Inference of the Xenopus tropicalis embryonic regulatory network and spatial gene expression patterns.
During embryogenesis, signaling molecules produced by one cell population direct gene regulatory changes in neighboring cells and influence their developmental fates and spatial organization. One of the earliest events in the development of the vertebrate embryo is the establishment of three germ layers, consisting of the ectoderm, mesoderm and endoderm. Attempts to measure gene expression in vivo in different germ layers and cell types are typically complicated by the heterogeneity of cell types within biological samples (i.e., embryos), as the responses of individual cell types are intermingled into an aggregate observation of heterogeneous cell types. Here, we propose a novel method to elucidate gene regulatory circuits from these aggregate measurements in embryos of the frog Xenopus tropicalis using gene network inference algorithms and then test the ability of the inferred networks to predict spatial gene expression patterns. We use two inference models with different underlying assumptions that incorporate existing network information, an ODE model for steady-state data and a Markov model for time series data, and contrast the performance of the two models. We apply our method to both control and knockdown embryos at multiple time points to reconstruct the core mesoderm and endoderm regulatory circuits. Those inferred networks are then used in combination with known dorsal-ventral spatial expression patterns of a subset of genes to predict spatial expression patterns for other genes. Both models are able to predict spatial expression patterns for some of the core mesoderm and endoderm genes, but interestingly of different gene subsets, suggesting that neither model is sufficient to recapitulate all of the spatial patterns, yet they are complementary for the patterns that they do capture. The presented methodology of gene network inference combined with spatial pattern prediction provides an additional layer of validation to elucidate the regulatory circuits controlling the spatial-temporal dynamics in embryonic development.


Synthesis and Characterization of Cyclopentadithiophene Heterofulvenes: Design Tools for Light-Activated Processes.
The development of new materials for solar-to-energy conversion should consider stability, ease of fabrication, and beneficial photophysical properties. In this context, a set of novel π-conjugated building blocks, with phospha- and arsaalkenes possessing a unique dithienyl annulated heterofulvenoid core, have been prepared as air- and moisture-stable sensitizers. These compounds unify electron-donor and -acceptor moieties, making them potential candidates for light-harvesting applications. Optical characterization of these systems was performed by steady-state and time-resolved absorption spectroscopy, supported by time-dependent DFT calculations. Tuning of the optical properties of these systems can be achieved by varying the pnictogen element at the bridgehead position, giving a bathochromic shift of ≈40 nm and coordinating the phosphaalkene towards gold AuI centers. The latter results in a ≈2000-fold extension of the ≈10 ps lifetime of uncoordinated systems well into the ns regime.


Application of far infrared rare earth mineral composite materials to liquefied petroleum gas.
Far infrared rare earth mineral composite materials were prepared by the coprecipitation method using tourmaline, cerium acetate, and lanthanum acetate as raw materials. The results of Fourier transform infrared spectroscopy show that tourmaline modified with the rare earths La and Ce has a better far infrared emitting performance. Through XRD analysis, we attribute the improved far infrared emission properties of the tourmaline to the unit cell shrinkage of the tourmaline arising from La enhancing the redox properties of nano-CeO2. The effect of the composite materials on the combustion of liquefied petroleum gas (LPG) was studied by the flue gas analysis and water boiling test. Based on the results, it was found that the composite materials could accelerate the combustion of LPG, and that the higher the emissivity of the rare earth mineral composite materials, the better the effects on combustion of LPG. In all activation styles, both air and LPG to be activated has a best effect, indicating the activations having a cumulative effect.


A mechanistic model for anaerobic phototrophs in domestic wastewater applications: Photo-anaerobic model (PAnM).
Purple phototrophic bacteria (PPB) have been recently proposed as a key potential mechanism for accumulative biotechnologies for wastewater treatment with total nutrient recovery, low greenhouse gas emissions, and a neutral to positive energy balance. Purple phototrophic bacteria have a complex metabolism which can be regulated for process control and optimization. Since microbial processes governing PPB metabolism differ from traditional processes used for wastewater treatment (e.g., aerobic and anaerobic functional groups in ASM and ADM1), a model basis has to be developed to be used as a framework for further detailed modelling under specific situations. This work presents a mixed population phototrophic model for domestic wastewater treatment in anaerobic conditions. The model includes photoheterotrophy, which is divided into acetate consumption and other organics consumption, chemoheterotrophy (including simplified fermentation and anaerobic oxidation) and photoautotrophy (using hydrogen as an electron donor), as microbial processes, as well as hydrolysis and biomass decay as biochemical processes, and is single-biomass based. The main processes have been evaluated through targeted batch experiments, and the key kinetic and stoichiometric parameters have been determined. The process was assessed by analyzing a continuous reactor simulation scenario within a long-term wastewater treatment system in a photo-anaerobic membrane bioreactor.


Efficacy of cilostazol-based dual antiplatelet treatment in patients undergoing carotid artery stenting.
It is essential that patients undergoing carotid artery stenting (CAS) receive optimal antiplatelet inhibition. Although a reduction in platelet reactivity and improved clinical outcomes occur when using adjunctive cilostazol with dual antiplatelet therapy, this can lead to an increased risk of hemorrhagic complications. Therefore, our current study examined patients undergoing CAS and evaluated the impact of cilostazol-based dual antiplatelet treatment on the outcomes. Between 2010 and 2015, 137 consecutive patients underwent CAS. From 2010 to 2011 (period 1), 28 patients underwent CAS in conjunction with aspirin and clopidogrel dual antiplatelet treatment (DAPT). From 2010 to 2013 (period 2), 44 patients underwent a preoperative assessment of their platelet function, with the clopidogrel-resistant patients receiving adjunctive cilostazol in addition to the aspirin and clopidogrel. From 2013 to 2015 (period 3), 65 patients underwent CAS in conjunction with cilostazol and clopidogrel treatment. In all patients, the incidence of new ipsilateral ischemic lesions observed by diffusion-weighted imaging on the day after CAS, and ischemic or hemorrhagic events occurring within 30 days were assessed. Clopidogrel resistance was identified in 43% of the patients in period 1, in 16% in period 2, and in 5% in period 3 (P < 0.001). The on-treatment platelet reactivity results indicated that the PRU value during cilostazol-based DAPT was significantly lower than that observed for the standard DAPT (P < 0.05). New ipsilateral ischemic lesions decreased by 9% and 8% in periods 2 and 3, respectively, versus a 25% decrease in period 1 (P = 0.047). However, there were no significant differences noted for any of the hemorrhagic or thromboembolic events. Compared to the standard aspirin and clopidogrel dual antiplatelet therapy, cilostazol-based dual antiplatelet treatment reduces the rate of clopidogrel resistance and suppresses new ischemic lesions without hemorrhagic complications.


A technique for extending by ∼10(3) the dynamic range of compact proton spectrometers for diagnosing ICF implosions on the National Ignition Facility and OMEGA.
Wedge Range Filter (WRF) proton spectrometers are routinely used on OMEGA and the NIF for diagnosing ρR and ρR asymmetries in direct- and indirect-drive implosions of D(3)He-, D2-, and DT-gas-filled capsules. By measuring the optical opacity distribution in CR-39 due to proton tracks in high-yield applications, as opposed to counting individual tracks, WRF dynamic range can be extended by 10(2) for obtaining the spectral shape, and by 10(3) for mean energy (ρR) measurement, corresponding to proton fluences of 10(8) and 10(9) cm(-2), respectively. Using this new technique, ρR asymmetries can be measured during both shock and compression burn (proton yield ∼10(8) and ∼10(12), respectively) in 2-shock National Ignition Facility implosions with the standard WRF accuracy of ±∼10 mg/cm(2).


Foodborne Snow Mountain agent gastroenteritis in a school cafeteria.
In 1984, an outbreak of gastroenteritis occurred at a school with 1,860 students in Brooklyn, NY. In a single-stage cluster sample of 375 students, 129 (34%) had illnesses that met our case definition of vomiting or diarrhea. The mean incubation period was 26 hours, and the mean illness duration was 24 hours. All case students had eaten in the cafeteria on at least one day between Nov 13 and 16, compared with 174/214 (81%) noncase students (P = 10(-8), Fisher exact test). Foods implicated were french fries (relative risk 1.7, 95% confidence limits 1.4, 2.0) and hamburgers (relative risk 1.6, 95%, confidence limits 1.2, 2.1). Two cafeteria employees had served those foods while affected by diarrhea. By a recently developed blocking enzyme-linked immunosorbent assay, six of 11 (55%) case students showed fourfold antibody increases between acute- and convalescent-phase serum samples for Snow Mountain agent, a Norwalk-like virus, compared with one of ten (10%) noncase students (P = .04, Fisher exact test). We strongly suspect, but cannot document conclusively, that the Snow Mountain agent was spread to students on a vector of hot foods contaminated by ill food handlers. Implicated foods conferred low relative risks and could only have accounted for 74% of cases of illness. The strong association between cafeteria exposure and illness, therefore, suggests that additional modes of spread occurred.


Larvicidal activity of Acacia nilotica extracts and isolation of D-pinitol--a bioactive carbohydrate.
A low-molecular-weight, sugar-like compound other than glucose, fructose, sucrose, or myo-inositol showing lipophilic nature was isolated from the EtOH extract of Acacia nilotica. The structure of the compound was determined by spectral methods. This alicyclic polyalcohol was found to be D-pinitol (= 3-O-methyl-D-chiro-inositol; 1). The configuration of the compound was confirmed by single-crystal X-ray analysis. The compound 1 is known from Soybean, Australian mangroves, Fagonia indica, Arachis hypogaea, etc., but we have isolated this compound for the first time from the aerial parts of A. nilotica. Very few references have been cited for compound 1 for its entomological activity, and there are no reports on mosquitoes. Therefore, the crude extracts of A. nilotica were tested for its biological activity against mosquito larvae. Acetone extract at 500-ppm concentration showed chronic toxicity against Aedes aegypti and Culex quinquefasciatus IVth instar mosquito larvae. Such a biological activity has been observed for the first time for this plant. This study could be a stepping stone to a solution for destroying larval species as well as consumption of such a widely grown, problem weed, A. nilotica. This larvicidal agent, since it is derived from plant, is eco-friendly, cost effective, non-hazardous to non-target organisms and would be safe unlike commercially available insecticides.


