Fertility preservation options in breast cancer patients.
The purpose of this review is to analyse current options for fertility preservation in young women with breast cancer (BC). Considering an increasing number of BC survivors, owing to improvements in cancer treatment and delaying of childbearing, fertility preservation appears to be an important issue. Current fertility preservation options in BC survivors range from well-established standard techniques to experimental or investigational interventions. Among the standard options, random-start ovarian stimulation protocol represents a new technique, which significantly decreases the total time of the in vitro fertilisation cycle. However, in patients with oestrogen-sensitive tumours, stimulation protocols using aromatase inhibitors are currently preferred over tamoxifen regimens. Cryopreservation of embryos and oocytes are nowadays deemed the most successful techniques for fertility preservation in BC patients. GnRH agonists during chemotherapy represent an experimental method for fertility preservation due to conflicting long-term outcome results regarding its safety and efficacy. Cryopreservation of ovarian tissue, in vitro maturation of immature oocytes and other strategies are considered experimental and should only be offered within the context of a clinical trial. An early pretreatment referral to reproductive endocrinologists and oncologists should be suggested to young BC women at risk of infertility, concerning the risks and benefits of fertility preservation options.


Racial differences in self-reported infertility and risk factors for infertility in a cohort of black and white women: the CARDIA Women's Study.
To determine racial differences in self-reported infertility and in risk factors for infertility in a cohort of black and white women. A cross-sectional analysis of data from the longitudinal Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective, epidemiologic investigation of the determinants and evolution of cardiovascular risk factors among black and white young adults and from the ancillary CARDIA Women's Study (CWS). Population-based sample from four US communities (Birmingham, AL; Chicago, IL; Minneapolis, MN; Oakland, CA). Women aged 33-44 years who had complete data (n = 764). None. Self-report of ever having unprotected sexual intercourse for at least 12 months without becoming pregnant. Among nonsurgically sterile women, blacks had a twofold increased odds (95% confidence interval [CI] 1.3-3.1) of infertility compared with whites after adjustment for socioeconomic position (education and ability to pay for basics), correlates of pregnancy intent (marital status and hormonal contraceptive use), and risk factors for infertility (age, smoking, T, fibroid presence, and ovarian volume). The corresponding odds ratio among all women was 1.5 (95% CI 1.0-2.2). Difficulty paying for basics and ovarian volume were associated with infertility among black but not white women. In this population-based sample, black women were more likely to have experienced infertility. This disparity is not explained by common risk factors for infertility, such as smoking and obesity, and among nonsurgically sterile women, it is not explained by gynecologic risk factors such as fibroids and ovarian volume.


4-Chloro-4'-biphenylol as an uncoupler and an inhibitor of mitochondrial oxidative phosphorylation.
4-Chloro-4'-biphenylol (4'-OH-4-CB), a metabolite of 4-chlorobiphenyl (4-CB), stimulated state 4 respiration and released oligomycin-inhibited state 3 respiration of rat liver mitochondria with succinate as the respiratory substrate. When glutamate/malate and beta-hydroxybutyrate were used as the substrates, however, 4'-OH-4-CB was ineffective on these parameters. This indicates that 4'-OH-4-CB uncouples oxidative phosphorylation with succinate, but not with glutamate/malate and beta-hydroxybutyrate. 4'-OH-4-CB severely inhibited 2,4-dinitrophenol (DNP)-stimulated respiration with glutamate/malate (ID50, 25 microM) and beta-hydroxybutyrate (ID50, 32 microM) because of the blockade of electron transfer between NADH and CoQ span, masking the uncoupling action of 4'-OH-4-CB. On the other hand, the inhibition of the respiration with succinate was only apparent at high 4'-OH-4-CB concentrations (ID50, 260 microM). 4'-OH-4-CB also inhibited the oxidation of NADH in submitochondrial particles (ID50, 35 microM). State 3 respiration was more intensely inhibited by 4'-OH-4-CB in the presence of either glutamate/malate (ID50, 23 microM) or beta-hydroxybutyrate (ID50, 26 microM) than that in the presence of succinate (ID50, 220 microM). Thus, 4'-OH-4-CB acts as both an uncoupler and an inhibitor of oxidative phosphorylation. The overall in vitro effect is to prevent ATP synthesis, which may be an important factor in the mechanism underlying the toxicity of 4-CB.


A poly(glycerol sebacate)-coated mesoporous bioactive glass scaffold with adjustable mechanical strength, degradation rate, controlled-release and cell behavior for bone tissue engineering.
Various requirements in the field of tissue engineering have motivated the development of three-dimensional scaffold with adjustable physicochemical properties and biological functions. A series of multiparameter-adjustable mesoporous bioactive glass (MBG) scaffolds with uncrosslinked poly(glycerol sebacate) (PGS) coating was prepared in this article. MBG scaffold was prepared by a modified F127/PU co-templating process and then PGS was coated by a simple adsorption and lyophilization process. Through controlling macropore parameters and PGS coating amount, the mechanical strength, degradation rate, controlled-release and cell behavior of the composite scaffold could be modulated in a wide range. PGS coating successfully endowed MBG scaffold with improved toughness and adjustable mechanical strength covering the bearing range of trabecular bone (2-12MPa). Multilevel degradation rate of the scaffold and controlled-release rate of protein from mesopore could be achieved, with little impact on the protein activity owing to an "ultralow-solvent" coating and "nano-cavity entrapment" immobilization method. In vitro studies indicated that PGS coating promoted cell attachment and proliferation in a dose-dependent manner, without affecting the osteogenic induction capacity of MBG substrate. These results first provide strong evidence that uncrosslinked PGS might also yield extraordinary achievements in traditional MBG scaffold. With the multiparameter adjustability, the composite MBG/PGS scaffolds would have a hopeful prospect in bone tissue engineering. The design considerations and coating method of this study can also be extended to other ceramic-based artificial scaffolds and are expected to provide new thoughts on development of future tissue engineering materials.


Middle childhood and modern human origins.
The evolution of modern human life history has involved substantial changes in the overall length of the subadult period, the introduction of a novel early childhood stage, and many changes in the initiation, termination, and character of the other stages. The fossil record is explored for evidence of this evolutionary process, with a special emphasis on middle childhood, which many argue is equivalent to the juvenile stage of African apes. Although the "juvenile" and "middle childhood" stages appear to be the same from a broad comparative perspective, in that they begin with the eruption of the first molar and the achievement of the majority of adult brain size and end with sexual maturity, the detailed differences in the expression of these two stages, and how they relate to the preceding and following stages, suggest that a distinction should be maintained between them to avoid blurring subtle, but important, differences.


Chronologic comparison of postoperative results in gastric cancer surgery.
Patients who underwent gastric cancer surgery in our clinic during a 12-year period from 1960--1971 were divided into two groups. Group A is comprised of patients who were treated in the first, and group B of patients treated in the second half of this 12-year period and the short- and long-term results were evaluated and compared for both groups. We discovered that both short- and long-term results were better in group B than in group A. Group B contained more cases of histologically early cancer stages and extensive lymph node resection was performed more frequently in group B than in group A. These factors may account for the better results obtained for group B. In addition, performance of gastrectomy combined with the resection of other neighboring organs may have effected the better long-term results observed in group B.


Somatic H-2Kk variants reveal nonidentity of serological and cytotoxic T cell-defined Kk determinants.
The relationship of serologically defined determinants to determinants recognized by cytotoxic T cells on molecules encoded by the Kk gene of the murine major histocompatibility complex (H-2) has been analyzed. For this purpose we used three somatic variants of a Kk-expressing lymphoma line lacking individual determinants of the Kk molecule, as defined by monoclonal antibodies (mAb), as target cells for Kk-specific alloreactive and Kk-restricted cytotoxic T lymphocytes (CTL) cloned by limiting dilution. Neither alloreactive nor fluorescein isothiocyanate, influenza- or Newcastle disease virus-specific Kk-restricted CTL clones were found to distinguish between variants and wild type cells, indicating that the serologically defined determinants lost by the variants were not essential for antigen recognition of CTL with these specificities. On the other hand, two of the variants lacking either one of a pair of serological determinants were discriminated from Kk wild type cells by about 40% of Kk-restricted, trinitrophenol (TNP)-specific CTL clones. The third variant, lacking both of the determinants, however, was lysed by all CTL clones to the same extent as wild type cells. From these results we conclude that the determinants restricting the TNP-specific CTL were also not identical with those defined by mAb. In experiments performed to optimize the conditions for the limiting dilution analysis we found that the specificity of the CTL stimulation was strongly dependent on the concentration of T cell growth factor (interleukin 2) in the cultures during CTL stimulation. High concentrations of IL2 resulted in a drastic increase in the frequency of CTL clones. Part of these clones, however, were found not to be specific for antigens present on the stimulator cells.


Time Course of Reendothelialization with Polyzene-F Nanocoated Cobra PzF™ Coronary Stent on Rabbit Iliac Arteries.
Evaluation of reendothelialization with a new thin struts cobalt chromium alloy stent coated with a nano-layer of Polyzene™-F (PzF) in a rabbit iliac artery model. Fifteen stented external rabbit iliac arteries were harvested at Day 7 for electron microscopy analysis following Cobra PzF stents implantation to assess reendothelialization and compare to historical data. Ten additional rabbits were used to assess time course of reendothelialization at 3 and 5 days. At Day 7, almost complete coverage of endothelial cells was observed with a coverage of 99.54 ± 0.25% of the stented area. No thrombus area was noted. At Day 3, more than half of examined pieces was reendothelialized and reached 78.30 ± 3.7% at Day 5 (p < .01 between each group). All stents were well expanded against the arterial wall and no struts were mal-apposed. Reendothelialization was rapid and complete at Day 7. This is the fastest reendothelization process after stenting in this model. No stent occlusion was observed.


Rebound elevation of cortisol following cyproheptadine withdrawal in Cushing's disease from a pituitary macroadenoma.
A 44-year-old female with Cushing's disease associated with a pituitary macroadenoma was treated with cyproheptadine, 24 mg per day, after partial surgical resection of the tumor. A large residual tumor remained. There was no clear suppression of serum and urinary cortisol during therapy, but both levels rose markedly to beyond pre cyproheptadine levels, on withdrawal of the drug. This is the first report on the use of cyproheptadine in Cushing's disease associated with a pituitary macroadenoma. The response in this patient indicates an influence of cyproheptadine on ACTH secretion by the macroadenoma.


