has been demonstrated by nuclear imaging in adult patients presenting with lower limb dystonia. Furthermore, our literature study on the effect of a therapeutic trial to gain symptomatic relief revealed that l-dopa has occasionally proven beneficial in several established "non-DRDs" and may therefore be considered in selected cases of dystonia due to other causes. In summary, we argue against the application of l-dopa in every patient with early-onset dystonia and support a more rational therapeutic use.


Hybrid Deep Learning for Medication-Related Information Extraction From Clinical Texts in French: MedExt Algorithm Development Study.
Information related to patient medication is crucial for health care; however, up to 80% of the information resides solely in unstructured text. Manual extraction is difficult and time-consuming, and there is not a lot of research on natural language processing extracting medical information from unstructured text from French corpora. We aimed to develop a system to extract medication-related information from clinical text written in French. We developed a hybrid system combining an expert rule-based system, contextual word embedding (embedding for language model) trained on clinical notes, and a deep recurrent neural network (bidirectional long short term memory-conditional random field). The task consisted of extracting drug mentions and their related information (eg, dosage, frequency, duration, route, condition). We manually annotated 320 clinical notes from a French clinical data warehouse to train and evaluate the model. We compared the performance of our approach to those of standard approaches: rule-based or machine learning only and classic word embeddings. We evaluated the models using token-level recall, precision, and F-measure. The overall F-measure was 89.9% (precision 90.8; recall: 89.2) when combining expert rules and contextualized embeddings, compared to 88.1% (precision 89.5; recall 87.2) without expert rules or contextualized embeddings. The F-measures for each category were 95.3% for medication name, 64.4% for drug class mentions, 95.3% for dosage, 92.2% for frequency, 78.8% for duration, and 62.2% for condition of the intake. Associating expert rules, deep contextualized embedding, and deep neural networks improved medication information extraction. Our results revealed a synergy when associating expert knowledge and latent knowledge.


[Diagnosis and treatment of headache combined with orthopedic disorders in children and adolescents].
To study characteristics of headache combined with orthopedic disorders in children and adolescents and to develop treatment approaches, we examined 116 patients aged from 5 to 17 years. Headache of tension was found in 89 (77%) and chronic headache in 27 (23%) patients. Along with clinical/neurological and orthopedic examination, all patients were studied using a special device that allowed to quantitatively measure the bearing (in three dimensions) and biomechanic body balance. Electroencephalography, Doppler ultrasound and transcranial tests of neck vessels and ophthalmological examination were carried out. Based on the features of headache characteristic of some groups of patients, the authors suggest using a multidiscipline approach including the day-to-day interaction between neurologist and orthopedist, pharmacological therapy, therapeutic physical training, specific orthopedic inner sole and other rehabilitation methods. This treatment has led to better recovery of patients compared to the treatment using only neurological or orthopedic techniques.


Beta-adrenergic stimulation of skeletal muscle HSL can be overridden by AMPK signaling.
Hormone-sensitive lipase (HSL), an important regulatory enzyme for triacylglycerol hydrolysis within skeletal muscle, is controlled by beta-adrenergic signaling as well as intrinsic factors related to contraction and energy turnover. In the current study, we tested the capacity of 5'AMP-activated protein kinase (AMPK) to suppress beta-adrenergic stimulation of HSL activity. Eight male subjects completed 60 min of cycle exercise at 70% VO2 peak on two occasions: either with normal (CON) or low (LG) pre-exercise muscle glycogen content, which is known to enhance exercise-induced AMPK activity. Muscle samples were obtained before and immediately after exercise. Pre-exercise glycogen averaged 375 +/- 35 and 163 +/- 27 mmol x kg(-1) dm for CON and LG, respectively. AMPK alpha-2 was not different between trials at rest and was increased (3.7-fold, P<0.05) by exercise during LG only. HSL activity did not differ between trials at rest and increased (0 min: 1.67 +/- 0.13; 60 min: 2.60 +/- 0.26 mmol x min(-1) x kg(-1) dm) in CON. The exercise-induced increase in HSL activity was attenuated by AMPK alpha-2 activation in LG. The attenuated HSL activity during LG occurred despite higher plasma epinephrine levels (60 min: CON, 1.96 +/- 0.29 vs LG, 4.25 +/- 0.60 nM, P<0.05) compared with CON. Despite the attenuated HSL activity in LG, IMTG was decreased by exercise (0 min: 27.1 +/- 2.0; 60 min: 22.5 +/- 2.0 mmol x kg(-1) dm, P<0.05), whereas no net reduction occurred in CON. To confirm the apparent effect of AMPK on HSL activity, we performed experiments in muscle cell culture. The epineprine-induced increase in HSL activity was totally attenuated (P<0.05) by AICAR administration in L6 myotubes. These data provide new evidence indicating that AMPK is a major regulator of skeletal muscle HSL activity that can override beta-adrenergic stimulation. However, the increased IMTG degradation in LG suggests factors other than HSL activity are important for IMTG degradation.


Impact of Electronic Fluctuations and Their Description on the Exciton Dynamics in the Light-Harvesting Complex PE545.
Temperature-dependent fluctuations of both site energies and electronic couplings are known to affect the excitation energy transfer in light-harvesting complexes. Environment effects on such fluctuations as well as possible spatial correlations among them are investigated here in the PE545 complex from cryptophyte algae using ensemble-averaged wave packet dynamics to extract the exciton dynamics. This strategy directly uses the time-dependent fluctuations of the system Hamiltonian, as described by quantum mechanics/molecular mechanics calculations performed along a classical MD trajectory. Neither the fluctuations in the couplings nor spatial correlations including cross-correlations between site energies and couplings are found to be important in the exciton dynamics of the complex. This finding does not change if a polarizable embedding is used instead of its electrostatic counterpart. The impact of variations in spectral densities and screening of excitonic couplings based on the electrostatic and polarizable embeddings are discussed as well.