Permeability Barrier and Microstructure of Skin Lipid Membrane Models of Impaired Glucosylceramide Processing.
Ceramide (Cer) release from glucosylceramides (GlcCer) is critical for the formation of the skin permeability barrier. Changes in β-glucocerebrosidase (GlcCer'ase) activity lead to diminished Cer, GlcCer accumulation and structural defects in SC lipid lamellae; however, the molecular basis for this impairment is not clear. We investigated impaired GlcCer-to-Cer processing in human Cer membranes to determine the physicochemical properties responsible for the barrier defects. Minor impairment (5-25%) of the Cer generation from GlcCer decreased the permeability of the model membrane to four markers and altered the membrane microstructure (studied by X-ray powder diffraction and infrared spectroscopy), in agreement with the effects of topical GlcCer in human skin. At these concentrations, the accumulation of GlcCer was a stronger contributor to this disturbance than the lack of human Cer. However, replacement of 50-100% human Cer by GlcCer led to the formation of a new lamellar phase and the maintenance of a rather good barrier to the four studied permeability markers. These findings suggest that the major cause of the impaired water permeability barrier in complete GlcCer'ase deficiency is not the accumulation of free GlcCer but other factors, possibly the retention of GlcCer bound in the corneocyte lipid envelope.


Simple Chemical Treatment to n-Dope Transition-Metal Dichalcogenides and Enhance the Optical and Electrical Characteristics.
The optical and electrical properties of monolayer transition-metal dichalcogenides (1L-TMDs) are critically influenced by two dimensionally confined exciton complexes. Although extensive studies on controlling the optical properties of 1L-TMDs through external doping or defect engineering have been carried out, the effects of excess charges, defects, and the populations of exciton complexes on the light emission of 1L-TMDs are not yet fully understood. Here, we present a simple chemical treatment method for n-dope 1L-TMDs, which also enhances their optical and electrical properties. We show that dipping 1Ls of MoS2, WS2, and WSe2, whether exfoliated or grown by chemical vapor deposition, into methanol for several hours can increase the electron density and also can reduce the defects, resulting in the enhancement of their photoluminescence, light absorption, and the carrier mobility. This methanol treatment was effective for both n- and p-type 1L-TMDs, suggesting that the surface restructuring around structural defects by methanol is responsible for the enhancement of optical and electrical characteristics. Our results have revealed a simple process for external doping that can enhance both the optical and electrical properties of 1L-TMDs and help us understand how the exciton emission in 1L-TMDs can be modulated by chemical treatments.


[Heat illness in children].
A child's heatstroke is an unexpected accident; however, we are able to prevent it analyzing the situation which occurred, and its cause. The large-scale research about a child's heatstroke had not been carried out to the past in Japan. According to Heatstroke STUDY, more than 90% of a child's heatstroke were aged 6 and over; furthermore, 70% of those children were doing sports. I expect that this result will lead to prevention of a child's heatstroke further from now on.


PLGA-linked alendronate enhances bone repair in diaphysis defect model.
Alendronate (ALN) is known as an anti-resorptive drug for the treatment of osteoporosis. Recently, ALN was found to stimulate osteogenic differentiation in mesenchymal stem cells and enhance new bone formation in calvarial bone defects. Previous in vitro and in vivo studies found that the effective concentration of ALN was approximately 1-10 μm. In the present study, a poly (lactic-co-glycolic acid) (PLGA) cross-linked ALN (PLGA-ALN) with a short-term controlled-release property for local application to enhance bone repair was developed. An in vitro drug-release kinetic test showed that PLGA-ALN microspheres released an effective concentration (50-100 nm) of ALN for 9 days. The effect of PLGA-ALN on bone repair was tested in a rat femoral bone defect model. The biomechanical study results showed that the maximal strength, stiffness and energy absorption were significantly increased in the PLGA-ALN group compared with the PLGA group. The microstructure of the newly formed bone at the defect site was analysed using microcomputed tomography. The PLGA-ALN group significantly improved the trabecular bone volume at the defect site compared with the PLGA group. The fibril collagen and immunolocalized bone morphogenetic protein 2 were evident in the newly formed trabecular bone in the PLGA-ALN group. Local use of newly developed PLGA-ALN-enhanced bone repair was attributable to increasing bone matrix formation, which improved the ultrastructure of the newly formed bone and thus increased the biomechanical properties of the repaired bone. It is suggested that PLGA-ALN may be a potential bone graft substitute to enhance bone repair. Copyright © 2016 John Wiley & Sons, Ltd.


Non-surgical treatment of vaginal agenesis using a simplified version of Ingram's method.
Non-surgical vaginal dilation is a safe and effective method for the creation of neovagina in the patient with vaginal agenesis. Compared to surgical methods, non-surgical vaginal dilation has the advantage of low morbidity, the creation of a more physiologic vaginal milieu, and no surgical scarring. To overcome some technical limitations of original Frank's method, in 1981 Ingram proposed a modification of the technique that used dilators of gradually increasing size mounted on a bicycle seat stool. Although several studies have shown satisfactory outcomes using Ingram's method, there are some practical difficulties in making and handling the bicycle seat stool. This article reports a case of a 24-year-old woman with Mayer-Rokitansky-Küster-Hauser syndrome whose vaginal agenesis is successfully treated with a simplified version of Ingram's method. This method uses dilators of gradually increasing size mounted on an ordinary chair instead of a bicycle seat stool. When necessary, the patient may use a fulcrum under the dilator.


In vitro metabolism of piperaquine is primarily mediated by CYP3A4.
Piperaquine (PQ) is part of a first-line treatment regimen for Plasmodium falciparum malaria recommended by the World Health Organization (WHO). We aimed to determine the major metabolic pathway(s) of PQ in vitro. A reliable, validated tandem mass spectrometry method was developed. Concentrations of PQ were measured after incubation with both human liver microsomes (HLMs) and expressed cytochrome P450 enzymes (P450s). In pooled HLMs, incubations with an initial PQ concentration of 0.3 µM resulted in a 34.8 ± 4.9% loss of substrate over 60 min, corresponding to a turnover rate of 0.009 min(-1) (r(2) = 0.9223). Miconazole, at nonspecific P450 inhibitory concentrations, resulted in almost complete inhibition of PQ metabolism. The greatest inhibition was demonstrated with selective CYP3A4 (100%) and CYP2C8 (66%) inhibitors. Using a mixture of recombinant P450 enzymes, turnover for PQ metabolism was estimated as 0.0099 min(-1); recombinant CYP3A4 had a higher metabolic rate (0.017 min(-1)) than recombinant CYP2C8 (p < .0001). Inhibition of CYP3A4-mediated PQ loss was greatest using the selective inhibitor ketoconazole (9.1 ± 3.5% loss with ketoconazole vs 60.7 ± 5.9% with no inhibitor, p < .0001). In summary, the extent of inhibition of in vitro metabolism with ketoconazole (83%) denotes that PQ appears to be primarily catalyzed by CYP3A4. Further studies to support these findings through the identification and characterization of PQ metabolites are planned.


Reaction patterns of islet-cell autoantibodies in Macaca nigra.
Circulating islet-cell autoantibodies (ICAAs) that reacted specifically with cytoplasmic components have been found in the blood of prediabetic Macaca nigra. The three distinct reaction patterns observed involved the majority of islet cells throughout the islet; a moderate number of cells, mainly at the islet periphery and around the vasculature; and a few cells scattered throughout the islet. Pancreas sections incubated with sera containing ICAAs followed with peroxidase-conjugated antibody were then reacted with anti-insulin, antiglucagon, or antisomatostatin antisera. The pattern associated with most of the islet cells was shown to be reactive to beta cells and was termed B-ICAA; the pattern with cells at the periphery was identified as alpha cells (A-ICAA); and the scattered cells contained somatostatin (D-ICAA). None of the three islet hormones were able to block ICAA reaction after overnight incubation, so the ICAAs are not anti-islet hormone antibodies. The varied reactions with antigens of different secretory cells indicate release of a variety of immunogens from islet cells as they necrose and cause the formation of different ICAAs.


[Injury among the elderly: the challenge to integrate preventive activities in public and individual levels].
In Brazil and all over the world the elderly are increasing as a result of the raise in life expectancy. This group still faces a significant risk for some diseases as well as injuries. The proposal of this study was to describe fatal and nonfatal injuries among people aged 60 years and older in Brazil. Brazil, the last year available was 2000. The data from 13,383 injury deaths and 87,177 outcomes among people aged 60 years and older were analyzed. The data sets were obtained from Federal Health Department of Brazil from Mortality System Information (from death certificates) and Hospitalization Information System (from discharges registered in public hospitals). The mortality rate is 92.1/100,000 (135.3/100,000 for male and 56.8/100,000 for female) that are higher than overall population rates, especially for women. The lead cause is transport accidents (27.5% of total injury deaths) which mortality rate is 25.3/100,000 and 48.2% are pedestrian. Homicides rate is 9.5/100,000, it is almost three times lower than for total population in Brazil. Falls rate is 14.0/100,000, it is the third place in injury deaths for men and women and suicide rate is 6.9/100,000, lower than developed countries. Opposite to mortality, falls are the major cause of nonfatal injuries hospitalization for both men and women, accounting for 48,940 discharges (56.1%). Fractures are 52.8% of all injuries, especially in falls and transport accidents. It is crucial to develop injury preventive activities in both public and individual level. Falls should receive emphasis in injury prevention efforts.


Communication: One-photon phase control of cis-trans isomerization in retinal.
We computationally demonstrate the one-photon phase control of retinal isomerization under conditions of low laser intensity. The calculations, utilizing the multiconfigurational time dependent Hartree method, include coupling between the two modes that are active in isomerization and the background molecular vibrational environment. Noting previously unsuccessful computations highlights the significance of this result.


Chomping at the Bit: A Descriptive Report on Pediatric Clenbuterol Ingestion.
Clenbuterol hydrochloride is a selective beta-2 adrenergic agonist with uses in both humans and animals. Ingestions occurring within the United States are generally due to incidental ingestion of a veterinary product, use as a cutting agent for illicit substances, or illegal use for performance-enhancing purposes. A four-and-a-half year-old male presented approximately two-and-a-half hours after an accidental ingestion of an unknown quantity of clenbuterol. Initial laboratory results and electrocardiogram were remarkable for hyperglycemia, hypokalemia, and hypophosphatemia, with an electrocardiogram demonstrating sinus tachycardia. Heart rate ranged from 126 to 147 beats per minute while other vitals remained within normal limits. The patient was observed for 24 hours and discharged with normalized vital signs, laboratory results, and electrocardiogram. Clenbuterol hydrochloride is a beta-agonist with high potency, extended half-life, and bioavailability of 70% to 80%. Tachycardia occurs due to beta-1 receptor stimulation, as well as a homeostatic reflex to peripheral vasodilation. Hyperglycemia is not uncommon in exposures and intracellular shifting of potassium causes hypokalemia. Treatment is primarily supportive in nature, with hemodynamic management representing the primary focus of initial triage.


