Structural prediction during language comprehension revealed by electrophysiology: Evidence from Italian auxiliaries.
Prediction in language comprehension has become a key mechanism in recent psycholinguistic theory, with evidence from lexical prediction as a primary source. Less work has focused on whether comprehenders also make structural predictions above the lexical level. Previous research shows that processing is facilitated for syntactic structures which are predictable based on context; however, there is so far no direct evidence that speakers formulate structural predictions ahead of encountering input. We investigated whether subject noun animacy cues comprehenders to predict different verb phrase (VP) structures, with the incompatibility between a low animacy subject and an Agent interpretation of transitives/unergative VPs predicting a derived (passive/unaccusative) VP structure, using Italian auxiliaries. Native Italian speakers read sentences with subject nouns varying from high to low animacy followed by the auxiliary avereHAVE, which is compatible with underived VPs, or essereBE, which is compatible with derived VPs. The auxiliary avereHAVE elicited greater frontal negativity when preceded by a subject noun with lower animacy. The auxiliary essereBE elicited no differential ERP given subject animacy. We propose that this frontal negativity reflects violation of a structural prediction, with amplitude reflecting the strength of initial commitment or difficulty in revising a predicted structure. Differences between auxiliaries are proposed to follow from the more specific distribution of avereHAVE. We argue that this evidence unambiguously supports a predictive mechanism for phrase-level structure. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Adenovirus-mediated transfer and expression of beta-gal in injured hippocampus after traumatic brain injury in mice.
In models of focal cerebral ischemia, adenoviral gene transfer is often attenuated or delayed versus naive. After controlled cortical impact (CCI)-induced traumatic brain injury in mice, CA1 and CA3 hippocampus exhibit delayed neuronal death by 3 days, with subsequent near complete loss of hippocampus by 21 days. We hypothesized that adenoviral-mediated expression of the reporter gene beta-Galactosidase (beta-Gal) in hippocampus would be attenuated after CCI in mice. C57BL6 mice (n = 16) were subjected to either CCI to left parietal cortex or sham (burr hole). Adenovirus carrying the beta-Gal gene (AdlacZ; 1 x 10(9) plaque-forming units [pfu]/mL) was then injected into left dorsal hippocampus. At 24 or 72 h, beta-Gal expression was quantified (mU/mg protein). Separate mice (n = 10) were used to study beta-Gal spatial distribution in brain sections. Beta-Gal expression in left hippocampus was similar in shams at 24 h (48.4 +/- 4.1) versus 72 h (68.8 +/- 8.8, not significant). CCI did not reduce beta-Gal expression in left hippocampus (68.8 +/- 8.8 versus 88.1 +/- 7.0 at 72 h, sham versus CCI, not significant). In contrast, CCI reduced beta-Gal expression in right (contralateral) hippocampus versus sham (p < 0.05 at both 24 and 72 h). Beta-Gal was seen in many cell types in ipsilateral hippocampus, including CA3 neurons. Despite eventual loss of ipsilateral hippocampus, adenovirus-mediated gene transfer was surprisingly robust early after CCI providing an opportunity to test novel genes targeting delayed hippocampal neuronal death.


Treating osteoarticular infections in a Role 2 in Chad: a bacterial epidemiological study.
The treatment of osteoarticular infections in Africa is a medical and surgical challenge due to the difficulties in managing antibiotic therapy after the surgical procedure. The objectives of this study were to identify the types of bacteria in osteoarticular lesions in patients treated in Chad and to determine the spectrum of resistance encountered and the efficacy of available antibiotics. This is a retrospective study of all intraoperative osteoarticular and soft tissue samples taken in a French Role 2 Medical Treatment Facility of N'Djamena during surgery for chronic osteoarticular infections, in Chad, for 1 year. A total of 160 bacterial strains were identified, with a predominance of Gram-negative bacillus (GNB) and staphylococcus infections. Among staphylococci, 80% were methicillin-sensitive streptococci which were generally multidrug-sensitive. Enterococci were resistant to third-generation cephalosporins, first-generation fluoroquinolones and gentamycin. Among GNB, there was a predominance of enterobacteria compared with non-fermenting GNB, of which 52% were multidrug-resistant and produced extended spectrum beta-lactamases (ESBL). Staphylococcus aureus infections are most often sensitive to available antibiotics and therefore have better prognoses than infections caused by other bacteria. In contrast, in half of the cases of GNB, infections were caused by bacteria producing ESBL, thus posing the problem of multidrug-resistance, the risks of which are increased in precarious situations. Therefore, the type of bacteria appears to be a major prognostic factor in the treatment of osteoarticular infections in a Role 2 in Chad. This criterion will need to be considered before any treatment decisions are made.


Identification and antimicrobial susceptibility of 100 Klebsiella animal clinical isolates.
The objectives of this study were to determine the distribution of Klebsiella species and phylogenetic groups in animal clinical samples and to determine the levels of antimicrobial resistance of animal Klebsiella clinical isolates. One hundred Klebsiella veterinary clinical isolates were identified using gyrA PCR-RFLP and rpoB gene sequencing as a confirmatory method. Klebsiella pneumoniae phylogenetic group KpI was dominant (78 isolates), but KpII, KpIII (K. variicola), K. oxytoca, K. planticola and K. terrigena were also represented. The relative frequencies in animal infections of Klebsiella species and phylogenetic groups were similar to those observed in human nosocomial infections, suggesting that similar ecological and molecular factors cause Klebsiella infections in both situations. Resistance was common against ampicillin (99%) and cephalexin (43%) but not against ceftazidime, ceftiofur, tetracycline, enrofloxacin, gentamicin and trimethoprim-sulfamethoxazole. Thirteen isolates resistant to three or more antimicrobials or combinations thereof were found, but acquired antimicrobial resistance remains lower among animal isolates than among human nosocomial isolates.


Screening of anticancer drugs for chemoembolization of hepatocellular carcinoma.
The aim of this study was to select the best candidate drug for transarterial chemoembolization by in-vitro cytotoxic evaluations of 11 anticancer drugs on three human hepatocellular carcinoma (HCC) cell lines. The SNU-398, HepG2, and SNU-449 human HCC cell lines were exposed for 30 min to 11 concentrations of doxorubicin, epirubicin, idarubicin, mitoxantrone, carboplatin, cisplatin, oxaliplatin, 5-fluorouracil, gemcitabine, mitomycin C, or paclitaxel. Cytotoxicity was measured using a quantitative colorimetric assay. For each drug and cell line, we calculated the drug concentration that caused 90% cell death (IC90). To enable comparisons of drugs with different concentration ranges, we computed the cytotoxic index (CyI) as the ratio of maximal drug concentration of more than IC90. Parameters were estimated using nonlinear regression models. Idarubicin was the most active drug on all three cell lines. With SNU-398 cells, the idarubicin CyI was 2.4-fold, 2.5-fold, 57-fold, 148-fold, and more than 58 748-fold higher than the CyIs of mitoxantrone, epirubicin, doxorubicin, gemcitabine, and other drugs, respectively. With HepG2 cells, the idarubicin CyI was 27-fold, 28-fold, 51-fold, and more than 1343-fold higher than the CyIs of doxorubicin, epirubicin, mitoxantrone, and other drugs, respectively. On the resistant SNU-449 cell line, the idarubicin CyI was 2.9-fold and 14-fold higher than the CyIs of paclitaxel and gemcitabine, respectively, the only other drugs effective on this cell line. Among 11 chemotherapeutic agents including doxorubicin, cisplatin, and epirubicin, the most effective on three HCC cell lines was idarubicin. Further clinical investigations are needed to evaluate the safety and efficacy of idarubicin for transarterial chemoembolization in HCC.


[Endometrial polyp transformed into carcinosarcoma].
A case of polyp of the endometrium in a female patient, 52 years of age, with malignization of both the stroma and the glandular component, is described. Planocellular metaplasia of the epithelium of the glands with its marked proliferation, dystrophic changes, buried growth of the type of adenoacanthoma were observed. The stroma was characterized by overgrowth of polymorphic spindle-shaped cells with the presence of mitosis figures. The general picture of sarcocarcinoma was observed. A favourable 4-year catamnesis was established.


Parenting efficacy and its relationship to the prevention of childhood obesity.
Childhood obesity has become a topic of interest for the health sciences research community due to the childhood obesity epidemic. Pediatric nurse practitioners are in the frontline of prevention for children who are obese or at risk of becoming obese. Serving in this role requires the nurses' ability to measure parenting practices, parents' inner beliefs, and parental control over their child's eating practices. Questionnaires and other tools are needed to understand parents' thoughts on how satisfied they are as parents, their locus of control in their parent-child relationship, and how competent they feel in the parenting role. Many parenting scales related to self-efficacy, competence, locus of control, and satisfaction have been developed over the past decades, but little research development has occurred in relation to child's eating behaviors within nursing. This article will review the current parent efficacy literature and examine its relationship to childhood obesity.


Multivitamin and dietary supplements, body weight and appetite: results from a cross-sectional and a randomised double-blind placebo-controlled study.
Two studies were conducted to compare characteristics of consumers and non-consumers of vitamin and/or dietary supplements (study 1) and to assess the effect of a multivitamin and mineral supplementation during a weight-reducing programme (study 2). Body weight and composition, energy expenditure, and Three-Factor Eating Questionnaire scores were compared between consumers and non-consumers of micronutrients and/or dietary supplements in the Québec Family Study (study 1). In study 2, these variables and appetite ratings (visual analogue scales) were measured in forty-five obese non-consumers of supplements randomly assigned to a double-blind 15-week energy restriction ( - 2930 kJ/d) combined with a placebo or with a multivitamin and mineral supplement. Compared with non-consumers, male consumers of vitamin and/or dietary supplements had a lower body weight (P < 0.01), fat mass (P < 0.05), BMI (P < 0.05), and a tendency for greater resting energy expenditure (P = 0.06). In women, the same differences were observed but not to a statistically significant extent. In addition, female supplements consumers had lower disinhibition and hunger scores (P < 0.05). In study 2, body weight was significantly decreased after the weight-loss intervention (P < 0.001) with no difference between treatment groups. However, fasting and postprandial appetite ratings were significantly reduced in multivitamin and mineral-supplemented women (P < 0.05). Usual vitamin and/or dietary supplements consumption and multivitamin and mineral supplementation during a weight-reducing programme seems to have an appetite-related effect in women. However, lower body weight and fat were more detectable in male than in female vitamin and/or dietary supplements consumers.