[Effect of 24-hour intravenous administration of nitroglycerin on the status of the focus of a lesion in patients with an acute myocardial infarct].
Nitroglycerin was drip-infused for 24 hours to 35 patients with acute myocardial infarction. Thirty-three patients were taken as controls. Intergroup comparisons were made of the patterns of precordial cartograms from 35 leads and serial measurements of plasma MB CPK activity. The treatment was shown to reduce significantly the activity of MB CPK and total ST elevation, the effect being particularly pronounced with the drug administered within the first 6 hours of the attack. It was also shown that 24-hour intravenous nitroglycerin infusion produced a significant decrease in the end diastolic pressure of the pulmonary artery that occurred by the 15th minute and persisted till the end of the administration.


glo-3, a novel Caenorhabditis elegans gene, is required for lysosome-related organelle biogenesis.
Gut granules are specialized lysosome-related organelles that act as sites of fat storage in Caenorhabditis elegans intestinal cells. We identified mutations in a gene, glo-3, that functions in the formation of embryonic gut granules. Some glo-3(-) alleles displayed a complete loss of embryonic gut granules, while other glo-3(-) alleles had reduced numbers of gut granules. A subset of glo-3 alleles led to mislocalization of gut granule contents into the intestinal lumen, consistent with a defect in intracellular trafficking. glo-3(-) embryos lacking gut granules developed into adults containing gut granules, indicating that glo-3(+) function may be differentially required during development. We find that glo-3(+) acts in parallel with or downstream of the AP-3 complex and the PGP-2 ABC transporter in gut granule biogenesis. glo-3 encodes a predicted membrane-associated protein that lacks obvious sequence homologs outside of nematodes. glo-3 expression initiates in embryonic intestinal precursors and persists almost exclusively in intestinal cells through adulthood. GLO-3GFP localizes to the gut granule membrane, suggesting it could play a direct role in the trafficking events at the gut granule. smg-1(-) suppression of glo-3(-) nonsense alleles indicates that the C-terminal half of GLO-3, predicted to be present in the cytoplasm, is not necessary for gut granule formation. Our studies identify GLO-3 as a novel player in the formation of lysosome-related organelles.


Ethnic differences in the relationship between pericardial adipose tissue and coronary artery calcified plaque: African-American-diabetes heart study.
Calcified atherosclerotic plaque (CP) is less prevalent and less severe in African-Americans (AA), relative to European Americans (EA). Because pericardial adipose tissue (PAT) is associated with CP in the neighboring coronary arteries, we explored ethnic-specific relationships between PAT and CP. PAT volume and coronary and aortic CP were measured in 561 EA and 575 AA subjects with type 2 diabetes using single and multidetector computed tomography. Generalized estimating equations with exchangeable correlation and the sandwich estimator of the variance were used to test for associations between PAT and CP. Mean (sd) ages of AA and EA participants were 56.7 (9.5) and 62.0 (8.9) yr, respectively; diabetes duration was 10.5 (8.1) and 10.1 (7.3) yr; and PAT volume was 86.9 (38.6) and 131.7 (55.3) cm3/45 mm. In AA and EA participants, respectively, mean (sd) coronary CP mass scores were 803 (1,889) and 1,465 (2,847) mg calcium; and aortic CP, 5,407 (10,651) and 10,090 (15,087) mg calcium. Adjusting for age, gender, body mass index, blood pressure, height, smoking, lipid-lowering medications, C-reactive protein, albuminuria, high-density lipoprotein-cholesterol, and triglycerides, parameter estimates for the relationship between PAT and log(coronary CP+1) were 0.012 in AA (P<0.0001) and 0.003 (P=0.24) in EA, with a significant ethnic difference (P=0.019). No significant relationships or ethnic differences were observed between PAT and aortic CP (P=0.24, fully adjusted model). Pericardial adiposity is strongly associated with coronary atherosclerosis in AA with type 2 diabetes. Novel cardiovascular disease risk factors such as PAT may contribute to ethnic disparities in susceptibility to development of coronary atherosclerosis.


The changes in plasma serotonin levels after hormone therapy and their relationship with estrogen responsiveness on bone in postmenopausal women.
Selective serotonin reuptake inhibitors have shown to be associated with an increased risk of fractures. It has been suggested that circulating serotonin is an important regulatory factor and that estrogen may regulate bone metabolism through the serotonin pathway. Our objective was to determine the association between plasma serotonin level and bone turnover before and after hormone therapy (HT) in postmenopausal women. In this parallel comparative study using age-matched controls, 80 postmenopausal women (21 control, 59 receiving HT) aged 46-64 yr were assessed. The plasma levels of serotonin, serum concentrations of osteocalcin and carboxyterminal telopeptides, and bone mineral density (BMD) were measured at baseline and after 3 months and 1 yr of HT. The plasma serotonin level was significantly correlated with serum total alkaline phosphatase level at baseline (r = -0.223, P = 0.048) but not with serum osteocalcin (r = -0.217, P = 0.056) or carboxyterminal telopeptides (r = -0.217, P = 0.054). There was no significant association between baseline serotonin and BMD measured at the spine or femur. The median decrements of circulating serotonin from baseline were -9.3% (interquartile range -34.0 to 53.6%) and -7.2% (-25.5 to 64.5%) at 3 months and 1 yr of HT, respectively. These changes were not significantly different from those in the control group. The short-term changes of circulating serotonin at 3 months after HT did not show significant association with the changes in BMD measured at the lumbar spine or proximal femur 1 year after HT. Our results suggest that circulating serotonin may reflect bone turnover status, but it is not a strong enough predictor of bone loss to use as a bone marker. Moreover, serial measurements of plasma serotonin after short-term treatment with estrogen cannot predict the long-term responsiveness of bone to estrogen, suggesting that the bone-preserving effect of estrogen is independent of the peripheral action of serotonin on bone.