Tristetraprolin induces cell cycle arrest in breast tumor cells through targeting AP-1/c-Jun and NF-κB pathway.
The main characteristic of cancers, including breast cancer, is the ability of cancer cells to proliferate uncontrollably. However, the underlying mechanisms of cancer cell proliferation, especially those regulated by the RNA binding protein tristetraprolin (TTP), are not completely understood. In this study, we found that TTP inhibits cell proliferation in vitro and suppresses tumor growth in vivo through inducing cell cycle arrest at the S phase. Our studies demonstrate that TTP inhibits c-Jun expression through the C-terminal Zn finger and therefore increases Wee1 expression, a regulatory molecule which controls cell cycle transition from the S to the G2 phase. In contrast to the well-known function of TTP in regulating mRNA stability, TTP inhibits c-Jun expression at the level of transcription by selectively blocking NF-κB p65 nuclear translocation. Reconstitution of NF-κB p65 completely abolishes the inhibition of c-Jun transcription by TTP. Moreover, reconstitution of c-Jun in TTP-expressing breast tumor cells diminishes Wee1 overexpression and promotes cell proliferation. Our results indicate that TTP suppresses c-Jun expression that results in Wee1 induction which causes cell cycle arrest at the S phase and inhibition of cell proliferation. Our study provides a new pathway for TTP function as a tumor suppressor which could be targeted in tumor treatment.


Rethinking volitional control over task choice in multitask environments: use of a stimulus set selection strategy in voluntary task switching.
Under conditions of volitional control in multitask environments, subjects may engage in a variety of strategies to guide task selection. The current research examines whether subjects may sometimes use a top-down control strategy of selecting a task-irrelevant stimulus dimension, such as location, to guide task selection. We term this approach a stimulus set selection strategy. Using a voluntary task switching procedure, subjects voluntarily switched between categorizing letter and number stimuli that appeared in two, four, or eight possible target locations. Effects of stimulus availability, manipulated by varying the stimulus onset asynchrony between the two target stimuli, and location repetition were analysed to assess the use of a stimulus set selection strategy. Considered across position condition, Experiment 1 showed effects of both stimulus availability and location repetition on task choice suggesting that only in the 2-position condition, where selection based on location always results in a target at the selected location, subjects may have been using a stimulus set selection strategy on some trials. Experiment 2 replicated and extended these findings in a visually more cluttered environment. These results indicate that, contrary to current models of task selection in voluntary task switching, the top-down control of task selection may occur in the absence of the formation of an intention to perform a particular task.


Synthesis, structural investigations, hydrogen-deuterium exchange studies, and molecular modeling of conformationally stablilized aromatic oligoamides.
Biasing the conformational preferences of aromatic oligoamides by internally placing intramolecular hydrogen bonds has led to a series of stably folded molecular strands. This article presents the results from extensive solid-state, solution, and computational studies on these folding oligomers. Depending on its backbone length, an oligoamide adopts a crescent or helical conformation. Surprisingly, despite the highly repetitive nature of the backbone, the internally placed, otherwise very similar intramolecular hydrogen bonds showed significantly different stabilities as demonstrated by hydrogen-deuterium exchange data. It was also observed that the hydrogen-bonding strength can be tuned by adjusting the substituents attached to the exterior of the aromatic backbones. Examining the amide hydrogen-deuterium exchange rates of trimers revealed that a six-membered hydrogen bond nearing the ester end is the weakest among all the four intramolecular hydrogen bonds of a molecule. This observation was verified by ab initio quantum mechanical calculations at the level of B3LYP/6-31G*. Such a "weak point" creates the "battle of the bulge" where backbone twisting is centered, which is consistently observed in the solid-state structures of the four trimer molecules studied. In the solid state, the oligomers assemble into interesting one-dimensional structures. A pronounced columnar packing of short oligomers (i.e., dimers, trimers, and tetramer) and channel-like, potentially ion-conducting stacks of longer oligomers (i.e., tetramer, pentamer, and hexamer) were observed.


Hyper- and hypocardiodynamic states are associated with externalization and internalization, respectively, of alpha-adrenergic receptors in rat heart during sepsis.
Alterations in the distribution of alpha-adrenergic receptors (alpha ARs) in two subcellular organelles, the sarcolemmal membrane and the light vesicle, of rat heart during the progression of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). alpha ARs were assayed by using [3H]prazosin binding and photoaffinity labeling with [125I]arylazidoprazosin in combination with polyacrylamide gel electrophoresis. Septic rat hearts exhibit two distinct phases: an initial hypercardiodynamic (9 h after CLP; early sepsis) followed by a hypocardiodynamic (18 h after CLP; late sepsis) phase. [3H]prazosin binding studies show that during early sepsis, the Bmax (maximal binding capacity) was increased by 21.4% in sarcolemma but was decreased by 22.5% in light vesicles, while during late sepsis, the Bmax was decreased by 25.4% in sarcolemma but was increased by 60.8% in light vesicles. The photoaffinity labeling studies revealed three binding peptides with M(r) of 77, 68, and 39 kDa. The total binding for the three label peptides during early sepsis was increased by 25.5% in sarcolemma but was decreased by 40% in light vesicles, while during late sepsis, the total binding was decreased by 32.1% in sarcolemma but was increased by 35.8% in light vesicles. These data indicate that alpha ARs in the rat heart were externalized from light vesicles to sarcolemma during early hypercardiodynamic phase while they were internalized from surface membranes to intracellular compartment during late hypocardiodynamic phase of sepsis. Because alpha ARs play an important role in regulating myocardial contractility, an initial externalization followed by internalization of alpha ARs may contribute to the development of the initial hypercardiodynamic and the subsequent hypocardiodynamic states during sepsis.


Differential Distribution of Laminin N-Terminus α31 Across the Ocular Surface: Implications for Corneal Wound Repair.
Laminin N-terminus (LaNt) α31 is a relatively unstudied protein derived from the laminin α3 gene but structurally similar to netrins. LaNt α31 has, to date, been investigated only in two-dimensional (2D) keratinocyte culture where it influences cell migration and adhesion, processes integral to wound repair. Here we investigated LaNt α31 distribution in ocular surface epithelium, during limbal stem cell activation, and corneal wound healing. Human, mouse, and pig eyes, ex vivo limbal explant cultures, and alkali burn wounds were processed for immunohistochemistry with antibodies against LaNt α31 along with progenitor cell-associated proteins. LaNt α31 expression was induced via adenoviral transduction into primary epithelial cells isolated from limbal explants, and cell spreading and migration were analyzed using live imaging. LaNt α31 localized to the basal layer of the conjunctival, limbal, and corneal epithelial cells. However, staining was nonuniform with apparent subpopulation enrichment, and some suprabasal reactivity was also noted. This LaNt α31 distribution largely matched that of keratin 15, epidermal growth factor receptor, and transformation-related protein 63α (p63α), and displayed similar increases in expression in activated limbal explants. During active alkali burn wound repair, LaNt α31 displayed increased expression in limbal regions and loss of basal restriction within the cornea. Distribution returned to predominately basal cell restricted once the wounded epithelium matured. Cultured corneal epithelial cells expressing LaNt α31 displayed increased 2D area and reduced migration, suggesting a functional link between this protein and key wound repair activities. These data place LaNt α31 in position to influence laminin-dependent processes including wound repair and stem cell activation.


The human thromboxane A2 receptor alpha isoform (TP alpha) functionally couples to the G proteins Gq and G11 in vivo and is activated by the isoprostane 8-epi prostaglandin F2 alpha.
To establish whether the thromboxane A2 (TXA2) receptor (TP) functionally couples to the Gq family of heterotrimeric G proteins in vivo, we have coexpressed the cDNAs coding for the human platelet/placental TP alpha isoform (TP alpha) and the alpha subunits of Gq or G11 in human embryonic kidney (HEK) 293 cells. TP activation in response to ligand stimulation was monitored by analyzing mobilization of intracellular calcium (Ca++i) in FURA2/AM-loaded transfected HEK 293 and in platelets. Second, we wished to examine the possible interaction of the isoprostane 8-epi prostaglandin F2 alpha with the TP alpha, in transfected HEK 293 cells and with the TPs expressed in platelets. Thus both the prostaglandin endoperoxide/TXA2 analog (U46619) and the 8-epi PGF2 alpha were utilized as ligand probes of TP alpha activation. The results demonstrate that each ligand induced elevations of Ca++i levels in HEK 293 cells, cotransfected with either the TP alpha and G alpha q or the TP alpha and G alpha 11, and also in platelets. Initial stimulation of these cells with U46619 or 8-epi PGF 2 alpha desensitized a subsequent rise in [Ca++]i in response to U46619 or 8-epi PGF 2 alpha, respectively. Moreover, prestimulation with U46619 desensitized a subsequent rise in Ca++i concentration in response to 8-epi PGF 2 alpha, and vice versa. These responses were blocked by the TP antagonist SQ29,548 in both cell types. In contrast, prestimulation of the transfected HEK 293 cells or platelets with thrombin did not desensitize a subsequent rise in [Ca++]i in response to U46619 or 8-epi PGF 2 alpha. After stimulation with either U46619 or 8-epi PGF 2 alpha, no significant rise in Ca++i levels was observed in HEK 293 cells transfected with the TP alpha receptor only or in control cells transfected with the vector pCMV5. These results demonstrate that the TP alpha isoform functionally couples with either Gq or G11 in vivo, whether activated by a PG/TXA2 analog or by the F2 isoprostane 8-epi PGF2 alpha.


Anticancer therapy induced cardiotoxicity: review of the literature.
Innovative anticancer strategies have contributed to an improved survival of patients suffering from malignancies, and in some cases, have turned cancer into a chronic disease. Therefore, the early and particularly late onsets of adverse cardiovascular effects of systemic anticancer treatments are of increasing interest. Among a rapidly increasing variety of anticancer drugs, the anthracyclines and the monoclonal antibody, trastuzumab, are the agents with a well-known cardiotoxicity. The diagnostic work-up, the cardiotoxic risk of anthracyclines and trastuzumab, and additionally, cardiotoxicity as a risk factor of a multimodal therapeutic approach in breast cancer patients is discussed in this study.