Intelligent Platform for Simultaneous Detection of Multiple Aminoglycosides Based on a Ratiometric Paper-Based Device with Digital Fluorescence Detector Readout.
A digital fluorescence detector (DFD), a handheld fluorescence detection device, can convert the fluorescence signal of samples into the corresponding fluorescer concentration. Herein, by adopting a DFD as the readout, a novel intelligent platform was developed based on a ratiometric paper-based device (RPD) for multiple aminoglycoside detection. There are five layers and four parallel channels contained in the designed RPD, functioning as reagent storage, fluidic path control and signal processing, respectively. The rationale of this design lies in the fact that aptamer/graphitic carbon nitride nanosheet (Apt/g-C3N4 NS) modified layers can catalyze o-phenylenediamine to fluorescent 2,3-diaminophenazine (DAP) in the presence of H2O2. When Apt was removed from nanosheets via the Apt-target reaction, the peroxidase-like activity would be decreased, thus decreasing the production of DAP. All the changes of the fluorescence DAP signal can be read out using a portable DFD. Based on the DFD signal change related to the concentration of the target, a quantitative reaction platform was established. Furthermore, the sample flow and Apt-target reaction time can be reasonably regulated using the H2O2-cleavable hydrophobic compound modified layer placed between the target recognition region and detection region. Then, the practicality of this platform was verified through realizing sensitive analysis of streptomycin, tobramycin, and kanamycin simultaneously. Overall, with merits including portability and ease of operation, the platform shows great potential in on-site simultaneous detection of multiple targets, especially in resource-limited settings.


Vertical ionization potential benchmarks from Koopmans prediction of Kohn-Sham theory with long-range corrected (LC) functional.
The Kohn-Sham density functional theory (KS-DFT) with the long-range corrected (LC) functional is applied to the benchmark dataset of 401 valence ionization potentials (IPs) of 63 small molecules of Chong, Gritsenko and Baerends (the CGB set). The vertical IP of the CGB set are estimated as negative orbital energies within the context of the Koopmans' prediction using the LCgau-core range-separation scheme in combination with PW86-PW91 exchange-correlation functional. The range separation parameterμof the functional is tuned to minimize the error of the negative HOMO orbital energy from experimental IP. The results are compared with literature data, includingab initioIP variant of the equation-of-motion coupled cluster theory with singles and doubles (IP-EOM-CCSD), the negative orbital energies calculated by KS-DFT with the statistical averaging of orbital potential, and those with the QTP family of functionals. The optimally tuned LC functional performs better than other functionals for the estimation of valence level IP. The mean absolute deviations (MAD) from experiment and from IP-EOM-CCSD are 0.31 eV (1.77%) and 0.25 eV (1.46%), respectively. LCgau-core performs quite well even with fixedμ(not system-dependent). Aμvalue around 0.36 bohr-1gives MAD of 0.40 eV (2.42%) and 0.33 eV (1.96%) relative to experiment and IP-EOM-CCSD, respectively. The LCgau-core-PW86-PW91 functional is an efficient alternative to IP-EOM-CCSD and it is reasonably accurate for outer valence orbitals. We have also examined its application to core ionization energies of C(1s), N(1s), O(1s) and F(1s). The C(1s) core ionization energies are reproduced reasonably [MAD of 46 cases is 0.76 eV (0.26%)] but N(1s), O(1s) and F(1s) core ionization energies are predicted less accurately.


Whole transcriptome sequencing reveals genes involved in plastid/chloroplast division and development are regulated by the HP1/DDB1 at an early stage of tomato fruit development.
The phenotype of tomato high pigment-1 (hp1) mutant is characterized by overproduction of pigments including chlorophyll and carotenoids during fruit development and ripening. Although the increased plastid compartment size has been thought to largely attribute to the enhanced pigmentation, the molecular aspects of how the HP1/DDB1 gene manipulates plastid biogenesis and development are largely unknown. In the present study, we compared transcriptome profiles of immature fruit pericarp tissue between tomato cv. Ailsa Craig (WT) and its isogenic hp1 mutant. Over 20 million sequence reads, representing > 1.6 Gb sequence data per sample, were generated and assembled into 21,972 and 22,167 gene models in WT and hp1, respectively, accounting for over 60 % official gene models in both samples. Subsequent analyses revealed that 8,322 and 7,989 alternative splicing events, 8833 or 8510 extended 5'-UTRs, 8,263 or 8,939 extended 3'-UTRs, and 1,136 and 1,133 novel transcripts, exist in WT and hp1, respectively. Significant differences in expression level of 880 genes were detected between the WT and hp1, many of which are involved in signaling transduction, transcription regulation and biotic and abiotic stresses response. Distinctly, RNA-seq datasets, quantitative RT-PCR analyses demonstrate that, in hp1 mutant pericarp tissue at early developmental stage, an apparent expression alteration was found in several regulators directly involved in plastid division and development. These results provide a useful reference for a more accurate and more detailed characterization of the molecular process in the development and pigmentation of tomato fruits.


Conditioned place aversion produced by microinjections of semicarbazide into the periaqueductal gray of the rat.
Previous studies have shown that the blockade of GABA-ergic neurotransmission in the periaqueductal gray (PAG) of the rat induce flight reactions. The present study examined whether a negative affective state was produced by such a blockade. Microinjections of semicarbazide, a GABA synthesis inhibitor, into the PAG were found to produce a conditioned place aversion. In a second experiment, it was found that the potent GABA agonist muscimol antagonized the effects of semicarbazide, without producing a conditioned place preference or aversion by itself. These results suggest that the blockade of the tonic inhibition exerted by GABAergic terminals in the PAG results in both an aversive experience and an overt flight reaction.


Lagged Association of Ambient Outdoor Air Pollutants with Asthma-Related Emergency Department Visits within the Pittsburgh Region.
Asthma affects millions of people globally and is especially concerning in populations living with poor air quality. This study examines the association of ambient outdoor air pollutants on asthma-related emergency department (ED) visits in children and adults throughout the Pittsburgh region. A time-stratified case-crossover design is used to analyze the lagged effects of fine particulate matter (PM2.5) and gaseous pollutants, e.g., ozone (O3), sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO) on asthma-related ED visits (n = 6682). Single-, double-, and multi-pollutant models are adjusted for temperature and analyzed using conditional logistic regression. In children, all models show an association between O3 and increased ED visits at lag day 1 (OR: 1.12, 95% CI, 1.03-1.22, p < 0.05) for the double-pollutant model (OR: 1.10, 95% CI: 1.01-1.20, p < 0.01). In adults, the single-pollutant model shows associations between CO and increased ED visits at lag day 5 (OR: 1.13, 95% CI, 1.00-1.28, p < 0.05) and average lag days 0-5 (OR: 1.22, 95% CI: 1.00-1.49, p < 0.05), and for NO2 at lag day 5 (OR: 1.04, 95% CI: 1.00-1.07, p < 0.05). These results show an association between air pollution and asthma morbidity in the Pittsburgh region and underscore the need for mitigation efforts to improve public health outcomes.


Preparation and evaluation of novel bio-based Bis-GMA-free dental composites with low estrogenic activity.
Although bisphenol Aglycidyl methacrylate (Bis-GMA) are widely used in the dental composite, its raw materials include the petroleum-based product bisphenol A (BPA) with high estrogenic activity (EA). In this study, two new BPA-free dimethacrylate monomers from bio-based material creosol were synthesized and evaluated. The renewable bisphenol monomer 5, 5'-methylenedicreosol (BCF) was prepared from bio-based material creosol. By the human breast cancer cells (MCF-7 cells) proliferation assay, a risk assessment of BCF was performed to determine if BCF possessed reduced EA in comparison to BPA. Then, the novel monomers 5, 5'-methylenedicreosol diglycidyl ether diacrylate (BCF-EA) and 5, 5'-methylenedicreosol diglycidyl ether dimethacrylate (BCF-GMA) were synthesized from BCF with epichlorohydrin and (meth)acrylate. All products were investigated by 1H NMR and FT-IR spectra. The control resin was a mixture based on Bis-GMA and tri(ethyleneglycol) dimethacrylate (TEGDMA) with a weight ratio of 5:5 (5B5T). Similarly, experimental resin matrix was a mixture based on BCF-EA/TEGDMA (5E5T) and BCF-GMA/TEGDMA (5G5T). And their corresponding composites were then prepared with corresponding resin matrices and hybrid SiO2 (5E5TC, 5G5TC and 5B5TC). The properties of these composites were investigated according to the standard or referenced methods. Each sample was evaluated for double bond conversion (DC), shrinkage stress (SS) and volumetric polymerization shrinkage (VS). Water sorption (WS), water solubility (SL), mechanical properties and cytotoxicity were also measured. 1H NMR and FT-IR spectra confirmed the chemical structure of each monomer. EA test revealed that bio-based bisphenol monomer BCF as the precursor of BCF-EA and BCF-GMA showed lower EA than BPA. Cured resin matrix: Both 5E5T and 5G5T had nearly the same DC (p < 0.05), which was higher than 5B5T (p < 0.05); 5E5T and 5G5T had lower VS, SL and cytotoxicity than 5B5T (p < 0.05); mechanical properties of 5E5T and 5G5T were all better than those of 5B5T (p < 0.05). Cured composite: There was no significant difference in conversion (p < 0.05); 5E5TC and 5G5TC had significantly lower VS (p < 0.05); WS of 5E5TC and 5G5TC were similar (p < 0.05), but higher compared to 5B5TC (p < 0.05); 5E5TC and 5G5TC had the deeper depth of cure (p > 0.05); before water immersion, there was no significant difference in flexural strength between 5E5TC and 5G5TC (p > 0.05), and higher than 5B5TC (p < 0.05); 5E5TC and 5G5TC showed less cytotoxicity than 5B5TC (p < 0.05). The new BPA-free di(meth)acrylates are promising photocurable dental monomers owning to bio-based raw material, high degree of conversion coupled with low curing shrinkage and good mechanical properties. Therefore, BCF-EA and BCF-GMA has a potential to be used as the substitution for Bis-GMA to prepare Bis-GMA-free dental composite.


Phenol-Soluble Modulins Contribute to Early Sepsis Dissemination Not Late Local USA300-Osteomyelitis Severity in Rabbits.
In bone and joint infections (BJIs), bacterial toxins are major virulence factors: Panton-Valentine leukocidin (PVL) expression leads to severe local damage, including bone distortion and abscesses, while α-hemolysin (Hla) production is associated with severe sepsis-related mortality. Recently, other toxins, namely phenol-soluble modulins (PSMs) expressed by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA300 (LAC WT) were shown to have ex vivo intracellular cytotoxic activity after S. aureus invasion of osteoblasts, but their in vivo contribution in a relatively PVL-sensitive osteomyelitis model remains poorly elucidated. We compared the outcomes of experimental rabbit osteomyelitises induced with pvl+hla+psms+ LAC WT and its isogenic Δpsm derivatives (LAC Δpsmα and LAC Δpsmαβhld) using an inoculum of 3 × 108 CFUs. Mortality, hematogenous spread (blood culture, spleen and kidney), lung and bone involvements were assessed in two groups (non-survivors of severe sepsis and survivors sacrificed on day (D) 14). Severe sepsis-related mortality tended to be lower for Δpsm derivatives (Kaplan-Meier curves, P = .06). Non-survivors' bone LAC-Δpsmα (6.9 log10 CFUs/g of bone, P = .04) or -Δpsmαβhld (6.86 log10 CFUs/g of bone, P = .014) densities were significantly higher than LAC WT (6.43 log10 CFUs/g of bone). Conversely, lung Δpsmαβhld CFUs were significantly lower than LAC WT (P = .04). LAC Δpsmα, Δpsmαβhld and WT induced similar bone damage in D14 survivors, with comparable bacterial densities (respectively: 5.89, 5.91, and 6.15 log10 CFUs/g of bone). Meanwhile, pulmonary histological scores of inflammation were significantly higher for LAC Δpsmα- and Δpsmαβhld-infected rabbits compared to LAC WT (P = .04 and .01, respectively) but with comparable lung bacterial densities. Our experimental results showed that deactivating PSM peptides significantly limited bacterial dissemination from bone during the early phase of infection, but did not affect local severity of USA300 rabbit osteomyelitis.