Altered functional connectivity in the fear network of firefighters with repeated traumatic stress.
Firefighters are routinely exposed to various traumatic events and often experience a range of trauma-related symptoms. Although these repeated traumatic exposures rarely progress to the development of post-traumatic stress disorder, firefighters are still considered to be a vulnerable population with regard to trauma.AimsTo investigate how the human brain responds to or compensates for the repeated experience of traumatic stress. We included 98 healthy firefighters with repeated traumatic experiences but without any diagnosis of mental illness and 98 non-firefighter healthy individuals without any history of trauma. Functional connectivity within the fear circuitry, which consists of the dorsal anterior cingulate cortex, insula, amygdala, hippocampus and ventromedial prefrontal cortex (vmPFC), was examined using resting-state functional magnetic resonance imaging. Trauma-related symptoms were evaluated using the Impact of Event Scale - Revised. The firefighter group had greater functional connectivity between the insula and several regions of the fear circuitry including the bilateral amygdalae, bilateral hippocampi and vmPFC as compared with healthy individuals. In the firefighter group, stronger insula-amygdala connectivity was associated with greater severity of trauma-related symptoms (β = 0.36, P = 0.005), whereas higher insula-vmPFC connectivity was related to milder symptoms in response to repeated trauma (β = -0.28, P = 0.01). The current findings suggest an active involvement of insular functional connectivity in response to repeated traumatic stress. Functional connectivity of the insula in relation to the amygdala and vmPFC may be potential pathways that underlie the risk for and resilience to repeated traumatic stress, respectively.Declaration of interestNone.


Lympho-geographical concepts in vaccine delivery.
The key triggers and regulators of immune responses are antigens and their appearance in immune-privileged secondary lymphatic organs. Currently, the majority of vaccines are administered intramuscularly or subcutaneously, although neither the muscular tissue nor the subcutis is particularly rich in immuno-competent cells. Thus, introducing antigens at sites with a higher density of immune-competent cells, such as the dermis, lymph nodes, or afferent lymphatic conducts, with appropriate formulations and injection devices may induce more efficacious immune responses and protection. In this work, we first reviewed the geographical and functional map of the most important lymphatic elements that play a key role in the induction of a specific immune response, such as site of injection, choice of adjuvants and etc. In a first set of experiments, we demonstrated that short intervals of boosting (daily versus weekly) increase the production of IgG2a antibody against the injected model antigen, while increasing rather than constant booster doses increase the number of antigen-specific CD8(+) IFN-γ producing cells. Such antigen presentation patterns reflect the initially increasing amounts of antigen associated with natural infections by highly virulent and replicating pathogens. In a second set of experiments, we studied the importance of administration route (subcutaneous, intradermal, intramuscular, intralymphatic) for the induction of antigen-specific IgG2a, and of IFN-γ produced by antigen-specific lymphocytes when using PLGA microparticles for delivery of antigen. Interestingly, both IgG2a and IFN-γ production were significantly enhanced after intramuscular and intra-lymph node administration when compared to the other two routes. In conclusion, the results suggest that traditional vaccination schedules and administration routes should be reconsidered in vaccine development, particularly when using more advanced formulations and delivery systems such as micro- and nanoparticles or combinations of antigen and immune-response modifiers.


Surgical Management of Diastasis Recti: A Systematic Review of Insurance Coverage in the United States.
As elective surgery becomes more popular, the stringency of insurance coverage policies has increased exponentially. Many patients with diastasis recti (DR) are denied coverage of the corrective surgery that has been shown to improve function and quality of life in this patient population. Plastic surgeons are frustrated by the lack of guidelines and sparsity of coverage for surgical correction of DR. Fifty-four US insurance companies and Medicare were reviewed to determine their policies of coverage. These policies were compared with the guidelines set forth by the American Society of Plastic surgery and current literature on DR. Insurance company policy for DR repair is not clear nor well established. Of the 55 policies reviewed in this study, 51 had an established policy. Forty of these companies would not cover abdominoplasty to repair DR under any circumstances. Eleven companies required preauthorization to ensure that the patient met the requirements of medical necessity. These requirements differed from company to company. A comprehensive list was compiled of details required for preauthorization. Insurance company policies do not recognize the spectrum of patients with DR and the necessity of abdominoplasty to relieve symptoms of patients with severe debilitation. The current Common Procedural Terminology coding classifies abdominoplasty to repair DR solely as a cosmetic procedure. Policies for DR repair should be amended to include a functional procedure reimbursement for severe DR and include detailed guidelines for coverage requirements to simplify the reimbursement process.


Inflammatory cells in the middle ear mucosa in cases of chronic otitis media.
Middle ear mucosal biopsy specimens were taken from 12 patients with chronic otitis media. The specimens from 11 cases contained enough inflammatory cells for a detailed study of the inflammatory cell subtypes in the lamina propria. T lymphocytes, mononuclear phagocytes, and plasma cells were the most frequent cell types except in two patients, in whom most of the inflammatory lymphocytes were B lymphocytes. The relative scarcity of B lymphocytes could be caused by activation and transformation to plasma cells. The close contact between different immunocompetent cells suggests T- and B-cell interactions. However, pseudolymphoid transformation with primary and secondary lymphatic follicles was observed in only one patient. The relative scarcity of granulocytes in the submucosal infiltrate could be caused by the movement of these cells through the epithelium into the discharge.