Performance of an integrated system combining microalgae and vertical flow constructed wetlands for urban wastewater treatment.
The present study investigated the performance of an integrated system, combining the sequential use of microalgae (MA) and vertical flow constructed wetland (VFCW) for the treatment of wastewaters produced at a university campus. Ecotoxicity and phytotoxicity assays were performed using respectively Daphnia magna and Lactuca sativa, whereas the genotoxicity of the wastewaters was assessed by using D. magna and Allium cepa. The results revealed that the major environmental impacts of the studied wastewaters are associated with the high eutrophication potential, due to high N-NH3 (68.8 ± 25.7 mg L-1), total P (7.71 ± 2.5 mg L-1), and BOD5 (526.4 ± 177 mg L-1) values, pathogenic load, and genototoxicity (p < 0.0001). The results also showed that the integrated system (MA + VFCW) was not able to satisfactory reduce the total p values (only 4%). Nevertheless, the MA + VFCW system achieved very promising results for the nitrogen removal, with emphasis on N-NH3 removal (100%) and the highest BOD5 removal (57%). Neither the raw wastewaters nor the treated wastewaters were phytotoxic. The integrated system completely eliminated the ecotoxicity (100%) and genotoxicity (n.s.) of the raw wastewater and showed decontamination potential. Thus, the integrated system emerges as an innovative environmental technology and, with minor adjustments, might be efficiently used in large scale and eventually replace conventional wastewater treatment systems.


Physiological factors with impact on the drug behaviour in the gastrointestinal tract.
Orally administered drugs are passed through the gastrointestinal tract (GIT), which influences their next metabolism in the body. In the case of systemic administration, the drug is released from the dosage form, is dissolved and eventually absorbed. The residual amount is excreted in the faeces. The main factors influencing administered drugs are particularly pH, passage time, solubilizers or the oxido-reductive potential in different parts of the GIT. These factors are directly related to the release, absorption and stability of drugs. They can be used for simulation of the GIT environment in vitro and for the overall design of the dosage form in vivo. Because some literature data are not given in context and sometimes they are contradictory, this paper summarizes elementary values of the above-mentioned physiological parameters in the form of a review.


Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease.
Vitamin A (retinoid) is required in the adult brain to enable cognition, learning, and memory. While brain levels of retinoid diminish over the course of normal ageing, retinoid deficit is greater in late onset Alzheimer disease (LOAD) brains than in normal-aged controls. This paper reviews recent evidence supporting these statements and further suggests that genes necessary for the synthesis, transport and function of retinoid to and within the ageing brain are appropriate targets for treatment of LOAD. These genes tend to be clustered with genes that have been proposed as candidates in LOAD, are found at chromosomal regions linked to LOAD, and suggest the possibility of an overall coordinated regulation. This phenomenon is termed Chromeron and is analogous to the operon mechanism observed in prokaryotes. Suggested treatment targets are the retinoic-acid inactivating enzymes (CYP26)s, the retinol binding and transport proteins, retinol-binding protein (RBP)4 and transthyretin (TTR), and the retinoid receptors. TTR as a LOAD target is the subject of active investigation. The retinoid receptors and the retinoid-inactivating enzymes have previously been proposed as targets. This is the first report to suggest that RBP4 is an amenable treatment target in LOAD. RBP4 is elevated in type-2 diabetes and obesity, conditions associated with increased risk for LOAD. Fenretinide, a novel synthetic retinoic acid (RA) analog lowers RBP4 in glucose intolerant obese mice. The feasibility of using fenretinide either as an adjunct to present LOAD therapies, or on its own as an early prevention strategy should be determined.


Efficiency and thermal changes during implantoplasty in relation to bur type.
Implantoplasty is one of the options in treating peri-implantitis. The efficacy of the dental bur used can reduce the time needed for the procedure and, as a consequence, minimize the risk of overheating that can negatively affect the remaining bone surrounding the implant. The aim of this study was to evaluate the efficacy of three dental burs in removing implant substance (titanium) and to determine the amount of heat generated by each bur. Four burs with different surface properties (diamond, diamond - Premium Line, carbide, and smooth bur - control [Strauss Co., Raanana, Israel]) were attached to a high-speed handpiece and applied to a titanium implant for a total of 60 seconds after cooling by water spray. Variations in temperature were recorded every 5 seconds, and the amount of implant substance removed (reduction in weight of the implant) was evaluated. The diamond Premium Line bur removed 59.24 mg; carbide, 29.39 mg; diamond, 11.35 mg; and smooth bur (control) 0.19 mg, statistically significant. Only minimum thermal changes (∼1.5°C) were recorded for all four burs. There are considerable differences in efficiency of different burs working on titanium. Selecting the proper bur can reduce working time. Under proper cooling conditions, implantoplasty does not generate excess temperature increases that can damage soft tissue or bone surrounding the treated implant.


Fasting decreases apolipoprotein B mRNA editing and the secretion of small molecular weight apoB by rat hepatocytes: evidence that the total amount of apoB secreted is regulated post-transcriptionally.
Two different molecular weight forms of apoB are produced from a common initial transcript via editing of a Gln codon (CAA) to a stop codon (UAA), leading to a truncated translation product (apo BS) that consists of the amino terminal half of the larger form (apoBL). Previous studies have shown that fasting coordinately decreases lipogenesis and the secretion of very low density lipoprotein (VLDL) lipids and apoBS. Secretion of the apoBL is unaffected by fasting. We studied whether editing of apoB RNA is repressed by fasting, thus accounting for the selective decreased secretion of apoBS. Column chromatography of [35S]methionine-labeled lipoproteins secreted by hepatocytes from fed rats showed that essentially all of apoBL is secreted in the VLDL fraction, whereas a significant amount (15%) of apoBS is secreted associated as lipoproteins eluting in the HDL fractions. Fasting decreased the relative amount of apoBS that eluted in the VLDL fractions and increased the amount secreted in the HDL fractions. Consistent with previous results, hepatocytes from fasted rats show a selective twofold decrease in apoBS secretion. Fasting did not affect the relative abundance of apoB RNA, determined by slot blot hybridization assays using two different 32P-labeled cDNA probes coding either for both molecular weight forms or for only the large molecular weight form. However, quantitative of the editing of apoB RNA showed that fasting caused a 60% decrease in the amount of apoB RNA possessing the stop codon. These data show that the editing of apoB RNA is sensitive to metabolic state (i.e., fasting) resulting in a selective decrease in the secretion of apoBS. However, since the total secretion of apoB was decreased by fasting, while apoB mRNA levels remained constant, additional (post-transcriptional) mechanisms play a role in regulating apoB secretion.


[Mandibular condyle fractures: conservative treatment versus surgical treatment].
A review of medical literature on the various principles of medical care of condylar fractures confirms that the treatment is still controversial. For a long period of time, the conservative functional treatment of condylar fractures was a dominant philosophy. However, rigid internal fixation of condylar fractures is increasingly accepted as an alternative which presents an improved stability provided by the use of plate and screw fixation techniques. The purpose of this study is to compare the clinical and radiographic long-term results of patients with condylar fractures treated between 1984 and 1992 in our department. 51 patients were treated in a conservative functional way. Rigid internal fixation was performed in 25 patients using an intraoral approach, according to a technique described by Steinhäuser in 1964. The results of this retrospective analysis indicate that in fractures of the condylar head a conservative functional treatment is the therapy of choice. Fractures of the subcondylar region and also--in selected clinical circumstances--fractures of the condylar neck represent indications for a carefully executed rigid internal fixation. The intraoral approach has been proved to cause minimal morbidity and complications.


Systematic functional interrogation of human pseudogenes using CRISPRi.
The human genome encodes over 14,000 pseudogenes that are evolutionary relics of protein-coding genes and commonly considered as nonfunctional. Emerging evidence suggests that some pseudogenes may exert important functions. However, to what extent human pseudogenes are functionally relevant remains unclear. There has been no large-scale characterization of pseudogene function because of technical challenges, including high sequence similarity between pseudogene and parent genes, and poor annotation of transcription start sites. To overcome these technical obstacles, we develop an integrated computational pipeline to design the first genome-wide library of CRISPR interference (CRISPRi) single-guide RNAs (sgRNAs) that target human pseudogene promoter-proximal regions. We perform the first pseudogene-focused CRISPRi screen in luminal A breast cancer cells and reveal approximately 70 pseudogenes that affect breast cancer cell fitness. Among the top hits, we identify a cancer-testis unitary pseudogene, MGAT4EP, that is predominantly localized in the nucleus and interacts with FOXA1, a key regulator in luminal A breast cancer. By enhancing the promoter binding of FOXA1, MGAT4EP upregulates the expression of oncogenic transcription factor FOXM1. Integrative analyses of multi-omic data from the Cancer Genome Atlas (TCGA) reveal many unitary pseudogenes whose expressions are significantly dysregulated and/or associated with overall/relapse-free survival of patients in diverse cancer types. Our study represents the first large-scale study characterizing pseudogene function. Our findings suggest the importance of nuclear function of unitary pseudogenes and underscore their underappreciated roles in human diseases. The functional genomic resources developed here will greatly facilitate the study of human pseudogene function.


A within-group design of nontreatment seeking 5-HTTLPR genotyped alcohol-dependent subjects receiving ondansetron and sertraline.
Serotonergic mechanisms are associated with the development of alcohol dependence (AD), however, studies evaluating serotonergic medications have produced conflicting results. One hypothesis suggests that differential response may be due to a functional polymorphism of the 5-HTTLPR promoter region of the serotonin re-uptake transporter (5-HTT). The L/L genotype is postulated to be associated with early onset alcoholism and the S/S or S/L genotypes associated with late onset alcoholism. The aim of this study was to match and mismatch L/L, S/S, or S/L genotypes with administration of ondansetron and sertraline. Fifteen nontreatment seeking alcohol-dependent individuals were randomized to 1 of 2 counterbalanced arms to receive either 200 mg/d of sertraline or ondansetron 0.5 mg/d for 3 weeks followed by an alcohol self-administration experiment (ASAE), then received placebo for 3 weeks followed by a second ASAE. Participants then received the alternate drug for 2 weeks followed by a third ASAE. At the first ASAE compared to sertraline, ondansetron significantly improved drinking outcomes for the L/L genotype for the ASAE volume consumed (100% reduction based on between-subjects comparison, t = 2.35), and for drinks per drinking day during the 7 days prior to the ASAE (79% reduction and t = 4.34). Compared with ondansetron for S/S or S/L genotypes, outcomes at ASAE 1 for sertraline and S/S or S/L genotypes are opposite than hypothesized. Overall, subjects reduced drinking across their participation in the trial, as there appears to be an order effect. This study suggests that ondansetron may reduce alcohol consumption in alcohol-dependent individuals who have the L/L genotype as measured naturalistically and during the ASAE. By contrast there was no support that sertraline reduces alcohol use in individuals who have S/S or S/L genotypes. Evidence in the literature suggests that AD in some individuals may be influenced by a gene by socio-environmental interaction making pharmacological treatment with serotonergic drugs complex. Research must consider that typologies may predict successful treatment of AD in future trials.