Duplication of primate and rodent B7-H3 immunoglobulin V- and C-like domains: divergent history of functional redundancy and exon loss.
B7-H3 is a novel protein structurally related to the B7 family of ligands by the presence of a single set of immunoglobulin-V-like and immunoglobulin-C-like (VC) domains. By multiplex PCR, the dominantly expressed form of human B7-H3 was found to be a splice variant containing tandemly duplicated VC domains (VCVC). In contrast, mouse B7-H3 cDNA contained only one single VC form due to an exon structure corresponding to V-(pseudoexon C)-(pseudoexon V)-C. Comparisons of human, monkey, mouse, and hamster genomic B7-H3 reveal that primates, but not rodents, exhibited a higher degree of intramolecular sequence similarity between VC duplications than between molecules. Both VC and VCVC forms of human B7-H3 inhibited CD4(+) T cell proliferation and downregulated cytokine production upon TCR activation. These results suggest independent, but convergent, paths of B7-H3 active domain duplication followed by divergent histories of exon degeneration in rodents and exon maintenance by humans.


A non-coding variant in the Kozak sequence of RARS2 strongly decreases protein levels and causes pontocerebellar hypoplasia.
Bi-allelic variants in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been involved in early-onset encephalopathies classified as pontocerebellar hypoplasia (PCH) type 6 and in epileptic encephalopathy. A variant (NM_020320.3:c.-2A > G) in the promoter and 5'UTR of the RARS2 gene has been previously identified in a family with PCH. Only a mild impact of this variant on the mRNA level has been detected. As RARS2 is non-dosage-sensitive, this observation is not conclusive in regard of the pathogenicity of the variant.We report and describe here a new patient with the same variant in the RARS2 gene, at the homozygous state. This patient presents with a clinical phenotype consistent with PCH6 although in the absence of lactic acidosis. In agreement with the previous study, we measured RARS2 mRNA levels in patient's fibroblasts and detected a partially preserved gene expression compared to control. Importantly, this variant is located in the Kozak sequence that controls translation initiation. Therefore, we investigated the impact on protein translation using a bioinformatic approach and western blotting. We show here that this variant, additionally to its effect on the transcription, also disrupts the consensus Kozak sequence, and has a major impact on RARS2 protein translation. Through the identification of this additional case and the characterization of the molecular consequences, we clarified the involvement of this Kozak variant in PCH and on protein synthesis. This work also points to the current limitation in the pathogenicity prediction of variants located in the translation initiation region.


Pre-Exposure to TiO2-NPs Aggravates Alcohol-Related Liver Injury by Inducing Intestinal Barrier Damage in Mice.
The wide application of titanium dioxide nanoparticles (TiO2-NPs) and the increase in opportunities for its release into the environment undoubtedly compound the potential of these materials to harm people. Research on the effects of pre-exposure to TiO2-NPs on disease development is scarce. The purpose of this work was to assess whether pre-exposure to TiO2-NPs (20 and 200 mg/kg) for 28 days aggravates the development of alcohol-related liver injury in mice. Results showed that oral administration of 200 mg/kg TiO2-NPs induced only modest changes in liver function parameters, but could induce intestinal inflammation and destroy the integrity of intestinal barrier. After the subsequent alcohol intervention, pre-exposure to TiO2-NPs (200 mg/kg) was found to aggravate alcohol-related liver injury, including significantly increases in serum aspartate aminotransferase, alanine aminotransferase, total glycerol, and total cholesterol, as well as steatosis and inflammation in the liver. Further investigation revealed that alcohol could increase intestinal permeability and reduce the expression of tight junction proteins in mice pre-exposed high dosage of TiO2-NPs, thereby inducing the transfer of more lipopolysaccharides into the liver, ultimately triggering more severe liver inflammation. This study emphasizes that pre-exposed of TiO2-NPs (high doses of up to 200 mg/kg) can potentially promote the development of alcoholic liver diseases. Furthermore, this study provides new insights into evaluating the safety of NPs.


Effects of calcium antagonists on muscarinic receptor subtypes in the rat brain.
The effects of several calcium antagonists, including nicardipine, nifedipine, verapamil, and diltiazem, on muscarinic acetylcholine antagonist binding were studied in the P2 fraction of the rat cerebral cortex using either [3H]quinuclidinyl benzilate ([3H]QNB) or [3H]pirenzipine as the radioactive ligand. (1) The potency of [3H]QNB binding inhibition was in the order nicardipine greater than verapamil greater than diltiazem greater than nifedipine. The IC50 values of nicardipine, verapamil, and diltiazem were 2.56 X 10(-6) M, 1.28 X 10(-5) M, and 6.00 X 10(-5) M, respectively. (2) The inhibition of [3H]QNB binding by nicardipine was significantly decreased in the presence of Ca ions. (3) In saturation experiments of [3H]QNB binding in the presence of nicardipine, the Kd value appeared to be significantly affected, but the Bmax value was unchanged. This indicated that nicardipine probably inhibited [3H]QNB binding allosterically. On the other hand, (4) nicardipine inhibited [3H]pirenzipine binding completely with an IC50 value of 7.87 X 10(-7) M. It was concluded that nicardipine had an inhibitory effect on M1-receptor binding.


Correlations of understory herb distribution patterns with microhabitats under different tree species in a mixed mesophytic forest.
This study examines the role of canopy trees in the formation and maintenance of different herb microhabitats in a mixed mesophytic forest stand. Herb abundance and reproductive success were recorded in 54 circular plots under seven species of canopy trees and in 15 circular control plots>2 m from any tree. Soil moisture, soil nutrient levels, litter depth, and light intensity were measured in a subset of these plots. Ordination of plots by both herb relative abundance and by reproductive success of common species indicated that herb assemblages under most canopy tree species were similar to those away from trees. However, herb assemblages under Fagus grandifolia trees differed moderately from the others while plots under Quercus alba trees supported significantly different herb assemblages. Analyses of variance revealed that several herb species occurred at significantly closer mean distance to the base of Q. alba or Fagus trees or at higher densities under these tree species. Soils around Q. alba trees had significantly higher concentrations of calcium and sulfate ions, and higher pH than plots under other tree species and control plots. This correlated closely with Q. alba stemflow which had higher concentrations of calcium and sulfate ions and lower concentrations of hydrogen ions than stemflow from other trees at this site. The slightly lower soil pH near the base of Fagus trees may have been related to the high volumes of stemflow produced by this species. Stepwise regression showed significant correlations between abundances of five common herb species and soil nutrient patterns. Maintenance of spatial heterogeneity in forest floor resources by the presence of different species of canopy trees may therefore be important in the maintenance of diversity in these understory herb communities.


Quantitative relationships between ingested and intestinal flows of linoleic and alpha-linolenic acids, body weight and milk performance in mid-lactation dairy cows.
Linoleic acid (LA) and alpha-linolenic acid (ALA) are essential fatty acids found in variable quantities in ruminant feedstuffs. Revision of French feed unit systems in 2018 has proposed the reassessment of energy requirements through a between-experiment approach expressing metabolisable energy supply as a function of the energy expenditures for maintenance and production, with these expenditures that reflect homeorhetic regulations. Based on the same approach, LA and ALA intake can be related to animal characteristics (i.e., BW) reflecting maintenance expenditures and secretion characteristics (i.e., milk yield, milk fat content and contents of LA and ALA in milk fat). Therefore, the objective of this work was to analyse the between-experiment relationships between ingested, duodenal, or absorbed flows of LA and ALA, BW and milk LA and ALA secretion by meta-analysis in mid-lactation dairy cows. These relationships were analysed using LA and ALA subsets of 96 and 99 experiments, respectively. Between-experiment regressions of daily flows of ingested, duodenal or absorbed LA and ALA on BW and milk LA and ALA flows were studied, with statistical unit defined as the mean of within-experiment treatments. For LA, the BW-associated coefficient was 0.019 (±0.0034) g absorbed LA/d per kg BW and milk LA secretion-associated coefficient was 0.70 (±0.081) g absorbed LA/g of LA secreted into milk. For ALA, the BW-associated coefficient was 0.0058 (±0.00093) g absorbed ALA/d per kg BW and milk ALA secretion-associated coefficient was 0.57 (±0.097) g absorbed ALA/g of ALA secreted into milk. When coding the diets as either control or milk fat depression diets, the BW-associated coefficient for LA was 0.017 (±0.0032) g absorbed LA/d per kg BW for both diets. For milk fat depression diets, milk LA secretion-associated coefficient was 1.02 (±0.119) g absorbed LA/g of LA secreted into milk, whereas it was 0.70 (±0.075) g absorbed LA/g of LA secreted into milk for control diets. Significant BW and milk performance coefficients were obtained in all LA and ALA equations, allowing the calculation of ingested and intestinal flows of LA and ALA based on measured BW, milk fat yield and milk fat content of LA and ALA. The relationships between ingested and intestinal flows of LA and ALA, BW and milk performance obtained in the present work could be integrated into renewed feed unit systems for energy and protein in dairy cows.


Characterization of the plastid genome of Cratoxylum species (Hypericaceae) and new insights into phylogenetic relationships.
To expand the genomic information of Hypericaceae, particularly on Cratoxylum, we characterized seven novel complete plastid genomes (plastomes) of five Cratoxylum and two of its allied taxa, including C. arborescens, C. formosum subsp. formosum, C. formosum subsp. pruniflorum, C. maingayi, C. sumatranum, Hypericum hookerianum, and Triadenum breviflorum. For Cratoxylum, the plastomes ranged from 156,962 to 157,792 bp in length. Genomic structure and gene contents were observed in the five plastomes, and were comprised of 128-129 genes, which includes 83-84 protein-coding (CDS), 37 tRNA, and eight rRNA genes. The plastomes of H. hookerianum and T. breviflorum were 138,260 bp and 167,693 bp, respectively. A total of 110 and 127 genes included 72 and 82 CDS, 34 and 37 tRNA, as well as four and eight rRNA genes. The reconstruction of the phylogenetic trees using maximum likelihood (ML) and Bayesian inference (BI) trees based on the concatenated CDS and internal transcribed spacer (ITS) sequences that were analyzed separately have revealed the same topology structure at genus level; Cratoxylum is monophyletic. However, C. formosum subsp. pruniflorum was not clustered together with its origin, raising doubt that it should be treated as a distinct species, C. pruniflorum based on molecular evidence that was supported by morphological descriptions.