E-cadherin alterations in atypical lobular hyperplasia and lobular carcinoma in situ of the breast.
Tumor development from an early lesion through to invasive disease is not a clearly defined progression in the breast. Studies of invasive lobular carcinoma have reported mutations, loss of heterozygosity (LOH) and loss of protein expression in epithelial (E)-cadherin, a protein involved in cell adhesion. Our study examines in situ lobular neoplastic lesions without concurrent invasive carcinoma for E-cadherin gene alterations and protein expression, beta-catenin, alpha-catenin and p120-catenin protein expression, and LOH at the chromosome 16q locus, with the goal of determining the events occurring at the stage of lobular neoplasia. In all, 13 atypical lobular hyperplasia lesions and 13 lobular carcinoma in situ lesions from archived cases were examined. E-cadherin sequence alterations were evaluated using single strand conformation polymorphism and DNA sequencing, and PCR-based LOH analysis was carried out for the 16q locus. Using immunohistochemistry, we assessed protein expression. A total of 23 of 24 lesions evaluated by immunohistochemistry were negative for both E-cadherin and beta-catenin protein expression, and 21 of 23 lesions were negative for alpha-catenin. Cytoplasmic (rather than membrane) localization of p120-catenin was observed in 20 of 21 cases. Lobular carcinoma in situ cases were characterized by mutations; however, atypical lobular hyperplasia cases were not. LOH at 16q was an infrequent event. From our study, we conclude that an altered E-cadherin adhesion complex is an early event affecting atypical lobular hyperplasia as well as lobular carcinoma in situ and occurs prior to progression to invasive disease. However, the loss of protein expression is accompanied by E-cadherin DNA alterations in lobular carcinoma in situ but not in atypical lobular hyperplasia. These cases lacking both protein expression and gene alterations suggest that another mechanism is involved, possibly as early as at the hyperplastic stage, causing silencing of the E-cadherin complex.


Early therapy of vertical human immunodeficiency virus type 1 (HIV-1) infection: control of viral replication and absence of persistent HIV-1-specific immune responses.
Studies of potent antiretroviral combination regimens were undertaken in young infants to evaluate the potential for long-term suppression of viral replication and to evaluate the immune consequences of such therapies. Early combination antiretroviral therapy led to a loss of plasma viremia, cultivable virus, and labile extrachromosomal replication intermediates. Despite preservation of immune function, persistent human immunodeficiency type 1 (HIV-1)-specific immune responses were not detected in most infants. The absence of detectable, persisting immune responses in most HIV-1-infected infants treated early contrasts with what is typically seen in adults who are treated early. These results are consistent with the notion that early combination antiretroviral therapy of HIV-1-infected infants allows the long-term suppression of viral replication.


Effect of hCG vs. GnRH at the beginning of the Ovsynch on first ovulation and conception rates in cyclic lactating dairy cows.
Ovulatory response to the first GnRH of Ovsynch is a very important factor for determining the outcome of a successful synchronization. The aim of the present study was to develop a protocol to increase the percentage of cows that ovulated in response to the first administration of Ovsynch. This study was designed to compare ovulation rates in response to GnRH or hCG at the beginning of Ovsynch and to evaluate the effects of this manipulation on pregnancy. Cows (n = 371) with corpus luteum (CL) and at least one follicle greater than 10 mm diameter size on either ovary were included in the study. Cows were divided into two groups. The Ovsynch protocol began with GnRH (10 mug) in the GPG group (n = 161; GnRH-7d-PGF2alpha-56h-GnRH-18h-AI), whereas in the HPG group, the first GnRH of the Ovsynch was replaced with 1500 IU hCG (n = 210; hCG-7d-PGF2alpha-56h-GnRH-18h-AI). Ovarian ultrasonography was performed at the times of GnRH or hCG and of PGF2alpha administration, at the time of artificial insemination (AI) and seven days after AI, to determine ovulation. Maximal follicle size at the beginning of the Ovsynch did not affect on response to the first GnRH/hCG treatment. Conception rate (31 d) was 0.6 times more likely to be higher (P < 0.001) in cows that responded to the first hormonal administration of Ovsynch than in those that did not respond (95% CI = 0.29-0.71). Conception rate was found to be different between the HPG (37.6%, 79/210) and the GPG groups (48.4%, 78/161). Thus, beginning of the Ovsynch protocol with hCG did not increase ovulation and conception rate in lactating dairy cows, suggesting that hCG is not a suitable replacement of the first GnRH of Ovsynch. However, our results do show that increasing the ovulation rate in response to the first hormonal administration of Ovsynch can have a significant effect on conception rate.


Improving Deep Metric Learning by Divide and Conquer.
Deep metric learning (DML) is a cornerstone of many computer vision applications. It aims at learning a mapping from the input domain to an embedding space, where semantically similar objects are located nearby and dissimilar objects far from another. The target similarity on the training data is defined by user in form of ground-truth class labels. However, while the embedding space learns to mimic the user-provided similarity on the training data, it should also generalize to novel categories not seen during training. Besides user-provided groundtruth training labels, a lot of additional visual factors (such as viewpoint changes or shape peculiarities) exist and imply different notions of similarity between objects, affecting the generalization on the images unseen during training. However, existing approaches usually directly learn a single embedding space on all available training data, struggling to encode all different types of relationships, and do not generalize well. We propose to build a more expressive representation by jointly splitting the embedding space and the data hierarchically into smaller sub-parts. We successively focus on smaller subsets of the training data, reducing its variance and learning a different embedding subspace for each data subset. Moreover, the subspaces are learned jointly to cover not only the intricacies, but the breadth of the data as well. Only after that, we build the final embedding from the subspaces in the conquering stage. The proposed algorithm acts as a transparent wrapper that can be placed around arbitrary existing DML methods. Our approach significantly improves upon the state-of-the-art on image retrieval, clustering, and re-identification tasks evaluated using CUB200-2011, CARS196, Stanford Online Products, In-shop Clothes, and PKU VehicleID datasets.