Effect of palmitic acid and linoleic acid on expression of ICAM-1 and VCAM-1 in human bone marrow endothelial cells (HBMECs).
The amount and type of fatty acids (FAs) in the diet influence the risk of atherosclerosis. Palmitic acid and linoleic acid exist at high levels in Iranian edible oils. In this study, we investigated the effect of palmitic acid and linoleic acid on expression of soluble and cell-associated forms of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human bone marrow endothelial cells (HBMECs). The endothelial cells were induced with bacterial lipopolysaccharide (LPS) or tumor necrosis factor α (TNF-α), and thereafter incubated with palmitic or linoleic acid. The level of soluble and cell-associated VCAM-1 and ICAM-1 were analyzed using ELISA and western blot. Our findings indicated that palmitic acid up-regulates the expression of ICAM-1 and VCAM-1 in HBMECs when these cells are induced with TNF-α or LPS. In addition, the results suggest that linoleic acid could sustain up-regulated ICAM-1 and VCAM-1 in activated endothelial cells. Chronic activation of endothelial cells in the presence of palmitic and linoleic may account for pathogenesis of cardiovascular events. These findings provide further support for the detrimental effects of these fatty acids, especially palmitic acid, in promotion and induction of cardiovascular diseases which are prevalent in the Iranian population.


A comprehensive review on multi-colored emissive carbon dots as fluorescent probes for the detection of pharmaceutical drugs in water.
Exposure to constituent hazardous chemicals in medical products has become a threat to environmental health across the globe. Excessive medication and the mishandling of pharmaceutical drugs can lead to the increased presence of chemicals in the aquatic environment, causing water pollution. Only a few nanomaterials exist for the detection of these chemicals and they are limited in use due to their adverse toxicity, instability, cost, and low aqueous solubility. In contrast, carbon dots (C-dots), a member of the family of carbon-based nanomaterials, have various beneficial properties including excellent biocompatibility, strong photoluminescence, low photobleaching, tunable fluorescence, and easy surface modification. Herein, we summarize recent advancements in various synthetic strategies for high-quality tunable fluorescent C-dots. The root of fluorescence has been briefly explained via the quantum confinement effect, surface defects, and molecular fluorescence. The surface functional moieties of C-dots have been investigated in depth to recognize the various types of pharmaceutical drugs that are used for the treatment of patients. The modulation of C-dot fluorescence in the course of their interactions with these drugs has been carefully explained. Different types of interaction mechanisms behind the C-dot fluorescence alteration have been discussed. Finally, the challenges and future perspectives of C-dots have been proposed for the vibrant field development of C-dot-based drug sensors.


Four-week prevalence of mental disorders in patients with cancer across major tumor entities.
To provide the 4-week prevalence estimates of mental disorders in cancer populations. We enrolled adult patients with cancer from in- and outpatient care facilities, using a proportional stratified random sample based on the nationwide cancer incidence in Germany. Patients who scored 9 or above on the Patient Health Questionnaire (PHQ-9) were administered to the standardized computer-assisted Composite International Diagnostic Interview for mental disorders adapted for cancer patients (CIDI-O). A random sample of those with a PHQ-9 score that was less than 9 were selected for a CIDI-O. A total of 5,889 patients were identified, which led to 4,020 participants (a 68.3% response rate); of those, 2,141 patients were interviewed. The 4-week total prevalence for any mental disorder was 31.8% (95% CI, 29.8% to 33.8%); this included any anxiety disorder (11.5%; 95% CI, 10.2% to 12.9%), any adjustment disorder (11.1%; 95% CI, 9.7% to 12.4%), any mood disorder (6.5%; 95% CI, 5.5% to 7.5%), any somatoform/conversion disorder (5.3%; 95% CI, 4.3% to 6.2%), nicotine dependence (4.5%; 95% CI, 3.6% to 5.4%), alcohol abuse/dependence (0.3%; 95% CI, 0.1% to 0.6%), any mental disorder resulting from general medical condition (2.3%; 95% CI, 1.7% to 2.9%), and any eating disorder (0%). The highest prevalence for any mental disorder was found in patients with breast cancer (41.6%; 95% CI, 36.8% to 46.4%), followed by patients with head and neck cancer (40.8%; 95% CI, 28.5% to 53.0%). The lowest prevalence was found in patients with pancreatic cancer (20.3%; 95% CI, 8.9% to 31.6%) and stomach/esophagus cancers (21.2%; 95% CI, 12.8% to 29.6%). Our findings provide evidence for the strong need for psycho-oncological interventions.


A reciprocal 15N-labeling proteomic analysis of expanding Arabidopsis leaves subjected to osmotic stress indicates importance of mitochondria in preserving plastid functions.
Plants respond to environmental stress by dynamically reprogramming their growth. Whereas stress onset is accompanied by rapid growth inhibition leading to smaller organs, growth will recover and adapt once the stress conditions become stable and do no threaten plant survival. Here, adaptation of growing Arabidopsis thaliana leaves to mild and prolonged osmotic stress was investigated by means of a complete metabolic labeling strategy with the (15)N-stable isotope as a complement to a previously published transcript and metabolite profiling. Global analysis of protein changes revealed that plastidial ATPase, Calvin cycle, and photorespiration were down-regulated, but mitochondrial ATP synthesis was up-regulated, indicating the importance of mitochondria in preserving plastid functions during water stress. Although transcript and protein data correlated well with the stable and prolonged character of the applied stress, numerous proteins were clearly regulated at the post-transcriptional level that could, at least partly, be related to changes in protein synthesis and degradation. In conclusion, proteomics using the (15)N labeling helped understand the mechanisms underlying growth adaptation to osmotic stress and allowed the identification of candidate genes to improve plant growth under limited water.


An efficient rank based approach for closest string and closest substring.
This paper aims to present a new genetic approach that uses rank distance for solving two known NP-hard problems, and to compare rank distance with other distance measures for strings. The two NP-hard problems we are trying to solve are closest string and closest substring. For each problem we build a genetic algorithm and we describe the genetic operations involved. Both genetic algorithms use a fitness function based on rank distance. We compare our algorithms with other genetic algorithms that use different distance measures, such as Hamming distance or Levenshtein distance, on real DNA sequences. Our experiments show that the genetic algorithms based on rank distance have the best results.


Bioethics and the contemporary Jewish community.
David Novak takes up the methodological issue of how substantive religious perspectives can be communicated in a pluralistic society. Novak notes that while "secularism" was historically welcomed by the Jewish community, Jewish thinkers now likewise face the challenge of speaking out of a tradition to a secular audience. Novak holds up Jewish-Christian dialogue as a model for constructing a public philosophy.


Governing stem cell therapy in India: regulatory vacuum or jurisdictional ambiguity?
Stem cell treatments are being offered in Indian clinics although preclinical evidence of their efficacy and safety is lacking. This is attributed to a governance vacuum created by the lack of legally binding research guidelines. By contrast, this paper highlights jurisdictional ambiguities arising from trying to regulate stem cell therapy under the auspices of research guidelines when treatments are offered in a private market disconnected from clinical trials. While statutory laws have been strengthened in 2014, prospects for their implementation remain weak, given embedded challenges of putting healthcare laws and professional codes into practice. Finally, attending to the capacities of consumer law and civil society activism to remedy the problem of unregulated treatments, the paper finds that the very definition of a governance vacuum needs to be reframed to clarify whose rights to health care are threatened by the proliferation of commercial treatments and individualized negligence-based remedies for grievances.


Interference of Salmonella enteritidis and Lactobacillus spp. with IL-8 levels and transepithelial electrical resistance of enterocyte-like Caco-2 cells.
Caco-2 cells (exhibiting characteristics of mature villus enterocytes) were used to determine bacteria (Salmonella enteritidis causing human gastroenteritis)-intestinal cell interactions. The interference of bacteria with the transepithelial electrical resistance (TEER) of filter-grown Caco-2 cells and the production of IL-8 after exposure of the cells to S. enteritidis 857 and/or Lactobacillus strains (L. gasseri LF221 and L. rhamnosus BGT10) was evaluated. The strain 857 decreased TEER of filter-grown Caco-2 cells; in contrast, lactobacilli had a little or no effect. The effect of S. enteritidis on the TEER decreased if Caco-2 cells were pre-incubated with lactobacilli. This strain induced high levels of IL-8 (which can lead to cell damage). Compared to the IL-8 synthesis after exposure of Caco-2 cells to S. enteritidis 857, simultaneous exposure of Caco-2 cells to S. enteritidis and lactobacilli inhibited the IL-8 synthesis after short recovery periods.


Patterns of long bone growth in a mid-19th century documented sample of the urban poor from Bethnal Green, London, UK.
Studies of male and female long bone growth in past populations are limited and usually constrained by the lack of personal identification. This article aimed to evaluate long bone growth in a series of mid-19th century documented burials associated with the urban poor from Bethnal Green, London, UK. Maximum diaphyseal lengths from 74 males and 70 females (2 months to 12 years) were compared to modern reference data from North America. Diaphyseal lengths were expressed as a percentage of expected length and an average percentage value was calculated across all available long bones. An index of growth progression was introduced to explore differences in the progress of males and females towards their projected adult size. Deviation from the expected growth attainment was evident in both sexes in the archaeological series by 2-4 months of age. Only 19.4% (28/144) of the children had attained an average long bone length >90% of the predicted mean in the reference series. The percentage of expected growth attainment decreased steadily in both sexes during infancy and early childhood. Overall, females deviated further from their expected growth progression than males. Growth faltering in both males and females was established during infancy (<1 year) with no evidence for recovery in older age groups. Early weaning and inadequate artificial feeding, together with impoverished living conditions and limited sanitary provision, most likely impacted on childhood growth.