High aerobic capacity does not attenuate aortic stiffness in hypertensive subjects.
It is unknown whether increased physical fitness reduces aortic stiffness in hypertensive individuals. The purpose of this cross-sectional study was to examine, in a cohort of community-dwelling subjects with no history of cardiac events, differences in the impact of aerobic capacity on aortic stiffness between normotensive and hypertensive subjects. The study sample included 275 subjects representing a large age range (21-85 years). Of these, 61 subjects (hypertensive cohort) were either hypertensive at enrollment or were taking antihypertensive medication. The remaining 214 subjects (normotensive cohort) had no history of hypertension. The study protocol included maximal cardiopulmonary exercise testing (determination of maximal oxygen consumption, or VO2max) and measurement of aortic wave velocity (AWV) using a novel magnetic resonance-based method. Overall, the hypertensive cohort exhibited significantly elevated AWV in comparison to a subset of normotensives matched for age, sex, and aerobic fitness. Each cohort was then subdivided according to the percentage of predicted VO2max achieved (< 100% = "unfit," > or = 100% = "fit"). Differences between subgroups were assessed by unpaired t test. In the normotensive cohort, AWV was significantly lower in the fit versus the unfit subgroup. However, in the hypertensive cohort, AWV was not significantly different between fit and unfit subgroups nor between treated and untreated subgroups. Unlike the situation in healthy normotensive subjects, higher peak aerobic capacity is not associated with lower aortic stiffness in hypertensive individuals.


Obstructive sleep apnea in epilepsy: a preliminary Egyptian study.
The extent and clinical relevance of the association between epilepsy and sleep apnea are not previously studied in Egypt. What we wanted to know was the frequency of sleep apnea in Egyptian children with epilepsy and its influence on seizure frequency, other seizure characteristics, sleep complaint, and architecture. All patients with epilepsy, aged up to 18 years, who underwent polysomnography were studied. Patients with any neurological disease apart from epilepsy, with psychiatric illness, had hypnotics, or sedatives or those with liver or kidney failure were excluded from the study. The patients were divided into two subgroups according to apnea/hypopnea index: group (1) patients without obstructive sleep apnea (OSA) and group (2) patients with OSA. For control group, we choose 12 healthy individuals, with age and sex matched to that of our patients. We studied the clinical characteristics of epilepsy, sleep history, and polysomnographic recording of the patients with epilepsy and the control. EEG digital and video monitoring was done for all patients. Eleven patients (42.3%) were found to have obstructive sleep apnea. Seizure frequency was significantly higher in the patients with OSA. Apart from apnea and hypopnea indices, all other sleep parameters did not differ between patients' subgroups. Hypopnea index in REM positively correlates with number of awaking. Apnea index in REM positively correlates with latency to deep sleep and to periodic leg movement. Sleep apnea is frequent in patients with epilepsy. OSA may contribute to increase seizure frequency. We recommend investigating sleep apnea in all patients with epilepsy.


[Gender Aspects of Clinical and Functional Associations of Secondary Mitral Regurgitation in Patients With Ischemic Heart Disease Without Myocardial Infarction].
to identify factors associated with moderate and severe secondary mitral regurgitation (MR) in ischemic heart disease patients without myocardial infarction depending on gender. From the Register of coronary angiography we selected men and women with significant coronary stenosis (≥75 % of lumen in at least one epicardial artery) who had no acute or previous myocardial infarction: 1001 men without and 66 men with moderate or severe MR, 183 women without and 20 women with moderate or severe MR. According to mulrivariate analysis irrespective of gender MR was independently associated with disorders of cardiac rhythm and conduction (odds ratio [OR] 7.92, 95 % confidence interval [CI] 3.21-19.57, р.


Rates of trisomies 21, 18, 13 and other chromosome abnormalities in about 20 000 prenatal studies compared with estimated rates in live births.
Data were analyzed on the results of 19675 prenatal cytogenetic diagnoses reported to two chromosome registries on women aged 35 or over for whom there was no known cytogenetic risk for a chromosome abnormality except parental age. The expected rates at amniocentesis of 47, + 21; 47, + 18; 47, + 13; XXX; XXY; XYY; and other clinically significant cytogenetic defects by maternal age were obtained from a regression analysis on the observed rates, using a first degree exponential model. After an adjustment for maternal age, these rates were compared with previously estimated rates by maternal age in live births. The rates of 47, + 21 at amniocentesis and live birth are approximately parallel, with the latter about 80% of the amniocentesis rates. The rates of 47, + 18 at amniocentesis and live birth are approximately parallel, with the live birth rates about 30% of the amniocentesis rates, consistent with high fetal mortality of 47, + 18 after amniocentesis. The rates of 47, + 13 at amniocentesis indicate an increase in maternal age that is not as marked as that previously estimated in live births. The rates at amniocentesis for XXX and XXY increase with maternal age, with the rates of XXY almost identical to those estimated previously in live births, suggesting no late fetal mortality of XXY. The rates of XYY show a slight decrease with maternal age also consistent with little late fetal mortality of XYY. No consistent trend with age is seen for the pooled group of other clinically significant defects.


Brief Report: Trends in Hospitalizations Due to Acute Coronary Syndromes and Stroke in Patients With Systemic Lupus Erythematosus, 1996 to 2012.
Cardiovascular disease (CVD) has been recognized as a major cause of morbidity in patients with systemic lupus erythematosus (SLE), but it is not clear whether increased awareness of these risks has translated into improvements in CVD morbidity at the population level. The aim of this study was to examine trends in hospitalization rates for CVD events in a representative sample of adult patients with SLE in the US from 1996 to 2012. We used the Nationwide Inpatient Sample to estimate the rates of hospitalization for acute myocardial infarction (MI), unstable angina, and ischemic stroke from 1996 to 2012 in patients with SLE. We compared these trends with those in the general population. During the study years, there were an estimated 31,012 hospitalizations for acute MI, 4,160 hospitalizations for unstable angina, and 26,144 hospitalizations for ischemic stroke among patients with SLE. The rates of hospitalization for acute MI and ischemic stroke increased over time in patients with SLE, while the rates for unstable angina decreased. The rates for all 3 conditions decreased in the general population over these years, with hospitalization rates for unstable angina decreasing faster in the general population than in patients with SLE. Increased awareness of the burden of CVD in patients with SLE has not yet translated into decreased rates of hospitalization for acute MI or stroke. This may be due to barriers in implementation of CVD risk factor modification or to SLE-specific risks that have not yet been identified or effectively targeted.


Methylene Blue Ameliorates Ischemia/Reperfusion-Induced Cerebral Edema: An MRI and Transmission Electron Microscope Study.
The neuroprotective effect of methylene blue (MB) has been identified against various brain disorders, including ischemic stroke. In the present study, we evaluated the effects of MB on postischemic brain edema using magnetic resonance imaging (MRI) and transmission electron microscopy (TEM). Adult male rats were subjected to transient focal cerebral ischemia induced by 1 h middle cerebral artery occlusion (MCAO), followed by reperfusion. MB was infused intravenously immediately after reperfusion (3 mg/kg) and again at 3 h post-occlusion (1.5 mg/kg). Normal saline was administered as vehicle control. Sequential MRIs, including apparent diffusion coefficient (ADC) and T2-weighted imaging (T2WI), were obtained at 0.5, 2.5, and 48 h after the onset of stroke. Separated groups of animals were sacrificed at 2.5 and 48 h after stroke for ultrastructural analysis by TEM. In addition, final lesion volumes were analyzed by triphenyltetrazolium chloride (TTC) staining at 48 h after stroke. Ischemic stroke induced ADC lesion volume at 0.5 h during MCAOs that were temporally recovered at 1.5 h after reperfusion. No significant difference in ADC-defined lesion was observed between vehicle and MB treatment groups. At 48 h after stroke, MB significantly reduced ADC lesion and T2WI lesion volume and attenuated cerebral swelling. Consistently, MB treatment significantly decreased TTC-defined lesion volume at 48 h after stroke. TEM revealed remarkable swollen astrocytes, astrocytic perivascular end-feet, and concurrent shrunken neurons in the penumbra at 2.5 and 48 h after MCAO. MB treatment attenuated astrocyte swelling, the perivascular astrocytic foot process, and endothelium and also alleviated neuron degeneration. This study demonstrated that MB could decrease postischemic brain edema and provided additional evidence that future clinical investigation of MB for the treatment of ischemic stroke is warrented.


The effects of QMix and EndoActivator on postoperative pain in mandibular molars with nonvital pulps: a randomized clinical trial.
The purpose of this study was to compare the effects of different irrigation solutions when used EndoActivator on postoperative pain. A total of 104 subjects with nonvital pulps were selected and randomly assigned to four experimental groups; (G) 1 (n = 26) 2.5% NaOCl + conventional endodontic syringe, (G) 2 (n = 26) 2.5% NaOCl + EndoActivator, (G) 3 (n = 26) 2.5% NaOCl + QMix + conventional endodontic syringe, (G) 4 (n = 26) 2.5% NaOCl + QMix + EndoActivator. All the patients were prescribed ibuprofen 400 mg to be taken every 8 h in case of pain. The patients were asked to rate the severity of the postoperative pain on a visual analog scale (VAS) for 8th, 24th, 48th, and 72nd hours after the visit. The data were analyzed using Kruskal-Wallis, Mann-Whitney U, and Chi-Square tests. G4 resulted in lesser postoperative pain levels on 8th, 24th, 48th, and 72nd hours than the G2, G3, and G1 did. There was no significant difference between G4 and G2 and between G3 and G1 in terms of the postoperative pain levels at any time interval (P > 0.05). It was determined that the postoperative values of the groups, in which EA was used, were statistically significantly lower than in the other groups. The combined use of QMix and EA provided the most significant decrease in the postoperative pain values. Successful management of postoperative pain is an important issue for the clinician. The combined use of Qmix and EA can be recommended to the clinicians.


Unwrapping Neurotrophic Cytokines and Histone Modification.
The conventional view that neuroinflammatory lesions contain strictly pro- and anti-inflammatory cytokines is being challenged. Some proinflammatory products e.g. TNF-α are crucial intermediates in axon regeneration, oligodendroglial renewal and remyelination. A more functional system of nomenclature classifies cytokines by their neuro 'protective' or 'suppressive' properties. Beyond the balance of these 'environmental' or 'extrinsic' signals, specific 'intrinsic' determinants of cytokine signalling appear to influence the outcome of axoglial regeneration. In this commentary, we examine the potential importance of cytokine-induced histone modification on oligodendrocyte differentiation. Neuroinflammation mediates the release of astrocytic leukaemia inhibitory factor (LIF) and erythropoietin (EPO) which potentiates oligodendrocyte differentiation and myelin production. Meanwhile, histone deacetylation strongly suppresses important inhibitors of oligodendrocyte differentiation. Given that LIF and EPO induce histone deacetylases in other systems, future studies should examine whether this mechanism significantly influences the outcome of cytokine-induced remyelination, and whether epigenetic drug targets could potentiate the effects of exogenous cytokine therapy.


