Metal ion mediated transition from random coil to β-sheet and aggregation of Bri2-23, a natural inhibitor of Aβ aggregation.
Furin-dependent maturation of the BRI2 protein generates the Bri2-23 fragment that is able to arrest the aggregation of amyloidβ, the peptide implicated in Alzheimer's disease (AD). Bri2-23 contains cysteines at positions 5 and 22, which are likely to bind to metal ions such as Cu(i). Metal ions may play a role in the etiology of neurodegenerative disorders such as AD, and in this work we explore the metal ion induced folding and aggregation of Bri2-23 using Hg(ii) and Ag(i) as spectroscopic probes with structural and ligand preferences similar to those of Cu(i), while not displaying redox activity under the experimental conditions. In general, interaction of Bri2-23 with soft metal ions changes the structural properties and solution behavior of the peptide that tune to increasing metal to peptide stoichiometry. Potentiometric, (199m)Hg PAC and ESI-MS data indicate that addition of up to 0.5 equivalents of Hg(ii) to Bri2-23 yields a two-coordinated HgS2 structure at the metal site. While the free peptide is inherently unstructured, the presence of Ag(i) and Hg(ii) gives rise to β-sheet formation. NMR spectroscopy supports the formation of β-sheet structure in the presence of 0.5 equivalents of Hg(ii), and displays an interesting and marked change in the TOCSY spectra when increasing the Hg(ii) to peptide stoichiometry from 0.5 to 0.7 equivalents, indicating the equilibrium between two structural analogues of the complex. Addition of more than 0.7 equivalents of Hg(ii) gives rise to line broadening, presumably reflecting aggregation. This is further supported by ThT fluorescence studies showing that the Bri2-23 peptide does not aggregate over 24 hours, while addition of over 0.7 equivalents of Ag(i) or Hg(ii) leads to increase of fluorescence, indicating that these metal ions induce aggregation. Thus, a model integrating all data into a coherent picture is that the metal ion binding to the two thiolates gives rise to folding of the peptide into a structure that is prone to aggregation, forming aggregates with a considerable amount of β-sheets. Molecular dynamics simulations initiated with structures that agree with NMR data additionally support this model.


Ramucirumab (IMC-1121B): a novel attack on angiogenesis.
Angiogenesis is a critical hallmark of malignancy, and attempts to inhibit this process have characterized the age of biologic anticancer therapies for solid tumors. VEGF receptor-2 is the premier receptor responsible for many of the cancer-driven VEGF-induced spectrum of biologic changes, including modification of blood vessel structure and function, proliferation and migration. Unlike all clinically approved angiogenesis inhibitors, the fully human monoclonal antibody ramucirumab (IMC-1121B) specifically and potently inhibits VEGF receptor-2. Phase I clinical trials have shown safety across a wide range of ramucirumab doses with impressive, albeit early, evidence of both stable disease and partial responses in a variety of tumor types. In this article, we review the current data on ramucirumab and make comparisons with commercially available antiangiogenic agents.


MutS HOMOLOG1 mediates fertility reversion from cytoplasmic male sterile Brassica juncea in response to environment.
Spontaneous fertility reversion has been documented in cytoplasmic male sterile (CMS) plants of several species, influenced in frequency by nuclear genetic background. In this study, we found that MutS HOMOLOG1 (MSH1) mediates fertility reversion via substoichiometric shifting (SSS) of the CMS-associated mitochondrial Open Reading Frame 220 (ORF220), a process that may be regulated by pollination signalling in Brassica juncea. We show that plants adjust their growth and development in response to unsuccessful pollination. Measurable decrease in MSH1 transcript levels and evidence of ORF220 SSS under non-pollination conditions suggest that this nuclear-mitochondrial interplay influences fertility reversion in CMS plants in response to physiological signals. Suppression of MSH1 expression induced higher frequency SSS in CMS plants than occurs normally. Transcriptional analysis of floral buds under pollination and non-pollination conditions, and the response of MSH1 expression to different sugars, supports the hypothesis that carbon flux is involved in the pollination signalling of fertility reversion in CMS plants. Our findings suggest that facultative gynodioecy as a reproductive strategy may incorporate environmentally responsive genes like MSH1 as an "on-off" switch for sterility-fertility transition under ecological conditions of reproductive isolation.


Estrogens and female liver health.
Due to declining estrogen levels during menopause, NAFLD prevalence is higher in postmenopausal women compared to in premenopausal women or in men. Postmenopausal women are more susceptible to weight gain, fat redistribution and dyslipidemia, all major hallmarks of metabolic syndrome associated with increased NAFLD risk. Gut microbiota plays important roles in development of gastrointestinal tract, metabolism and immunity. Host-microbe interactions allows regulation of a wide range of pathways that affect healthy and diseased physiology. Recent advances in - omics technologies, such as microbiome, transcriptome and metabolome analysis, provided evidence that estrogens and intestinal microbiota (IM) can collectively influence obesity, inflammatory disease, diabetes, and cancers. By understanding underlying mechanisms of estrogens and microbiota crosstalk, we might design dietary and pharmacological interventions to alleviate the metabolic syndrome and NAFLD.


Reactive force fields for modeling oxidative degradation of organic matter in geological formations.
In an attempt to better explore organic matter reaction and properties, at depth, to oxidative fluid additives, we have developed a new ReaxFF potential to model and describe the oxidative decompositions of aliphatic and aromatic hydrocarbons in the presence of the oxychlorine ClO n - oxidizers. By carefully adjusting the new H/C/O/Cl parameters, we show that the potential energies in both training and validation sets correlate well with calculated density functional theory (DFT) energies. Our parametrization yields a reliable empirical reactive force field with an RMS error of ∼1.57 eV, corresponding to a 1.70% average error. At this accuracy level, the reactive force field provides a reliable atomic-level picture of thermodynamically favorable reaction pathways governing oxidative degradation of H/C/O/Cl compounds. We demonstrate this capability by studying the structural degradation of small aromatic and aliphatic hydrocarbons in the presence of oxychlorine oxidizers in aqueous environments. We envision that such reactive force fields will be critical in understanding the oxidation processes of organic matter in geological reservoirs and the design of the next generation of reactive fluids for enhanced shale gas recovery and improved carbon dioxide adsorption and sequestration.


Effect of regular and irregular stimulation cycles of dexamethasone on circadian clock in NIH3T3 cells.
Animal studies have shown that irregular light-dark cycles cause circadian desynchronization, while few studies have addressed the effect of regular/irregular stimulation cycles of signaling hormones on the cellular clock in vitro. Here, we examined how cellular clocks respond to regular and irregular stimulation cycles of dexamethasone, using NIH3T3 cells transfected with the Bmal1 promoter-driven luciferase (Bmal1-Luc) reporter gene. Cyclic stimulation with dexamethasone at different time intervals (18-28 h, 3 times regularly) revealed that Bmal1-Luc bioluminescence rhythms can be entrained to 22 and 24 h cycles during the stimulation period, but not to other cycles. The rhythm entrained for 24 h cycles persisted for at least one day after the last stimulation. Irregular dexamethasone treatment (16, 24, and 16 h, sequentially; short-term jet lag protocol) resulted in an overall upregulation and phase shifts of the temporal expression of several clock genes and cell cycle genes, including c-Myc and p53. Regular dexamethasone stimulation three times with 24 h cycles also caused upregulation of Per1 and Per2 expression, but not c-Myc and p53 expression. In conclusion, our study identified the entrainable range of the circadian clock in NIH3T3 cells to the dexamethasone stimulation cycle and demonstrated that irregular dexamethasone treatment could disturb the expression of cell cycle genes.


Reverse-Transcriptase PCR Detection of Leptospira: Absence of Agreement with Single-Specimen Microscopic Agglutination Testing.
Reference diagnostic tests for leptospirosis include nucleic acid amplification tests, bacterial culture, and microscopic agglutination testing (MAT) of acute and convalescent serum. However, clinical laboratories often do not receive paired specimens. In the current study, we tested serum samples using a highly sensitive real-time nucleic acid amplification test for Leptospira and compared results to MAT performed on the same specimens. 478 serum samples from suspected leptospirosis cases in Rio de Janeiro were tested using a real-time RT-PCR for the diagnosis of leptospirosis, malaria and dengue (the Lepto-MD assay). The Lepto-MD assay detects all species of Leptospira (saprophytic, intermediate, and pathogenic), and in the current study, we demonstrate that this assay amplifies both Leptospira RNA and DNA. Dengue virus RNA was identified in 10 patients, and no cases of malaria were detected. A total of 65 samples (13.6%) were positive for Leptospira: 35 samples (7.3%) in the Lepto-MD assay, 33 samples (6.9%) by MAT, and 3 samples tested positive by both (kappa statistic 0.02). Poor agreement between methods was consistent regardless of the titer used to define positive MAT results or the day of disease at sample collection. Leptospira nucleic acids were detected in the Lepto-MD assay as late as day 22, and cycle threshold values did not differ based on the day of disease. When Lepto-MD assay results were added to the MAT results for all patients in 2008 (n=818), the number of detected leptospirosis cases increased by 30.4%, from 102 (12.5%) to 133 (16.3%). This study demonstrates a lack of agreement between nucleic acid detection of Leptospira and single-specimen MAT, which may result from the clearance of bacteremia coinciding with the appearance of agglutinating antibodies. A combined testing strategy for acute leptospirosis, including molecular and serologic testing, appears necessary to maximize case detection.


Enhancement of Prebiotic Peptide Formation in Cyclic Environments.
The dynamic behaviors of prebiotic reaction networks may be critically important to understanding how larger biopolymers could emerge, despite being unfavorable to form in water. We focus on understanding the dynamics of simple systems, prior to the emergence of replication mechanisms, and what role they may have played in biopolymer formation. We specifically consider the dynamics in cyclic environments using both model and experimental data. Cyclic environmental conditions prevent a system from reaching thermodynamic equilibrium, improving the chance of observing interesting kinetic behaviors. We used an approximate kinetic model to simulate the dynamics of trimetaphosphate (TP)-activated peptide formation from glycine in cyclic wet-dry conditions. The model predicts that environmental cycling allows trimer and tetramer peptides to sustain concentrations above the predicted fixed points of the model due to overshoot, a dynamic phenomenon. Our experiments demonstrate that oscillatory environments can shift product distributions in favor of longer peptides. However, experimental validation of certain behaviors in the kinetic model is challenging, considering that open systems with cyclic environmental conditions break many of the common assumptions in classical chemical kinetics. Overall, our results suggest that the dynamics of simple peptide reaction networks in cyclic environments may have been important for the formation of longer polymers on the early Earth. Similar phenomena may have also contributed to the emergence of reaction networks with product distributions determined not by thermodynamics, but rather by kinetics.