Arsenite Methyltransferase Is an Important Mediator of Hematotoxicity Induced by Arsenic in Drinking Water.
Chronic arsenic exposures via the consumption of contaminated drinking water are clearly associated with many deleterious health outcomes, including anemia. Following exposure, trivalent inorganic arsenic (AsIII) is methylated through a series of arsenic (+III oxidation state) methyltransferase (As3MT)-dependent reactions, resulting in the production of several intermediates with greater toxicity than the parent inorganic arsenicals. The extent to which inorganic vs. methylated arsenicals contribute to AsIII-induced hematotoxicity remains unknown. In this study, the contribution of As3MT-dependent biotransformation to the development of anemia was evaluated in male As3mt-knockout (KO) and wild-type, C57BL/6J, mice following 60-day drinking water exposures to 1 mg/L (ppm) AsIII. The evaluation of hematological indicators of anemia revealed significant reductions in red blood cell counts, hemoglobin levels, and hematocrit in AsIII-exposed wild-type mice as compared to unexposed controls. No such changes in the blood of As3mt-KO mice were detected. Compared with unexposed controls, the percentages of mature RBCs in the bone marrow and spleen (measured by flow cytometry) were significantly reduced in the bone marrow of AsIII-exposed wild-type, but not As3mt-KO mice. This was accompanied by increased levels of mature RBCS in the spleen and elevated levels of circulating erythropoietin in the serum of AsIII-exposed wild-type, but not As3mt-KO mice. Taken together, the findings from the present study suggest that As3MT-dependent biotransformation has an essential role in mediating the hematotoxicity of AsIII following drinking water exposures.


EUS fine-needle pancreatic core biopsy can determine eligibility for tumor-agnostic immunotherapy.
Background and study aims The US FDA recently approved a cancer treatment with pembrolizumab based upon the tumor biomarker status of deficient mismatch repair (dMMR) rather than a specific disease-based approach. We sought to determine if endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) could determine dMMR and quantification of PD-L1 expression to potentially guide the delivery of tumor agnostic immunotherapy. Patients and methods Immunohistochemistry was performed on archived pancreas core biopsy specimens. Tumors with absent nuclear staining of DNA mismatch repair proteins represented dMMR. Tumors were considered to have any or high PD-L1 expression, if expressed in ≥ 1 % or ≥ 50 % of tumor cells. Results Histologic specimen adequacy for MMR status assessment was satisfactory in 97.2 % of tumors. dMMR and high PD-L1 expression was identified in 3 % and 8.1 % of the cohort. Conclusion In the setting of tumor type agnostic immunotherapy, it is projected that at least 3 % of malignant pancreas lesions will be sensitive to pembrolizumab and up to 8 % sensitive to the family of immune checkpoint inhibitors. This highlights the expanding role of EUS-FNB in the field of precision immuno-oncology.


A generic TG-186 shielded applicator for commissioning model-based dose calculation algorithms for high-dose-rate 192 Ir brachytherapy.
A joint working group was created by the American Association of Physicists in Medicine (AAPM), the European Society for Radiotherapy and Oncology (ESTRO), and the Australasian Brachytherapy Group (ABG) with the charge, among others, to develop a set of well-defined test case plans and perform calculations and comparisons with model-based dose calculation algorithms (MBDCAs). Its main goal is to facilitate a smooth transition from the AAPM Task Group No. 43 (TG-43) dose calculation formalism, widely being used in clinical practice for brachytherapy, to the one proposed by Task Group No. 186 (TG-186) for MBDCAs. To do so, in this work a hypothetical, generic high-dose rate (HDR) 192 Ir shielded applicator has been designed and benchmarked. A generic HDR 192 Ir shielded applicator was designed based on three commercially available gynecological applicators as well as a virtual cubic water phantom that can be imported into any DICOM-RT compatible treatment planning system (TPS). The absorbed dose distribution around the applicator with the TG-186 192 Ir source located at one dwell position at its center was computed using two commercial TPSs incorporating MBDCAs (Oncentra® Brachy with Advanced Collapsed-cone Engine, ACE™, and BrachyVision ACUROS™) and state-of-the-art Monte Carlo (MC) codes, including ALGEBRA, BrachyDose, egs_brachy, Geant4, MCNP6, and Penelope2008. TPS-based volumetric dose distributions for the previously reported "source centered in water" and "source displaced" test cases, and the new "source centered in applicator" test case, were analyzed here using the MCNP6 dose distribution as a reference. Volumetric dose comparisons of TPS results against results for the other MC codes were also performed. Distributions of local and global dose difference ratios are reported. The local dose differences among MC codes are comparable to the statistical uncertainties of the reference datasets for the "source centered in water" and "source displaced" test cases and for the clinically relevant part of the unshielded volume in the "source centered in applicator" case. Larger local differences appear in the shielded volume or at large distances. Considering clinically relevant regions, global dose differences are smaller than the local ones. The most disadvantageous case for the MBDCAs is the one including the shielded applicator. In this case, ACUROS agrees with MC within [-4.2%, +4.2%] for the majority of voxels (95%) while presenting dose differences within [-0.12%, +0.12%] of the dose at a clinically relevant reference point. For ACE, 95% of the total volume presents differences with respect to MC in the range [-1.7%, +0.4%] of the dose at the reference point. The combination of the generic source and generic shielded applicator, together with the previously developed test cases and reference datasets (available in the Brachytherapy Source Registry), lay a solid foundation in supporting uniform commissioning procedures and direct comparisons among treatment planning systems for HDR 192 Ir brachytherapy.


Molecular orientation of membrane-anchored mucin glycoprotein mimics.
Mucin glycoproteins contribute to a wide range of cell-surface phenomena. Their dense glycosylation is believed to confer structural rigidity as well as molecular extension beyond the glycocalyx, crucial to interaction with the cellular environment. However, controlled investigations of the relationships between glycosylation, rigidity, and extension of membrane-bound mucins or similar macromolecules are lacking, largely because of the absence of tractable experimental models. We have therefore made use of recently developed synthetic mucin mimetics, in which the core alpha-GalNAc monosaccharides of natural mucins are conjugated to a lipidated polymer backbone and anchored to fluid, solid-supported lipid membranes, and fluorescence interference contrast microscopy, an optical technique that provides nanometer-scale topographic information about objects near a reflective interface, to measure the orientation of the mucin mimics relative to the membrane plane. Data from two independent probes, fluorophores conjugated directly to the polymer backbone and fluorescent proteins bound to the sugar groups, unexpectedly show that the mucin mimic molecules lie flat along the membrane. Rigidity and core glycosylation are therefore insufficient to ensure molecular projection outward from a membrane surface.


A New Fight Against Colon Cancer: As Cancer Rates Rise Among Younger Adults, Researchers Look for New Screening and Treatment Options.
Although the overall incidence of colon cancer has been falling over the past few decades, a pair of recent studies revealed a startling trend. In February 2017, researchers published a report showing that colon cancer rates were rising among younger adults. Some skeptics suggested the spike might simply reflect earlier detection and not necessarily represent a real increase in the disease. But a follow-up study found that Gen-Xers and millenials aren't just getting cancer diagnoses earlier; they are dying from colon cancer at slightly higher rates than in previous decades. Death rates among adults aged 20-54 have increased slightly, to 4.3 deaths per 100,000 people in 2014, up from 3.9 per 100,000 in 2004.


Inhibition of aquaporin-3 water channel in the colon induces diarrhea.
Aquaporin (AQP) 3, which is predominantly expressed in the colon, is considered to play an important role in regulating the fecal water content in the colon. In this study, the role of AQP3 in the colon was examined using HgCl(2) and CuSO(4), which are known to inhibit AQP3 function. The fecal water content was measured up to 1 h after the rectal administration of HgCl(2) or CuSO(4) to rats. The results showed that the fecal water content in the HgCl(2) administration group increased significantly to approximately 4 times that in the control group, and severe diarrhea was observed. However, no changes were observed in the mRNA expression level of the osmoregulatory genes (sodium myo-inositol transporter and taurine transporter) and the level and distribution of AQP3 protein expression, as determined 1 h after the administration of HgCl(2). Comparable results were observed in the CuSO(4) administration group. The results of this study indicated that the inhibition of AQP3 function in the colon caused diarrhea. Therefore, it has been revealed that the fecal water content in the colon is controlled by the transport of water from the luminal side to the vascular side, which is mediated by AQP3. Our findings suggest that a drug that modulates the function or expression of AQP3 in the colon may represent a new target for the development of laxatives.


Treatment for comorbid borderline personality disorder and alcohol use disorders: a review of the evidence and future recommendations.
There is a high degree of comorbidity between borderline personality disorder (BPD) and alcohol use disorders (AUDs). There is some evidence that this pattern of comorbidity may be associated with poorer prognosis. Although there are many different psychotherapeutic and pharmacological treatments for BPD and AUDs when they occur alone, there are very few treatment options when they occur together. The objective of this article was to review the existing treatment options-both psychotherapeutic and pharmacological-for patients with dual diagnoses of BPD and AUDs and to explore alternative treatment options that warrant further study. There have been a number of studies that have examined the efficacy of specific psychotherapies targeting drinking among patients with comorbid BPD; however, their efficacy in reducing BPD symptoms is unknown. There are also three psychotherapies that were specifically developed for patients with BPD and substance use disorders (SUDs), but only one of these (Dynamic Deconstructive Psychotherapy) has been tested among patients with dual diagnoses of BPD and AUDs. Research on pharmacotherapy for dual diagnoses of BPD and AUD is scarce, and no study has yet explored medication options that can concurrently manage symptoms of BPD and decrease alcohol consumption. Interestingly, there is growing evidence that anticonvulsants and second generation antipsychotics, the recent medications of choice for the management of BPD symptoms, may also reduce alcohol craving and consumption. Although premature, these findings are encouraging especially for this population of patients for whom treatment options are very limited.


Kidney Research UK's: a better life through education and empowerment.
Over 3 million people are affected by chronic kidney disease (CKD). Kidney Research UK, a national charity dedicated to research that will lead to better treatment and cures for kidney disease has developed the innovative and successful 'A better life through education and empowerment' (ABLE) programme which researches and raises awareness of the issues among 'at risk' groups and helps prevent or slow its progression. Initially the programme focused on the black and minority ethnic (BME) communities who are up to 5 times more likely to develop kidney failure than white caucasians. This is largely due to hypertension and type 2 diabetes. Recently the scope of the programme was broadened to encompassall those at risk and the useful lessons learned from the 7 initial projects are being used to inform the future of ABLE and other CKD projects. The programme has been funded by a cross section of organizations including the Department of Health and the Big Lottery Fund. Outcomes from the first two completed projects as well as an update on the other ABLE work are summarized.