Thermoregulation, gas exchange, and ventilation in Adelie penguins (Pygoscelis adeliae).
Adelie penguins (Pygoscelis adeliae) experience a wide range of ambient temperatures (Ta) in their natural habitat. We examined body temperature (Tb), oxygen consumption (VO2), carbon dioxide production (VCO2), evaporative water loss (mH2O), and ventilation at Ta from -20 to 30 degrees C. Body temperature did not change significantly between -20 and 20 degrees C (mean Tb = 39.3 degrees C). Tb increased slightly to 40.1 degrees C at Ta = 30 degrees C. Both VO2 and VCO2 were constant and minimal at Ta between -10 and 20 degrees C, with only minor increases at -20 and 30 degrees C. The minimal VO2 of adult penguins (mean mass 4.007 kg) was 0.0112 ml/[g.min], equivalent to a metabolic heat production (MHP) of 14.9 Watt. The respiratory exchange ratio was approximately 0.7 at all Ta. Values of mH2O were low at low Ta, but increased to 0.21 g/min at 30 degrees C, equivalent to 0.3% of body mass/h. Dry conductance increased 3.5-fold between -20 and 30 degrees C. Evaporative heat loss (EHL) comprised about 5% of MHP at low Ta, rising to 47% of MHP at Ta = 30 degrees C. The means of ventilation parameters (tidal volume [VT], respiration frequency [f], minute volume [VI], and oxygen extraction [EO2]) were fairly stable between -20 and 10 degrees C (VT did not change significantly over the entire Ta range). However, there was considerable inter- and intra-individual variation in ventilation patterns. At Ta = 20-30 degrees C, f increased 7-fold over the minimal value of 7.6 breaths/min, and VI showed a similar change.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of emulsifiers on drying stress and intercellular cohesion in human stratum corneum.
Emulsifier molecules, with their amphiphilic character, are ubiquitous in moisturizing creams and primarily serve to disperse the water-insoluble molecules such as emollients, oils, lipids and fats in water. The objective of this study was to investigate the effect of emulsifier molecules on the barrier and biomechanical properties of human stratum corneum (SC) and to compare the efficacy of emulsifier molecules when used in a fully formulated moisturizing cream. We employed methods based on thin-film mechanics to measure the drying stress and intercellular cohesion in the SC. The emulsifier molecules or moisturizing creams formulated with them were applied to a fully hydrated SC adhered to a glass substrate. In-plane stress developed in the SC during drying was then measured by tracking changes in the curvature of the glass substrate. The intercellular cohesion within the SC was measured by means of a double cantilever beam (DCB) set-up, where the treated or untreated SC was sandwiched between two substrates, and the delamination energy calculated by measuring the force required to drive a crack through the SC. Moisturizing cream diffusivity through the stratum corneum was measured by spectroscopic technique and related to internal SC stress and fracture energy. We observe significant differences in the biomechanical behaviour of SC when moisturizing creams with different emulsifier molecules are applied on isolated stratum corneum ex vivo. The reduction in maximum stress varied between 12% and 26% depending on the emulsifier molecules used in the formulation. The intercellular cohesion and the diffusion of molecules in the formulated moisturizing creams through the SC were also found to be strongly dependent on the type of emulsifier molecule used in the formulation. The biomechanical and barrier properties of the human stratum corneum show strong dependence on the emulsifier molecule used in the moisturizing creams, even when the creams included only ~3 weight% emulsifier molecules. Moreover, we found that the reduction in SC peak stress was strongly correlated with the formulation diffusivity into the SC. The moisturizing creams diffusing fastest into the SC had the largest reduction in peak stress and vice versa.


Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiac disease and is characterised by unexplained ventricular myocardial hypertrophy. HCM is highly heterogeneous and is primarily caused by the mutation of genes encoding sarcomere proteins. As a result of its genetic basis, we investigated the underlying cause of HCM in a Chinese family by whole-exome sequencing. Whole-exome sequencing was performed for seven clinically diagnosed HCM family members and the resulting single nucleotide variants associated with cardiac hypertrophy or heart development were analysed by a polymerase chain reaction and Sanger sequencing. A non-frameshift deletion mutation (p.S527del) of Formin Homology 2 Domain Containing 3 (FHOD3) was detected in all of the affected family members and was absent in all unaffected members, with the exception of one young member. Moreover, three single nucleotide variants associated with heart development and morphogenesis were identified in the proband but were absent in the other affected subjects. This is the first HCM family case of FHOD3 (p.S527del) variation in Asia. Additionally, RNF207 (p.Q268P), CCM2 (p. E233K) and SGCZ (p.Q134X) may be related to the clinical heterogeneity of the family. The present study could enable the provision of genetic counseling for this family and provide a basis for future genetic and functional studies.


Beta-adrenergic signal transduction following carvedilol treatment in hypertensive cardiac hypertrophy.
Treatment with the beta-blocker carvedilol leads to an improvement of outcome and ejection fraction in heart failure. These effects occur without affecting the number of beta-adrenergic receptors, as determined in right ventricular biopsies from patients with heart failure. This study was aimed at investigating the effects of carvedilol on beta-adrenergic signal transduction alterations in a model of left ventricular pressure overload, which is characterized by sympathetic activation and a desensitized beta-adrenergic signal transduction. Transgenic rats with overexpression of renin [TG(mREN2)27] were treated with carvedilol (30 micrograms/kg) or held under control conditions and were compared with Sprague-Dawley rats. Myocardial beta-adrenoceptors (125I-labeled iodocyanopindolol binding), Gi alpha (pertussis toxin labeling), Gs alpha-activity (reconstitution into cyc--S49 membranes) and adenylyl cyclase activity were measured. Blood pressure and heart rate, increase in heart rate during sacrifice and pressure rate products were determined. beta-Adrenoceptors were downregulated and Gi alpha-protein levels were significantly increased, producing a desensitization of basal, isoprenaline- and guanine nucleotide-stimulated adenylyl cyclase activity compared to controls. Carvedilol reduced heart rate, blood pressure and pressure rate product in TG(mREN2)27. Carvedilol did not restore biochemical alterations, but even further reduced beta-adrenoceptor numbers and adenylyl cyclase. It exhibited a two affinity state, guanine nucleotide-sensitive binding to cardiac beta-adrenergic receptors similar to isoprenaline but different from metoprolol. Carvedilol did not restore beta-adrenergic signal transduction at concentrations producing antiadrenergic effects in vivo. This effect might be due to an atypical guanine nucleotide-dependent interaction with beta-adrenergic receptors. Thus, ancillary properties could explain the recently reported beneficial effects in patients with heart failure independent from an upregulation of beta-adrenergic receptors.


Combined effect of starch and sucrose on carbonic anhydrase VI activity in saliva and biofilm of children with early childhood caries. Exposure to starch and sucrose alters carbonic anhydrase VI activity in saliva and biofilm.
This study aimed to investigate whether combined exposure to starch and sucrose modifies the activity of carbonic anhydrase VI (CA VI) in saliva (Study 1) and biofilm (Study 2) of children with early childhood caries (ECC). For Study 1 and Study 2, respectively, 54 and 46 preschoolers aged 4 to 5 were allocated into two groups: caries-free (CF) and with ECC. Children were exposed to rinses with sucrose, starch, and sucrose plus starch solutions. CA VI activity, pH, and buffering capacity (BC) were evaluated in saliva and biofilm. In Study 1, a significant reduction in saliva pH was observed after sucrose and sucrose plus starch rinses. CA VI activity was influenced by ECC independently of the type of carbohydrate to which children were exposed. CA VI activity was higher in children with ECC; however, after rinses, CA VI activity was reduced. In Study 2, biofilm pH and BC were reduced after rinses with sucrose and sucrose plus starch. CA VI activity was significantly high before rinse in ECC group when compared with CF group; however, no difference was observed between groups after rinses. In saliva, exposure to starch and sucrose (isolated or combined) induced a reduction in CA VI activity in children with ECC. In biofilm, the combination of starch and sucrose did not modify CA VI activity in ECC children. The responsivity of the CA VI reflects directly in important parameters related to the pH maintenance on the oral cavity.


CD8+ T lymphocytes enhance the anabolic effect of intermittent parathyroid hormone on cementoblasts.
Root resorption is usually inflammatory in nature and has a tight link with immune system. Intermittent parathyroid hormone (iPTH) could promote cementum regeneration. The cross-talk of immune cells and cementoblasts may play an important role in the regeneration which stayed to be elucidated. In this study, a CD8+ T cells-OCCM-30 cells coculture system was established in vitro to investigate whether CD8+ T cells could enhance the anabolic effect of iPTH on cementoblasts and to find out the potential link of the effect with Wnt signal pathway. Determined by real-time PCR and Western Blot, we found an amplified cementogenesis in the OCCM-30 cells from coculture system, including increased mRNA and protein expression of Alp, Opn and Runx2, ALP activity and mineralization. We also found iPTH could increase the expression of Wnt10b in CD8+ T cells by ELISA. In addition, Wnt10b would promote the proliferation of OCCM-30 cells, while the effect on differentiation was various in different culture medium. These results demonstrated that the stimulating effect of iPTH on cementoblasts could be mediated through an interaction with CD8+ T cells, and T-cell-induced Wnt10b might be a key mechanism in the mediation.


Quantification of human and veterinary antibiotics in water and sediment using SPE/LC/MS/MS.
An analytical method was developed and tested for four different groups of veterinary antibiotics in both river water and sediment matrices. Solid phase extraction (SPE) was used to enrich and to clean up the aqueous sample. Also, Mcllvaine and ammonium hydroxide buffer solutions were used to extract the compounds from the sediment matrix. High performance liquid chromatography (HPLC) equipped with tandem mass spectrometry (MS/MS) was used to separate and quantify the samples. The range of recoveries (in percent) for tetracyclines (TCs), sulfonamides (SAs), macrolides (MLs), and ionophore polyethers (IPs) in the water matrix were 102.2-124.8, 76.6-124.3, 89.5-114.7, 82.7-117.5 with 1-13 (%) of relative standard deviation respectively with three different concentrations. For sediment, the percent recovery ranges were 32.8-114.8, 62.4-108.9, 53.4-128.4 and 51.3-105.4 for TCs, SAs, MLs and IPs, respectively. The relative standard deviation ranged from 16 - 27 (%) over three different concentrations. The limit of quantification (LOQ) was determined by two different methods and calculated to be in the range of 0.01-0.04 microg/l and 0.3-2.5 microg/kg for TCs, SAs, and MLs in water and sediment, respectively. For IPs, the LOQ was 0.001-0.003 microg/l in river water and 0.4-3.6 microg/kg for sediment. The sediment concentration measured in an agriculture-influenced river was much higher than in the overlying water matrix, indicating a high degree of sediment partitioning for these compounds.