Trends over time in the use of laparoscopic hysterectomy for the treatment of endometrial cancer.
To determine the rates of laparoscopy compared to laparotomy over time for the treatment of endometrial cancer in the province of Ontario, Canada, and to determine factors associated with having laparoscopic surgery. This was a population-based retrospective cohort study using healthcare administrative databases. Incident cases of endometrial cancer from April 2002-March 2011 were identified in the provincial cancer registry. Record linkages were made with other healthcare databases to determine type of hysterectomy (laparoscopic or abdominal±staging), year of diagnosis, comorbidities, location of residence, surgeon and hospital type. 12,104 patients with endometrial cancer treated with hysterectomy were identified, of which 2116 had laparoscopic surgery (17.5%). Rates of laparoscopy increased over time from 6.5% in 2002 to 30.2% in 2011 (p<0.0001). The median length of hospital stay after abdominal hysterectomy was significantly longer (3 days vs 1 day, p<0.0001). Adjusting for age, comorbidity score, income quintile and type of hospital (community versus academic), the probability of admission or emergency room visit within 30 days of surgery was significantly higher in patients with abdominal surgery (OR 1.61) (95% CI 1.36-1.92) (p<0.0001). The odds of having laparoscopic surgery was higher with a gynecologic oncologist (OR 2.85, 95% CI 1.61-5.85) or a general gynecologist at an academic hospital (OR 2.07, 95% CI 1.09-3.95) compared to a general gynecologist at a community hospital. This population-based cohort study confirms the increased use over time of laparoscopic surgery to treat endometrial cancers in Ontario, and demonstrates the benefits of decreased hospital stay and decreased patient morbidity.


Purification and characterization of recombinant mouse interferon-beta.
Recombinant mouse interferon-beta (rMuIFN-beta) produced in Escherichia coli was purified to homogeneity and characterized. The purified protein exhibited a single band of Mr 19,900 on SDS-polyacrylamide gel electrophoresis under both reducing and nonreducing conditions, and also exhibited a single band on native polyacrylamide gel electrophoresis at pH 4.3. The observed molecular weight corresponded to that of the polypeptide moiety of natural MuIFN-beta of Mr 19,700. The amino acid composition and the amino-terminal sequence of the purified rMuIFN-beta were identical to those predicted from cDNA sequence. These results indicate that the purified protein is a nonglycosylated MuIFN-beta, which forms no disulfide-linked dimer and probably exists as a monomeric form.


First-Principles Study of Bi-Doping Effects in Hg0.75Cd0.25Te.
First-principles calculations based on density functional theory have been performed for exploring the structural and electronic properties of Bi-doped Hg0.75Cd0.25Te (MCT), using the state-of-the-art computational method with the Heyd-Scuseria-Ernzerhof (HSE) of hybrid functional to correct the band gap. Structural relaxations, charge densities, electron localization functions (ELFs), density of states (DOSs), band structures, and band decomposed charge density were obtained to reveal the amphoteric behavior of Bi in Hg0.75Cd0.25Te. The bonding characteristics between Bi and host atoms were discussed by analyzing charge densities and ELFs. The influence of Bi impurity on the electronic structure of Bi-doped Hg0.75Cd0.25Te was also analyzed by the calculated DOSs, band structures, and the band decomposed charge density of the defect band. It has been demonstrated that Bi can show a typical amphoteric substitution effect of group V elements.


Amorphous Ropinirole-Loaded Mucoadhesive Buccal Film: A Potential Patient-Friendly Tool to Improve Drug Pharmacokinetic Profile and Effectiveness.
Nowadays the therapeutic strategies to manage Parkinson's Disease are merely symptomatic and consist of administering L-DOPA and/or dopamine receptor agonists. Among these, Ropinirole (ROP) is a widely orally-administered molecule, although it is extensively susceptible to hepatic metabolism. Since literature reports the buccal mucosa as a potentially useful route to ROP administration, the development of novel, effective, and comfortable oromucosal formulations should prove desirable in order to both enhance the therapeutic efficacy of the drug and allow a personalized therapeutic strategy able to meet the patient's needs. The results of the proposed ROP film as a new dosage form show that it is flexible; uniform; and characterized by suitable surface pH; good mucoadhesiveness; low swelling degree; and fast, complete drug release. Moreover, after ex vivo evaluation on a film having an area of 0.282 cm2 and dose of 2.29 mg, the results of drug flux through the buccal mucosa are closely comparable to the amount of ROP that reaches the bloodstream at the steady-state condition after ROP-PR 4 mg oral administration, calculated according to the literature (0.237 mg/cm2·h-1 vs. 0.243 mg/h, respectively). Moreover, drug flux and ROP dose could be accurately modulated time-by-time depending on the patient's need, by varying the administered disk area. In addition, the proposed ROP film displays no lag time, producing an immediate drug input in the bloodstream, which could result in a prompt therapeutic response. These findings make ROP film a potentially comfortable and patient-friendly formulation, and a promising candidate for further clinical trials.


Nonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse Transcriptase.
Substitutions at residue Y181 in HIV-1 reverse transcriptase (RT), in particular, Y181C, Y181I, and Y181V, are associated with nonnucleoside RT inhibitor (NNRTI) cross-resistance. In this study, we used kinetic and thermodynamic approaches, in addition to molecular modeling, to gain insight into the mechanisms by which these substitutions confer resistance to nevirapine (NVP), efavirenz (EFV), and rilpivirine (RPV). Using pre-steady-state kinetics, we found that the dissociation constant (Kd ) values for inhibitor binding to the Y181C and Y181I RT-template/primer (T/P) complexes were significantly reduced. In the presence of saturating concentrations of inhibitor, the Y181C RT-T/P complex incorporated the next correct deoxynucleoside triphosphate (dNTP) more efficiently than the wild-type (WT) complex, and this phenotype correlated with decreased mobility of the RT on the T/P substrate. Interestingly, we found that the Y181F substitution in RT-which represents a transitional mutation between Y181 and Y181I/V, or a partial revertant-conferred hypersusceptibility to EFV and RPV at both the virus and enzyme levels. EFV and RPV bound more tightly to Y181F RT-T/P. Furthermore, inhibitor-bound Y181F RT-T/P was less efficient than the WT complex in incorporating the next correct dNTP, and this could be attributed to increased mobility of Y181F RT on the T/P substrate. Collectively, our data highlight the key role that Y181 in RT plays in NNRTI binding.


The dopamine and 5-hydroxytryptamine content of locust and cockroach salivary neurones.
The salivary glands of the cockroach and locust are innervated primarily from two pairs of motoneurones, designated SN1 and SN2, in the suboesophageal ganglion. Intracellular cobalt fills and subsequent silver intensification were used to reveal the morphology of these cells in both species. Fluorescent microscopy, following treatment of the ganglion with glyoxylic acid, showed that in both species only the SN1 neurones contained catecholamines. A radioenzymatic assay for dopamine, performed on the locust SN1 neurones, confirmed that this catecholamine was present. A radioenzymatic assay for 5-hydroxytryptamine (5-HT), performed on both pairs of salivary neurones in the locust, revealed small quantities of this amine in the SN2 neurones, but no significant amount in the SN1 neurones. In the cockroach, 5-HT was assayed in the SN2 neurones only. In contrast to the locust, however, the 5-HT content of these cells was not significantly above that of control cells taken from other ganglia. These observations demonstrate that only the SN1 neurones are the source of the catecholaminergic fibres investing the locust and cockroach salivary glands. The difference in neurotransmitter content between the SN1 and SN2 neurones suggests that these neurones have separate functions in the control of salivary secretion.


Gap pre-pulse inhibition of the cortical auditory evoked potentials as a possible objective tinnitus assessment tool.
The objective assessment tests overcome the variability of subjective methods. Cortical recordings with gap pre-pulse inhibition of the acoustic startle reflex stimulus have been used as objective tinnitus assessments in humans. This study aims to investigate this possible objective tinnitus test and compare gap-induced inhibition in different stimulus parameters and brain regions. Twenty People (18-50 years old) without hearing loss and tinnitus were included. The sound stimuli consisted of continuous background noise with a loud startle tone preceded by a silent gap (20 and 40 ms duration, 120 and 150 ms distance from the startle). The N1-P2 complex amplitude and topoplot maps were extracted in 27-channel cortical response recording after signal processing. Four brain regions of interest (ROI) of anterior-frontal, centro-frontal, right, and left temporal were investigated. The results showed that the maximum inhibition occurred in a 40 ms gap duration and 150 ms distance in all 4 ROIs. In comparing ROIs, the centro-frontal and left temporal regions revealed the most inhibition (p<0.05). The decrease in the amplitude of the N1 and P2 in that region could also be traced in the 100 and 200 ms topoplots. Gap-induced inhibition was observed in all gap-embedded stimuli and all ROIs. However, the 40-150 mode and centro-frontal and left temporal regions had maximum inhibition in normal subjects. It provides a promising tool for objectively assessing tinnitus in humans with particular implications in children.


A molecular mechanism directly linking E-cadherin adhesion to initiation of epithelial cell surface polarity.
Mechanisms involved in maintaining plasma membrane domains in fully polarized epithelial cells are known, but when and how directed protein sorting and trafficking occur to initiate cell surface polarity are not. We tested whether establishment of the basolateral membrane domain and E-cadherin-mediated epithelial cell-cell adhesion are mechanistically linked. We show that the basolateral membrane aquaporin (AQP)-3, but not the equivalent apical membrane AQP5, is delivered in post-Golgi structures directly to forming cell-cell contacts where it co-accumulates precisely with E-cadherin. Functional disruption of individual components of a putative lateral targeting patch (e.g., microtubules, the exocyst, and soluble N-ethylmaleimide-sensitive factor attachment protein receptors) did not inhibit cell-cell adhesion or colocalization of the other components with E-cadherin, but each blocked AQP3 delivery to forming cell-cell contacts. Thus, components of the lateral targeting patch localize independently of each other to cell-cell contacts but collectively function as a holocomplex to specify basolateral vesicle delivery to nascent cell-cell contacts and immediately initiate cell surface polarity.


Latex allergies: what is your responsibility as a manager?
Natural Rubber Latex (NRL) is found in over 40,000 products and presents many challenges for the home care manager who is faced with the task of providing "reasonable accommodations" to keep the employee safe in the work environment. In addition, patient care must also be modified in order to keep latex sensitive patients safe. This article presents the background of latex allergies and describes how to better manage both the employee and the patient with this allergy based on the most current information.


Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of oligonucleotides.
MALDI-MS is one of the most useful techniques available for determining biomolecule mass. It offers high mass accuracy, good sensitivity, simplicity, and speed. Because singly charged ions of oligonucleotides are typically observed, MALDI-MS spectra are easy to interpret. This unit presents protocols for sample preparation and purification, matrix preparation, and matrix/analyte sample preparation. It provides an introduction to the instrumentation and its calibration, and a discussion of some of the useful applications of MALDI-MS analysis in the study of oligonucleotides. This technique is typically used for 120-mer or smaller oligonucleotides.