Human disturbances affect the topology of food webs.
Networks describe nodes connected by links, with numbers of links per node, the degree, forming a range of distributions including random and scale-free. How network topologies emerge in natural systems still puzzles scientists. Based on previous theoretical simulations, we predict that scale-free food webs are favourably selected by random disturbances while random food webs are selected by targeted disturbances. We assume that lower human pressures are more likely associated with random disturbances, whereas higher pressures are associated with targeted ones. We examine these predictions using 351 empirical food webs, generally confirming our predictions. Should the topology of food webs respond to changes in the magnitude of disturbances in a predictable fashion, consistently across ecosystems and scales of organisation, it would provide a baseline expectation to understand and predict the consequences of human pressures on ecosystem dynamics.


Maternal age and gonadotrophin elevation cooperatively decrease viable ovulated oocytes and increase ootoxicity, chromosome-, and spindle-misalignments: '2-Hit' and 'FSH-OoToxicity' mechanisms as new reproductive aging hypotheses.
While there is consensus that advanced maternal age (AMA) reduces oocyte yield and quality, the notion that high FSH reduces oocyte quality and causes aneuploidy remains controversial, perhaps due to difficulties controlling the confounding variables of age and FSH levels. Here, contributions of age and gonadotrophin elevation were separately controlled using a mouse model of human female reproductive aging. Ovulated oocytes were collected from young and midlife mice after 0-, 2.6-, or 17-day treatment with the FSH analog equine chorionic gonadotrophin (eCG), to model both exogenous FSH elevation within a single treatment cycle (as in controlled ovarian stimulation (COS)), and chronic endogenous FSH elevation during multiple cycles (as in diminished ovarian reserve). After 17-day eCG, fewer total oocytes/mouse are ovulated in midlife than young mice, and a precipitous decline in viable oocytes/mouse is observed in midlife but not young mice throughout eCG treatment. eCG is potently ootoxic to ovulatory oocytes and strongly induces chromosome- and spindle-misalignments within 2.6 days of eCG in midlife, but only after 17 days in young mice. These data indicate that AMA increases susceptibility to multiple adverse effects of elevated FSH activity in ovulated oocytes, including declines in total and viable oocytes/mouse, and induction of ootoxicity and aneuploidy. Two hypotheses are proposed for underlying causes of infertility in women. The FSH OOToxicity Hypothesis ('FOOT Hypothesis') posits that high FSH is ootoxic to ovulatory oocytes and that FSH ootoxicity is a root cause of low pregnancy success rates in naturally cycling women with high FSH and IUI patients undergoing COS. The '2-Hit Hypothesis' posits that AMA increases susceptibility to FSH-induced ootoxicity and aneuploidy.


Carbohydrate uptake from xylem vessels and its distribution among stem tissues and buds in walnut (Juglans regia L.).
Bud break pattern is a key determinant of tree architecture. The mechanisms leading to the precedence of certain buds over the others are not yet fully explained, but the availability of soluble sugars may play a significant role, especially those in the xylem sap at the onset of the growing period. Here, we measured carbon availability in the different tissues (bud, xylem and bark). To assess the capacity of buds to use the xylem sap carbohydrates, the fluxes between xylem vessels and parenchyma cells, bark and buds of walnut (Juglans regia cv 'Franquette') were measured during the rest period until bud break. This uptake capacity varies according to the temperature, the sugar and the position on the branch of the fragment studied. Between December and March, in xylem tissues, the active component of sucrose uptake was predominant compared with diffusion (90% of the total uptake), whereas the active component accounted for more moderate amounts in buds (50% of the uptake). The active uptake of hexoses took place belatedly (April) in xylem. The flow rates between xylem vessels and buds increased 1 month before bud break and reached 2000 microg sucrose h(-)(1) g DW(-)(1). Fluxes seemed to depend on bud position on the branch. However, this study strongly suggests that they were mainly dependent on the sink strength of the buds and on the sink competition between bud, xylem parenchyma and bark.


Measuring mechanical strain and twist using helical photonic crystal fiber.
Solid-core photonic crystal fiber (PCF) with a permanent helical twist exhibits dips in its transmission spectrum at certain wavelengths. These are associated with the formation of orbital angular momentum states in the cladding. Here we investigate the tuning of these states with mechanical torque and axial tension. The dip wavelengths are found to scale linearly with both axial strain and mechanical twist rate. Analysis shows that the tension-induced shift in resonance wavelength is determined both by the photoelastic effect and by the change in twist rate, while the torsion-induced wavelength shift depends only on the change in twist rate. Twisted PCF can act as an effective optically monitored torque-tension transducer, twist sensor, or strain gauge.


Advantages of transanal hemorrhoidal dearterialization as compared to other surgical techniques for the treatment of hemorrhoidal disease.
Transanal hemorrhoidal dearterialization (THD) is a new surgical technique used for the treatment of hemorrhoidal disease. It is known for its easy performance and low perioperative risk. 44 patients have been operated by this method at the Clinic of General, Liver and Pancreatic Surgery for a period of 22 months. A comparative analysis was performed between the postoperative results with the use of transanal hemorrhoidal dearterialization, modified hemorrhoidectomy of Milligan-Morgan, and Whitehead's hemorrhoidectomy. When comparing transanal hemorrhoidal dearterialization with other methods, we found that it has an excellent aesthetic effect, requires shorter hospital stay and less analgesics, and causes less discomfort in the postoperative period.


Structure and mechanism of Staphylococcus aureus TarM, the wall teichoic acid α-glycosyltransferase.
Unique to Gram-positive bacteria, wall teichoic acids are anionic glycopolymers cross-stitched to a thick layer of peptidoglycan. The polyol phosphate subunits of these glycopolymers are decorated with GlcNAc sugars that are involved in phage binding, genetic exchange, host antibody response, resistance, and virulence. The search for the enzymes responsible for GlcNAcylation in Staphylococcus aureus has recently identified TarM and TarS with respective α- and β-(1-4) glycosyltransferase activities. The stereochemistry of the GlcNAc attachment is important in balancing biological processes, such that the interplay of TarM and TarS is likely important for bacterial pathogenicity and survival. Here we present the crystal structure of TarM in an unusual ternary-like complex consisting of a polymeric acceptor substrate analog, UDP from a hydrolyzed donor, and an α-glyceryl-GlcNAc product formed in situ. These structures support an internal nucleophilic substitution-like mechanism, lend new mechanistic insight into the glycosylation of glycopolymers, and reveal a trimerization domain with a likely role in acceptor substrate scaffolding.


Kartagener's syndrome with motile cilia and immotile spermatozoa: axonemal ultrastructure and function.
A 35-yr-old infertile man with chronic sinobronchial disease and dextrocardia (Kartagener's syndrome) was found to have immotile sperm and motile nasal cilia in vitro. Ciliary beat frequency in vitro was normal, but in vivo nasal mucociliary clearance was markedly prolonged. Quantitative electron microscopy demonstrated a severe reduction in spermatozoal outer and inner dynein arms compared with normal (p less than 0.001) but normal numbers of outer doublets, central microtubules, and radial spokes were seen. In 2 samples of nasal cilia collected 14 months apart, the number of inner dynein arms was significantly reduced from normal (p less than 0.001), but normal numbers of radial spokes and microtubule structures were seen. Ciliary outer dynein arms were slightly reduced in 1 specimen (p less than 0.001) but were normal in the other. It is suggested that the reduction in the number of ciliary inner dynein arms does not affect ciliary motility in vitro but that, under the increased load of mucus in vivo, this defect prevents the cilia from functioning normally. The difference in axonemal ultrastructure between cilia and spermatozoa from the same patient further suggests a separate genetic control of their structural components.


Predictors of outcome in cognitive and behavioural interventions for irritable bowel syndrome. A meta-analysis.
Cognitive behavioural therapy (CBT) has small to medium effects in alleviating emotional distress and psychosomatic symptoms in irritable bowel syndrome (IBS). However, the mechanism through which CBT exerts its effects is less studied. Mediation analysis examines the extent to which intermediate variables explain the effect of the intervention on outcomes. The meta-analysis aims to identify and assess the impact of CBT mediators identified in previous research on IBS. An extensive search of studies investigating the effects of CBT for IBS published before January 2018 was conducted. A total of 699 studies were identified through database search and 6 studies including data from 638 patients were analysed. The selected studies had to clearly define the CBT intervention, include IBS patients, report sufficient data to allow calculation of effect sizes and provide a clear mediation analysis of one or several variables on the outcome. The total effect of CBT was significant for both categories of outcomes (i.e. IBS symptom severity and psychosocial distress), with a low-to-moderate effect on psychosocial distress (r=0.222) and a medium-to-large effect on IBS symptom severity (r=0.413). In fact, the total effect of CBT on IBS symptom severity is significantly higher than the total effect on psychosocial distress Q(1)= 5.06, p= 0.024. Both behaviours and emotions (r=0.158) as well as cognitions (r=0.141) generated significant mediated effects on psychosocial distress, with no significant differences between them (Q(1)= 0.05, p=0.825). Behaviours and emotions mediated 71.1% of the total effect of CBT on psychosocial distress and cognitions mediated 63.5% of the total effect. Although significant for both outcomes, the statistical analysis revealed CBT interventions have a greater effect on alleviating IBS symptoms severity rather than on reducing psychological distress. Of the mediators investigated, behaviours, emotions and cognitions seem to have a small to moderating effect in reducing IBS symptom and psychological distress.


Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice.
Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by dominant mutations in the collagen I genes COL1A1/COL1A2, whereas rarer recessive OI is often caused by mutations in genes encoding collagen I-interacting proteins. Recently, mutations in the gene for the proteinase bone morphogenetic 1 (BMP1) were reported in two recessive OI families. BMP1 and the closely related proteinase mammalian tolloid-like 1 (mTLL1) are co-expressed in various tissues, including bone, and have overlapping activities that include biosynthetic processing of procollagen precursors into mature collagen monomers. However, early lethality of Bmp1- and Tll1-null mice has precluded use of such models for careful study of in vivo roles of their protein products. Here we employ novel mouse strains with floxed Bmp1 and Tll1 alleles to induce postnatal, simultaneous ablation of the two genes, thus avoiding barriers of Bmp1(-/-) and Tll1(-/-) lethality and issues of functional redundancy. Bones of the conditionally null mice are dramatically weakened and brittle, with spontaneous fractures-defining features of OI. Additional skeletal features include osteomalacia, thinned/porous cortical bone, reduced processing of procollagen and dentin matrix protein 1, remarkably high bone turnover and defective osteocyte maturation that is accompanied by decreased expression of the osteocyte marker and Wnt-signaling inhibitor sclerostin, and by marked induction of canonical Wnt signaling. The novel animal model presented here provides new opportunities for in-depth analyses of in vivo roles of BMP1-like proteinases in bone and other tissues, and for their roles, and for possible therapeutic interventions, in OI.


Hugan Buzure Granule Alleviates Acute Kidney Injury in Mice by Inhibiting NLRP3/Caspase-1 Pathway and TLR4/NF-κB Pathway.
Hugan Buzure Granule (HBG) is a traditional prescription of Uygur nationality in China mainly used to treat liver cold, stomachache, spleen and rib pain, arthralgia, rheumatism and urinary system diseases. Its mechanism of action in treating acute kidney injury (AKI) continues to remain unconfirmed. This study's objective was to investigate the pharmacodynamics and mechanism of HBG in the management of AKI. The damage to the kidney tissue was examined by using H&E (Hematoxylin-eosin) staining. The BUN (Blood Urea Nitrogen) and Cr (Creatinine) in serum were examined by biochemical kit. The content of ROS (Reactive oxygen species) in kidney tissue was determined by ROS frozen section staining, while the amount of MDA (Malondialdehyde), GSH (Glutathione), and the enzymes of CAT (Catalase) and SOD (Superoxide dismutase) were assessed by using a biochemical kit. The tissue apoptosis was seen by using the TUNEL assay. ELISA kit was utilized to assess the content of IL-6, TNF-α, and IL-1β in serum. Immunohistochemistry and Western blot were utilized to identify the translation of proteins associated to the NLRP3/Caspase-1 pathway and the TLR4/NF-κB pathway in various tissues. HBG considerably improved the renal injury in mice and decreased their kidney coefficient in contrast with the Control group. Immunohistochemistry and Western blot demonstrated that the translation of NLRP3, Caspase-1, IL-18, IL-1β, TLR4, NF-κB, IL-6, TNF-α were down-regulated in HBG groups. HBG may have a protective effect against AKI through anti-oxidative stress, inhibition of apoptosis and reduction of serum inflammatory factor levels. The mechanisms involved inhibiting NLRP3/Caspase-1 pathway and TLR4/NF-κB pathway.


Optical grating evaluator: a device for detailed measurement of diffraction grating efficiencies in the vacuum ultraviolet.
A device for detailed measurement of diffraction grating efficiencies and over-all performance in the VUV has been designed and constructed at the Naval Research Laboratory. The system employs semiautomated mechanisms to scan the face of the grating with a narrow monochromatic beam, and an efficiency map of the grating surface is produced on a strip chart recorder. Grating efficiency in the various diffracted orders and intensity of light scattered between orders may also be measured. A unique feature is the ability to determine the angle and effectiveness of grating blaze and variations in blaze under different conditions of illumination.


Prion diseases of humans and animals: their causes and molecular basis.
Prion diseases are transmissible neurodegenerative conditions that include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals. Prions appear to be composed principally or entirely of abnormal isoforms of a host-encoded glycoprotein, prion protein. Prion propagation involves recruitment of host cellular prion protein, composed primarily of alpha-helical structure, into a disease specific isoform rich in beta-sheet structure. The existence of multiple prion strains has been difficult to explain in terms of a protein-only infections agent, but recent studies suggest that strain specific phenotypes can be encoded by different prion protein conformations and glycosylation patterns. The ability of a protein to encode phenotypic information has important biological implications. The appearance of a novel human prion disease, variant CJD, and the clear experimental evidence that it is caused by exposure to BSE has highlighted the need to understand the molecular basis of prion propagation, pathogenesis, and the barriers limiting intermammalian transmission. It is unclear if a large epidemic of variant CJD will occur in the years ahead.


Ambient γ-Rays-Mediated Noble-Metal Deposition on Defect-Rich Manganese Oxide for Glycerol-Assisted H2 Evolution at Industrial-Level Current Density.
Developing novel synthesis technologies is crucial to expanding bifunctional electrocatalysts for energy-saving hydrogen production. Herein, we report an ambient and controllable γ-ray radiation reduction to synthesize a series of noble metal nanoparticles anchored on defect-rich manganese oxides (M@MnO2-x , M=Ru, Pt, Pd, Ir) for glycerol-assisted H2 evolution. Benefiting from the strong penetrability of γ-rays, nanoparticles and defect supports are formed simultaneously and bridged by metal-oxygen bonds, guaranteeing structural stability and active site exposure. The special Ru-O-Mn bonds activate the Ru and Mn sites in Ru@MnO2-x through strong interfacial coordination, driving glycerol electrolysis at low overpotential. Furthermore, only a low cell voltage of 1.68 V is required to achieve 0.5 A cm-2 in a continuous-flow electrolyzer system along with excellent stability. In situ spectroscopic analysis reveals that the strong interfacial coordination in Ru@MnO2-x balances the competitive adsorption of glycerol and OH* on the catalyst surface. Theoretical calculations further demonstrate that the defect-rich MnO2 support promotes the dissociation of H2 O, while the defect-regulated Ru sites promote deprotonation and hydrogen desorption, synergistically enhancing glycerol-assisted hydrogen production.


Central Limit Theorems and Uniform Laws of Large Numbers for Arrays of Random Fields.
Over the last decades, spatial-interaction models have been increasingly used in economics. However, the development of a sufficiently general asymptotic theory for nonlinear spatial models has been hampered by a lack of relevant central limit theorems (CLTs), uniform laws of large numbers (ULLNs) and pointwise laws of large numbers (LLNs). These limit theorems form the essential building blocks towards developing the asymptotic theory of M-estimators, including maximum likelihood and generalized method of moments estimators. The paper establishes a CLT, ULLN, and LLN for spatial processes or random fields that should be applicable to a broad range of data processes.


Using the CDC's Worksite Health ScoreCard as a Framework to Examine Worksite Health Promotion and Physical Activity.
Worksite health promotion programs are emerging as an effective approach for addressing the adult obesity epidemic and improving the overall health of employees. We conducted a scoping review to identify articles that described a physical activity component (eg, promoted increased physical or reduced sitting time) of a worksite health promotion intervention. Our search specified full-length articles published in English from January 2000 through July 2015. We used the Centers for Disease Control and Prevention's Worksite Health ScoreCard, a validated tool, as a framework to summarize information on organizational supports strategies (18 questions) and physical activity strategies (9 questions) implemented by worksite health promotion programs. We also determined whether or not the included studies reported significant (P < .05) improvements in physical activity. We identified 18 worksite health promotion programs; 11 produced significant improvements in physical activity. Incentives, health risk assessments, health promotion committees, leadership support, marketing, and subsidies or discounts for use of exercise facilities were the most effective organizational supports strategies cited, and physical activity seminars, classes, and workshops were the most effective physical activity strategies cited. The use of the Health ScoreCard allowed for a practical interpretation of our findings, which can inform next steps for the field. Future research should explore the relationships between components of worksite health promotion programs and their outcomes to further develop best practices that can improve worker health and promote physical activity.


Role of Akt/protein kinase B in the activity of transcriptional coactivator p300.
Akt/protein kinase B is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway and plays a critical role in promotion of cell survival. The function of transcriptional coactivator p300 is required by many transcription factors to either activate or repress gene expression. Here, we show that induction of PI3K enhances the metabolic stability of endogenous p300 protein. On the other hand, repression of PI3K by LY294002 induces p300 degradation through the 26S proteasome pathway and impedes the transcriptional activity of the coactivator. In addition, Akt interacts with the coactivator and the activity of Akt is required to maintain the steady-state level of p300. Our study provides a new insight into the molecular mechanisms by which the critical concentration of p300 protein is regulated and suggests a role for Akt in control of various cellular activities through the transcriptional coactivator p300.


[Neuroacanthocytosis update].
Neuroacanthocytosis is an inclusive term for a genetically heterogeneous group of disorders characterized by the association of neurological abnormalities with red cell acanthocytosis. In the late 1960s, Levine et al. reported a family with a syndrome of neurological deficits such as choreiform involuntary movements, epileptic seizures, intellectual impairment, and paranoid ideation along with acanthocytosis without any disturbance in either alpha- or beta-lipoproteins nor retinitis pigmentosa. Critchley et al. also reported familial cases with acanthocytosis and neurological disorders without beta-lipoproteinemia. These cases have been classified as the Levine-Critchley syndrome of neuroacanthocytosis. Cases of neuroacanthocytosis have been classified into 2 groups depending on the presence or absence of movement disorders such as chorea. One group comprises the core neuroacanthocytosis syndromes in which neurodegeneration occurs primarily in the basal ganglia, specifically the striatum, causing movement disorders. The core neuroacanthocytosis syndromes mainly comprise of the two diseases, chorea-acanthocytosis and the McLeod syndrome. Huntington's disease-like 2, and pantothenate kinase-associated neurodegeneration (PKAN) are very rare but these diseases can also be included in this group of syndromes. Advances in molecular genetics have enabled us to distinguish between these diseases. Recently, the hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration syndrome (HARP syndrome) has been genetically shown to be an allelic form of PKAN. The second group of neuroacanthocytosis syndromes includes abetalipoproteinemia (Bassen-Kornzweig disease) and hypobetalipoproteinemia that are characterized by the abnormal decay of lipoprotein with the intestinal malabsorption of fat leading to neurological abnormalities and acanthocytosis. In this type of neuroacanthocytosis shows a progressive spinocerebellar ataxia with peripheral neuropathy and retinitis pigmentosa are observed, but movement disorders are not seen.