High Order Compact Multigrid Solver for Implicit Solvation Models.
The electrostatic problem defined by the continuum solvation models used in molecular mechanics and ab initio molecular dynamics is solved in real space through multiscale methods. First, the Poisson equation is rewritten as a stationary convection-diffusion equation and discretized by a general mesh size fourth-order compact difference scheme. Then, the linear system associated with such a discrete version of the elliptic partial differential equation is solved by a parallel (geometric) multigrid solver whose convergence rates and robustness are improved by an iterant recombination technique in which the multigrid acts as a preconditioner of a Krylov subspace method. The numerical tests performed on ideal and physical systems described by linear Poisson equations under different boundary conditions show the good performance of this accelerated multigrid solver. Furthermore, nonlinear Poisson equations, like the regular modified Poisson-Boltzmann equation, can also be solved by using in addition simple iterative schemes.


The NAE Pathway: Autobahn to the Nucleus for Cell Surface Receptors.
Various growth factors and full-length cell surface receptors such as EGFR are translocated from the cell surface to the nucleoplasm, baffling cell biologists to the mechanisms and functions of this process. Elevated levels of nuclear EGFR correlate with poor prognosis in various cancers. In recent years, nuclear EGFR has been implicated in regulating gene transcription, cell proliferation and DNA damage repair. Different models have been proposed to explain how the receptors are transported into the nucleus. However, a clear consensus has yet to be reached. Recently, we described the nuclear envelope associated endosomes (NAE) pathway, which delivers EGFR from the cell surface to the nucleus. This pathway involves transport, docking and fusion of NAEs with the outer membrane of the nuclear envelope. EGFR is then presumed to be transported through the nuclear pore complex, extracted from membranes and solubilised. The SUN1/2 nuclear envelope proteins, Importin-beta, nuclear pore complex proteins and the Sec61 translocon have been implicated in the process. While this framework can explain the cell surface to nucleus traffic of EGFR and other cell surface receptors, it raises several questions that we consider in this review, together with implications for health and disease.


Low- and high-gamma oscillations deviate in opposite directions from zero-phase synchrony in the limbic corticostriatal loop.
The loop structure of cortico-striatal anatomy in principle enables both descending (cortico-striatal) and ascending (striato-cortical) influences, but the factors that regulate the flow of information in these loops are not known. We report that low- and high-gamma oscillations (∼50 and ∼80 Hz, respectively) in the local field potential of freely moving rats are highly synchronous between the infralimbic region of the medial prefrontal cortex (mPFC) and the ventral striatum (vStr). Strikingly, high-gamma oscillations in mPFC preceded those in vStr, whereas low-gamma oscillations in mPFC lagged those in vStr, with short (∼1 ms) time lags. These systematic deviations from zero-phase synchrony were consistent across measures based on amplitude cross-correlation and phase slopes and were robustly maintained between behavioral states and different individual subjects. Furthermore, low- and high-gamma oscillations were associated with distinct ensemble spiking patterns in vStr, even when controlling for overt behavioral differences and slow changes in neural activity. These results imply that neural activity in vStr and mPFC is tightly coupled at the gamma timescale and raise the intriguing possibility that frequency-specific deviations from this coupling may signal transient leader-follower switches.


Therapeutic Efficacy, Radiotoxicity and Abscopal Effect of BNCT at the RA-3 Nuclear Reactor Employing Oligo-Fucoidan and Glutamine as Adjuvants in an Ectopic Colon Cancer Model in Rats.
Boron neutron capture therapy (BNCT) is based on the preferential uptake of 10B compounds by tumors, followed by neutron irradiation. The aim of this study was to assess, in an ectopic colon cancer model, the therapeutic efficacy, radiotoxicity, abscopal effect and systemic immune response associated with (BPA/Borophenylalanine+GB-10/Decahydrodecaborate)-BNCT (Comb-BNCT) alone or in combination with Oligo-Fucoidan (O-Fuco) or Glutamine (GLN), compared to the "standard" BPA-BNCT protocol usually employed in clinical trials. All treatments were carried out at the RA-3 nuclear reactor. Boron biodistribution studies showed therapeutic values above 20 ppm 10B in tumors. At 7 weeks post-treatment, the ratio of tumor volume post-/pre-BNCT was significantly smaller for all BNCT groups vs. SHAM (p < 0.05). The parameter "incidence of tumors that underwent a reduction to ≤50% of initial tumor volume" exhibited values of 62% for Comb-BNCT alone, 82% for Comb-BNCT+GLN, 73% for Comb-BNCT+O-Fuco and only 30% for BPA-BNCT. For BPA-BNCT, the incidence of severe dermatitis was 100%, whereas it was significantly below 70% (p ≤ 0.05) for Comb-BNCT, Comb-BNCT+O-Fuco and Comb-BNCT+GLN. Considering tumors outside the treatment area, 77% of Comb-BNCT animals had a tumor volume lower than 50 mm3 vs. 30% for SHAM (p ≤ 0.005), suggesting an abscopal effect of Comb-BNCT. Inhibition of metastatic spread to lymph nodes was observed in all Comb-BNCT groups. Considering systemic aspects, CD8+ was elevated for Comb-BNCT+GLN vs. SHAM (p ≤ 0.01), and NK was elevated for Comb-BNCT vs. SHAM (p ≤ 0.05). Comb-BNCT improved therapeutic efficacy and reduced radiotoxicity compared to BPA-BNCT and induced an immune response and an abscopal effect.


[Activity of hydrogen sulfide production enzymes in kidneys of rats].
An experimental research of activity and kinetic descriptions of enzymes participating in formation of hydrogen sulfide in the kidney of rats has been carried out. It was established that cystein, homocystein and thiosulphate are the basic substrates for hydrogen sulfide synthesis. The higest activity for hydrogen sulfide production belongs to thiosulfate-dithiolsulfurtransferase and cysteine aminotransferase, less activity is characteristic of cystathionine beta-synthase and cystathio-nine gamma-lyase. The highest affinity to substrate is registered for thiosulfate-dithiolsulfurtransferase and cystathionine gamma-lyase. It is discovered that the substrate inhibition is typical of all hydrogen sulfide formation enzymes, although this characteristic is the most expressed thiosulfat-dithiolsulfurtransferase.


Proton transport inside the biofilm limits electrical current generation by anode-respiring bacteria.
Anode-respiring bacteria (ARB) in a biofilm anode carry out an oxidation half-reaction of organic matter, producing an electrical current from renewable biomass, including wastes. At the same time, ARB produce protons, usually one proton for every electron. Our study shows how current density generated by an acclimated ARB biofilm was limited by proton transport out of the biofilm. We determined that, at high current densities, protons were mainly transported out of the biofilm by protonating the conjugate base of the buffer system; the maximum current generation was directly related to the transport of the buffer, mainly by diffusion, into and out of the biofilm. With non-limiting acetate concentrations, the current density increased with higher buffer concentrations, going from 2.21 +/- 0.02 A m(-2) with 12.5-mM phosphate buffer medium to 9.3 +/- 0.4 A m(-2) using a 100-mM phosphate buffer at a constant anode potential of E(anode) = -0.35 V versus Ag/AgCl. Increasing the concentration of sodium chloride in the medium (0-100 mM) increased current density by only 15%, indicating that ion migration was not as important as diffusion of phosphate inside the biofilm. The current density also varied strongly with medium pH as a result of the buffer speciation: The current density was 10.0 +/- 0.8 A m(-2) at pH 8, and the pH giving one-half the maximum rate was 6.5. A j-V curve analysis using 100 mM phosphate buffer showed a maximum current density of 11.5 +/- 0.9 A m(-2) and half-saturation potential of -0.414 V versus Ag/AgCl, a value that deviated only slightly from the standard acetate potential, resulting in small anode-potential losses. We discuss the implications of the proton-transport limitation in the field of microbial fuel cells and microbial electrolytic cells.


Sex ratio at birth in Zaria, Nigeria.
The objectives of this study were to determine the sex ratio at birth in Ahmadu Bello University Teaching Hospital, Zaria, Nigeria and its relationship with certain pathologies including breech presentation, twin delivery, major degree placenta praevia and abruptio placentae. A retrospective analysis of records of all deliveries in the hospital between 1 January 1991 and 31 December 2002 (10 years) was carried out. To minimize bias, breech presentation included singletons only and placenta praevia included only major degrees confirmed at Caesarean section. The total number of deliveries during the study period was 12 845. The male:female ratio was 1.12. Sex ratio at birth was not significantly associated with any of the conditions studied, although there was a slight male preponderance with placenta praevia (57.3% in babies born to mothers with major degree placenta praevia compared to 52.7% in babies born to mothers without placenta praevia) and first twins (56.3% compared to 52.7% among singletons), and a slight female preponderance with singleton breech presentation (50.9% compared to 47.2% among non-breech deliveries). The findings in this study may reflect racial, dietary or environmental variations or a combination of these factors. They may also be as a result of bias from hospital data, emphasizing the need for accurate population-based records of births and other vital statistics.


Understanding 'anticipatory governance'.
Anticipatory governance is 'a broad-based capacity extended through society that can act on a variety of inputs to manage emerging knowledge-based technologies while such management is still possible'. It motivates activities designed to build capacities in foresight, engagement, and integration--as well as through their production ensemble. These capacities encourage and support the reflection of scientists, engineers, policy makers, and other publics on their roles in new technologies. This article reviews the early history of the National Nanotechnology Initiative in the United States, and it further explicates anticipatory governance through exploring the genealogy of the term and addressing a set of critiques found in the literature. These critiques involve skepticism of three proximities of anticipatory governance: to its object, nanotechnology, which is a relatively indistinct one; to the public, which remains almost utterly naive toward nanotechnology; and to technoscience itself, which allegedly renders anticipatory governance complicit in its hubris. The article concludes that the changing venues and the amplification within them of the still, small voices of folks previously excluded from offering constructive visions of futures afforded by anticipatory governance may not be complete solutions to our woes in governing technology, but they certainly can contribute to bending the long arc of technoscience more toward humane ends.


Digital polymerase chain reaction technology - recent advances and future perspectives.
Digital polymerase chain reaction (dPCR) technology has remained a "hot topic" in the last two decades due to its potential applications in cell biology, genetic engineering, and medical diagnostics. Various advanced techniques have been reported on sample dispersion, thermal cycling and output monitoring of digital PCR. However, a fully automated, low-cost and handheld digital PCR platform has not been reported in the literature. This paper attempts to critically evaluate the recent developments in techniques for sample dispersion, thermal cycling and output evaluation for dPCR. The techniques are discussed in terms of hardware simplicity, portability, cost-effectiveness and suitability for automation. The present paper also discusses the research gaps observed in each step of dPCR and concludes with possible improvements toward portable, low-cost and automatic digital PCR systems.