From play to proficiency: The ontogeny of stone-tool use in coastal-foraging long-tailed macaques (Macaca fascicularis) from a comparative perception-action perspective.
Macaques crack shellfish in coastal environments with specialized stone-hammering techniques. I provide the first examination of skill development from 866 object-manipulation and 7,400 tool-use bouts, collected over 15 months, using longitudinal analyses of infants' object manipulation (N = 7) and cross-sectional comparisons of manipulative and tool-use behavior (N = 69). I adopt a Perception-action approach, examining how the emergence of actions on objects relate to the spatial-relational and percussive challenges of tool use. Infants begin manipulating single items, particularly stones, at 1-2 months. Combining objects predominates (78%) by 1.5-2.5 years, and bouts involving food and tools but with incorrect spatial relations and action sequences prevail (73%) by 2.5-3.5 years. Placing, precedes rubbing objects on surfaces. Percussion emerges last, as disorganized striking before becoming consistent and targeted. Macaques manipulate combinations of stones and oysters, before stones, anvils, and motile shellfish, but success on either food type is only observed at 2.5-3.5 years. After competence, success rates and strike accuracy improve within 3 months on oysters and 5 months on motile shellfish. Older tool users (>4.5 years) had higher success rates, strike accuracy, strike efficiency, and tool fidelity. Macaque tool-use appears facilitated by a propensity for stone manipulation, but challenged by mastering spatial relations and percussion. I relate my findings to the development of stone-tool use in capuchins and chimpanzees, stone-handling in related macaque species, object play in Old World monkeys, and percussion in children, to further understand how biological propensities, environments, and social influences contribute to perception-action learning across species. (PsycINFO Database Record


Disruption of mitochondrial activities in rabbit and human hepatocytes by a quinoxalinone anxiolytic and its carboxylic acid metabolite.
The quinoxalinone anxiolytic, panadiplon, was dropped from clinical development due to unexpected hepatic toxicity in human volunteers. Subsequent experimental studies in rabbits demonstrated a hepatic toxicity that resembled Reye's syndrome. In the present studies, we examined the effects of panadiplon and a metabolite, cyclopropane carboxylic acid (CPCA) on hepatic mitochondrial activities in vitro and ex vivo. Acute inhibition of beta-oidation of [14C]palmitate was observed in rabbit and human hepatocyte suspensions incubated with 100 microM panadiplon. Panadiplon (30 microM) also reduced mitochondrial uptake of rhodamine 123 (R123) in cultured rabbit and human, but not rat hepatocytes, following 18 h exposure. CPCA also impaired beta-oxidation and R123 uptake in rabbit and human hepatocytes. R123 uptake and beta-oxidation in cells from some donors was not impaired by either agent, and cell death was not observed in any experiment. Hepatocytes isolated from panadiplon-treated rabbits had reduced palmitate beta-oxidation rates and inhibited mitochondrial R123 uptake; R123 uptake remained inhibited until 48-72 h in culture. Rabbit mitochondrial respiration experiments revealed a slightly lower ratio of ATP formed/oxygen consumed in panadiplon-treated animals: direct exposure of normal rabbit liver mitochondria to panadiplon did not have this effect. Hepatocytes isolated from panadiplon-treated rabbits showed reduced respiratory control ratios and lower oxygen consumption compared to controls. Our results indicate that panadiplon induces a mitochondrial dysfunction in the liver, and suggest that this dysfunction may be attributed to the carboxylic acid metabolite.


Core-shell nanowires of NiCo2O4@α-Co(OH)2 on Ni foam with enhanced performances for supercapacitors.
The composites of NiCo2O4 with unique structures are extensively explored as promising electrodes. In this work, core-shell structured nanowires anchored on nickel foam are synthesized by the hydrothermal synthesis of NiCo2O4 as core and subsequent electrodeposition of α-Co(OH)2 as shell. The core-shell composites exhibit enhanced electrochemical performances ascribing to the synergistic reactions from both materials, showing higher specific capacitance than any single component. By changing the deposition time, the mass loading of α-Co(OH)2 can be easily controlled. The electrochemical performances of the hybrid electrodes are diverse with the mass loading of Co(OH)2. The optimized hybrid electrode with 3 mins electrodeposition exhibits the highest specific capacitance (1298 F g-1 at 1 A g-1) among all electrodes. The redox reaction is a main contributor to the total specific capacitance through electrochemical kinetics analysis. An asymmetric supercapacitor assembled by the optimized material as positive electrode and activated carbon as negative electrode can achieve a relatively high energy density of 39.7 Wh kg-1 at a power density of 387.5 W kg-1 (at 0.5 A g-1) in a voltage of 1.55 V.


rTg-D: A novel transgenic rat model of cerebral amyloid angiopathy Type-2.
Cerebral amyloid angiopathy (CAA) is common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a transgenic rat model of capillary CAA type-1 that develops many pathological features of human disease. However, a complementary rat model of larger vessel CAA type-2 disease has been lacking. A novel transgenic rat model (rTg-D) was generated that produces human familial CAA Dutch E22Q mutant amyloid β-protein (Aβ) in brain and develops larger vessel CAA type-2. Quantitative biochemical and pathological analyses were performed to characterize the progression of CAA and associated pathologies in aging rTg-D rats. rTg-D rats begin to accumulate Aβ in brain and develop varying levels of larger vessel CAA type-2, in the absence of capillary CAA type-1, starting around 18 months of age. Larger vessel CAA was mainly composed of the Aβ40 peptide and most prominent in surface leptomeningeal/pial vessels and arterioles of the cortex and thalamus. Cerebral microbleeds and small vessel occlusions were present mostly in the thalamic region of affected rTg-D rats. In contrast to capillary CAA type-1 the amyloid deposited within the walls of larger vessels of rTg-D rats did not promote perivascular astrocyte and microglial responses or accumulate the Aβ chaperone apolipoprotein E. Although variable in severity, the rTg-D rats specifically develop larger vessel CAA type-2 that reflects many of the pathological features of human disease and provide a new model to investigate the pathogenesis of this condition.


Prolonged electrical stimulation of the nipples evokes intermittent milk ejection in the anaesthetised lactating rat.
Intermittent and continuous electrical stimulation of the nipples elicited milk-ejection responses in the lactating rat. The responses occurred intermittently, with similar amplitudes and periodicity as those seen in suckled rats. The responses were always associated with synchronization of the electroencephalogram (EEG), but some rats with synchronized EEG activity did not milk eject during stimulation. Since continuous stimulation also resulted in intermittent milk ejection it seems unlikely that the periodicity of the reflex in suckled rats depends upon changes in the intensity of sensory stimulation. The techniques of nipple stimulation may be a useful method with which to study neural pathways and other phenomena such as gating involved in oxytocin release and milk ejection. The success of the technique depends on a variety of factors such as parameters of the stimulation and state of anaesthesia.


Frequency, cause and effect on operative outcome of depressed left ventricular ejection fraction in mitral stenosis.
To assess the incidence, pathophysiology and influence on operative outcome of a depressed left ventricular (LV) ejection fraction (EF) in patients with mitral stenosis (MS), demographic, hemodynamic and cineangiographic data on 72 patients (16 men, 56 women, aged 19 to 75 years) with isolated MS were reviewed. Of the 45 who had mitral commissurotomy or replacement, operative course and functional class before and after surgery were assessed. Of the 72 patients, 21 (29%) had an LVEF < or = 0.50. These 21 were similar to the 51 with an LVEF > 0.50 in age, gender, heart rate, intracardiac pressures, transvalvular gradient and valve area, but they had larger LV end-diastolic (79 +/- 19 [mean +/- SD] vs 59 +/- 15 ml/m2, p < 0.001) and end-systolic volumes (46 +/- 13 vs 23 +/- 8 ml/m2, p < 0.0001). Of the 45 subjects undergoing surgery, operative outcome was similar in the 14 with a depressed and the 31 with a normal LVEF. Thus, about 1/3 of patients with isolated MS have a depressed LVEF. Compared with those with MS and a normal LVEF, these subjects have hemodynamic derangements of similar severity, but they have larger LV end-diastolic and end-systolic volumes, suggesting that impaired LV contractile function or excessive afterload (rather than diastolic underfilling), or both, is the cause of a low LVEF. Those with an LVEF < or = 0.50 who undergo valve surgery have a similar operative outcome as those with an LVEF > 0.50.


Acute stress to excised vocal fold epithelium from reactive oxygen species.
Vocal fold epithelium is exposed to reactive oxygen species from the inhaled environment and from tissue inflammation. The objective of this study was to explore the functional and structural consequences of reactive oxygen species exposure on vocal fold epithelium. In vitro, prospective study design. Hydrogen peroxide (H(2)O(2)), a common reactive oxygen species, was utilized in this study. Freshly excised, viable porcine vocal fold epithelia (N = 32) were exposed to H(2) O(2) or sham challenge for 2 hours. Electrophysiology, western blotting, and light microscopy were used to quantify the functional and structural effects of reactive oxygen species on vocal fold epithelia. Exposure to reactive oxygen species did not significantly alter transepithelial resistance. There was a small, nonsignificant trend for decreased concentration of epithelial junctional complex protein with reactive oxygen species challenge. Minimal changes to the gross structural appearance of vocal fold epithelia were also noted. The stratified squamous epithelia of the vocal folds effectively defend against an acute reactive oxygen species challenge. The current study lays the groundwork for future investigations on the effects of reactive oxygen species on vocal fold epithelia that are compromised from phonotrauma.


Prevalence, clinical course and outcomes of COVID-19 in peritoneal dialysis (PD) patients: a single-center experience.
There are limited data on the effects of COVID-19 on peritoneal dialysis (PD) patients. This study aimed to describe the impact of COVID-19 on the PD population. A monocentric retrospective observational study was conducted on 146 consecutive PD patients followed from January 2020 to March 2022 at the University Hospital of Modena, Italy. Twenty-seven (18.4%) PD patients experienced 29 episodes of SARS-CoV-2 infection, corresponding to an incidence rate of 0.16 episodes/patient-year. Median age of COVID-19 patients was 60.4 (interquartile range [IQR] 50.2-66.5) years. In unvaccinated patients (n. 9), COVID-19 was always symptomatic and manifested with fever (100%) and cough (77.7%). COVID-19 caused hospital admission of three (33.3%) patients and two (22.2%) died of septic shock. COVID-19 was symptomatic in 83.3% of vaccinated subjects (n.18) and manifested with fever (61.1%) and cough (55.6%). Hospital admission occurred in 27.8% of the subjects but all were discharged home. Median SARS-CoV-2 shedding was 32 and 26 days in the unvaccinated and vaccinated groups, respectively. At the end of the follow-up, COVID-19 triggered the shift from PD to HD in two subjects without affecting the residual renal function of the remaining patients. Overall, COVID-19 caused an excess death of 22.2%. COVID-19 vaccination refusal accounted for only 1.6% in this cohort of patients. COVID-19 incident rate was 0.16 episodes/patient-year in the PD population. About one-third of the patients were hospitalized for severe infection. Fatal outcome occurred in two (7.4%) unvaccinated patients. A low vaccination refusal rate was observed in this population.