How does the central nervous system address the kinetic redundancy in the lumbar spine? Three-dimensional isometric exertions with 18 Hill-model-based muscle fascicles at the L4-L5 level.
The human motor system is organized for execution of various motor tasks in a different and flexible manner. The kinetic redundancy in the human musculoskeletal system is a significant property by which the central nervous system achieves many complementary goals. An equilibrium-based biomechanical model of isometric three-dimensional exertions of trunk muscles has been developed. Following the definition and role of the uncontrolled manifold, the kinetic redundancy concept is explored in mathematical terms. The null space of the kinetically redundant system when a certain joint moment and/or stiffness are needed is derived and discussed. The aforementioned concepts have been illustrated, using a three-dimensional three-degrees-of-freedom biomechanical model of the spine with 18 anatomically oriented Hill-type-model muscle fascicles. The considerations of stability and its consequence on the internal loading of the spine and coactivation consequences are discussed in both general and specific cases. The results can shed light on the interaction mechanisms in muscle activation patterns seen in various tasks and exertions and can provide a significant understanding for future research studies and clinical practices related to low-back disorders. Alteration of recruitment patterns in low-back-pain patients has been explained on the basis of this biomechanical analysis. The higher coactivation results in higher internal loading while providing higher joint stiffness that enhances spinal stability, which guards against spinal deformation in the presence of any perturbations.


Epidemiology of nonalcoholic fatty liver disease in Europe: a systematic review and meta-analysis.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the developed countries. The aim of this study was to evaluate the NAFLD prevalence in European adults and children/adolescents of the general population and specific subgroups. Search for all articles published between 01/1990-06/2019 reporting NAFLD prevalence from European countries. Nineteen studies with adults and 9 with children/adolescents were included. Pooled NAFLD prevalence in adults was 26.9%, being higher in studies using ultrasonography (27.2%) or fatty liver index (FLI) (30.1%) than liver biochemical tests (19.1%) and without differences between Mediterranean and non-Mediterranean countries or publication periods. Pooled NAFLD prevalence was higher in men than women (32.8% vs. 19.6%) and in patients with than those without metabolic syndrome (75.3% vs. 17.9%) or any of its components (always P<0.01). Ultrasound and FLI performed equally in estimating NAFLD prevalence in most subgroups. A higher prevalence was reported using FLI in obese and in diabetic patients, whereas a higher prevalence was observed with ultrasound in non-obese patients and in individuals without metabolic syndrome. NAFLD prevalence was 2.7% in unselected and 31.6% in obese/overweight children/adolescents. NAFLD prevalence exceeds 25% in European adults, being higher in those with metabolic syndrome component(s)-related comorbidities. It remains low in unselected NAFLD population, but increased in overweight/obese European children/adolescents, particularly from Mediterranean countries.


New methods to assess susceptibilities of Aspergillus isolates to caspofungin.
Echinocandins are a group of antifungal agents that target 1,3-beta-glucan synthase, causing disruption of mold growth at cells compromising tips and branch points. In part because echinocandins do not induce clear growth inhibition end points using broth dilution techniques, methods to test susceptibility have not yet been standardized. We developed a novel susceptibility assay that measures growth of Aspergillus species on solid agar media that contain serial dilutions of caspofungin (agar dilution). Results of agar dilution testing of multiple isolates were compared to results obtained by broth microdilution (MIC), microscopic evaluation (minimal effective concentration [MEC]), and a new method to measure fungal burden, quantification of secreted hyphal antigen. MICs obtained by the agar dilution method were within 1 dilution of MECs for 85% of the Aspergillus isolates; the highest agreement was observed for isolates of Aspergillus niger (95%), which were particularly susceptible to caspofungin. Agar dilution MICs were also consistent with those obtained by quantifying antigen secretion. MICs obtained by broth microdilution were different than MICs by any other method. Several Aspergillus isolates with decreased susceptibility to caspofungin were identified. Agar dilution is simple and reproducible, and results were consistent with the results of more technically demanding techniques. This method may be appropriate for use in the clinical laboratory.


Neurogenic vasodilation in human skeletal muscle: possible role in contraction-induced hyperaemia.
Whether or not neurally mediated vasodilation contributes to the rise in skeletal muscle blood flow during exercise in humans remains unknown. Such a mechanism might serve as an important 'feed-forward' regulatory signal causing blood flow to rise prior to the development of a metabolic demand. Research in animal species has identified three neurally mediated vasodilating mechanisms with the potential to increase skeletal muscle blood flow during exercise. These include sympathetic vasodilator nerves, the potential for substances released by motor nerves to evoke vasodilation and the possibility of an 'intrinsic' vasodilator nerve system within the walls of blood vessels. In humans, sympathetic vasodilator nerves are present in several vascular beds (e.g. cutaneous). However, more recent information suggests that the human skeletal muscle is not innervated by this class of nerves. Along these lines, the vasodilator response to exercise is unaffected by sympathectomy or by blockade of the traditional transmitters associated with neurally mediated vasodilation. The possibility that spillover of substances released from motor neurones evokes vasodilation is provocative. For example, acetylcholine could produce both skeletal muscle contraction via nicotinic receptors and vasodilation via endothelial muscarinic receptors. However, in many species including humans, atropine has no effect on exercise hyperaemia. While the concept of an 'intrinsic' vasodilator pathway within the walls of the skeletal muscle vascular bed is fascinating, limited information is available on this mechanism in animals and none is available in humans. Taken together, the current information suggests that neurally mediated vasodilating mechanisms may not exist in human skeletal muscle. Additionally, even if such mechanisms exist, they do not play an obligatory role in governing the rise in muscle blood flow during exercise in humans.


Clinical characteristics of children receiving antipsychotic medication.
This study explored the demographic and diagnostic features of children who were currently receiving antipsychotics compared to children who were receiving other psychotropics in a cohort of children with and without elevated symptoms of mania (ESM). Participants were recruited from 10 child outpatient mental health clinics associated with four universities. Guardians with children between 6-12 years who presented for new clinical evaluations completed the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M). All children who scored ≥12 on the PGBI-10M and a select demographically matched comparison group of patients who scored ≤11 were invited to participate. Children were divided into two groups: those receiving at least one antipsychotic medication and those receiving other psychotropic medications. The groups were compared on demographics, diagnoses, psychiatric symptoms, functioning, and past hospitalizations. Of the 707 children enrolled in the Longitudinal Assessment of Manic Symptoms (LAMS) study, 443 (63%) were prescribed psychotropic medication at baseline: 157 (35%) were receiving an antipsychotic and 286 (65%) were prescribed other agents. Multivariate results indicated that being prescribed antipsychotics was related to being white, previous hospitalization, having a psychotic or bipolar 1 disorder and the site where the child was receiving services (p<0.001). In this sample, it is relatively common for a child to be prescribed an antipsychotic medication. However, the only diagnoses associated with a greater likelihood of being treated with an antipsychotic were psychotic disorders or unmodified DSM-IV bipolar 1 disorder.


Effects of hypertonic saline versus lactated Ringer's solution on cerebral oxygen transport during resuscitation from hemorrhagic shock.
Hypertonic saline successfully restores systemic hemodynamics in dogs and humans with severe hemorrhagic shock and, in contrast to lactated Ringer's solution, does not increase intracranial pressure (ICP). This study compares cerebral oxygen delivery in 12 dogs subjected to hemorrhagic shock by the rapid removal of blood (mean arterial pressure of 40 mm Hg maintained for 30 minutes), and then resuscitated with lactated Ringer's solution (six dogs) or 7.5% saline solution (six dogs) to restore systolic arterial pressure. Both solutions effectively restored systemic hemodynamic stability, increasing cardiac output and systolic blood pressure while decreasing mean and diastolic arterial pressure and systemic vascular resistance. The ICP was significantly lower after resuscitation in the hypertonic saline group (p less than 0.05), but cerebral blood flow, which had decreased during shock, was not restored by either fluid, and cerebral oxygen transport fell further secondary to a hemodilutional reduction of hemoglobin. Although hypertonic saline may improve systemic hemodynamics and maintain a low ICP during resuscitation, it fails, as does Ringer's solution, to restore cerebral oxygen transport to prehemorrhagic shock levels.


Lessons from the modern battlefield: successful upper extremity injury reconstruction in the subacute period.
Reconstructive techniques and protocols for limb salvage of upper extremity battlefield injuries remains poorly defined. Our study describes the types of flaps, the timing of reconstruction, and success rates of war upper extremity reconstruction during a 30-month period using the Bethesda limb salvage protocol. Soldiers with significant upper extremity injuries with complex open fractures from Operation Iraqi Freedom and Operation Enduring Freedom-Afghanistan who underwent tissue transfer flaps were reviewed (n = 26, free flaps n = 6). Data analysis included mechanism of injury, associated injuries, types of flap, postoperative complications, wound infection rates, and outcome data. The cause of injury consisted of improvised explosive device (61%), rocket-propelled grenades (15%), motor vehicle crash (8%), land mine (8%), and gunshot wound (4%). Mean age was 25 years. Mean number of prereconstructive washouts was six (range, 3-22). Forty-six percent of wounds were culture positive at admission (75% were Acinetobacter species). All patients had other coexisting extremity, trunk or facial injuries. Average time to flap reconstruction was 31 days (range, 9-161). In 66% of the cases, a fasciocutaneous flap was used, and in the remaining cases, muscle (19%) and adipofascial (15%) flaps were performed. Flap success rate was 96%, with one flap loss because of venous congestion (managed with limb shortening). Infection rate was 8%. Complete coverage was achieved in all upper extremity wounds and early occupational therapy resulted in improved return to function. Despite massive bone and soft tissue defects, high preoperative wound colonization, and delays in definitive reconstruction, devastating war wounds can be successfully reconstructed in the subacute period with low flap failure, infection, and amputation rates.