Leprosy patients with lepromatous disease have an up-regulated IL-8 response that is unlinked to TNF-alpha responses.
Tumor necrosis factor (TNF-alpha) in conjunction with interferon-gamma (IFN-gamma) plays an important role in lymphocyte recruitment and granuloma formation in mycobacterial diseases. Lepromatous leprosy infections are typically associated with low to absent T cell responses and the absence of INF-gamma secretion. Chemokines such as IL-8, MCP-1, and MIP-1beta, have also been shown to recruit neutrophils and lymphocytes to the site of mycobacterial infections. We have studied IL-8 expression in relation to TNF-alpha and TGF-beta in monocytes from lepromatous patients (LL) as compared with healthy endemic controls. In endemic controls, no spontaneous expression of IL-8, TNF-alpha, and TGF-beta was observed, but BCG and M. leprae induced activation of all three cytokines. Lepromatous leprosy monocytes spontaneously expressed high levels of IL-8 and TGF-beta but negligible levels of TNF-alpha. A further increase in IL-8 secretion or gene expression by BCG or M. leprae was not significant. BCG, but not M. leprae, was able to stimulate TNF-alpha activation in lepromatous leprosy subjects. TGF-beta responses in LL were parallel to those of IL-8. This suggests a vigorous and active ongoing IL-8 response in lepromatous disease that is independent of TNF-alpha activation. Therefore, in the absence of IFN-gamma and TNF-alpha activation, IL-8 may assume a pivotal role in cell recruitment in leprosy patients with disseminated mycobacterial infections.


Cell interactions and planar polarity in the abdominal epidermis of Drosophila.
The integument of the Drosophila adult abdomen bears oriented hairs and bristles that indicate the planar polarity of the epidermal cells. We study four polarity genes, frizzled (fz), prickle (pk), Van gogh/strabismus (Vang/stbm) and starry night/flamingo (stan/fmi), and note what happens when these genes are either removed or overexpressed in clones of cells. The edges of the clones are interfaces between cells that carry different amounts of gene products, interfaces that can cause reversals of planar polarity in the clone and wild-type cells outside them. To explain, we present a model that builds on our earlier picture of a gradient of X, the vector of which specifies planar polarity and depends on two cadherin proteins, Dachsous and Fat. We conjecture that the X gradient is read out, cell by cell, as a scalar value of Fz activity, and that Pk acts in this process, possibly to determine the sign of the Fz activity gradient. We discuss evidence that cells can compare their scalar readout of the level of X with that of their neighbours and can set their own readout towards an average of those. This averaging, when it occurs near the edges of clones, changes the scalar response of cells inside and outside the clones, leading to new vectors that change polarity. The results argue that Stan must be present in both cells being compared and acts as a conduit between them for the transfer of information. And also that Vang assists in the receipt of this information. The comparison between neighbours is crucial, because it gives the vector that orients hairs--these point towards the neighbour cell that has the lowest level of Fz activity. Recently, it has been shown that, for a limited period shortly before hair outgrowth in the wing, the four proteins we study, as well as others, become asymmetrically localised in the cell membrane, and this process is thought to be instrumental in the acquisition of cell polarity. However, some results do not fit with this view--we suggest that these localisations may be more a consequence than a cause of planar polarity.


The functional neuroanatomy of voluntary swallowing.
Swallowing is a complex physiological process involving voluntary and reflexive motor activity, sensorimotor integration, salivation, and visceral regulation. Despite the numerous processes required for normal deglutition, traditional models of the central control of swallowing only emphasize the involvement of the brainstem and the inferior precentral gyrus (IPCG). However a number of neurological disorders involving other brain regions also cause dysphagia. To determine the brain regions participating in voluntary swallowing, we assayed regional cerebral blood flow (rCBF) with positron emission tomography (PET) while healthy human subjects swallowed, performed lateral tongue movements, or rested with their eyes closed. Voluntary swallowing produced strong rCBF increases within the IPCG bilaterally, the right anterior insula/claustrum, and the left cerebellum. The maxima in these regions differed from those induced by lateral tongue movements. Swallowing also produced rCBF increases in the putamen, thalamus, and several additional cortical areas, but these foci were not as clearly distinguishable from activity arising during tongue movements. These findings indicate that swallowing involves the recruitment of a large-scale distributed neural network that includes the anterior insula and cerebellum. The distributed nature of this network helps to explain why so many neurological conditions produce dysphagia.


Differential phase-shift-keying demodulation by coherent perfect absorption in silicon photonics.
We demonstrate a novel differential phase-shift-keying (DPSK) demodulator based on coherent perfect absorption (CPA). Our DPSK demodulator chip device, which incorporates a silicon ring resonator, two bus waveguide inputs, and monolithically integrated detectors, operates passively at a bit rate of 10 Gbps at telecommunication wavelengths, and fits within a mm-scale footprint. Critical coupling is used to achieve efficient CPA by tuning the gap between the ring and bus waveguides. The device has a vertical eye opening of 12.47 mV and a quality factor exceeding 3×104. The fundamental principle behind this photonic circuit can be extended to other formats of integrated demodulators.


Extracellular ATP induces spikes in cytosolic free Ca(2+) but not in NADPH oxidase activity in neutrophils.
In order to establish whether non-mitochondrial oxidase activity in human neutrophils is tightly related to cytosolic Ca(2+) concentration, we simultaneously measured Ca(2+) oscillations induced by ATP and oxidant production in single adherent neutrophils using confocal microscopy. ATP induced fast damped Ca(2+) spikes with a period of 15s and slower irregular spikes with a period greater than 50s. Spikes in Ca(2+) occurred in the absence of Ca(2+) influx, but the amplitude was damped by inhibition of Ca(2+) influx. Using the oxidation of hydroethidine as a cytosolic marker of oxidant production, we show that the generation of reactive oxygen species by neutrophils adherent to glass was accelerated by ATP. The step-up in NADPH oxidase activity followed the first elevation of cytosolic Ca(2+) but, despite subsequent spikes in Ca(2+) concentration, no oscillations in oxidase activity could be detected. ATP induced spikes in Ca(2+) in a very reproducible way and we propose that the Ca(2+) signal is an on-switch for oxidase activity, but the activity is apparently not directly correlated with spiking activity in cytosolic Ca(2+).


Systematic identification of genes regulating synaptic remodeling in the Drosophila visual system.
In many animals, neural activity contributes to the adaptive refinement of synaptic properties, such as firing frequency and the number of synapses, for learning, memorizing and adapting for survival. However, the molecular mechanisms underlying such activity-dependent synaptic remodeling remain largely unknown. In the synapses of Drosophila melanogaster, the presynaptic active zone (AZ) forms a T-shaped presynaptic density comprising AZ proteins, including Bruchpilot (Brp). In a previous study, we found that the signal from a fusion protein molecular marker consisting of Brp and mCherry becomes diffuse under continuous light over three days (LL), reflecting disassembly of the AZ, while remaining punctate under continuous darkness. To identify the molecular players controlling this synaptic remodeling, we used the fusion protein molecular marker and performed RNAi screening against 208 neuron-related transmembrane genes that are highly expressed in the Drosophila visual system. Second analyses using the STaR (synaptic tagging with recombination) technique, which showed a decrease in synapse number under the LL condition, and subsequent mutant and overexpression analysis confirmed that five genes are involved in the activity-dependent AZ disassembly. This work demonstrates the feasibility of identifying genes involved in activity-dependent synaptic remodeling in Drosophila, and also provides unexpected insight into the molecular mechanisms involved in cholesterol metabolism and biosynthesis of the insect molting hormone ecdysone.


Inflammatory pseudotumour of the colon.
Introduction A colorectal inflammatory myofibroblastic tumour (IMT) is a rare but benign entity masquerading as a malignant tumour. Although the lung is considered the most common site of occurrence, IMTs may arise in diverse extrapulmonary locations. We describe a case of a colonic IMT in a patient who presented in the emergency setting. Case History A 77-year-old man was admitted at our emergency department with acute abdominal pain. Physical examination revealed vague tenderness of the lower abdomen and non-palpable masses. Preoperative evaluation revealed a mass in the right lower quadrant of the abdomen, possibly originating from the terminal ileum, 1-2cm from the caecum. Owing to the clinical impression of a potentially malignant lesion, the patient underwent subtotal colectomy and omentectomy. The pathology report suggested the morphological and immunohistochemical features were more compatible with a colonic IMT. Conclusions A colorectal IMT is a rare clinical entity that can easily mimic a highly malignant tumour and cannot be distinguished clinically or radiologically. An accurate diagnosis is based on histological examination and surgical resection is therefore usually required.


Profiles in patient safety: emergency care transitions.
A 59-year-old man presented to the emergency department (ED) with the chief complaint of "panic attacks." In total, he was evaluated by 14 faculty physicians, 2 fellows, and 16 residents from emergency medicine, cardiology, neurology, psychiatry, and internal medicine. These multiple transitions were responsible, in part, for the perpetuation of a failure to accurately diagnose the patient's underlying medical illness. The case illustrates the discontinuity of care that occurs at transitions, which may threaten the safety and quality of patient care. Considerable effort must be directed at making transitions effective and safe. Recommendations to improve transitions include a heightened awareness of cognitive biases operating at these vulnerable times, improving team situational awareness and communication, and exploring systems to facilitate effective transfer of relevant data.


Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.
Altered brain metabolism is associated with progression of Alzheimer's Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD. We identified a previously unknown mitochondrial fission arrest phenotype that results in elongated interconnected organelles, "mitochondria-on-a-string" (MOAS). Our data suggest that MOAS formation may occur at the final stages of fission process and was not associated with altered translocation of activated dynamin related protein 1 (Drp1) to mitochondria but with reduced GTPase activity. Since MOAS formation was also observed in the brain tissue of wild-type mice in response to hypoxia or during chronological aging, fission arrest may represent fundamental compensatory adaptation to bioenergetic stress providing protection against mitophagy that may preserve residual mitochondrial function. The discovery of novel mitochondrial phenotype that occurs in the brain tissue in response to energetic stress accurately detected only using 3D EM reconstruction argues for a major role of mitochondrial dynamics in regulating neuronal survival.