[Hyperlipidemia and atherosclerosis].
One of the critical events in the early stage of atherosclerosis is the focal accumulation of lipid-laden foam cells derived from macrophages. In various cholesterol-fed animal models of atherosclerosis, it was found that localized attachment of circulating monocytes to arterial endothelial cells appears to precede the formation of foam cells. It has been suggested that monocyte recruitment into early lesions is depend upon the endothelial adhesiveness for monocytes and lymphocytes. In vivo and in vitro experiments have identified molecules, such as ICAM-1, VCAM-1 and P-selecin, those can support the adhesion of monocytes and lymphocytes. Moreover oxidized LDL, lysophosphatidylcholine and oxidized fatty acids induce the expression of not only these adhesion molecules but also scavenger receptors, such as CD-36, SR-A and LOX-1. Recently we isolated and characterized the novel receptors for oxidized LDL, named LOX-1 and SR-PSOX. The expression of LOX-1 is found on endothelial cells, smooth muscle cells and macrophages. Whereas SR-PSOX expresses on macrophages. We address in this paper on the significance of hyperlipidemia, especially oxidized LDL and its receptors in terms of atherosclerosis.


Exposure to air pollution and incidence of atopic dermatitis in the general population: A national population-based retrospective cohort study.
To date, little evidence is available to determine whether atopic dermatitis (AD) can be caused by exposure to air pollutants, including gases and particulate matter. We aimed to evaluate the relationship between air pollutants and incidence of AD using the National Health Insurance Service-National Sample Cohort database. We included 209,168 subjects from the general population previously not diagnosed with AD between 2008 and 2013. Long-term average concentration of air pollutants before diagnosis was calculated for each subject. For 1,030,324 person-years, incident cases of AD were observed in 3203 subjects. There was a significant positive association between incidence of AD and long-term average concentration of particulate matter smaller than 2.5 μm in diameter (hazard ratio [HR], 1.420; 95% CI, 1.392-1.448; for 1 μg/m3), particulate matter smaller than 10 μm in diameter (HR, 1.333, 95% CI, 1.325-1.341; for 1 μg/m3), sulfur dioxide (HR, 1.626; 95% CI, 1.559-1.695; for 1 parts per billion), nitrogen dioxide (HR, 1.200; 95% CI, 1.187-1.212; for 1 parts per billion), and carbon monoxide (HR, 1.005; 95% CI, 1.004-1.005; for 1 parts per billion) after adjusting for age, sex, income, comorbid diseases, and meteorologic variables. The National Health Insurance Service database lacks detailed information on individual subjects. This study demonstrated that long-term exposure to air pollutants, including gases and particulate matter, is an independent risk factor for developing AD.


Asymmetric skeletal anomalies in siblings.
We describe two siblings with asymmetric limb reduction malformations. Such anomalies are usually considered to result from sporadic events, but the recurrence in siblings without any identifiable teratogenic insult suggests a genetic etiology. This finding becomes important when parents are counseled about future pregnancies. The use of prenatal diagnostic techniques during subsequent pregnancies should be considered.


Efficient All-Solution Processed Quantum Dot Light Emitting Diodes Based on Inkjet Printing Technique.
Quantum dot light emitting diodes (QLEDs) are increasingly attractive owing to their compatibility with the inkjet printing process and potential application in low-cost large-area full-color pixelated display. The strategy for controlling the morphology of the quantum dot layer is definitely critical for realizing all-solution processed QLEDs with high performance, which certainly requires in-depth thinking regarding the design of ink composition and their optimization in the printing process. Herein, by carefully controlling the quantum dot ink composition and physicochemical properties, we demonstrate that the viscosity, contact angle, and the three-phase contact line moving would affect the final morphology of the quantum dot film formed by inkjet printing. We achieved coffee ring-free and low-roughness quantum dot film, and all-solution processed QLEDs with normal structure were fabricated for the first time. The devices have a low turn-on voltage of 2.0 V, a luminance of 12100 cd/m2 at the voltage of 12 V, and a maximum current efficiency of 4.44 cd/A at the luminance of 1974 cd/m2, which is the best result to date for inkjet-printed red QLEDs. The results will pave the way for future application of inkjet printing in solution processed pixelated QLED display.


Intra-oral shape recognition by 138 mentally retarded subjects.
Among Ss with normal intelligence, oral shape-recognition tests have shown a relationship between articulatory ability and oral sensory integrity. This investigation explored oral sensory impairment as a possible contributory cause of the articulatory difficulties exhibited by the mentally retarded. The Florida Oral-form Recognition Measure (FORM), a task requiring the intra-oral identification of 10 geometric shapes, was administered to 138 mentally retarded Ss. Twenty Ss were retested to establish reliability. Ss were placed in groups according to etiological categories (AAMD classification) and were assigned speech ratings by a speech pathologist. Of the total sample, 86% had varying degrees of defective speech or language. Mean FORM score was 3.5, and preliminary analysis yielded significant correlations between FORM score and IQ and between speech and language rating. Further multivariate analysis with IQ held as a co-variant indicated no significant relationship between FORM score and communicative ability. This suggests caution in inferring that intra-oral shape-recognition scores reflect degree of oral sensory integrity. Perhaps a battery of oral perceptual tasks might more validly assess oral sensation-perception and aid in clarifying its relationship to speech.


Clinicoradiologic Characteristics of Intradural Extramedullary Conventional Spinal Ependymoma.
Distinguishing intradural extramedullary (IDEM) spinal ependymoma from myxopapillary ependymoma is challenging due to the location of IDEM spinal ependymoma. This study aimed to investigate the utility of clinical and MR imaging features for differentiating between IDEM spinal and myxopapillary ependymomas. We compared tumor size, longitudinal/axial location, enhancement degree/pattern, tumor margin, signal intensity (SI) of the tumor on T2-weighted images and T1-weighted image (T1WI), increased cerebrospinal fluid (CSF) SI caudal to the tumor on T1WI, and CSF dissemination of pathologically confirmed 12 IDEM spinal and 10 myxopapillary ependymomas. Furthermore, classification and regression tree (CART) was performed to identify the clinical and MR features for differentiating between IDEM spinal and myxopapillary ependymomas. Patients with IDEM spinal ependymomas were older than those with myxopapillary ependymomas (48 years vs. 29.5 years, p < 0.05). A high SI of the tumor on T1W1 was more frequently observed in IDEM spinal ependymomas than in myxopapillary ependymomas (p = 0.02). Conversely, myxopapillary ependymomas show CSF dissemination. Increased CSF SI caudal to the tumor on T1WI was observed more frequently in myxopapillary ependymomas than in IDEM spinal ependymomas (p < 0.05). Dissemination to the CSF space and increased CSF SI caudal to the tumor on T1WI were the most important variables in CART analysis. Clinical and radiological variables may help differentiate between IDEM spinal and myxopapillary ependymomas.


Thoracoscopy in Chest Wall Ewing's Sarcoma.
Minimally invasive surgery has a role in planning the resection of malignant chest wall tumors in the pediatric population. We studied the role of thoracoscopy in both the diagnosis and definitive surgery of chest wall Ewing's sarcoma tumors.


The 5'UTR-intron of the Gladiolus polyubiquitin promoter GUBQ1 enhances translation efficiency in Gladiolus and Arabidopsis.
There are many non-cereal monocots of agronomic, horticultural, and biofuel importance. Successful transformation of these species requires an understanding of factors controlling expression of their genes. Introns have been known to affect both the level and tissue-specific expression of genes in dicots and cereal monocots, but there have been no studies on an intron isolated from a non-cereal monocot. This study characterizes the levels of GUS expression and levels of uidA mRNA that code for β-glucuronidase (GUS) expression in leaves of Gladiolus and Arabidopsis using GUBQ1, a polyubiquitin promoter with a 1.234 kb intron, isolated from the non-cereal monocot Gladiolus, and an intronless version of this promoter. Gladiolus and Arabidopsis were verified by Southern hybridization to be transformed with the uidA gene that was under control of either the GUBQ1 promoter (1.9 kb), a 5' GUBQ1 promoter missing its 1.234 kb intron (0.68 kb), or the CaMV 35 S promoter. Histochemical staining showed that GUS was expressed throughout leaves and roots of Gladiolus and Arabidopsis with the 1.9 kb GUBQ1 promoter. GUS expression was significantly decreased in Gladiolus and abolished in Arabidopsis when the 5'UTR-intron was absent. In Arabidopsis and Gladiolus, the presence of uidA mRNA was independent of the presence of the 5'UTR-intron. The 5'-UTR intron enhanced translation efficiency for both Gladiolus and Arabidopsis. The GUBQ1 promoter directs high levels of GUS expression in young leaves of both Gladiolus and Arabidopsis. The 5'UTR-intron from GUBQ1 resulted in a similar pattern of β-glucuronidase translation efficiency for both species even though the intron resulted in different patterns of uidA mRNA accumulation for each species.


Strategies for the AFM-based manipulation of silver nanowires on a flat surface.
Silver nanowires (Ag NWs) are a promising material for building various sensors and devices at the nanoscale. However, the fast and precise placement of individual Ag NWs is still a challenge today. Atomic force microscopy (AFM) has been widely used to manipulate nanoparticles, yet this technology encounters many difficulties when being applied to the movement of Ag NWs as well as other soft one-dimensional (1D) materials, since the samples are easily distorted or even broken due to friction and adhesion on the substrate. In this paper, two novel manipulation strategies based on the parallel pushing method are presented. This method applies a group of short parallel pushing vectors (PPVs) to the Ag NW along its longitudinal direction. Identical and proportional vectors are respectively proposed to translate and rotate the Ag NWs with a straight-line configuration. The rotation strategy is also applied to straighten flexed Ag NWs. The finite element method simulation is introduced to analyse the behaviour of the Ag NWs as well as to optimize the parameter setting of the PPVs. Experiments are carried out to confirm the efficiency of the presented strategies. By comprehensive application of the new strategies, four Ag NWs are continuously assembled in a rectangular pattern. This study improves the controllability of the position and configuration of Ag NWs on a flat substrate. It also indicates the practicability of automatic nanofabrication using common AFMs.


Relationship between obesity and prevalence of dental anomalies: Does body mass index play a role?
The aim of this study was to investigate the prevalence of dental anomalies in different body mass index (BMI) percentile child and adolescent subjects. Panoramic radiographs of 186 subjects (68 males and 118 females) were evaluated. The subjects were divided into three groups according to BMI percentile: Normal-weight (93), overweight (40), and obese (43) subjects. Supernumerary tooth, tooth agenesis, dens invaginatus, dens evaginatus, tooth impaction, taurodontism, pulp stone, and root dilaceration were assessed. Root dilaceration was found in 11.3% of the obese subjects and 17.5% of the overweight subjects. There was a statistically significant difference in the root dilaceration prevalence among the groups (p=0.015). However, other dental anomalies did not display statistically significant differences among the groups (p>0.05). While there was no statistically significant difference in the dental anomalies prevalence among different BMI percentile groups in males (p>0.05), a statistically significant difference in the root dilaceration prevalence was detected among different BMI percentile groups in females (p=0.036). The data were analysed using chi-square and Fisher's exact tests. The prevalence of root dilaceration was significantly greater in obese and overweight subjects than in normal-weight subjects.