Modulation of human cytotrophoblastic leptin secretion by interleukin-1alpha and 17beta-oestradiol and its effect on HCG secretion.
To investigate the role of leptin during pregnancy, we assessed leptin production by pure cultured human cytotrophoblastic cells (CTB), its regulation by cytokines and 17beta-oestradiol and its effects on human chorionic gonadotrophin (HCG) secretion. Purified CTB from first trimester placenta were incubated in duplicates in the presence or absence of cytokines or 17beta-oestradiol. Medium was harvested on day 2 and the culture stopped on day 4. Results were corrected for protein content of each individual well and expressed as percent of controls per day (mean +/- SEM). Basal CTB leptin production was 25.2 +/- 2.6 (ng/mg prot). In comparison with controls, leptin production was stimulated to 320 +/- 16% (P < 0.0001) and 195 +/- 3.2% (P < 0.0004) by 3 and 10 ng/ml of interleukin-1alpha respectively. 17beta-oestradiol 10(-6) to 10(-9) mol/l increased basal leptin production 5-9-fold, while 10(-5) mol/l had no such effect. Basal CTB HCG secretion was 5722 +/- 1055 (mIU/mg prot). There was a dose-dependent leptin-induced increase in HCG secretion (P = 0.0039) reaching a 5-fold increase with a leptin concentration of 1 microg/ml (P < 0.006). Gonadotrophin-releasing hormone (GnRH) 8.5 x 10(-8) mol/l significantly increased HCG secretion to 140 +/- 21% of controls (P = 0.031). Cetrorelix (0.1 microg/ml) inhibited leptin-induced HCG secretion (P = 0.0028).


Removal of ammonia from contaminated air in a biotrickling filter - denitrifying bioreactor combination system.
The removal of gaseous ammonia in a system consisting of a biotrickling filter, a denitrification reactor and a polishing bioreactor for the trickling liquid was investigated. The system allowed sustained treatment of ammonia while preventing biological inhibition by accumulating nitrate and nitrite and avoiding generation of contaminated water. All bioreactors were packed with cattle bone composite ceramics, a porous support with a large interfacial area. Excellent removal of ammonia gas was obtained. The critical loading ranged from 60 to 120 gm(-3)h(-1) depending on the conditions, and loadings below 56 gm(-3)h(-1) resulted in essentially complete removal of ammonia. In addition, concentrations of ammonia, nitrite, nitrate and COD in the recycle liquid of the inlet and outlet of each reactor were measured to determine the fate of nitrogen in the reactor, close nitrogen balances and calculate nitrogen to COD ratios. Ammonia absorption and nitrification occurred in the biotrickling filter; nitrate and nitrite were biologically removed in the denitrification reactor and excess dissolved COD and ammonia were treated in the polishing bioreactor. Overall, ammonia gas was very successfully removed in the bioreactor system and steady state operation with respect to nitrogen species was achieved.


A study of the fate of pairs of cadaver kidneys.
Follow-up data collected by the EDTA Registration Committee have been linked to donor and transplant information recorded by UK Transplant by forming a 'data interface' between the two Registries. The joint data have been used to study the fate of 243 pairs of kidneys used for first cadaver grafts in 1975 and 1976. The results of this preliminary study suggest that the transportation of kidneys and the cause of donor death do not affect graft survival. With a very small amount of data, analysis of the cause of failure suggests that this is not influenced by donor origins. The clinical condition at the time of grafting does not appear to have a major influence on the outcome of the graft. There seems little evidence to support the hypothesis that kidneys from the same donor share the same post-grafting fate.


Identification of regions responsible for the function of the plant K+ channels KAT1 and AKT2 in Saccharomyces cerevisiae and Xenopus laevis oocytes.
The Arabidopsis K+ channel KAT1 complements in K+-limited medium the growth of the K+ uptake defective Saccharomyces cerevisiae mutant strain CY162, while another K+ channel, AKT2, does not. To gain insight into the structural basis for this difference, we constructed 12 recombinant chimeric channels from these two genes. When expressed in CY162, only three of these chimeras fully rescued the growth of CY162 under K+-limited conditions. We conclude that the transmembrane core region of KAT1 is important for its activity in S. cerevisiae. This involves not only the pore region but also parts of its voltage-sensor domain.


Tumor necrosis factor enhances the in vitro and in vivo efficacy of chemotherapeutic drugs targeted at DNA topoisomerase II in the treatment of murine bladder cancer.
Recombinant human tumor necrosis factor (rTNF) is a macrophage secretory protein with antitumor activity. The murine bladder tumor cell line MBT-2 was used to evaluate the in vitro and in vivo antitumor effects of rTNF in combination with chemotherapeutic drugs targeted at DNA topoisomerase II. These drugs, such as adriamycin and etoposide (VP 16), are in widespread use in the treatment of human cancer. The rTNF significantly enhanced the cytotoxic efficacy of the topoisomerase-targeted drugs actinomycin D, adriamycin, etoposide (VP 16) and teniposide (VM 26) against MBT-2 cells in vitro. The rTNF alone had no effect upon the cells in the same assay. When examined in vivo using MBT-2 tumor-bearing C3H/HeJ mice, these same antitumor relationships were seen. The addition of rTNF to actinomycin D or VP 16 resulted in a significant reduction in tumor volume at 20 days compared to untreated animals. Actinomycin D, VP 16 or rTNF treatment alone had no significant effect on 20 day tumor volume. The data provide a reasonable basis for the addition of rTNF to experimental protocols for the treatment of human bladder cancer using topoisomerase-targeted drugs such as adriamycin both intravesically and systemically. These observations may also be relevant to other human cancers currently treated with these drugs.


An Automatic Method for Sublingual Image Segmentation and Color Analysis.
Automatic segmentation of sublingual images and color quantification of sublingual vein are of great significance to disease diagnosis in traditional Chinese medicine. With the development of computer vision, automatic sublingual image processing provides a noninvasive way to observe patients' tongue and is convenient for both doctors and patients. However, current sublingual image segmentation methods are not accurate enough. Besides, the differences in subjective judgments by different doctors bring more difficulties in color analysis of sublingual veins. In this paper, we propose a method of sublingual image segmentation based on a modified UNet++ network to improve the segmentation accuracy, a color classification approach based on triplet network, and a color quantization method of sublingual vein based on linear discriminant analysis to provide intuitive one-dimensional results. Our methods achieve 88.2% mean intersection over union (mIoU) and 94.1% pixel accuracy on tongue dorsum segmentation, and achieves 69.8% mIoU and 82.7% pixel accuracy on sublingual vein segmentation. Compared with the state-of-art methods, the segmentation mIoUs are improved by 5.8% and 5.3% respectively. Our sublingual vein color classification method has the highest overall accuracy of 81.2% and the highest recall for the minority class of 77.5%, and the accuracy of color quantization is 90.5%.Clinical Relevance- The methods provide accurate and quantified information of the sublingual image, which can assist doctors in diagnosis.


Intracellular routes and selective retention of antigens in mildly acidic cathepsin D/lysosome-associated membrane protein-1/MHC class II-positive vesicles in immature dendritic cells.
Immature dendritic cells (DC) use both macropinocytosis and mannose receptor-mediated endocytosis to internalize soluble Ags efficiently. These Ags are ultimately presented to T cells after DC maturation and migration into the lymph nodes. We have previously described the immortalized myeloid cell line FSDC as displaying the characteristics of early DC precursors that efficiently internalize soluble Ags. To describe the different routes of Ag uptake and to identify the Ag retention compartments in FSDC, we followed the intracellular fate of FITC-coupled OVA, dextran (DX), transferrin, and Lucifer Yellow using flow cytometry, confocal microscopy, and immunoelectron microscopy. OVA and DX gained access into macropinosomes and early endosomes. DX was preferentially sorted into endosomal compartments, while most of the OVA entered macropinosomes via fluid phase uptake. We found a long-lasting retention of DX and OVA of up to 24 h. After 6 h of chase, these two molecules were concentrated in common vesicular compartments. These retention compartments were distinct from endosomes and lysosomes; they were much larger, only mildly acidic, and lacked the small GTP binding protein rab7. However, they were positive for lysosome-associated membrane protein-1, the protease cathepsin D, and MHC class II molecules, thus representing matured macropinosomes. These data suggest that the activity of vacuolar proteases is reduced at the mildly acidic pH of these vesicles, which explains their specific retention of an Ag. The retention compartments might be used by nonlymphoid tissue DC to store peripheral Ags during their migration to the lymph node.


Aneurysmal bone cysts of the spine. Report of 17 cases.
Seventeen cases of aneurysmal bone cyst of the spine are reported. Clinical manifestations, methods of investigation, differential diagnosis, treatment, and pathogenesis are discussed. The condition is essentially a benign lesion, affects a young age group, and grows rapidly, often producing a paravertebral mass. Occasionally it becomes acutely exacerbated, causing irreversible damage to the spinal cord. For these reasons, prompt diagnosis and timely treatment are important. Excision of the lesion is the treatment of choice but, if not feasible, thorough curettage and radiotherapy not exceeding 2000 rads are indicated. With a two-stage operation, excision of the lesion is often possible, and the stability of the vertebral column is assured with bone-graft fusions.


Composition of protein supplements used for human embryo culture.
To determine the composition of commercially available protein supplements for embryo culture media and test if differences in protein supplement composition are biologically relevant in a murine model. Amino acid, organic acid, ion and metal content were determined for 6 protein supplements: recombinant human albumin (AlbIX), human serum albumin (HSA and Buminate), and three complex protein supplements (SSS, SPS, LGPS). To determine if differences in the composition of these supplements are biologically relevant, mouse one-cell embryos were collected and cultured for 120 hours in each protein supplement in Global media at 5 and 20 % oxygen in an EmbryoScope time-lapse incubator. The compositions of six protein supplements were analyzed for concentrations of 39 individual amino acids, organic acids, ions and elements. Blastocyst development and cell cycle timings were calculated at 96-hours of culture and the experiments were repeated in triplicate. Blastocyst gene expression was analyzed. Recombinant albumin had the fewest undefined components , the lowest concentration of elements detected, and resulted in high blastocyst development in both 5 and 20 % oxygen. Buminate, LGPS and SPS had high levels of transition metals whereas SSS had high concentrations of amino acids. Pre-compaction mouse embryo development was delayed relative to embryos in AlbIX for all supplements and blastocyst formation was reduced in Buminate, SPS and SSS. The composition of protein supplements are variable, consisting of previously undescribed components. High concentrations of pro-oxidant transition metals were most notable. Blastocyst development was protein dependent and showed an interaction with oxygen concentration and pro-oxidant supplements.


Non-classical inhibition of uricase by cyanide.
The interactions of Aspergillus flavus uricase with the substrates O2 and urate and the inhibitors xanthine, cyanide, periodate and hydroxylamine were investigated. Under equilibrium conditions O2 does not bind directly to the enzyme, and the absence of O2 had no effect on either the binding stoicheiometry or binding constant for xanthine, as measured by equilibrium dialysis and microcalorimetry. Cyanide, periodate and hydroxylamine inhibit uricase in a non-classical manner. A decrease in initial velocity to a steady-state inhibited velocity can be observed on a time scale of minutes. The time-dependence, which is unaltered by prior incubation with the inhibitors, is consistent with a first-order transition. Rate constants for induction of inhibition are linearly dependent on inhibitor concentration, but independent of urate and O2 concentrations. Radioactively labelled urate forms a stable but reversible complex with uricase in the presence of cyanide and O2. These results were used to deduce the nature of enzyme-bound intermediates and thus for the proposal of a novel mechanism for cyanide inhibition.