Amino acid sequence of the rabies virus glycoprotein deduced from its cloned gene.
Double-stranded complementary DNA was synthesized from rabies virus-specific glycoprotein mRNA and inserted into the Pst I site of pBR322. The glycoprotein inserted sequence contains approximately 1.75 kilobase pairs and lacks only approximately 35 nucleotides from the 5' terminus of the glycoprotein mRNA. The nucleotide sequence indicates a polypeptide of 524 amino acids beginning with an initiation codon ATG and ending with a termination of codon TGA. The first 19 amino acids make up a signal peptide preceding the sequence lys-phe-pro-ile-tyr-thr- which has been identified by the N-terminal analysis of amino acids of the purified rabies virus glycoprotein.


Protein hijacking: key proteins held captive against their will.
Proteins travel to their appropriate intracellular homes by means of the targeting signals they carry. It now seems that a short, but important, list of key regulatory proteins are victims of protein hijacking: Bid, Bim, NF-kappaB, SREBP, and perhaps the intracellular portion of MUC1. These provide critical functions within a particular subcellular compartment, but are initially prevented from finding their way to this intracellular home. Only in response to specific physiological signals are these proteins released to find the site at which they act.


Why We Need to Bust Some Myths about AI.
In this piece, Daniel Leufer introduces his project, aimyths.org, a website that tackles eight of the most harmful myths and misconceptions about artificial intelligence. By showing the damage caused by everything from misleading headlines about AI progress to attempts to use machine learning to predict complex social outcomes, Leufer's project underlines the importance of getting beyond the hype around AI.


Retinal pathology in spontaneous opticospinal experimental autoimmune encephalitis mice.
Retinal ganglion cells (RGC) are lost as a sequela of optic nerve inflammation in myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD), but the mechanisms of injury remain incompletely understood and there remains a need to characterize the murine model of MOGAD. Several studies have shown that RGC loss occurs in association with optic neuritis in MOG35-55 experimental autoimmune encephalomyelitis (EAE), but retinal pathology has not been studied in the double transgenic opticospinal EAE (OSE) model, in which animals develop spontaneous disease associated with MOG35-55 peptide specific T cells and B cells producing MOG-specific antibodies. Herein, we show that at 8-weeks OSE mice develop optic nerve inflammation, reactive astrogliosis, and RGC loss. By 10-weeks of age, affected mice have a 50% reduction in RGCs as compared to age matched wild type mice without EAE. The retinal pathology that ensues from spontaneous optic neuritis in OSE mice mirrors that seen following human optic neuritis and may be a useful model for screening neuroprotective compounds for MOGAD and other diseases with optic neuritis.


Characterization of H2 photoproduction by marine green alga Tetraselmis subcordiformis integrated with an alkaline fuel cell.
To investigate the feasibility of coupling carbonyl cyanide m-chlorophenylhydrazone-regulated photohydrogen production by Tetraselmis subcordiformis in a photobioreactor to an alkaline fuel cell (AFC). H2 evolution kinetics in the AFC integrated process was characterized. The duration of H2 evolution was prolonged and its yield was improved about 1.5-fold (to 78 ± 5 ml l(-1)) compared with that of the process without AFC. Improved H2 yield was possibly caused by removal of H2 feedback inhibition by H2 consumption in situ. Decreases in the H2 production rate correlated with the gradual deactivation of PSII and hydrogenase activities. The H2 yield was closely associated with catabolism of starch and protein. A marine green algal CO2-supplemented culture integrated with in situ H2-consumption by an AFC system was developed as a viable protocol for the H2 production.


Moderate-Intensity Treadmill Exercise Promotes mTOR-Dependent Motor Cortical Neurotrophic Factor Expression and Functional Recovery in a Murine Model of Crush Spinal Cord Injury (SCI).
Treadmill exercise is widely considered an effective strategy for restoration of skilled motor function after spinal cord injury (SCI). However, the specific exercise intensity that optimizes recovery and the underlying mechanistic basis of this recovery remain unclear. To that end, we sought to investigate the effect of different treadmill exercise intensities on cortical mTOR activity, a key regulator of functional recovery following CNS trauma, in an animal model of C5 crush spinal cord injury (SCI). Following injury, animals were subjected to treadmill exercise for 4 consecutive weeks at three different intensities (low intensity [LEI]; moderate intensity [MEI]; and high intensity [HEI]). Motor function recovery was assessed by horizontal ladder test, cylinder rearing test, and electrophysiology, while neurotrophic factors and cortical mechanistic target of rapamycin (mTOR) pathway-related proteins were assessed by Western blotting. The activation of the cortical mTOR pathway and axonal sprouting was evaluated by immunofluorescence and the changes of plasticity in motor cortex neurons were assessed by Golgi staining. In keeping with previous studies, we found that 4 weeks of treadmill training resulted in improved skilled motor function, enhanced nerve conduction capability, increased neuroplasticity, and axonal sprouting. Importantly, we also demonstrated that when compared with the LEI group, MEI and HEI groups demonstrated elevated expression of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), phosphorylated ribosomal S6 protein (p-S6), and protein kinase B (p-Akt), consistent with an intensity-dependent activation of the mTOR pathway and neurotrophic factor expression in the motor cortex. We also observed impaired exercise endurance and higher mortality during training in the HEI group than in the LEI and MEI groups. Collectively, our findings suggest that treadmill exercise following SCI is an effective means of promoting recovery and highlight the importance of the cortical mTOR pathway and neurotrophic factors as mediators of this effect. Importantly, our findings also demonstrate that excessive exercise can be detrimental, suggesting that moderation may be the optimal strategy. These findings provide an important foundation for further investigation of treadmill training as a modality for recovery following spinal cord injury and of the underlying mechanisms.


Is styrene competitive for dopamine receptor binding?
The potential role of styrene oxide in altering the dopaminergic pathway in the ear is investigated by means of molecular docking and molecular dynamics simulations. We estimate the binding affinity of both styrene oxide and dopamine to the dopaminergic receptor DrD2 by computing the free-energy difference, ∆G, between the configuration where the ligand is bound to the receptor and the situation in which it is "infinitely" far away from it. The results show that the styrene oxide has a somewhat lower affinity for binding with respect to dopamine, which, however, may not be enough to prevent exogenous high concentration styrene oxide to compete with endogenous dopamine for DrD2 binding.


To study the protective effect of Huangqi Baihe Granules on Radiation brain injury based on network pharmacology and experiment.
Huangqi baihe Granules (HQBHG), which is a key Chinese medical prescription, has a remarkable efficacy in oxidative stress and inflammation. Nevertheless, the therapeutic effect on Radiation brain injury (RBI) has rarely been studied. The study aimed to verify the effect of HQBHG against RBI and explore its potential mechanism. The potential targets and mechanisms of HQBHG against RBI were predicted by network pharmacology and verified by established rat model of RBI Firstly, the therapeutic effect of HQBHG in RBI was confirmed by water maze test, HE staining and Enzyme-linked immunosorbent assay (ELISA). Secondly, the potential critical anti-RBI pathway of HQBHG was further explored by water maze, HE staining, immunofluorescence assays, ELISA and western blot. A total of 43 HQBHG anti-RBI targets were obtained. Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotations showed that the treatment of HQBHG in RBI might be mainly related to oxidative stress, inflammation and PI3K/AKT pathway. Experimental studies have indicated that HQBHG can improve spatial learning and memory ability, alleviate pathological damage of brain tissue in RBI of rats. HQBHG also can down-regulate the levels of IL-1β, TNF-α, ROS and MDA, meanwhile, GSH was significantly up-regulated. In addition, the HQBHG can increase the protein expression phosphorylations PI3K (p-PI3K), phosphorylations AKT(p-AKT) and Nrf2 in the brain tissue of RBI. HQBHG may alleviated RBI by regulated oxidative stress and inflammatory response through PI3K/AKT/Nrf2 pathway.


Intubation of newborns and infants: a solution to the problem of water condensation.
Treatment with humidified air in intubated newborns and infants its often complicated by the embarrassing problem of water condensation. This problem is solved by the humidification system described below, in which the tube delivering humidified air is surrounded by an Armaflex-insulated spiral-wire tube. Through the space between the two tubes, an adjustable air warmer delivers dry air at a temperature and flow rate such that the temperature of the humidified air in the delivery tube is maintained above its dew-point temperature.


Specific, high-affinity binding sites for human luteinizing hormone (hLH) and human chorionic gonadotrophin (hCG) in Candida species.
The presence of specific binding sites for [125I]-labelled hLH and hCG is described in Candida species. Binding was present in three strains of Candida albicans, and in Candida tropicalis, and was greatest in microsomes, though binding was also present in cytosol fractions. hLH and hCG mutually competed for these binding sites. Other hormones did not bind and did not compete for hLH binding sites. Scatchard plots showed two classes of binding sites, one with high affinity, low capacity and the other with lower affinity, high capacity binding in both microsomes and cytosol. This is the first report of specific binding sites for mammalian peptide hormones in a yeast.


Carbohydrate sulfotransferases: mediators of extracellular communication.
Sulfated carbohydrates mediate diverse extracellular recognition events in both normal and pathological processes. The sulfotransferases that generate specific carbohydrate 'sulfoforms' have recently been recognized as key modulators of these processes and therefore represent potential therapeutic targets.


Prognosis of patients with coronary artery disease treated in different therapy units at department of cardiology: a retrospective cohort study.
Coronary artery disease (CAD) is a major health problem in global. Benefit from different care unit for various type of CAD is remaining unknown. We investigate if coronary care unit (CCU) reduces the incidence of major adverse cardiovascular events (MACEs). 806 CAD patients including stable angina (SA) and acute coronary syndrome (ACS) who treated in department of cardiology were involved in the study as two groups. Each group involved two subgroups according to the therapy unit including CCU and normal unit. 12-48 months follow-up was carried out. The primary end point was all cause mortality. For SA, death from any cause occurred in 1.0% of the patients in the normal group (1 of 108), as compared with 5.1% in the CCU group (3 of 59) (hazard ratio [HR], 0.164; 95% confidence interval [CI], 0.017 to 1.580; P=0.118). Kaplan-Meier survival analysis showed that there were no significant differences between the two subgroups with respect to the risk of death (P=0.074), revascularization (P=0.660), stroke (P=0.497), heart failure (P=0.658) and hemorrhage (P=0.096). For ACS, death occurred in 1.9% of the patients in the normal subgroup (5 of 267), as compared with 1.3% in the CCU subgroup (5 of 372) (HR, 1.403; 95% CI, 0.406-4.846; P=0.593). Kaplan-Meier survival analysis showed that there were no significant differences between the two subgroups with respect to the risk of death (P=0.591), revascularization (P=0.996), stroke (P=0.425), heart failure (P=0.625). CAD patients treated in CCU obtain little benefits compared with normal.