Mediators of hypersensitivity in the sputum of young, symptomatic cigarette smokers.
We have measured the concentrations of mediators of hypersensitivity in the sputum of twenty-five young, symptomatic cigarette smokers who regularly expectorated and twenty-three matched non-smokers with a respiratory infection. The measurements included sputum and blood eosinophils, IgE, IgG, IgA and IgM and also sputum histamine. We found a significant increase of sputum histamine, and a higher sputum/serum ratio of IgE in smokers when compared to non-smokers. These findings support the view that the bronchial inflammatory response in smokers, as in chronic bronchitis, involves the participation of mediators of hypersensitivity.


Evidence for age-associated disinhibition of the wake drive provided by scoring principal components of the resting EEG spectrum in sleep-provoking conditions.
Age-associated changes in different bandwidths of the human electroencephalographic (EEG) spectrum are well documented, but their functional significance is poorly understood. This spectrum seems to represent summation of simultaneous influences of several sleep-wake regulatory processes. Scoring of its orthogonal (uncorrelated) principal components can help in separation of the brain signatures of these processes. In particular, the opposite age-associated changes were documented for scores on the two largest (1st and 2nd) principal components of the sleep EEG spectrum. A decrease of the first score and an increase of the second score can reflect, respectively, the weakening of the sleep drive and disinhibition of the opposing wake drive with age. In order to support the suggestion of age-associated disinhibition of the wake drive from the antagonistic influence of the sleep drive, we analyzed principal component scores of the resting EEG spectra obtained in sleep deprivation experiments with 81 healthy young adults aged between 19 and 26 and 40 healthy older adults aged between 45 and 66 years. At the second day of the sleep deprivation experiments, frontal scores on the 1st principal component of the EEG spectrum demonstrated an age-associated reduction of response to eyes closed relaxation. Scores on the 2nd principal component were either initially increased during wakefulness or less responsive to such sleep-provoking conditions (frontal and occipital scores, respectively). These results are in line with the suggestion of disinhibition of the wake drive with age. They provide an explanation of why older adults are less vulnerable to sleep deprivation than young adults.


Downregulation of glial scarring after brain injury: the effect of purine nucleoside analogue ribavirin.
The weak regenerative capacity of self-repair after injury to the adult brain is caused by the formation of glial scar due to reactive astrogliosis. In the present study the beginning of reactive astrogliosis in the adult, as shown immunocytochemically by upregulation of glial fibrillary acidic protein (GFAP) and vimentin, was seen two days after the left sensorimotor cortex lesion, being maximal during the first two weeks and declining by 30 days after the lesion. This was accompanied by intensive glial scarring. Conversely, after the neonatal lesion a lack of gliotic scar was seen until 30 days postsurgery, although the pattern of GFAP and vimentin expression during recovery period was the same. The aim of the study was to define an appropriate therapeutic intervention that could modulate astrocyte proliferation and diminish glial scar formation after adult brain lesion. For this purpose the effects of an antiproliferative agent, the purine nucleoside analogue ribavirin was examined. It was shown that daily injection of ribavirin for 5 and 10 days considerably decreased the number of reactive astrocytes, while slight GFAP labeling was restricted to the lesion site. Obtained results show that ribavirin treatment downregulates the process of reactive astrogliosis after adult brain injury, and thus may be a useful approach for improving neurological recovery from brain damage.


Quantitative analysis of the interaction between l-methionine derivative and oligonucleotides.
This study explores the use of l-methionine derivative as a potential affinity ligand for nucleic acids purification. The l-methionine derivative is synthesized by activation of the carboxylic acid group with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide follow by immobilization on amine sensor surface, previously activated and treated with ethylenediamine. Their affinity towards oligonucleotides has been determined by surface plasmon resonance biosensor. The highest affinity is found for cytosine and thymine, followed by adenine, whereas the lowest affinity is found for guanine. For hetero-oligonucleotides the affinity order is CCCTTT > CCCAAA ≈ AAATTT > GGGTTT, showing that nucleotides with cytosine have the highest affinity, and the presence of guanine reduces the affinity, corroborating with the results obtained with homo-oligonucleotides.


Prognostic value of PD-L1 expression in patients with pancreatic cancer: A PRISMA-compliant meta-analysis.
Programmed cell death ligand 1 (PD-L1) expression was reported to be associated with poor prognosis in various solid tumors. However, the prognosis value of PD-L1 in pancreatic cancer remained inconclusive. We performed a meta-analysis to assess the clinical value of PD-L1 as a novel prognostic biomarker of pancreatic cancer. PubMed, Embase, and Web of Science were searched up to October 2018. The HRs and 95% CIs for overall survival (OS) and cancer-specific survival (CSS) according to the expressional status of PD-L1 were pooled. The combined odd ratios (ORs) and 95% CIs were utilized to assess the association between PD-L1 and clinicopathological characteristics. A total of 9 studies with 993 patients were included. Elevated PD-L1 expression was related with poor OS (HR = 1.63, 95% CI = 1.34-1.98, P < .001) and CSS (HR = 1.86, 95% CI = 1.34-2.57, P < .001). Furthermore, high PD-L1 expression was also demonstrated to be associated with positive N stage (OR = 1.81, 95% CI = 1.21-2.71, P = .004), advanced T stage (OR = 1.86, 95% CI = 1.08-3.19, P = .025), and low differentiation (OR = 2.24, 95% CI = 1.16-4.33, P = .017). However, PD-L1 has nonsignificant correlation with M stage, gender, or age. This study suggests that PD-L1 is a potential prognostic biomarker and may be helpful to clinicians aiming to select the appropriate immunotherapy for pancreatic cancer.


Sleepiness and sleep in a simulated "six hours on/six hours off" sea watch system.
Ships are operated around the clock using rapidly rotating shift schedules called sea watch systems. Sea watch systems may cause fatigue, in the same way as other irregular working time arrangements. The present study investigated subjective sleepiness and sleep duration in connection with a 6 h on/6 h off duty system. The study was performed in a bridge simulator, very similar to those found on ships. Twelve officers divided into two groups participated in the study that lasted 66 h. Half of the subjects started with the 06:00-12:00 h watch and the other half with the 12:00-18:00 h watch. The subjects alternated between off-duty and on-duty for the remainder of the experimental period. Approximately halfway through the experiment, the 12:00-18:00 h watch was divided into two 3 h watches/off-duty periods. The effect of this was to reverse the on-duty/off-duty pattern between the two groups. This enabled all subjects to work the four possible watches (00:00-06:00 h, 06:00-12:00 h, 12:00-18:00 h, and 18:00-24:00 h) in an order that was essentially counterbalanced between groups. Ratings of sleepiness (Karolinska Sleepiness Scale; KSS) were obtained every 30 min during on-duty periods and if subjects were awake during off-duty periods. The subjectively rated duration of sleep was recorded after each off-duty period that preceded watch periods when KSS was rated. The results showed that the average level of sleepiness was significantly higher during the 00:00-06:00 h watch compared to the 12:00-18:00 h and 18:00-24:00 h watches, but not to the 06:00-12:00 h watch. Sleepiness also progressed significantly from the start toward the end of each watch, with the exception of the 06:00-12:00 h watch, when levels remained approximately stable. There were no differences between groups (i.e., the order between watches). Sleep duration during the 06:00-12:00 h off-duty period (3 h 29 min) was significantly longer than during the 12:00-18:00 h period (1 h 47 min) and the 18:00-24:00 h period (2 h 7 min). Sleep during the 00:00-06:00 h period (4 h 23 min) was longer than all sleep periods except the 06:00-12:00 h period. There were no differences between groups. In spite of sufficient opportunities for sleep, sleep was on the average around 1-1 h 30 min shorter than the 7-7 h 30 min that is considered "normal" during a 24 h period. This is probably a consequence of the difficulty to sleep during daytime due to the alerting effects of the circadian rhythm. Also, sleepiness during the night and early mornings reached high levels, which may be explained by a combination of working close to or during the circadian trough of alertness and the relatively short sleep periods obtained. An initial suppression of sleepiness was observed during all watches, except for the 06:00-12:00 h watch. This suppression may be explained by the "masking effect" exerted by the relative high levels of activity required when taking over the responsibility of the ship. Toward the end of watches, the levels of sleepiness progressively increased to relatively high levels, at least during the 00:00-06:00 h watch. Presumably, initially high levels of activity are replaced by routine and even boredom.


Rescue permanent iliac vein pacing after epicardial lead failure: an unusual reversal of pacing fortune.
Surgical lead placement is generally considered as a last resort for patients who require permanent pacing and who are unable to accommodate transvenous leads. The technique is limited by the need for direct epicardial access and reduced reliability of epicardial leads (compared with modern transvenous leads) [Belott and Reynolds. Permanent pacemaker and implantable cardioverter defibrillator implantation. In Ellenbogen KA, Kay GN, Lau CP, Wilkoff BL (eds). Clinical Cardiac Pacing, Defibrillation, and Resynchronization Therapy. Philadelphia: Saunders Elsevier, 2007; pp. 561-651]. We report a patient with limited venous access and a poorly functioning epicardial ventricular lead, who was successfully upgraded to a dual-chamber endocardial pacing system via the iliac vein. Pacemaker lead implantation from the iliac vein is an often overlooked option for patients with limited central venous access. In our patient, a pacing upgrade was achieved after the presumptive final option had been exhausted.


Collaborative group testing benefits high- and low-performing students.
We used collaborative group testing in a veterinary physiology course (65 students) to test the hypothesis that all students (e.g., high-performing and low-performing students of each group) benefit from collaborative group testing. In this format, students answered questions in the traditional format as individuals. Immediately after completing the exam as individuals, students answered the same questions in groups of two, and, finally, the same questions were discussed by the instructor and students. We measured two learning outcomes for every student: individual and group test scores. Based on individual test scores, students were categorized as "high performing" (students with higher individual scores) or "low performing" (students with lower individual scores). Finally, student evaluations of the format were collected. Collaborative group testing enhanced student performance. Specifically, group scores were higher than individual scores (P < 0.001). Importantly, the size of the collaborative testing effect was large for the population and for the low-performing students; however, the collaborative testing effect was small for the high-performing students. Finally, student evaluations of this testing format were very positive. In conclusion, collaborative group testing was beneficial for all students; however, collaborative testing was significantly more beneficial for low-performing students.