Spices Volatilomic Fingerprinting-A Comprehensive Approach to Explore Its Authentication and Bioactive Properties.
Volatile organic metabolites (VOMs) present in different spices can provide distinct analytical biosignatures related to organoleptic properties and health benefits. This study aimed to establish the volatilomic fingerprint of six of the most consumed spices all over the world (saffron (Crocus sativus L.), cinnamon (Cinnamomum verum), cumin (Cuminum cyminum L.), black pepper, (Piper nigrum L.), sweet paprika (Capsicum annuum L.), and curry (a mix of different herbs and spices)). Based on headspace solid phase microextraction (HS-SPME) followed by gas chromatography-mass spectrometry (GC-MS) analysis, this is a powerful strategy to explore and establish the spice's volatile pattern and unravel the potential health benefits related to the most important VOMs identified in each spice. This comprehensive knowledge will help in the definition of their authenticity, while simultaneously protecting against potential frauds and adulterations. A total of 162 VOMs were identified. Semi-quantitative assessments revealed that terpenoids and sesquiterpenoids amounted to the major volatile class in the investigated spices, except for cinnamon, where carbonyl compounds are the major group. Most of the studied spices comprised key characteristics of aroma and health bioactive compounds, e.g., dihydrojuneol in saffron, cinnamaldehyde in cinnamon, cuminaldehyde in cumin and curry, and caryophyllene in black pepper. The principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) successfully discriminated the investigated spices, being α-cubebene, 3-methyl butanal, β-patchoulene and β-selinene, the most important VOMs (highest VIP's) that contributed to its discrimination. Moreover, some VOMs have a high influence on the spice's bioactive potential, helping to prevent certain diseases including cancer, inflammatory-related diseases, diabetes, and cardiovascular diseases.


The transcription factor PU.1 mediates enhancer-promoter looping that is required for IL-1β eRNA and mRNA transcription in mouse melanoma and macrophage cell lines.
The DNA-binding protein PU.1 is a myeloid lineage-determining and pioneering transcription factor due to its ability to bind "closed" genomic sites and maintain "open" chromatin state for myeloid lineage-specific genes. The precise mechanism of PU.1 in cell type-specific programming is yet to be elucidated. The melanoma cell line B16BL6, although it is nonmyeloid lineage, expressed Toll-like receptors and activated the transcription factor NF-κB upon stimulation by the bacterial cell wall component lipopolysaccharide. However, it did not produce cytokines, such as IL-1β mRNA. Ectopic PU.1 expression induced remodeling of a novel distal enhancer (located ∼10 kbp upstream of the IL-1β transcription start site), marked by nucleosome depletion, enhancer-promoter looping, and histone H3 lysine 27 acetylation (H3K27ac). PU.1 induced enhancer-promoter looping and H3K27ac through two distinct PU.1 regions. These PU.1-dependent events were independently required for subsequent signal-dependent and co-dependent events: NF-κB recruitment and further H3K27ac, both of which were required for enhancer RNA (eRNA) transcription. In murine macrophage RAW264.7 cells, these PU.1-dependent events were constitutively established and readily expressed eRNA and subsequently IL-1β mRNA by lipopolysaccharide stimulation. In summary, this study showed a sequence of epigenetic events in programming IL-1β transcription by the distal enhancer priming and eRNA production mediated by PU.1 and the signal-dependent transcription factor NF-κB.


Refugee, asylum seeker, immigrant women and postnatal depression: rates and risk factors.
Postnatal depression (PND) is recognised as a common maternal health problem, but little evidence examines PND among refugee, asylum seeker and immigrant women in developed country settings. This review aimed to identify the rates of PND and highlight common risk factors among this group of women. An iterative and dynamic literature search was conducted across ten databases to identify published articles on PND among immigrant, asylum-seeking and refugee women in developed country settings. Medical Subject Headings (MeSH) and 'free text' search terms, as well as thesaurus terms, acronyms and truncation were used where appropriate. Findings suggest that PND may affect up to 42% of migrant women, compared to around 10-15% of native-born women. Common risk factors for PND among migrant women include history of stressful life events, lack of social support and cultural factors. With a growing number of babies born to immigrant mothers, greater awareness of PND among this group is needed in order to respond to their particular maternal mental health needs. Maternity care providers should regard all recent immigrants as at high risk of PND and give closer observation and support as necessary.


Differential regulation of mitochondrial pyruvate carrier genes modulates respiratory capacity and stress tolerance in yeast.
Mpc proteins are highly conserved from yeast to humans and are necessary for the uptake of pyruvate at the inner mitochondrial membrane, which is used for leucine and valine biosynthesis and as a fuel for respiration. Our analysis of the yeast MPC gene family suggests that amino acid biosynthesis, respiration rate and oxidative stress tolerance are regulated by changes in the Mpc protein composition of the mitochondria. Mpc2 and Mpc3 are highly similar but functionally different: Mpc2 is most abundant under fermentative non stress conditions and important for amino acid biosynthesis, while Mpc3 is the most abundant family member upon salt stress or when high respiration rates are required. Accordingly, expression of the MPC3 gene is highly activated upon NaCl stress or during the transition from fermentation to respiration, both types of regulation depend on the Hog1 MAP kinase. Overexpression experiments show that gain of Mpc2 function leads to a severe respiration defect and ROS accumulation, while Mpc3 stimulates respiration and enhances tolerance to oxidative stress. Our results identify the regulated mitochondrial pyruvate uptake as an important determinant of respiration rate and stress resistance.


Visible light-enabled selective depolymerization of oxidized lignin by an organic photocatalyst.
The development of an economic, environmental-friendly and energy-saving process for the selective depolymerization of lignin is an outstanding challenge. Herein, a novel and efficient visible-light-induced photocatalytic process for the selective depolymerization of lignin model compounds and organosolv lignin was first developed by using perylene diimide (PDI) as a metal-free organocatalyst. Interestingly, it can completely decompose the oxidized lignin models to phenolic and ketone fragmentation molecules with very high selectivity at room temperature under visible light illumination. Furthermore, the use of a home-made photocatalytic continuous-flow reactor efficiently shortened the reaction time within an hour. Even for organosolv lignin, nearly 86% mass ratio of lignin was degraded to low-molecular-mass monoaromatic or diaromatic products. We found that superior performances were realized by single-electron transfer (SET) from the photoexcited strongly reducing PDI˙- anion to the ketone groups of the β-O-4 linkage in the lignin.


Significance of Parenchymal Brain Damage in Patients with Critical Illness.
To determine the prevalence, type, and significance of brain damage in critically ill patients with a primary non-neurological diagnosis developing acute brain dysfunction. This retrospective cohort study was performed at the Johns Hopkins University School of Medicine, an academic tertiary care hospital. Medical records were reviewed of 479 consecutive ICU patients who underwent brain magnetic resonance imaging (MRI) over a 2-year period. Patients were selected for analysis if MRI was obtained to evaluate an acute onset of brain dysfunction (altered mental status, seizures, and/or focal neurological deficit). Subjects with a history of a central nervous system disorder were excluded. The principal clinical endpoint was Glasgow Outcome Scale (GOS) assessed at discharge. MRI-defined brain abnormalities were classified according to type and location. Factors associated with MRI-defined abnormalities were assessed in uni- and multivariable models. 146 patients met inclusion criteria (mean age 54 ± 7 years). Brain damage was detected in 130 patients (89%). The most prevalent lesions were white matter hyperintensities (104/146, 71%) and acute cerebral infarcts (59/146, 40%). In a multivariable model, lesions on brain MRI were independently associated with unfavorable outcome (GOS1-3 in 71% of patients with lesions vs. 44% in those without, p = 0.007). No adverse events occurred in relation to transport and MRI scanning. In critically ill patients without known neurological disease who have acute brain dysfunction, MRI reveals an unexpectedly high burden of underlying brain damage, which is associated with unfavorable outcome. The results indicate that brain damage could be an important and under-recognized factor contributing to critical illness brain dysfunction.


Obesity is associated with folate metabolism.
Objective: The aim of the present study is to perform a systemic review of the previous studies executed on the association between obesity and folate. Method: In the present research, the selected keywords were scanned on the PubMed, Web of Science, Cochrane and Lilac databases between May and June, 2017 through Gazi University's network. In total, 4236 clinical, randomized controlled, cross-sectional and prospective studies were determined and 17 of these that specifically fit the aims of the present research were reviewed. This study involved an electronic literature search of databases on folic acid and obesity published in the English language between 2000 and 2016. Results: Of the 17 studies, 5 were based on folic acid supplementation and 12 were related with participants' folate status. As a general consequence of both intake and serum/status measurements of folic acid supplementation: It was found that obesity-associated metabolic changes might affect individual folate use and obese individuals had lower serum folate levels, although there was no change in folate intake. Conclusion: Overweight and obese individuals have lower serum folate concentrations when compared with individuals with normal weight. It is explained by increased use of folic acid, urinary excretion, dilution of blood volume, different levels in different tissues and changes in the endocrine functions of folate. Individuals with higher Body Mass Indexes have less supplement use, unhealthier diets and donot consume sufficient vegetables and fruits, all of which can affect decrease in folate levels. Furthermore, adiposity may affect folate absorption by intestinal epithelium.