Association of Progressive Cerebellar Atrophy With Long-term Outcome in Patients With Anti-N-Methyl-d-Aspartate Receptor Encephalitis.
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder that occurs with IgG antibodies against the GluN1 subunit of NMDAR. Some patients develop reversible diffuse cerebral atrophy (DCA), but the long-term clinical significance of progressive brain and cerebellar atrophy is unknown. To report the long-term clinical implications of DCA and cerebellar atrophy in anti-NMDAR encephalitis. A retrospective observational study and long-term imaging investigation was conducted in the Department of Neurology at Kitasato University. Fifteen patients with anti-NMDAR encephalitis admitted to Kitasato University Hospital between January 1, 1999, and December 31, 2014, were included; data analysis was conducted between July 15, 2015, and January 18, 2016. Neurologic examination, immunotherapy, and magnetic resonance imaging (MRI) studies were performed. Long-term MRI changes in association with disease severity, serious complications (eg, pulmonary embolism, septic shock, and rhabdomyolysis), treatment, and outcome. The clinical outcome of 15 patients (median age, 21 years, [range, 14-46 years]; 10 [67%] female) was evaluated after a median follow-up of 68 months (range, 10-179 months). Thirteen patients (87%) received first-line immunotherapy (intravenous high-dose methylprednisolone, intravenous immunoglobulin, and plasma exchange alone or combined), and 4 individuals (27%) also received cyclophosphamide; 2 patients (13%) did not receive immunotherapy. In 5 patients (33%), ovarian teratoma was found and removed. Serious complications developed in 4 patients (27%). Follow-up MRI revealed DCA in 5 patients (33%) that, in 2 individuals (13%), was associated with progressive cerebellar atrophy. Long-term outcome was good in 13 patients (87%) and poor in the other 2 individuals (13%). Although cerebellar atrophy was associated with poor long-term outcome (2 of 2 vs 0 of 13 patients; P = .01), other features, such as DCA without cerebellar atrophy, serious complications, ventilatory support, or prolonged hospitalization, were not associated with a poor outcome. Five patients with DCA had longer hospitalizations (11.1 vs 2.4 months; P = .002), required ventilatory support more frequently (5 of 5 vs 4 of 10 patients; P = .04), and developed more serious complications (4 of 5 vs 0 of 10 patients; P = .004) compared with those without DCA. Although DCA was reversible, cerebellar atrophy was irreversible. In anti-NMDAR encephalitis, DCA can be reversible and does not imply a poor clinical outcome. In contrast, cerebellar atrophy was irreversible and associated with a poor outcome. This observation deserves further study to confirm progressive cerebellar atrophy as a prognostic marker of poor outcome.


Different clinical features according to the anastomotic leakage subtypes after rectal cancer surgeries: contained vs. free leakages.
Anastomotic leakage can be classified by free and contained leakage according to clinical manifestations. The risk factors and their comparison between these leakage subtypes are uncertain. This study aims to evaluate anastomotic leakage patterns and to compare clinical features between free and contained leakages after low anterior resection for rectal cancer. Between January 2005 and December 2012, a total of 2035 consecutive patients who underwent low anterior resection for primary rectal cancer were evaluated retrospectively at two-tertiary referral centers. The primary end points of this study were to assess detailed clinical features among leakage subtypes. The secondary end point was to compare risk factors between free and contained leakages. Patients were subdivided into a no leakage group (n = 1890), free leakage group (n = 73), and contained leakage group (n = 72). Free leakage occurred more frequently in laparoscopic and robotic surgeries than open surgery (p = 0.015). On the other hand, contained leakage was developed in a higher rate of patients who received preoperative chemoradiotherapy (p<0.001). The mean development time was 4.6 days in the free leakage group, and 23.6 days in the contained leakage group. Patients with free leakage had a lower rate of a defunctioning stoma than contained leakage (5.5% vs. 29.2%, p<0.001). Risk factors for free leakage were smoking, tumor location, and laparoscopic surgery. However, tumor location and preoperative chemoradiotherapy increased the risk for contained leakage. Contained leakage in rectal cancer surgery showed different clinical manifestations and risk factors compared to free leakage. It is necessary to pay more attention to patients with particular risk factors for anastomotic leakage subtypes.


Sequence of the 305 degrees-307 degrees region of the Bacillus subtilis chromosome.
The nucleotide sequence of the Bacillus subtilis 168 chromosomal segment located between yvhJ (307 degrees) and secA (305 degrees) was determined. This 20.3 kb region encompasses 23 ORFs, 17 of which have been sequenced previously. Comparison of sequences obtained here with the previously obtained ones revealed seven discrepancies. The products of the sequenced genes are involved in the regulation of degradative enzymes, competence, flagellar motility and protein secretion. Putative functions of newly identified genes are based on sequence homologies.


Fasting activates the nonhuman primate hypocretin (orexin) system and its postsynaptic targets.
In rodents, hypocretin (HCRT, also called orexin) influences a variety of endocrine, autonomic, and metabolic functions. The present study was undertaken to determine whether the HCRT-producing circuit is involved in the hypothalamic regulation of homeostasis in primates as well. We studied female monkeys (Cercopithecus aethiops) that were either fed or fasted for 24 h. Immunocytochemistry revealed HCRT-producing perikarya exclusively in the lateral hypothalamus-perifornical region and dorsomedial hypothalamus of the monkey brain. HCRT axons and axon terminals were present in different parts of the hypothalamus and adjacent forebrain and thalamic nuclei. The 24-h fast resulted in an approximately 50% decline in circulating leptin levels and significantly elevated c-fos expression in the perifornical region; in the dorsomedial, ventromedial, and arcuate nuclei; and in the medial preoptic area. In the dorsomedial nucleus and perifornical region of fasted monkeys, three times more HCRT-neurons expressed nuclear c-fos than those of the normally fed controls. Neurons in different parts of the hypothalamus and basal forebrain that expressed c-fos, but did not contain HCRT, were targets of HCRT-immunopositive boutons establishing asymmetric synapses. In the arcuate nucleus, subsets of these HCRT-targeted c-fos-expressing cells contained neuropeptide Y. The present study provides the first experimental evidence to implicate HCRT in the hypothalamic regulation of homeostasis in primates. The fact that these lateral hypothalamic cells have leptin receptors and can be activated by a metabolic challenge and that they innervate diverse brain regions indicates that the HCRT system may be a key integrator of environmental cues in their regulation of diverse brain activity.


The sensitivity of motor response to needle nerve stimulation during ultrasound guided interscalene catheter placement.
Neurostimulation during single shot interscalene block has a significant false negative motor response rate. Compared with tangential needle approaches for single shot block, interscalene catheter (ISC) placement commonly involves Tuohy needles inserted longitudinally to the brachial plexus. This study aimed to determine the sensitivity of neurostimulation during ultrasound-guided ISC needle placement, and the feasibility of an ultrasound-guided ISC needle endpoint. One hundred fifty-five consecutive nonstimulating ISCs were placed with the needle tip position confirmed by the sonographic spread of 5 mL dextrose 5%. Catheter advancement was then blind 2 to 3 cm past the needle tip. A 0.8 mA electrical stimulus at 2 Hz was applied throughout. When a satisfactory image was obtained, neurostimulation was ignored and the minimum motor response amplitude noted. If imaging was equivocal, a brief appropriate motor response at 0.8 mA was sought. A sustained response at <0.5 mA was only sought if imaging was suboptimal. Prior to surgery conducted under general anesthesia, 30 mL ropivacaine 0.5% was administered through the ISC. Catheter success was defined as a recovery room numerical rating pain score of </=2 (scale, 0-10). In 57% of patients, a muscle response was not elicited. An ultrasound needle endpoint was used in 92% of ISC placements, of which 96% were successful. Sustained twitches at <0.5 mA were obtained in 12 (8%) patients, 6 (4%) of these deliberately sought because of suboptimal imaging. Catheter success overall was 95%. This study suggests that the false negative motor response rate for longitudinal ISC needle placement is higher than the false negative response rate associated with tangential needle approach interscalene block. An ultrasound guided ISC needle endpoint is a feasible alternative to a neurostimulation endpoint.


A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol.
Recent evidence underscores the utility of rapid-acting antidepressant interventions, such as ketamine, in alleviating symptoms of major depressive episodes (MDE). However, to date, there have been limited head-to-head comparisons of intravenous (IV) ketamine infusions with other antidepressant treatment strategies in large randomized trials. This study protocol describes an ongoing multi-centre, prospective, randomized, crossover, non-inferiority trial comparing acute treatment of individuals meeting diagnostic criteria for a major depressive episode (MDE) with ketamine and electroconvulsive therapy (ECT) on efficacy, speed of therapeutic effects, side effects, and health care resource utilization. A secondary aim is to compare a 6-month maintenance strategy for ketamine responders to standard of care ECT maintenance. Finally, through the measurement of clinical, cognitive, neuroimaging, and molecular markers we aim to establish predictors and moderators of treatment response as well as treatment-elicited effects on these outcomes. Across four participating Canadian institutions, 240 patients with major depressive disorder or bipolar disorder experiencing a MDE are randomized (1:1) to a course of ECT or racemic IV ketamine (0.5 mg/kg) administered 3 times/week for 3 or 4 weeks. Non-responders (< 50% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) crossover to receive the alternate treatment. Responders during the randomization or crossover phases then enter the 6-month maintenance phase during which time they receive clinical assessments at identical intervals regardless of treatment arm. ECT maintenance follows standard of care while ketamine maintenance involves: weekly infusions for 1 month, then bi-weekly infusions for 2 months, and finally monthly infusions for 3 months (returning to bi-weekly in case of relapse). The primary outcome measure is change in MADRS scores after randomized treatment as assessed by raters blind to treatment modality. This multi-centre study will help identify molecular, imaging, and clinical characteristics of patients with treatment-resistant and/or severe MDEs who would benefit most from either type of therapeutic strategy. In addition to informing clinical practice and influencing health care delivery, this trial will add to the robust platform and database of CAN-BIND studies for future research and biomarker discovery. ClinicalTrials.gov identifier NCT03674671. Registered September 17, 2018.


Serum Levels of Soluble IL-2R, CD4 and CD8 in Chronic Active HCV Positive Hepatitis.
The aim of the present study was to compare serum levels of soluble forms of interleukin-2 receptor, CD4 and CD8, released by lymphocytes during activation ofthe immune system, in patients with histologically verified chronic active hepatitis associated to hepatitis C virus infection, with those in healthy subjects. Significantly higher levels of soluble IL-2R and soluble CD8 were found in patients with chronic active hepatitis compared with controls. In contrast no difference was found for soluble CD4 values in the two groups. No correlations were found for both sIL-2R and sCD8 and these two molecules with other parameters of liver function. These results indicate that in these patients there is a general activation of the immune system, but the lack of correlation with parameters of liver function strengthens the suggestion that this activation does not play a role in the pathogenesis of chronic type C hepatitis.