[Clinical significance of serum transferrin receptor in differential diagnosis of anemia].
To study the clinical significance of the serum transferrin receptor (sTfR) and ferritin in distinguishing between iron deficiency anemia (IDA), anemia of chronic disease (ACD) and ACD with complicating IDA (ACD-IDA). One hundred and thirteen subjects enrolled into the study were divided into four groups including 28 health volunteers as control, 29 patients with IDA, 27 patients with ACD (sTfR level <or= 20.0 nmol/L, ACD1 group) and 29 patients with ACD-IDA (sTfR level > 20.0 nmol/L, ACD2 group). sTfR, serum ferritin (SF), serum iron (SI), total iron-binding capacity (TIBC), transferring saturation (TS) and complete blood count were measured in all the enrolled subjects or patients. Bone marrow iron stain was examined in 10 cases of ACD1 and 16 cases of ADC2. In IDA group, MCV (68.0 +/- 11.3) fl was the smallest; SI, TS and SF were significantly decreased but sTfR level was increased as compared with the control group (SI) (19.6 +/- 10.1) mg/L vs (81.7 +/- 30.6) mg/L, TS (5.5 +/- 2.3)% vs (27.0 +/- 12.0)%, SF (4.3 +/- 2.8) micro g/L vs (43.3 +/- 26.8) micro g/L and sTfR (67.2 +/- 40.3) nmol/L vs (15.6 +/- 4.1) nmol/L (P <or= 0.01). SI (60.7 +/- 28.7) mg/L, and TS (21.1 +/- 9.8)% were not different statistically (P > 0.05) but SF (627.3 +/- 40.3) micro g/L level was increased in ACD1 group as compared with the control group (P < 0.01). Bone marrow iron stain showed no iron deficiency in 10 cases of ACD1. In ACD2 group, SF (320.5 +/- 156.0) micro g/L level was higher than that of the control group, but lower than that of the ACD1 group (P <or= 0.01); bone marrow iron stain showed iron depletion in 14 of the 16 patients. High sTfR level may reflect iron deficiency status of the body and is a more sensitive parameter to diagnose iron deficiency anemia. sTfR level is less influenced by chronic inflammation, and able to distinguish ACD from ACD-IDA.


CrAsH-quantum dot nanohybrids for smart targeting of proteins.
Smart nanohybrids were prepared by conjugation of CrAsH to hydrosoluble and biocompatible quantum dots (QDs). The resulting probes were shown to bind efficiently and selectively to Cys-tagged proteins. The interaction with the protein was detected by an increase of the fluorescence emission of CrAsH. While the latter faded rapidly under continuous excitation, emission of the QD remained unaffected. The persistent fluorescence of the QD should thus allow extended monitoring of the target protein.


Differential influence of rearing conditions and methamphetamine on serotonin fibre maturation in the dentate gyrus of gerbils (Meriones unguiculatus).
Environmental experience and drugs are two parameters that affect the maturation of neurotransmitter systems. The influence of impoverished rearing (IR) versus enriched rearing (ER) was compared in conjunction with postnatal methamphetamine (MA) treatment. The densities of immunostained 5-HT fibres were quantified in septal and temporal regions of the hippocampal dentate gyrus (DG) in young adult gerbils. In the IR group, 5-HT fibre densities were significantly increased in the molecular, granular and polymorphic layers of the DG in the temporal plane. After postnatal MA treatment, the 5-HT fibre density in the ER group reached a level equivalent to that of the IR group in nearly all respects. Under IR conditions, the pharmacological intervention significantly increased the maturation of fibre densities in septal layers only in the right hemisphere with no significant alterations in the left hemisphere and in temporal regions of either hemisphere. According to our previous studies on hippocampal neurogenesis, adaptations of 5-HT fibre densities partly proved to be positively correlated to cell proliferation rates for each of the specific conditions. Thus, the induced MA sensitivity, caused by pharmacological intervention at day 14, was manifested as direct interaction of 5-HT fibre maturation and cell proliferation in dependence of environmental factors. Both IR and MA together give us a better understanding of raphe-hippocampal plasticity and offer new perspectives for pharmacological studies on the 5-HT participation in mental disorders.


Circ-ABCB10 Contributes to Paclitaxel Resistance in Breast Cancer Through Let-7a-5p/DUSP7 Axis.
Paclitaxel (PTX) is one of the widely used chemotherapy drugs in breast cancer (BC) treatment. Unfortunately, the survival rate of metastatic BC patients remains poor due to PTX resistance. Therefore, uncovering the underlying mechanism behind the PTX resistance of BC cells is crucial for BC therapy. The enrichment of circular RNA ATP binding cassette subfamily B member 10 (circ-ABCB10), let-7a-5p and dual specificity phosphatase 7 (DUSP7) was measured by quantitative real time polymerase chain reaction (qRT-PCR) in PTX-resistant and PTX-sensitive BC tissues and cells. Chemoresistance, apoptosis, invasion and autophagy of BC cells were measured by 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, transwell invasion assay and Western blot assay, respectively. The binding sites between let-7a-5p and circ-ABCB10 or DUSP7 were predicted by Starbase bioinformatic software, and the combination was confirmed by dual-luciferase reporter assay. The protein expression of DUSP7 was examined by Western blot assay. Murine xenograft model was established to confirm the role of circ-ABCB10 in vivo. Circ-ABCB10 depletion promoted the PTX sensitivity and apoptosis while suppressed the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 could bind to let-7a-5p in BC cells, and circ-ABCB10 contributed to PTX resistance of BC cells via let-7a-5p. DUSP7 is a direct target of let-7a-5p in BC cells, and the accumulation of DUSP7 reversed the promoting effects of let-7a-5p overexpression on the PTX sensitivity and apoptosis and the inhibitory impact on the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 interference suppressed the growth of BC tumors in vivo. Circ-ABCB10 mediated PTX resistance, apoptosis, invasion and autophagy of BC cells via let-7a-5p/DUSP7 axis.