Induction of the Histamine-Forming Enzyme Histidine Decarboxylase in Skeletal Muscles by Prolonged Muscular Work: Histological Demonstration and Mediation by Cytokines.
Recent studies suggest that histamine-a regulator of the microcirculation-may play important roles in exercise. We have shown that the histamine-forming enzyme histidine decarboxylase (HDC) is induced in skeletal muscles by prolonged muscular work (PMW). However, histological analysis of such HDC induction is lacking due to appropriate anti-HDC antibodies being unavailable. We also showed that the inflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-α can induce HDC, and that PMW increases both IL-1α and IL-1β in skeletal muscles. Here, we examined the effects (a) of PMW on the histological evidence of HDC induction and (b) of IL-1β and TNF-α on HDC activity in skeletal muscles. By immunostaining using a recently introduced commercial polyclonal anti-HDC antibody, we found that cells in the endomysium and around blood vessels, and also some muscle fibers themselves, became HDC-positive after PMW. After PMW, TNF-α, but not IL-1α or IL-1β, was detected in the blood serum. The minimum intravenous dose of IL-1β that would induce HDC activity was about 1/10 that of TNF-α, while in combination they synergistically augmented HDC activity. These results suggest that PMW induces HDC in skeletal muscles, including cells in the endomysium and around blood vessels, and also some muscle fibers themselves, and that IL-1β and TNF-α may cooperatively mediate this induction.


[Prevention of erectile dysfunction in patients with metabolic syndrome].
The aim of the study was to test efficacy of erectile dysfunction prevention in patients with metabolic syndrome by correction of metabolic disorders and stimulation of endothelial NO-synthetase. In case of the above correction and stimulation combination, the risk of erectile dysfunction went up significantly compared to placebo group and patients with correction of metabolic disorders alone.


Sex-differences in grey-white matter structure in normal-reading and dyslexic adolescents.
MR images were used to look for brain structure irregularities in adolescent children with dyslexia by use of combined grey and white matter volume measurements and fractal dimension (FD) of the grey-white matter border. The data were collected from 13 dyslexic adolescent (8 boys and 5 girls) that were compared with 18 control subjects (8 boys and 10 girls). The MR images were first segmented, and the volume as well as the FD of the grey/white matter border for the whole brain and for each hemisphere was computed. Changes were found in the measured volumes of both grey and white matter and were best reflected in the ratio of grey/white matter and in FD values, especially in the left hemisphere. The results showed that, although dyslexia is less frequent in women, the structural differences in the brain are more pronounced in their case, pointing to an increased vulnerability of the female brain to morphological changes associated with dyslexia.


Left visual neglect: is the disengage deficit space- or object-based?
Attention can be directed to spatial locations or to objects in space. Patients with left unilateral spatial neglect are slow to respond to a left-sided target when it is preceded by a right-sided "invalid" cue, particularly at short cue-target intervals, suggesting an impairment in disengaging attention from the right side in order to orient it leftward. We wondered whether this deficit is purely spatial, or it is influenced by the presence of a right-sided visual object. To answer this question, we tested 10 right brain-damaged patients with chronic left-neglect and 41 control participants on a cued response time (RT) detection task in which targets could appear in either of two lateral boxes. In different conditions, non-informative peripheral cues either consisted in the brightening of the contour of one lateral box (onset cue condition), or in the complete disappearance of one lateral box (offset cue condition). The target followed the cue at different stimulus-onset asynchronies (SOAs). If the disengagement deficit (DD) is purely space-based, then it should not vary across the two cueing conditions. With onset cues, patients showed a typical DD at short SOAs. With offset cues, however, the DD disappeared. Thus, patients did not show any DD when there was no object from which attention must be disengaged. These findings indicate that the attentional bias in left-neglect does not concern spatial locations per se, but visual objects in space.


An open-label pilot trial of N-acetylcysteine and varenicline in adult cigarette smokers.
Varenicline (VAR) has demonstrated superior efficacy over other smoking cessation pharmacotherapies, though 50-60% of those treated do maintain abstinence. Some preclinical findings suggest that new nicotine dependence pharmacotherapies should target the glutamatergic system, given its demonstrated role in addiction. Attention has been given to N-acetylcysteine (NAC), which appears to restore normal glutamate signaling in animal models. It is possible that NAC and VAR may work in concert to promote abstinence at higher rates than with either medication alone. To demonstrate the feasibility and safety of co-administering NAC and VAR in nicotine-dependent participants. Participants (n = 19) were daily cigarette smokers, and did not need to be seeking treatment. They received 4 weeks of open-label treatment with NAC (1200 mg twice daily) and VAR (1 mg twice daily, following titration) and were assessed weekly for adverse events (AEs), smoking, craving and withdrawal. Sixteen participants reported a total of 40 AEs, and most were mild (88%). The most commonly reported AE was nausea (15%). Medication adherence, assessed via self-reports and pill counts, was excellent (98%). Exploratory analyses showed reductions in cigarettes per day, though point prevalence abstinence at the end of the study was low. These preliminary data provide the first demonstration of safety and feasibility of the co-administration of NAC and VAR in cigarette smokers. AEs were consistent with those typically reported for VAR and NAC. These data support future efficacy research on NAC and VAR for smoking cessation.


Detection of seizure activity in the paralyzed neonate using continuous monitoring.
In experimental animals neurologic damage may occur during seizure activity whether the seizure is accompanied by motor activity and hypoxemia or whether the animal is paralyzed and normoxemic. These findings suggest that it may be important to detect seizure activity in the paralyzed neonate. Nine infants who were mechanically ventilated and paralyzed with pancuronium had their condition diagnosed as seizure activity. Vital signs were continuously monitored and six infants had either oxygen saturation or transcutaneous oxygen measured during seizure activity. For the group as a whole, rhythmic fluctuations in vital signs, cardiac rhythm, and oxygenation occurred every four minutes (range one to seven minutes) and lasted two minutes (range one to four minutes). In seven patients whose seizures were not accompanied by cardiac arrhythmias the following mean increases were noted: systolic arterial blood pressure, 15 mm Hg (range 7 to 36 mm Hg); heart rate, ten beats per minute (-11 to 30/min); oxygen saturation, 12% (range 4% to 20%); and transcutaneous oxygen, 31 mm Hg (range 14 to 45 mm Hg). Seizures in the two patients with cardiac arrhythmias were accompanied by a decrease in systolic arterial blood pressure of 27 mm Hg (range 15 to 40 mm Hg) and in oxygen saturation of 24% (range 20% to 28%). The presence of rhythmic fluctuation in vital signs and oxygenation should alert the physician to the possibility of seizure activity in the paralyzed neonate.


Applying Classical Esthetic Principles to Create a Predictable Illusion of Symmetry While Using Digital Technology.
Having a thorough understanding of classical esthetic principles, including basic tooth shape and form rules, is crucial for clinicians to achieve successful esthetic outcomes, even when implementing digital technologies in their dental offices. The use of advanced, cutting-edge digital tools does not negate the need to adhere to timeless fundamentals of esthetic dentistry. This article reviews key esthetic principles and describes their application in treating a challenging cosmetic case. Showcasing the use of smile design software, the case illustrates the diagnosis, planning, and clinical execution used to mask a congenitally missing lateral incisor while preserving the natural dentition on the contralateral side. The principles of symmetry and harmony are employed to create a smile in which the restorative dentistry would be imperceptible and the remaining dentition protected from structural compromise.


Introducing directly induced microglia-like (iMG) cells from fresh human monocytes: a novel translational research tool for psychiatric disorders.
Microglia, glial cells with immunological functions, have been implicated in various neurological diseases and psychiatric disorders in rodent studies, and human postmortem and PET studies. However, the deeper molecular implications of living human microglia have not been clarified. Here, we introduce a novel translational research approach focusing on human microglia. We have recently developed a new technique for creating induced microglia-like (iMG) cells from human peripheral blood. Two cytokines, GM-CSF and IL-34, converted human monocytes into the iMG cells within 14 days, which show various microglial characterizations; expressing markers, forming a ramified morphology, and phagocytic activity with various cytokine releases. We have already confirmed the applicability of this technique by analyzing iMG cells from a patient of Nasu-Hakola disease (NHD; Ohgidani et al., 2014). We herein show possible applications of the iMG cells in translational research. We believe that this iMG technique will open the door to explore various unknown dynamic aspects of human microglia in psychiatric disorders. This also opens new routes for psychopharmacological approach such as drug efficacy screening and personalized medicine.


Synthesis and structure-activity relationship of 3beta-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane and 3beta-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters.
Early studies led to the identification of 3beta-(4-methoxyphenyl)tropane-2beta-carboxylic acid methyl ester (5) with high affinity at the DAT (IC(50)=6.5nM) and 5-HTT (K(i)=4.3nM), while having much less affinity at the NET (K(i)=1110nM). In the present study, we replaced the 4'-methoxy group of the 3beta-phenyl ring with a bioisosteric 4'-methylthio group to give 7a. We also synthesized a number of 3beta-(4-alkylthiophenyl)tropanes 7b-e, 3beta-(4-methylsulfinylphenyl) and 3beta-(4-methylsulfonylphenyl)tropane analogues 7f-h as well as the 3beta-(4-alkylthiophenyl)nortropane derivatives 8-11 to further characterize the structure-activity relationship of this type of compound for binding at monoamine transporters. With exception of the 4'-methylsulfonyl analogue 7h, all the tested compounds possessed high binding affinities at the 5-HTT. The K(i) values ranged from 0.19nM to 49nM. The 3beta-(4-methylthiophenyl)tropane 7a and its N-(3-fluoropropyl) analogue 9a and N-allyl analogue 10a are the most selective compounds for the 5-HTT over the NET (NET/5-HTT=314-364) in the series. However, none of the compounds showed selectivity similar to 5 for both the DAT and 5-HTT relative to the NET. This study provided useful SAR information for rational design of potent and selective monoamine transporter inhibitors.


A review of chronic inhalation studies with mainstream cigarette smoke in rats and mice.
In this paper, I review the results of a representative selection of chronic inhalation studies with rats and mice exposed to mainstream cigarette smoke and describe the inhalation exposures and the histopathological changes reported by various authors. Many of the studies used nose-only exposure systems, whereas others simply used large whole-body chambers. Smoke-induced epithelial hypertrophy, hyperplasia, and squamous metaplasia were reported in the conducting airways in most of the studies, along with increased numbers of intra-alveolar macrophages that were occasionally associated with alveolar metaplasia. Lung adenomas and adenocarcinomas were reported in only a few of the studies. No statistically significant increase in the incidence of malignant lung tumors was seen in either species as a result of smoke exposure, a finding that does not agree with the results of epidemiological studies in humans. Possible reasons for this lack of correlation are given.


[Pathogenic basis of intrauterine infections].
The literature and the authors' own results on pathogenesis of intrauterine infections are reviewed. Special attention is paid to the mechanisms of contamination, disease stages and cellular-humoral responses of the fetus. Implications of the above factors in the formation of multiple clinicomorphological manifestations of the intrauterine infections are pointed out.