Recovery of renal function after prolonged dialysis and transplantation.
Out of 250 patients with renal failure, seven (2.8%) treated by regular haemodialysis alone (four) or given cadaveric allografts (three) later showed recovery of function of their own kidneys lasting from one to four years. In the patients receiving haemodialysis alone recovery was easily recognised from their serum creatinine concentrations, but in those with transplants recovery was discovered unexpectedly during radionuclide scanning. These findings suggest that recovery of renal function may be more common than generally recognised, which should be borne in mind when beginning renal replacement treatment and particularly when contemplating bilateral nephrectomy.


Phylogeny of seed plants based on all three genomic compartments: extant gymnosperms are monophyletic and Gnetales' closest relatives are conifers.
Efforts to resolve Darwin's "abominable mystery"-the origin of angiosperms-have led to the conclusion that Gnetales and various fossil groups are sister to angiosperms, forming the "anthophytes." Morphological homologies, however, are difficult to interpret, and molecular data have not provided clear resolution of relationships among major groups of seed plants. We introduce two sequence data sets from slowly evolving mitochondrial genes, cox1 and atpA, which unambiguously reject the anthophyte hypothesis, favoring instead a close relationship between Gnetales and conifers. Parsimony- and likelihood-based analyses of plastid rbcL and nuclear 18S rDNA alone and with cox1 and atpA also strongly support a gnetophyte-conifer grouping. Surprisingly, three of four genes (all but nuclear rDNA) and combined three-genome analyses also suggest or strongly support Gnetales as derived conifers, sister to Pinaceae. Analyses with outgroups screened to avoid long branches consistently identify all gymnosperms as a monophyletic sister group to angiosperms. Combined three- and four-gene rooted analyses resolve the branching order for the remaining major groups-cycads separate from other gymnosperms first, followed by Ginkgo and then (Gnetales + Pinaceae) sister to a monophyletic group with all other conifer families. The molecular phylogeny strongly conflicts with current interpretations of seed plant morphology, and implies that many similarities between gnetophytes and angiosperms, such as "flower-like" reproductive structures and double fertilization, were independently derived, whereas other characters could emerge as synapomorphies for an expanded conifer group including Gnetales. An initial angiosperm-gymnosperm split implies a long stem lineage preceding the explosive Mesozoic radiation of flowering plants and suggests that angiosperm origins and homologies should be sought among extinct seed plant groups.


Updated three-stage model for the peopling of the Americas.
We re-assess support for our three stage model for the peopling of the Americas in light of a recent report that identified nine non-Native American mitochondrial genome sequences that should not have been included in our initial analysis. Removal of these sequences results in the elimination of an early (i.e. approximately 40,000 years ago) expansion signal we had proposed for the proto-Amerind population. Bayesian skyline plot analysis of a new dataset of Native American mitochondrial coding genomes confirms the absence of an early expansion signal for the proto-Amerind population and allows us to reduce the variation around our estimate of the New World founder population size. In addition, genetic variants that define New World founder haplogroups are used to estimate the amount of time required between divergence of proto-Amerinds from the Asian gene pool and expansion into the New World. The period of population isolation required for the generation of New World mitochondrial founder haplogroup-defining genetic variants makes the existence of three stages of colonization a logical conclusion. Thus, our three stage model remains an important and useful working hypothesis for researchers interested in the peopling of the Americas and the processes of colonization.


Optic nerve coloboma as extension of the phenotype of 22q11.23 duplication syndrome: a case report.
22q11.2 duplication syndrome (Dup22q11.2) has reduced penetrance and variable expressivity. Those affected may have intellectual disabilities, dysmorphic facial features, and ocular alterations such as ptosis, hypertelorism, nystagmus, and chorioretinal coloboma. The prevalence of this syndrome is unknown, there are only approximately 100 cases reported. However Dup22q11.2 should have a similar prevalence of DiGeorge syndrome (1 in each 4000 new-borns), in which the same chromosomal region that is duplicated in Dup22q11.2 is deleted. We report a patient with intellectual disability, psychomotor development delay, hearing loss with disyllable pronunciation only, hyperactivity, self-harm, hetero-aggressive behaviour, facial dysmorphism, left facial paralysis, post-axial polydactyly, and for the first time in patients with Dup22q11.2, optic nerve coloboma and dysplasia in optic nerve. Array comparative genomic hybridization showed a 22q11.23 duplication of 1.306 million base pairs. New ocular findings in Dup22q11.2 syndrome, such as coloboma and dysplasia in the optic nerve, are reported here, contributing to the phenotypic characterization of a rarely diagnosed genetic syndrome. A complete characterization of the phenotype is necessary to increase the rate of clinical suspicion and then the genetic diagnostic. In addition, through bioinformatics analysis of the genes mapped to the 22q11.2 region, it is proposed that deregulation of the SPECC1L gene could be implicated in the development of ocular coloboma.


[Use of extracorporeal hemosorption for the preoperative preparation of toxic goiter patients].
The method of extracorporal hemosorption was used by the authors first in the clinical practice for the preoperative preparation of patients with thyrotoxicosis. Oxygenated SKN carbons were used as sorbents. The hemosorption was used in 16 patients with thyrotoxic goiter by the method developed in the clinic. The authors make a conclusion that hemosorption is an expedient method for the preoperative preparation of patients with a toxic goiter.


Messenger RNA expression and methylation of candidate tumor-suppressor genes and risk of ovarian cancer-a case-control analysis.
To investigate the association of expression and promoter methylation of tumor-suppressor genes with risk of ovarian cancer, we conducted a case-control study of 102 patients with serous epithelial ovarian cancer and 100 patients without ovarian cancers. We measured mRNA expression levels (by real-time reverse transcription polymerase chain reaction) and methylation status (by methylation-specific polymerase chain reaction) of five candidate genes (BRCA1, BRCA2, hMLH1, MGMT, and DNMT3B) in tumors from the cases and normal ovaries from the controls. We found that mRNA expression levels of the five genes were decreased in tumors than in normal ovaries with 0.39-fold for BRCA1, 0.25-fold for BRCA2, 0.42-fold for hMLH1, 0.45-fold for MGMT, and 0.87-fold for DNMT3B, calculated by the 2(-ΔΔCT) method. Ovarian cancer risk (odds ratios, ORs) was associated with low expression of all genes (2.95 [95% confidence interval (CI), 1.51 - 5.78] for BRCA1, 3.65 (95% CI, 1.82 - 7.30) for BRCA2, 5.25 (95% CI, 2.52 - 10.96) for hMLH1, and 4.72 (95% CI, 2.32 - 9.62) for MGMT) but not DNMT3B. However, methylation status was not associated with gene expression levels in the tumors, except for hMLH1 whose mean (± SD) gene expression was significantly lower in methylated (13.0 ± 7.6) than in unmethylated (31.2 ± 44.8) tumors (P < 0.001). We concluded that low mRNA expression of these tumor-suppressor genes, likely due to molecular mechanisms in addition to the promoter methylation in some instances, may be a biomarker for ovarian cancer risk in this study population. Larger studies are needed to validate our findings.


Methods for reducing nonspecific interaction in antibody-antigen assay via atomic force microscopy.
We developed a method to measure the rupture forces between antibody and antigen by atomic force microscopy (AFM). Previous studies have reported that in the measurement of antibody-antigen interaction using AFM, the specific intermolecular forces are often obscured by nonspecific adhesive binding forces between antibody immobilized cantilever and substrate surfaces on which antigen or nonantigen are fixed. Here, we examined whether detergent and nonreactive protein, which have been widely used to reduce nonspecific background signals in ordinary immunoassay and immunoblotting, could reduce the nonspecific forces in the AFM measurement. The results showed that, in the presence of both nonreactive protein and detergent, the rupture forces between anti-ferritin antibodies immobilized on a tip of cantilever and ferritin (antigen) on the substrate could be successfully measured, distinguishing from nonspecific adhesive forces. In addition, we found that approach/retraction velocity of the AFM cantilever was also important in the reduction of nonspecific adhesion. These insights will contribute to the detection of specific molecules at nanometer scale region and the investigation of intermolecular interaction by the use of AFM.


Transcriptional activation by ETS and leucine zipper-containing basic helix-loop-helix proteins.
The immunoglobulin mu heavy-chain gene enhancer contains closely juxtaposed binding sites for ETS and leucine zipper-containing basic helix-loop-helix (bHLH-zip) proteins. To understand the mu enhancer function, we have investigated transcription activation by the combination of ETS and bHLH-zip proteins. The bHLH-zip protein TFE3, but not USF, cooperated with the ETS domain proteins PU.1 and Ets-1 to activate a tripartite domain of this enhancer. Deletion mutants were used to identify the domains of the proteins involved. Both TFE3 and USF enhanced Ets-1 DNA binding in vitro by relieving the influence of an autoinhibitory domain in Ets-1 by direct protein-protein associations. Several regions of Ets-1 were found to be necessary, whereas the bHLH-zip domain was sufficient for this effect. Our studies define novel interactions between ETS and bHLH-zip proteins that may regulate combinatorial transcription activation by these protein families.


Genetic Dissection of the Regulatory Mechanisms of Ace2 in the Infected Mouse Lung.
Acute lung injury (ALI) is an important cause of morbidity and mortality after viral infections, including influenza A virus H1N1, SARS-CoV, MERS-CoV, and SARS-CoV-2. The angiotensin I converting enzyme 2 (ACE2) is a key host membrane-bound protein that modulates ALI induced by viral infection, pulmonary acid aspiration, and sepsis. However, the contributions of ACE2 sequence variants to individual differences in disease risk and severity after viral infection are not understood. In this study, we quantified H1N1 influenza-infected lung transcriptomes across a family of 41 BXD recombinant inbred strains of mice and both parents-C57BL/6J and DBA/2J. In response to infection Ace2 mRNA levels decreased significantly for both parental strains and the expression levels was associated with disease severity (body weight loss) and viral load (expression levels of viral NA segment) across the BXD family members. Pulmonary RNA-seq for 43 lines was analyzed using weighted gene co-expression network analysis (WGCNA) and Bayesian network approaches. Ace2 not only participated in virus-induced ALI by interacting with TNF, MAPK, and NOTCH signaling pathways, but was also linked with high confidence to gene products that have important functions in the pulmonary epithelium, including Rnf128, Muc5b, and Tmprss2. Comparable sets of transcripts were also highlighted in parallel studies of human SARS-CoV-infected primary human airway epithelial cells. Using conventional mapping methods, we determined that weight loss at two and three days after viral infection maps to chromosome X-the location of Ace2. This finding motivated the hierarchical Bayesian network analysis, which defined molecular endophenotypes of lung infection linked to Ace2 expression and to a key disease outcome. Core members of this Bayesian network include Ace2, Atf4, Csf2, Cxcl2, Lif, Maml3, Muc5b, Reg3g, Ripk3, and Traf3. Collectively, these findings define a causally-rooted Ace2 modulatory network relevant to host response to viral infection and identify potential therapeutic targets for virus-induced respiratory diseases, including those caused by influenza and coronaviruses.