Comparative analyses of the Conserved Oligomeric Golgi (COG) complex in vertebrates.
The Conserved Oligomeric Golgi (COG) complex is an eight-subunit assembly that localizes peripherally to Golgi membranes and is involved in retrograde vesicular trafficking. COG subunits are organized in two heterotrimeric groups, Cog2, -3, -4 and Cog5, -6, -7, linked by a dimeric group formed by Cog1 and Cog8. Dysfunction of COG complex in humans has been associated with new forms of Congenital Disorders of Glycosylation (CDG), therefore highlighting its essential role. In the present study, we intended to gain further insights into the evolution of COG subunits in vertebrates, using comparative analyses of all eight COG proteins. We used protein distances and dN/dS ratios as a measure of the rate of proteins evolution. The results showed that all COG subunits are evolving under strong purifying selection, although COG1 seems to evolve faster than the remaining proteins. In addition, we also tested the expression of COG genes in 20 human tissues, and demonstrate their ubiquitous nature. COG complex has a critical role in Golgi structure and function, which, in turn, is involved in protein sorting and glycosylation. The results of this study suggest that COG subunits are evolutionary constrained to maintain the interactions between each other, as well with other partners involved in vesicular trafficking, in order to preserve both the integrity and function of the complex.


[Features of eosinophilic pneumonia course in the outpatient setting].
Simple eosinophilic pneumonia (Luffler's syndrome) is combination of "volatile" infiltrates, independently passing during one month and detecting only in chest organs roentgenography; often pass symptomless. There is a mild eosinophilia in the blood. Acute eosinophilic pneumonia is an antipode of simple eosinophilic pneumonia, has a clinical course with acute respiratory failure, pulmonary destruction, high eosinophilia and favorable prognosis under conditions of treatment with glucocorticoids. In chronic eosinophilic pneumonia infiltrates in the lungs recur more than 4 weeks; the disease has a course with fever, intoxication, high eosinophilia and pleural effusion. The special feature of this clinical case is a combination some symptoms of all kinds of eosinophilic pneumonia. Equally with symptomless course, normal number of eosinophils, there is an absence of tendency to spontaneous recovery, presence of pulmonary infiltrates up to therapy with glucocorticoids; non-typical roentgenological picture of chest organs in the beginning of disease.


Analytical model for designing a high-energy-efficiency granular double-layer X-ray scintillator with a diffuse reflection layer.
We propose a simple, efficient, and accurate analytical model for calculating the energy efficiency of a granular double-layer X-ray scintillator with a diffuse reflection layer, based on the first-order approximation of the radiative transfer equation by considering boundary conditions and exponential characteristics. Using the analytical model, we successfully analyze the characteristics of the double-layer X-ray scintillator, such as diffuse reflectance, transmittance, collection efficiency, and energy efficiency. We also suggest a design strategy for the high-energy-efficiency X-ray double-layer scintillator considering high diffuse reflectance and satisfaction of the target spatial resolution. Using the X-ray absorption ratio and the collection efficiency of the double-layer scintillator, the energy efficiency of the double-layer X-ray scintillator is calculated to achieve the best performance in terms of image brightness. Through calculation, we obtain the design of a double-layer X-ray scintillator with an energy efficiency of 8.7% with a computation time of less than a second.


The molecular mechanism and evolution of the GA-GID1-DELLA signaling module in plants.
Bioactive gibberellins (GAs) are diterpene phytohormones that modulate growth and development throughout the whole life cycle of the flowering plant. Impressive advances have been made in elucidating the GA pathway with the cloning and characterization of genes encoding most GA biosynthesis and catabolism enzymes, GA receptors (GIBBERELLIN INSENSITIVE DWARF1, GID1) and early GA signaling components. Recent biochemical, genetic and structural analyses demonstrate that GA de-represses its signaling pathway by GID1-induced degradation of DELLA proteins, which are master growth repressors, via a ubiquitin-proteasome pathway. Multiple endogenous signals and environmental cues also interact with the GA-GID1-DELLA regulatory module by affecting the expression of GA metabolism genes, and hence GA content and DELLA levels. Importantly, DELLA integrates different signaling activities by direct protein-protein interaction with multiple key regulatory proteins from other pathways. Comparative studies suggest that the functional GA-GID1-DELLA module is highly conserved among vascular plants, but not in the bryophytes. Interestingly, differentiation of the moss Physcomitrella patens is regulated by as yet unidentified ent-kaurene-derived diterpenes, which are distinct from the common active GAs in vascular plants.


Reassessment of the phylogenetic position of the bacterium associated with Whipple's disease and determination of the 16S-23S ribosomal intergenic spacer sequence.
Whipple's disease is a rare chronic illness associated with an unculturable bacterium that is constantly present in affected tissues. This bacterium was previously characterized at the molecular level by PCR and sequencing of the 16S rRNA gene. On the basis of 1,321 nucleotides of the sequence of its gene coding for 16S rRNA (16S rDNA), a phylogenetic relationship to the actinomycetes was established. In this study, we determined an almost complete 16S rDNA sequence (1,495 nucleotides), the 16S-23S ribosomal intergenic spacer sequence, and 200 nucleotides of the 23S rRNA gene. The 16S rDNA sequence was compared with the large number of actinomycete sequences that have been added to the database since the original study. Phylogenetic analysis revealed a branching position as the deepest branch of the cluster comprising the actinomycetes with group B peptidoglycan between this group and the family Cellulomonadaceae. This provides additional information on the phylogenetic position of this bacterium and some clues as to its characteristics. The spacer region between the 16S and 23S rRNA genes is 294 nucleotides long and does not contain tRNA genes. As has been shown in other instances, the increased variability of the ribosomal intergenic spacer compared with the 16S rRNA gene makes it a potential target for use in the differentiation of strains of the bacterium associated with Whipple's disease.