Chronic atrial fibrillation. Success of serial cardioversion therapy and safety of oral anticoagulation.
Serial electrical cardioversion is often used for treatment of atrial fibrillation, but its long-term efficacy has not been determined prospectively. To determine the long-term success rate of the serial electrical cardioversion approach in patients with chronic atrial fibrillation, to identify factors that predict its success, and to assess the efficacy and safety of oral anticoagulation in these patients. Patients with chronic (> 24 hours) atrial fibrillation received anticoagulant therapy for at least 4 weeks prior to electrical cardioversion. No prophylactic antiarrhythmic agent was given after the first shock. Relapses were managed by using repeated cardioversions, after which serial antiarrhythmic drug therapy was started. Treatment with anticoagulants was withdrawn after 4 weeks of sinus rhythm. Two hundred thirty-six patients were followed up for a mean +/- SD of 3.7 +/- 1.6 years. The actuarial cumulative percentages of patients who maintained sinus rhythm after serial cardioversion treatment was 42% and 27% after 1 and 4 years, respectively. Multivariate analysis showed that factors that were associated with failure of this approach included duration of atrial fibrillation that exceeded 36 months (risk ratio, 5.0; P < .001), poor exercise tolerance (functional class III; risk ratio, 1.8; P = .001), and age older than 56 years (risk ratio, 1.5; P = .04). The anticoagulation level (international normalized ratio, 2.4-4.8) was associated with an incidence of thromboembolic events and bleeding complications of 0.2% and 1.5%, respectively. Many patients with chronic atrial fibrillation failed to respond to the serial electrical cardioversion strategy. However, in younger patients with a fair exercise tolerance and a duration of atrial fibrillation shorter than 36 months, this approach may be worthwhile. In addition, thromboembolic events were infrequent in the patients who were subjected to this regimen.


Revealing nonlinear neural decoding by analyzing choices.
Sensory data about most natural task-relevant variables are entangled with task-irrelevant nuisance variables. The neurons that encode these relevant signals typically constitute a nonlinear population code. Here we present a theoretical framework for quantifying how the brain uses or decodes its nonlinear information. Our theory obeys fundamental mathematical limitations on information content inherited from the sensory periphery, describing redundant codes when there are many more cortical neurons than primary sensory neurons. The theory predicts that if the brain uses its nonlinear population codes optimally, then more informative patterns should be more correlated with choices. More specifically, the theory predicts a simple, easily computed quantitative relationship between fluctuating neural activity and behavioral choices that reveals the decoding efficiency. This relationship holds for optimal feedforward networks of modest complexity, when experiments are performed under natural nuisance variation. We analyze recordings from primary visual cortex of monkeys discriminating the distribution from which oriented stimuli were drawn, and find these data are consistent with the hypothesis of near-optimal nonlinear decoding.


Postoperative ileus: mechanisms and future directions for research.
Postoperative ileus (POI) is an abnormal pattern of gastrointestinal motility characterized by nausea, vomiting, abdominal distension and/or delayed passage of flatus or stool, which may occur following surgery. Postoperative ileus slows recovery, increases the risk of developing postoperative complications and confers a significant financial load on healthcare institutions. The aim of the present review is to provide a succinct overview of the clinical features and pathophysiological mechanisms of POI, with final comment on selected directions for future research.Terminology used when describing POI is inconsistent, with little differentiation made between the obligatory period of gut dysfunction seen after surgery ('normal POI') and the more clinically and pathologically significant entity of a 'prolonged POI'. Both normal and prolonged POI represent a fundamentally similar pathophysiological phenomenon. The aetiology of POI is postulated to be multifactorial, with principal mediators being inflammatory cell activation, autonomic dysfunction (both primarily and as part of the surgical stress response), agonism at gut opioid receptors, modulation of gastrointestinal hormone activity and electrolyte derangements. A final common pathway for these effectors is impaired contractility and motility and gut wall oedema. There are many potential directions for future research. In particular, there remains scope to accurately characterize the gastrointestinal dysfunction that underscores an ileus, development of an accurate risk stratification tool will facilitate early implementation of preventive measures and clinical appraisal of novel therapeutic strategies that target individual pathways in the pathogenesis of ileus warrant further investigation.


Diagnostic Algorithmic Proposal Based on Comprehensive Immunohistochemical Evaluation of 297 Invasive Endocervical Adenocarcinomas.
The International Endocervical Adenocarcinoma Criteria and Classification was developed to separate endocervical adenocarcinomas (ECAs) into 2 main categories on the basis of morphology such as human papilloma virus-associated (HPVA) and non-human papilloma virus-associated adenocarcinomas. We aimed to improve the diagnostic accuracy of International Endocervical Adenocarcinoma Criteria and Classification by performing a comprehensive immunohistochemical evaluation and constructing objective immunohistochemical-based algorithms for the classification of these tumors. Tissue microarrays were constructed from 297 of 409 cases used to develop the original classification. Immunostains included p16, p53, estrogen receptor (ER), progesterone receptor, androgen receptor, Vimentin, CK7, CK20, HER2, HIK1083, MUC6, CA-IX, SATB2, HNF-1beta, napsin A, PAX8, CDX2, GATA3, p63, p40, and TTF-1. High-risk human papilloma virus (HR-HPV) was detected by in situ hybridization (ISH) using probes against E6 and E7 mRNA expressed in 18 different virus types. Vimentin, ER, and progesterone receptor were expressed in a significant minority of ECAs, mostly HPVAs, limiting their use in differential diagnosis of endometrioid carcinoma when unaccompanied by HPV-ISH or p16. HR-HPV ISH had superior sensitivity, specificity, and negative and positive predictive values compared with p16, as published previously. HNF-1beta did not have the anticipated discriminatory power for clear cell carcinoma, nor did MUC6 or CA-IX for gastric-type carcinoma. HNF-1beta and napsin A were variably expressed in clear cell carcinoma, with HNF-1beta demonstrating less specificity, as it was ubiquitously expressed in gastric-type carcinoma and in the majority of HPV-associated mucinous (predominantly intestinal-type and invasive ECA resembling stratified mucin-producing intraepithelial lesion [iSMILE]) and usual-type carcinomas. HIK1083 was expressed in nearly half of gastric-type carcinomas, but not in the vast majority of other subtypes. GATA3 was positive in 10% of usual-type adenocarcinomas and in single examples of other subtypes. Rare gastric-type and HPVA mucinous carcinomas displayed HER2 overexpression. Androgen receptor was positive in 6% of usual-type adenocarcinomas. Aberrant p53 expression was found in only 3.6% of usual-type HPVA carcinomas, but it was more prevalent in mucinous (intestinal type and iSMILE) HPVAs and non-human papilloma virus-associates (particularly in gastric-type carcinoma, >50% of cases). The following diagnostic classification algorithms were developed with the above data. Carcinomas without overt cytoplasmic mucin (endometrioid, usual-type endocervical, clear cell, and mesonephric carcinomas) can be subclassified using HR-HPV ISH, ER, and GATA3, whereas carcinomas with easily appreciated cytoplasmic mucin (endometrioid carcinoma with mucinous features, HPVA mucinous, and gastric-type carcinomas) can be subclassified with HR-HPV ISH and ER.


Constructing higher-order miRNA-mRNA interaction networks in prostate cancer via hypergraph-based learning.
Dysregulation of genetic factors such as microRNAs (miRNAs) and mRNAs has been widely shown to be associated with cancer progression and development. In particular, miRNAs and mRNAs cooperate to affect biological processes, including tumorigenesis. The complexity of miRNA-mRNA interactions presents a major barrier to identifying their co-regulatory roles and functional effects. Thus, by computationally modeling these complex relationships, it may be possible to infer the gene interaction networks underlying complicated biological processes. We propose a data-driven, hypergraph structural method for constructing higher-order miRNA-mRNA interaction networks from cancer genomic profiles. The proposed model explicitly characterizes higher-order relationships among genetic factors, from which cooperative gene activities in biological processes may be identified. The proposed model is learned by iteration of structure and parameter learning. The structure learning efficiently constructs a hypergraph structure by generating putative hyperedges representing complex miRNA-mRNA modules. It adopts an evolutionary method based on information-theoretic criteria. In the parameter learning phase, the constructed hypergraph is refined by updating the hyperedge weights using the gradient descent method. From the model, we produce biologically relevant higher-order interaction networks showing the properties of primary and metastatic prostate cancer, as candidates of potential miRNA-mRNA regulatory circuits. Our approach focuses on potential cancer-specific interactions reflecting higher-order relationships between miRNAs and mRNAs from expression profiles. The constructed miRNA-mRNA interaction networks show oncogenic or tumor suppression characteristics, which are known to be directly associated with prostate cancer progression. Therefore, the hypergraph-based model can assist hypothesis formulation for the molecular pathogenesis of cancer.


Human security as biosecurity Reconceptualizing national security threats in the time of COVID-19.
Research within security studies has struggled to determine whether infectious disease (ID) represents an existential threat to national and international security. With the emergence of SARS-CoV-2 (COVID-19), it is imperative to reexamine the relationship between ID and global security. This article addresses the specific threat to security from COVID-19, asking, "Is COVID-19 a threat to national and international security?" To investigate this question, this article uses two theoretical approaches: human security and biosecurity. It argues that COVID-19 is a threat to global security by the ontological crisis posed to individuals through human security theory and through high politics, as evidenced by biosecurity. By viewing security threats through the lens of the individual and the state, it becomes clear that ID should be considered an international security threat. This article examines the relevant literature and applies the theoretical framework to a case study analysis focused on the United States.


Intranasal desmopressin-associated hyponatremia: a case report and literature review.
We present a case of a 29-year-old woman with a long history of nocturnal enuresis who developed symptomatic hyponatremia from water intoxication shortly after beginning desmopressin. A MEDLINE search in the English language revealed 13 prior case reports. All patients presented with seizure, mental status changes, or both. Two distinct presentations occurred: one group of patients maintained a stable course with desmopressin and developed symptoms related to an outside factor. The other group of patients were new to desmopressin and had a profound water intoxication response from its use. While the underlying cause was from simple overhydration, the quickness of this unanticipated adverse effect is noteworthy. The importance of counseling to ensure a family's and a patient's understanding of the effects of desmopressin as well as monitoring electrolytes periodically may help identify and prevent this serious iatrogenic complication.