Combined analyses of data from quantitative trait loci mapping studies. Chromosome 4 effects on porcine growth and fatness.
For many species several similar QTL mapping populations have been produced and analyzed independently. Joint analysis of such data could be used to increase power to detect QTL and evaluate population differences. In this study, data were collated on almost 3000 pigs from seven different F(2) crosses between Western commercial breeds and either the European wild boar or the Chinese Meishan breed. Genotypes were available for 31 markers on chromosome 4 (on average 8.3 markers per population). Data from three traits common to all populations (birth weight, mean backfat depth at slaughter or end of test, and growth rate from birth to slaughter or end of test) were analyzed for individual populations and jointly. A QTL influencing birth weight was detected in one individual population and in the combined data, with no significant interaction of the QTL effect with population. A QTL affecting backfat that had a significantly greater effect in wild boar than in Meishan crosses was detected. Some evidence for a QTL affecting growth rate was detected in all populations, with no significant differences between populations. This study is the largest F(2) QTL analysis achieved in a livestock species and demonstrates the potential of joint analysis.


15q12 variants, sputum gene promoter hypermethylation, and lung cancer risk: a GWAS in smokers.
Lung cancer is the leading cause of cancer-related mortality worldwide. Detection of promoter hypermethylation of tumor suppressor genes in exfoliated cells from the lung provides an assessment of field cancerization that in turn predicts lung cancer. The identification of genetic determinants for this validated cancer biomarker should provide novel insights into mechanisms underlying epigenetic reprogramming during lung carcinogenesis. A genome-wide association study using generalized estimating equations and logistic regression models was conducted in two geographically independent smoker cohorts to identify loci affecting the propensity for cancer-related gene methylation that was assessed by a 12-gene panel interrogated in sputum. All statistical tests were two-sided. Two single nucleotide polymorphisms (SNPs) at 15q12 (rs73371737 and rs7179575) that drove gene methylation were discovered and replicated with rs73371737 reaching genome-wide significance (P = 3.3×10(-8)). A haplotype carrying risk alleles from the two 15q12 SNPs conferred 57% increased risk for gene methylation (P = 2.5×10(-9)). Rs73371737 reduced GABRB3 expression in lung cells and increased risk for smoking-induced chronic mucous hypersecretion. Furthermore, subjects with variant homozygote of rs73371737 had a two-fold increase in risk for lung cancer (P = .0043). Pathway analysis identified DNA double-strand break repair by homologous recombination (DSBR-HR) as a major pathway affecting susceptibility for gene methylation that was validated by measuring chromatid breaks in lymphocytes challenged by bleomycin. A functional 15q12 variant was identified as a risk factor for gene methylation and lung cancer. The associations could be mediated by GABAergic signaling that drives the smoking-induced mucous cell metaplasia. Our findings also substantiate DSBR-HR as a critical pathway driving epigenetic gene silencing.


Feeding and rearing of infant baboons in captivity.
The feeding, housing and care of infant baboons (Papio ursinus) are discussed. At the time of capture all the baboons were aged less than 5 weeks, and problems such as soft stools, diarrhoea and a staphylococcal dermatitis that occurred during their 5 weeks adaptation to conditions in the animal house are reported. A time-saving method for force-feeding infant baboons is also described, while information is given regarding the capturing technique used.


The bidirectional relationship between vasomotor symptoms and depression across the menopausal transition: a systematic review of longitudinal studies.
To explore the nature of the bidirectional relationship between vasomotor symptoms (VMS) and depression, and to determine whether hot flashes and night sweats differentially affect the association between VMS and depression through their effect on sleep disruption. Multiple databases were searched from 1961 until July 31, 2016, and a manual search of reference lists of identified articles was conducted. Sixteen articles that involved 10,008 participants were identified and analyzed. The methods of analyses and measurement of VMS and depression varied across the studies. Two studies explored the bidirectional association, but only one was significant in both directions (odds ratio [OR] depression to VMS 3.06, 95% confidence interval [CI] 1.43-6.58; OR VMS to depression 8.88, 95% CI 2.57-30.68). In both cases, the association between VMS leading to depressive symptoms was stronger than the opposite. Eleven studies examined VMS leading to depression, but only five showed a significant effect (OR 1.57-1.81, P ≤ 0.02). Treating VMS and depressive symptoms as continuous variables (n = 3) diminished the relationship. Three studies showed a significant association of depression leading to VMS (OR 1.62-1.94, P ≤ 0.01). We found little evidence for a specific effect of night sweats on the association between VMS and depressive symptoms. The effect might not be related to sleep disruption. There is a bidirectional association between VMS and depressive symptoms. The menopausal transition appears to increase the risk of recurrent episodes of depression that might not be explained only by VMS. Further investigation is needed to explain the differential effect of night sweats and hot flashes on depression.


Laryngeal chondrosarcomas: the Mayo Clinic experience.
Laryngeal chondrosarcomas occur infrequently. Their management is often guided by inferences made from the management of sarcomas arising from more commonly afflicted organs. A retrospective analysis of patients with laryngeal chondrosarcomas treated at the Mayo Clinic between 1959 and 1992 was performed to assess prognostic factors and outcomes after various treatments. A total of 20 patients received treatment during this time period. All chondrosarcomas were low grade; 19 involved the cricoid cartilage and one arose in the supraglottic larynx. Initial treatment consisted of local excision (often subtotal removal) alone in 12 patients (60%), hemilaryngectomy in 2 (10%), near total laryngectomy in 2 (10%), and total laryngectomy in 4 (20%). Six patients (30%) had local recurrence: five initially had local excision and one had hemilaryngectomy. All local recurrences or tumor progression developed >3 years after initial treatment. Salvage surgery was performed in five of the six patients who had local recurrence, and the other patient was observed. Of the five patients who had salvage surgery, three required another resection because of a second recurrence. These results suggest that initial conservative subtotal laryngectomy should be explored further because this treatment may provide long-term voice preservation in most patients, and patients who experience a recurrence after local excision often have been given several years of voice preservation.


Learning and generalization from reward and punishment in opioid addiction.
This study adapts a widely-used acquired equivalence paradigm to investigate how opioid-addicted individuals learn from positive and negative feedback, and how they generalize this learning. The opioid-addicted group consisted of 33 participants with a history of heroin dependency currently in a methadone maintenance program; the control group consisted of 32 healthy participants without a history of drug addiction. All participants performed a novel variant of the acquired equivalence task, where they learned to map some stimuli to correct outcomes in order to obtain reward, and to map other stimuli to correct outcomes in order to avoid punishment; some stimuli were implicitly "equivalent" in the sense of being paired with the same outcome. On the initial training phase, both groups performed similarly on learning to obtain reward, but as memory load grew, the control group outperformed the addicted group on learning to avoid punishment. On a subsequent testing phase, the addicted and control groups performed similarly on retention trials involving previously-trained stimulus-outcome pairs, as well as on generalization trials to assess acquired equivalence. Since prior work with acquired equivalence tasks has associated stimulus-outcome learning with the nigrostriatal dopamine system, and generalization with the hippocampal region, the current results are consistent with basal ganglia dysfunction in the opioid-addicted patients. Further, a selective deficit in learning from punishment could contribute to processes by which addicted individuals continue to pursue drug use even at the cost of negative consequences such as loss of income and the opportunity to engage in other life activities.


Functionalized d-form self-assembling peptide hydrogels for bone regeneration.
Bone defects are very common in orthopedics, and there is great need to develop suitable bone grafts for transplantation in vivo. However, current bone grafts still encounter some limitations, including limited availability, immune rejection, poor osteoinduction and osteoconduction, poor biocompatibility and degradation properties, etc. Self-assembling peptide nanofiber scaffolds have emerged as an important substrate for cell culture and bone regeneration. We report on the structural features (eg, Congo red staining, circular dichroism spectroscopy, transmission electron microscopy, and rheometry assays) and osteogenic ability of d-RADA16-RGD peptide hydrogels (with or without basic fibroblast growth factor) due to the better stability of peptide bonds formed by these peptides compared with those formed by l-form peptides, and use them to fill the femoral condyle defect of Sprague Dawley rat model. The bone morphology change, two-dimensional reconstructions using microcomputed tomography, quantification of the microcomputed tomography analyses as well as histological analyses have demonstrated that RGD-modified d-form peptide scaffolds are able to enhance extensive bone regeneration.


Management and outcome of high-grade multicentric gliomas: a contemporary single-institution series and review of the literature.
Multicentric malignant gliomas are well-separated tumours in different lobes or hemispheres, without anatomical continuity between lesions. The purpose of this study was to explore the clinical features, the pathology and the outcome according to the management strategies in a consecutive series of patients treated at a single institution. In addition, an analysis of the existing literature is presented. For the institutional analysis, a retrospective review of all patients who underwent treatment for multicentric gliomas in the last 7 years was performed. For the analysis of the literature, a MEDLINE search with no date limitations was accomplished for surgical treatment of multicentric malignant gliomas. Two hundred and thirty-nine patients with glioma were treated in our department. Eighteen patients (7.5 %) with a mean age of 64 years (age range, 37-78 years) presented multicentric malignant gliomas. Thirteen patients (72 %) underwent surgical resection of at least one lesion that was followed by adjuvant treatment in all but one case. Five patients (28 %) underwent stereotactic biopsy and thereafter received chemotherapy. A survival advantage was associated with resection of at least one lesion followed by adjuvant treatment (median overall survival 12 months) compared with 4 months for stereotactic biopsy followed by chemotherapy. Similar results were obtained from the review of the literature. Resection of at least one lesion seems to play a significant role in the management of selected patients with multicentric malignant gliomas. Multi-institutional studies on larger series are warranted to define how aggressively the patients with malignant multicentric gliomas should be treated.