Structural Characterization of the Type IX Secretion System in Porphyromonas gingivalis.
The type IX secretion system (T9SS) is the most recently discovered secretion system in the gram-negative bacteria and is specific to the Bacteroidetes phylum. It is comprised of at least 19 proteins, which together allows for the secretion and cell surface attachment of a specific group of proteins (T9SS substrates), that harbor a signal sequence at the C-terminus. Here we describe the structural characterization of the PorK, PorN and PorG components of the Porphyromonas gingivalis T9SS using electron microscopy and cross-linking mass spectrometry.


A new resorbable magnesium scaffold for de novo coronary lesions (DREAMS 3): one-year results of the BIOMAG-I first-in-human study.
The third-generation coronary sirolimus-eluting magnesium scaffold, DREAMS 3G, is a further development of the DREAMS 2G (commercial name Magmaris), aiming to provide performance outcomes similar to drug-eluting stents (DES). The BIOMAG-I study aims to assess the safety and performance of this new-generation scaffold. This is a prospective, multicentre, first-in-human study with clinical and imaging follow-up scheduled at 6 and 12 months. The clinical follow-up will continue for 5 years. A total of 116 patients with 117 lesions were enrolled. At 12 months, after completion of resorption, in-scaffold late lumen loss was 0.24±0.36 mm (median 0.19, interquartile range 0.06-0.36). The minimum lumen area was 4.95±2.24 mm² by intravascular ultrasound and 4.68±2.32 mm² by optical coherence tomography. Three target lesion failures were reported (2.6%, 95% confidence interval: 0.9-7.9), all clinically driven target lesion revascularisations. Cardiac death, target vessel myocardial infarction and definite or probable scaffold thrombosis were absent. Data at the end of the resorption period of DREAMS 3G showed that the third-generation bioresorbable magnesium scaffold is clinically safe and effective, making it a possible alternative to DES. gov: NCT04157153.


Demographics, pattern of practice and clinical outcomes in rectal squamous cell carcinoma.
The aim of this study was to describe the baseline clinical features, treatment patterns and outcomes in rectal squamous cell carcinoma (SCC). This is a retrospective study of patients with rectal SCC treated at the Princess Margaret Cancer Centre (Toronto, Canada) between 1 January 1995 and 31 December 2020. Clinical factors associated with locoregional failure (LRF), distant metastases (DM), disease-free survival (DFS) and overall survival (OS), such as age, sex, HIV status, T-category, nodal status, grade and primary treatment, were investigated with univariate analysis (UVA). Twenty nine patients with rectal SCC were analysed with a median follow-up of 7.4 years (range 0.3-20.4 years). The median age at diagnosis was 52 years, with the majority presenting with clinical T3 disease or higher (n = 21, 72%) and positive regional lymph nodes (n = 16, 55%), while more than quarter of patients (28%) had metastatic disease. Definitive chemoradiation was the treatment modality of choice in more than half of all cases (n = 17, 59%) with a response rate of 100%. The 10-year cumulative incidence of LRF and DM was, respectively, 12% (95% CI 1.8%-32.9%) and 31% (95% CI: 12.0%-52.6%). The 5- and 10-year OS was 82% (95% CI 66.1%-100%). UVA revealed a trend towards an association of male gender (hazard ratio = 4.65, 95% CI 0.9%-24.1; p = 0.067) and primary surgical treatment (hazard ratio = 0.76, 95% CI 0.09-6.34; p = 0.061) with DFS. Definitive chemoradiation is an effective and preferred treatment for rectal SCC allowing for sphincter preservation with complete clinical response observed in all patients.


Dissolved microcystins in surface and ground waters in regions with high cancer incidence in the Huai River Basin of China.
Microcystins (MCs) are potent hepatotoxins and have also implicated in liver tumor promotion. The present study investigates the temporal and spatial variations of MCs in different water bodies in the Huai River Basin in China. Water samples including rivers, ponds and wells were collected every quarter during December 2008 and December 2009. MCs were determined by high pressure liquid chromatography after solid phase extraction. MCs concentrations in river samples were 0.741±0.623μgL(-1) with maximum of 1.846μgL(-1). MCs in pond were 0.597±0.960μgL(-1) with maximum of 2.298μgL(-1). MCs were also detected in 51.7% of the groundwater samples, MCs in groundwater were 0.060±0.085μgL(-1) with maximum of 0.446μgL(-1). MCs concentrations in groundwater did not differ significantly among different depths or towns (Wilcoxon test, p>0.05). The average MCs in groundwater in each sampling period were 0.068μgL(-1), 0.118μgL(-1), 0.052μgL(-1), 0.059μgL(-1) and 0.020μgL(-1). Through multi linear regression, the best fit model was built on MCs in groundwater with River B (R(2)=0.13, p<0.05), rather than with pond water. The results suggested that MCs contamination in groundwater originated from rivers, causing potential health risk on population who drink groundwater directly.


A case of conservatively managed gastric perforation at a recurrent hiatal hernia site after laparoscopic paraesophageal repair.
Gastric perforation due to a hiatal hernia is a rare cause of acute abdominal pain that often requires surgical intervention. Conservative management for this condition is an effective option in certain cases, although fewer reports of this exist. Herein, we report a unique case of gastric perforation caused by a recurrent hiatal hernia that was successfully treated with conservative management. A 74-year-old man developed a high fever and an elevated inflammatory response on the third day after a laparoscopic paraesophageal hernia repair using a mesh. Computed tomography confirmed the recurrence of the hiatal hernia, with gastric fundal prolapse into the mediastinum and surgical emphysema in the gastric wall. This was followed by a gastric perforation within the mediastinum. The patient was treated using an ileus tube through the perforation site. In similar cases, if the clinical symptoms are mild, there are no signs of serious infection, and the perforation remains in the mediastinum and can be appropriately drained, conservative treatment is considered an option. Under favorable conditions, conservative management can be an option for gastric perforation in patients with recurrent hiatal hernias, which is a serious potential postoperative complication.


Peripheral and central administration of neuropeptide Y in a rat middle cerebral artery occlusion stroke model reduces cerebral blood flow and increases infarct volume.
Recent studies have shown increased immunoreactivity for neuropeptide Y (NPY) within the perilesional cortex following experimental middle cerebral artery occlusion (MCAO) or focal excitotoxic damage. Downregulation of the NPY Y1 receptor gene using an antisense oligodeoxynucleotide produced a doubling of the infarct volume, implying that NPY may mediate neuroprotection against focal ischemia. The effects of treatment with NPY on infarct volume and hemodynamic parameters were investigated in the present study. Adult male Sprague-Dawley rats were anesthetized with sodium pentobarbital to undergo right-sided endovascular MCAO for 2 h. A single dose of NPY was given via intracarotid injection (10 microg/kg) at the beginning of reperfusion, intracisternal injection (10 or 30 microg/kg) at 30 min of ischemia, or intracerebroventricular (i.c.v.) injection (10 or 70 microg/kg) at 30 min of ischemia. Control groups received the vehicle only via the same route. Body temperature was maintained constant, and hemodynamic parameters were monitored during anesthesia. Laser Doppler flowmetry was used to monitor the regional cerebral blood flow (rCBF) during ischemia and reperfusion in some rats. The rats were decapitated on day 3, and their brains were cut into 2-mm thick coronal slices before reaction with a 2% solution of 2,3,5-triphenyltetrazolium chloride to reveal the infarct. Compared to the respective control groups, NPY treatment via any method of administration increased the relative infarct volume. Suppression of rCBF was observed during reperfusion. These results indicate that peripheral or central administration of NPY impairs reperfusion following experimental MCAO and worsens the outcome of focal cerebral ischemia.


Trace elements in the environment and in human organs. I. Methods and results.
The authors have determined by spectrophotometry the copper, zinc, lead, and cadmium content of the kidney, liver, lung, and adrenal derived from 1072 autopsies. The metallic content of food and drink was examined and the daily quantity consumed was stated by measuring and calculation. According to the results in Hungary the daily ingestion of these four microelements is small, as reflected by the metal content of the organs. An average 75% of the kidney's whole cadmium content is present in the cortex of the kidney. Lead in the medulla and zinc in the cortex are found in larger quantities. Analyzing the distribution according to sexes it was found that lead in the liver and kidney and cadmium in the kidney and lung of women is significantly lower than in the male. However, the element content in the adrenal is significantly higher for zinc and cadmium in women. The cadmium distribution in the kidney is similar to the essential elements. The correlation of the element pairs is better in the kidney and lung (Zn-Cu is 0.55 in the kidney and 0.51 in the lung).


Leptin, cortisol and distinct concurrent training sequences.
In order to investigate the effects of distinct concurrent training sequences on serum leptin and cortisol levels, 10 subjects (27.1±4.8 years, body mass index 25.38±0.09) were submitted to a control session, concurrent training 1 and concurrent training 2. Samples of leptin and cortisol were collected. Concurrent training 1 consisted of indoor cycling followed by strength training and concurrent training 2 of strength training followed by indoor cycling. No exercises were performed at the control session. Blood was collected once again to verify the same variables. Shapiro-Wilk, 2-way ANOVA and Tukey post-hoc tests were used. There was a reduction in leptin levels after concurrent training 1 (Δ%= - 16.04; p=0.05) and concurrent training 2 (Δ%= - 8.54; p=0.02). Cortisol decreased after concurrent training 1 (Δ%= - 26.32; p=0.02) and concurrent training 2 (Δ%= - 33.57; p=0.05). There was a high and significant correlation between blood variables only in CS (lep PRE X cort PRE and cort POST: r= - 0.80 and r= - 0.81; lep POST X cort PRE and cort POST: r= - 0.62 and r= - 0.62). Concurrent training promoted a reduction in leptin and cortisol levels irrespective of sequence.


Kinetic control of nascent protein biogenesis by peptide deformylase.
Synthesis of bacterial proteins on the ribosome starts with a formylated methionine. Removal of the N-terminal formyl group is essential and is carried out by peptide deformylase (PDF). Deformylation occurs co-translationally, shortly after the nascent-chain emerges from the ribosomal exit tunnel, and is necessary to allow for further N-terminal processing. Here we describe the kinetic mechanism of deformylation by PDF of ribosome-bound nascent-chains and show that PDF binding to and dissociation from ribosomes is rapid, allowing for efficient scanning of formylated substrates in the cell. The rate-limiting step in the PDF mechanism is a conformational rearrangement of the nascent-chain that takes place after cleavage of the formyl group. Under conditions of ongoing translation, the nascent-chain is deformylated rapidly as soon as it becomes accessible to PDF. Following deformylation, the enzyme is slow in releasing the deformylated nascent-chain, thereby delaying further processing and potentially acting as an early chaperone that protects short nascent chains before they reach a length sufficient to recruit other protein biogenesis factors.