Proteomic and Biological Analyses Reveal the Effect on Growth under Flooding Stress of Chickpea Irradiated with Millimeter Waves.
Chickpea cultivated on marginal lands in arid and semiarid tropics is one of the food legumes, and its growth is reduced by flooding stress. Millimeter-wave irradiation has influences on organisms, and it improves the growth of plants such as soybean. To reveal the dynamic effects of millimeter-wave irradiation on chickpea under flooding, gel- and label-free proteomic analysis was conducted. Millimeter-wave irradiation improved chickpea growth and its tolerance to flooding stress. According to functional categorization, oppositely changed proteins were correlated with photosynthesis, fermentation, and protein degradation. Immunoblot analysis confirmed that RuBisCO activase and large subunits decreased in leaves under flooding; however, they are recovered in irradiated chickpea even if it was in this condition. The activity and accumulation of alcohol dehydrogenase increased in roots under flooding; however, this followed the same pattern. Cell death was significantly increased and decreased by flooding on unirradiated and irradiated chickpeas, respectively. These findings suggest that irradiation with millimeter waves on chickpea seeds improves the recovery of plant growth through regulation of photosynthesis in leaves and fermentation in roots. Furthermore, millimeter-wave irradiation might promote chickpea tolerance under flooding via the regulation of cell death.


On the configuration of five-membered rings: a spin-spin coupling constant approach.
Five-membered rings are clearly among the most common structural motifs found in chemistry and biology. Nevertheless, the configuration of conformationally mobile five-membered rings is often difficult to assign from nuclear magnetic resonance (NMR) data. A simple, reliable, and efficient approach for the stereochemical analysis of five-membered rings based on the measurement of NMR coupling constants is presented. Density functional theory calculations using representative conformations of the full conformational space available to rings with different substitution patterns were used to identify differences between the accessible coupling constant values for cis and trans relative orientations of the substituents. The calculations were assessed experimentally using NMR data obtained from a number of models. This approach can be easily used to analyze different five-membered rings, such as oxolanes, cyclopentanes, furanosides and pyrrolidines, and their relative configuration can be determined without the need for making further conformational considerations.


Succession of indigenous Pseudomonas spp. and actinomycetes on barley roots affected by the antagonistic strain Pseudomonas fluorescens DR54 and the fungicide imazalil.
In recent years, the interest in the use of bacteria for biological control of plant-pathogenic fungi has increased. We studied the possible side effects of coating barley seeds with the antagonistic strain Pseudomonas fluorescens DR54 or a commercial fungicide, imazalil. This was done by monitoring the number of indigenous Pseudomonas organisms and actinomycetes on barley roots during growth in soil, harvest after 50 days, and subsequent decomposition. Bacteria were enumerated by traditional plate spreading on Gould's S1 agar (Pseudomonas) and as filamentous colonies on Winogradsky agar (actinomycetes) and by two quantitative competitive PCR assays. For this we developed an assay targeting Streptomyces and closely related genera. DR54 constituted more than 75% of the Pseudomonas population at the root base during the first 21 days but decreased to less than 10% at day 50. DR54 was not successful in colonizing root tips. Initially, DR54 affected the number of indigenous Pseudomonas organisms negatively, whereas imazalil affected Pseudomonas numbers positively, but the effects were transient. Although plate counts were considerably lower than the number of DNA copies, the two methods correlated well for Pseudomonas during plant growth, but after plant harvest Pseudomonas-specific DNA copy numbers decreased while plate counts were in the same magnitude as before. Hence, Pseudomonas was 10-fold more culturable in a decomposition environment than in the rhizosphere. The abundance of actinomycetes was unaffected by DR54 or imazalil amendments, and CFU and quantitative PCR results correlated throughout the experiment. The abundance of actinomycetes increased gradually, mostly in numbers of DNA copies, confirming their role in colonizing old roots.


Effects of system response delays on elderly humans' cognitive performance in a virtual training scenario.
Observed influences of system response delay in spoken human-machine dialogues are rather ambiguous and mainly focus on perceived system quality. Studies that systematically inspect effects on cognitive performance are still lacking, and effects of individual characteristics are also often neglected. Building on benefits of cognitive training for decelerating cognitive decline, this Wizard-of-Oz study addresses both issues by testing 62 elderly participants in a dialogue-based memory training with a virtual agent. Participants acquired the method of loci with fading instructional guidance and applied it afterward to memorizing and recalling lists of German nouns. System response delays were randomly assigned, and training performance was included as potential mediator. Participants' age, gender, and subscales of affinity for technology (enthusiasm, competence, positive and negative perception of technology) were inspected as potential moderators. The results indicated positive effects on recall performance with higher training performance, female gender, and less negative perception of technology. Additionally, memory retention and facets of affinity for technology moderated increasing system response delays. Participants also provided higher ratings in perceived system quality with higher enthusiasm for technology but reported increasing frustration with a more positive perception of technology. Potential explanations and implications for the design of spoken dialogue systems are discussed.


G-CSF and G-CSFR are highly expressed in human gastric and colon cancers and promote carcinoma cell proliferation and migration.
Granulocyte colony-stimulating factor (G-CSF) is a pro-inflammatory cytokine that stimulates myeloid stem cell maturation, proliferation, and migration into circulation. Despite being a known growth factor, the impact of G-CSF on solid tumours has not been well examined. G-CSF receptor (G-CSFR) is expressed by some tumours, and thus the aim of this study was to examine the expression and impact of G-CSF and G-CSFR on gastrointestinal tumours. In this study, G-CSF expression was examined in human gastric and colon tumours and by tumour-derived stromal myofibroblasts and carcinoma cells. G-CSFR expression was examined on carcinoma cells isolated from human tissues. The effects of G-CSF on gastric and colon carcinoma cell proliferation, migration, and signalling were examined. G-CSFR was highly expressed in 90% of human gastric and colon carcinomas. G-CSF was also found to be highly produced by stromal myofibroblasts and carcinoma cells. Exposure of carcinoma cells to G-CSF led to increased proliferation and migration, and expansion of a sub-population of carcinoma cells expressing stem-like markers. These processes were dependent on ERK1/2 and RSK1 phosphorylation. These data suggest that the G-CSF/R axis promotes gastric and colorectal cancer development and suggest they are potential tumour targets.


Safety and Efficacy of Chemotherapy Combined with Anlotinib Plus Anlotinib Maintenance in Chinese Patients with Advanced/Metastatic Soft Tissue Sarcoma.
Anlotinib, a newly developed oral small-molecule receptor tyrosine kinase inhibitor (TKI), has been shown to have encouraging activity against sarcoma. The purpose of this study was to retrospectively evaluate the safety and clinical efficacy of chemotherapy combined with anlotinib plus anlotinib maintenance in advanced/metastatic soft tissue sarcoma (STS) patients in a real-world setting in China. We retrospectively collected the medical data of thirty-two patients with advanced/metastatic STS who received chemotherapy combined with anlotinib plus anlotinib maintenance therapy. The objective response rate (ORR) and disease control rate (DCR) were calculated according to the RECIST 1.1 criteria. The progression-free rates (PFRs) at three and six months, the progression-free survival (PFS) time, and adverse events were recorded. On the basis of investigator assessments, two patients (6%) achieved CR (complete response) and nine patients (28%) achieved PR (partial response), with an ORR of 34%. Eleven patients (34%) achieved SD (stable disease), and ten patients (31%) achieved PD (progression disease), with a DCR of 69%. The progression-free rates (PFRs) at three and six months were 81% and 69%, respectively. The median PFS time was 8.2 months. The hematologic and non-hematologic toxicities were manageable. The most common grade 3 and 4 adverse events were febrile neutropenia (9%), leukopenia (19%), thrombocytopenia (3%), anemia (6%), anorexia (6%), vomiting (3%), and hypertension (6%). The combination therapy was generally well tolerated. Our study suggests that chemotherapy combined with anlotinib plus anlotinib maintenance therapy had good efficacy and resulted in more favorable survival with good tolerance among patients with advanced/metastatic STS.


Hydroxysafflor Yellow A Ameliorates Renal Fibrosis by Suppressing TGF-β1-Induced Epithelial-to-Mesenchymal Transition.
Renal fibrosis is the common pathological foundation of many chronic kidney diseases (CKDs). The aim of this study was to investigate whether Hydroxysafflor yellow A (HSYA) can preserve renal function by inhibiting the progression of renal fibrosis and the potential mechanisms. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) performed on 7-week-old C57BL/6 mice. HSYA (10, 50 and 100 mg/kg) were intragastrically administered. Sham group and model group were administered with the same volume of vehicle. Serum and kidney samples were collected 14 days after the UUO surgery. Serum biochemical indicators were measured by automatic biochemical analyzer. Histological changes were evaluated by HE and Masson staining. In vitro, the anti-fibrotic effect of HSYA was tested on human recombinant transforming growth factor-β1 (TGF-β1) stimulated HK-2 cells. The protein levels of α-SMA, collagen-I and fibronectin in kidney tissue and HK-2 cells were measured by immunohistochemistry and immunofluorescence. The protein levels of apoptosis-relative and TGF-β1/Smad3 signaling were detected by western blot. HSYA slowed the development of renal fibrosis both in vivo and in vitro. In UUO rats, renal function index suggested that HSYA treatment decreased the level of serum creatinine (Scr) and blood urea nitrogen (BUN) rose by UUO (P<0.05). HE staining and Masson staining demonstrated that kidney interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration were notably attenuated in the high-dose HSYA group compared with the model group. The expressions of α-SMA, collagen-I and fibronectin were decreased in the UUO kidney and HK-2 cells of the HSYA-treatment group. Moreover, HSYA reduced the apoptotic rate of HK-2 cells stimulated by TGF-β1. Further study revealed that HSYA regulated the TGF-β1/Smads signaling pathway both in kidney tissue and HK-2 cells. These results suggested that HSYA had a protective effect against fibrosis in renal cells, at least partly, through inhibiting TGF-β1/smad3-mediated Epithelial-mesenchymal transition signaling pathway.


Mental health activities of family physicians.
A questionnaire survey of residency trained graduates and nonresidency trained family physicians showed both groups reporting relatively infrequent practice of behavioral medicine. Referrals and counseling sessions/visits produce a combined total of 20 activities per month, or two to four percent of all patient encounters, even though the physicians in the sample reported that 33 percent of their diagnoses were behavioral/psychological. More than 85 percent of the physicians reported access to more than one mental health provider. The six most common health problems encountered in the office were depression, anxiety, obesity, marital discord, alcohol abuse, and sexual problems. Physicians responding to this survey expressed an interest in continuing education programs that emphasize individual, marital, and parenting counseling, and psychopharmacology. There is a major need to improve the mental health component of residency training, which will enable physicians to better manage psychosocial problems in practice settings.


A Critical Review on the Relevance of Paracetamol for Procedural Pain Management in Neonates.
Effective and safe pain relief in neonates matters. This is not only because of ethical constraints or human empathy, but even more because pain treatment is an important and crucial part of contemporary medical, paramedical, and nursing care to improve the outcome in neonatal intensive care graduates. Paracetamol (acetaminophen) is likely one of the pharmacological tools to attain this, with data on prescription practices suggesting that paracetamol is somehow the "rising star" in neonatal pain management. Besides very rare topical clinical scenarios like peripartal asphyxia and subsequent whole body hypothermia or the use of cardiorespiratory support devices, data on paracetamol pharmacokinetics and metabolism were reported throughout neonatal age or weight ranges, and we have summarized these data. In this review, we subsequently aimed to provide the reader with the currently available observations on the use of paracetamol as analgesic for different pain syndromes (major surgery, minor surgery or trauma, and procedural pain), with focus on the limitations of paracetamol when prescribed for neonatal procedural pain management. We hereby intentionally will not discuss other indications (patent ductus arteriosus and fever) for paracetamol administration in neonates. Based on the available evidence, paracetamol has opioid-sparing effects for major pain syndromes, is effective to treat minor to moderate pain syndromes, but fails for effective procedural pain management in neonates. This efficacy failure for procedural pain management should stimulate us to continue to search for more effective interventions, including non-pharmacological interventions and preventive strategies. Furthermore, there are also upcoming association type of epidemiological studies on the relation between exposure to analgesics-including paracetamol-and the negative short- or long-term outcome characteristics (neuro-behavioral, atopy, and fertility). Consequently and in addition to the search for effective alternatives to prevent or treat pain, studies on long-term outcome following paracetamol exposure are needed to inform all stakeholders on the full effect-side effect balance of the different strategies to treat pain.


Terahertz Time-Domain Investigation of Axial Optical Activity from a Sub-wavelength Helix.
Chiral media are characterized by preferential interaction with either left- or right- circularly polarized radiation, whereupon an optically active medium and its enantiomorph possess rotary powers of opposing sign due to mirror handedness of their micro- or nano-structures. Here, we report on the first time-resolved investigations of few-cycle pulse propagation along the axis of a sub-wavelength size helix. Time-resolved measurements of the electric field pulse scattered from the helix enable temporal discriminations of transient scattering mechanisms within the helix. Our main finding is that polarization circularization associated with axial propagation through the helix is non-instantaneous, and requires several picoseconds to develop before reaching steady state values. Using a 3D FDTD model, we describe the field and Poynting vector dynamics within the helix leading to steady state polarization circularization. Our conclusions not only support the established picture that optical activity arises from multiple scattering within the helical structure, but also show that this operative mechanism requires a finite time to induce steady state polarization circularization.


Effects of Accentuated Eccentric Loading on Muscle Properties, Strength, Power, and Speed in Resistance-Trained Rugby Players.
Douglas, J, Pearson, S, Ross, A, and McGuigan, M. Effects of accentuated eccentric loading on muscle properties, strength, power, and speed in resistance-trained rugby players. J Strength Cond Res 32(10): 2750-2761, 2018-The purpose of this study was to determine the effects of slow and fast tempo resistance training incorporating accentuated eccentric loading (AEL) compared with traditional resistance training (TRT) in trained rugby players. Fourteen subjects (19.4 ± 0.8 years, 1.82 ± 0.05 m, 97.0 ± 11.6 kg, and relative back squat 1 repetition maximum [1RM]: 1.71 ± 0.24 kg·BM) completed either AEL (n = 7) or TRT (n = 7) strength and power protocols. Two 4-week phases of training were completed. The first phase emphasized a slow eccentric tempo, and the second phase emphasized a fast eccentric tempo. Back squat 1RM, inertial load peak power, drop jump reactive strength index (RSI), 40-m speed, maximum sprinting velocity (Vmax), and vastus lateralis (VL) muscle architectural variables were determined at baseline and after each phase of training. Slow AEL elicited superior improvements in back squat 1RM (+0.12 kg·BM; effect size [ES]: 0.48; and 90% confidence interval [CI]: 0.14, 0.82), 40-m time (-0.07 seconds; ES: 0.28; and CI: 0.01-0.55), and Vmax (+0.20 m·s; ES: 0.52; and CI: 0.18-0.86) vs. slow TRT. Fast AEL elicited a small increase in RSI but impaired speed. There was a likely greater increase in peak power with fast TRT (+0.72 W·kg; ES: 0.40; and CI: 0.00-0.79) vs. fast AEL alongside a small increase in VL pennation angle. The short-term incorporation of slow AEL was superior to TRT in improving strength and maximum velocity sprinting speed in rugby players undertaking a concurrent preparatory program. The second 4-week phase of fast AEL may have exceeded recovery capabilities compared with fast TRT.


Novel β-1,3-d-glucan porous microcapsule enveloped folate-functionalized liposomes as a Trojan horse for facilitated oral tumor-targeted co-delivery of chemotherapeutic drugs and quantum dots.
In this study, a new type of β-1,3-d-glucan porous microcapsule (GPM)-enveloped and folate conjugated chitosan-functional liposome (FCL), FCL@GPM, was developed for the potential oral co-delivery of chemotherapeutic drugs and quantum dots (QDs) with facilitated drug absorption and antitumor efficacy. In this dual-particulate system, multiple FCLs serve as the cores for effective loading, folate-mediated tumor-targeting, facilitated intracellular accumulation, and pH-responsive controlled release of chemotherapeutic agents, while a GPM acts as the shell for affording macrophage-mediated tumor selectivity. Gefitinib (GEF) was selected as a chemotherapeutic agent, while acid degradable ZnO QDs were selected due to their dual role as an anticancer agent for synergistic chemotherapy and as a fluorescent probe for potential cancer cellular imaging. The GEF and ZnO QD co-loaded FCL@GPMs (GEF/ZnO-FCL@GPMs) exhibited a prolonged release manner with limited release before uptake by intestinal cells. Furthermore, Peyer's patch uptake, macrophage uptake, cytotoxicity, and biodistribution of FCL@GPMs were tested. In addition, GEF and ZnO QD co-loaded FCLs (GEF/ZnO-FCLs) not only have a tumor acidity responsive release property, but also induce a superior cytotoxicity on cancer cells as compared to GEF. Moreover, a 1.75-fold increase in the bioavailability of GEF delivered from GEF/ZnO-FCL@GPMs as compared to its trademarked drug (Iressa®). As a result, GEF/ZnO-FCL@GPMs exerted a superior antitumor efficacy (1.47-fold) as compared to the trademarked drug in mice. Considered together, the developed FCL@GPMs, combining the unique physicochemical and biological benefits of FCLs and GPMs, possess great potential as an efficient delivery system for the co-delivery of chemotherapeutic agents and quantum dots.


Phylogenetic analysis and comparative data: a test and review of evidence.
The question is often raised whether it is statistically necessary to control for phylogenetic associations in comparative studies. To investigate this question, we explore the use of a measure of phylogenetic correlation, lambda, introduced by Pagel (1999), that normally varies between 0 (phylogenetic independence) and 1 (species' traits covary in direct proportion to their shared evolutionary history). Simulations show lambda to be a statistically powerful index for measuring whether data exhibit phylogenetic dependence or not and whether it has low rates of Type I error. Moreover, lambda is robust to incomplete phylogenetic information, which demonstrates that even partial information on phylogeny will improve the accuracy of phylogenetic analyses. To assess whether traits generally show phylogenetic associations, we present a quantitative review of 26 published phylogenetic comparative data sets. The data sets include 103 traits and were chosen from the ecological literature in which debate about the need for phylogenetic correction has been most acute. Eighty-eight percent of data sets contained at least one character that displayed significant phylogenetic dependence, and 60% of characters overall (pooled across studies) showed significant evidence of phylogenetic association. In 16% of tests, phylogenetic correlation could be neither supported nor rejected. However, most of these equivocal results were found in small phylogenies and probably reflect a lack of power. We suggest that the parameter lambda be routinely estimated when analyzing comparative data, since it can also be used simultaneously to adjust the phylogenetic correction in a manner that is optimal for the data set, and we present an example of how this may be done.


Function of oval cells in hepatocellular carcinoma in rats.
To study oval cells' pathological characteristics and relationship with the occurrence of hepatocellular carcinoma (HCC); to observe the form and structural characteristics of oval cells; to explore the expression characteristics of C-kit, PCNA mRNA and c-myc gene during the occurrence and development of HCC and the effect of ulinastatin (UTI) on C-kit and PCNA expression. One hundred and twenty-five SD rats fed on 3,3'-diaminobenzidine (DAB) to construct HCC models were divided into control group, cancer-inducing group and UTI intervention group. In each group, rat liver samples were collected at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24 respectively to study pathological distribution characteristics of oval cells in the process of carcinogenesis under optical microscope. Oval cells were separated by the methods of improved density gradient centrifugation and their structural characteristics were observed under optical microscope and electronic microscope respectively; the oval cells expressing C-kit and PCNA in the collected samples were observed by the methods of immunohistochemistry and image analysis and the expression of c-myc mRNA was also detected by reverse transcription polymerase chain reaction (RT-PCR). Oval cells proliferated firstly in the portal area then gradually migrated into hepatic parenchyma in the inducing group and intervention group. The oval cells distributed inside and outside the carcinoma nodes. The oval cells presented the characteristics of undifferentiated cells: a high ratio of nucleolus and cellular plasm and obvious nucleoli, rare organelle in plasm. Only a few mitochondria and endoplasmic reticulum and some villus-like apophysis on surface of cells could be seen. Cells stained with C-kit and PCNA antibody were mainly oval cells distributed in the portal area. The expression of c-myc mRNA increased with the progression of HCC. However, in the intervention group, UTI could retard its increase. Oval cells work throughout the development of HCC, and might play important roles in this process. c-myc gene may be a kind of promoter gene of HCC, and play a key role in hepatic injury and development of HCC. UTI could retard the occurrence of HCC.