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This report is the first research study that aims to explore the molecular mechanisms involved in the in vitro pulmonary cytotoxicity triggered by long-term exposure to silicon-based quantum dots (QDs). Human lung fibroblasts (MRC-5 cell line) were exposed to 5 &micro, g/mL silicon-based QDs for 5 weeks and the concentration was increased up to 40 &micro, g/mL QDs during the next 4 weeks. Cell viability and population doubling level were calculated based on Trypan blue staining. The expression levels of proteins were established by Western blotting and the telomeres&rsquo, length was determined through Southern blotting. Prolonged exposure of lung fibroblasts to QDs reduced the cell viability by 10% compared to untreated cells. The level of p53 and apoptosis-inducing factor (AIF) expression increased during the exposure, the peak intensity being registered after the seventh week. The expressions of autophagy-related proteins, Beclin-1 and LC-3, were higher compared to untreated cells. Regarding the protein expression of Nrf-2, a progressive decrease was noticed, suggesting the downregulation of a cytoprotective response to oxidative stress. In contrast, the heat shock proteins&rsquo, (HSPs) expression was increased or maintained near the control level during QDs exposure in order to promote cell survival. Furthermore, the telomeres&rsquo, length was not reduced during this exposure, indicating that QDs did not induce cellular senescence. In conclusion, our study shows that silicon-based QDs triggered the activation of apoptotic and autophagy pathways and downregulation of survival signaling molecules as an adaptive response to cellular stress which was not associated with telomeres shortening.

Since the novel coronavirus outbreak of SARS-CoV-2 from the first cases whereof were reported in Wuhan, China, in December 2019, our globalized world has changed enormously. On the 11th of March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic, and nations around the world have taken drastic measures to reduce transmission of the disease. The situation is similar in Switzerland, a small high-income country in Central Europe, where the first COVID-19 case was registered on the 25th of February 2020. Through literature review as well as correspondence with public health professionals and experts in mathematical modeling, this case study focuses on the outbreak’s impact on Switzerland and on the measures this country has implemented thus far. Along with the rapid spread of the virus, the political organization, economy, healthcare system, and characteristics of the country greatly influence the approach taken in facing the crisis. Switzerland appears to be structurally well-prepared, but, according to mathematical modeling predictions, in order to avoid total collapse of healthcare facilities, the measures taken by the Swiss Government need to reduce the virus transmission chain by at least 70%. Fortunately, updated models on April 22nd show evidence that the non-pharmaceutical measures invoked have decreased transmission by an estimated 89%, proving effective management by the federal government and allowing for progressive deconfinement measures.

Two different types of nanoparticles (silicon dioxide and titanium dioxide) were selected within this study in order to analyze the interaction with bovine and human serum albumin. These particles were characterized by transmission and scanning electron microscopy (TEM and SEM), X-ray diffraction (XRD) and energy dispersive X-ray spectroscopy (EDXS). In addition, the hydrodynamic size and the zeta potential were measured for all these nanoparticles. The serum proteins were incubated with the nanoparticles for up to one hour, and the albumin adsorption on the particle surface was investigated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The effect induced on the secondary structure of proteins was analyzed by Fourier transform infrared spectroscopy (FTIR). The results showed that albumin adsorbed on the surface of both types of nanoparticles, but in different quantities. In addition, we noticed different changes in the structure of albumin depending on the physicochemical properties of each type of particle tested. In conclusion, our study provides a comparative analysis between the different characteristics of nanoparticles and the protein corona formed on the particle surface and effects induced on protein structure in order to direct the development of &ldquo, safe-by-design&rdquo, nanoparticles, as their demands for research and applications continue to increase.

The main objective of this study was to evaluate the in vivo toxicity of methanolic leaf extract of Vernonia lasiopus. To provide information on the safety of V. lasiopus, we evaluated its acute and sub-chronic toxicity in Wistar rats. For evaluation of acute toxicity of the plant extract, five Wistar rats were orally dosed with 2000 mg/kg body weight sequentially. Sub-chronic toxicity was tested in twenty Wistar rats using three extract doses 100, 300 and 1000 mg/kg body weight. They were orally administered for 28 days. Mortality and toxicity signs were monitored during the study period. At the end of the experiment, the animals were sacrificed, their internal organs weighed and blood samples collected for haematology and biochemical analysis. In acute toxicity, no single death was reported; leading to conclusion that the median lethal dose (LD50) of methanolic leaf extract of V. lasiopus is beyond 2000 mg/kg body weight. In sub-chronic toxicity studies, V. lasiopus lowered total proteins in all the study groups significantly. Albumin was also lowered at extract dose of 1000 mg/kg body weight. In addition, it resulted to significant neutropenia, lymphocytosis and thrombocytosis in the group administered with dose extract of 1000 mg/kg body weight (PA‹Â‚0.05). It was therefore concluded that methanolic leaf extract of V. lasiopus is safe for use when administered at therapeutic doses. The plant extract may also be useful in the management of haematological disorders especially thrombocytopenia.

Bile acid (BA) production in mice is regulated by hepatic farnesoid X receptors and by intestinal fibroblast growth factor (FGF)-15 (in humans, FGF-19), a suppressor of BA synthesis that also reduces serum triglycerides and glucose. Cholestyramine treatment reduces FGF-19 and induces BA synthesis, whereas plasma triglycerides may increase from unclear reasons. We explored whether FGF-19 may suppress BA synthesis and plasma triglycerides in humans by modulation of FGF-19 levels through long-term cholestyramine treatment at increasing doses. In a second acute experiment, metabolic responses from 1 day of cholestyramine treatment were monitored. Long-term treatment reduced serum FGF-19 by >90%; BA synthesis increased up to 17-fold, whereas serum BAs, triglycerides, glucose, and insulin were stable. After long-term treatment, serum BAs and FGF-19 displayed rebound increases above baseline levels, and BA and cholesterol syntheses normalized after 1 wk without rebound reductions. Acute cholestyramine treatment decreased FGF-19 by 95% overnight and serum BAs by 60%, while BA synthesis increased fourfold and triglycerides doubled. The results support that FGF-19 represses BA synthesis but not serum triglycerides. However, after cessation of both long-term and 1-day cholestyramine treatment, circulating FGF-19 levels were normalized within 2 days, whereas BA synthesis remained significantly induced in both situations, indicating that also other mechanisms than the FGF-19 pathway are responsible for stimulation of BA synthesis elicited by cholestyramine. Several of the responses during cholestyramine treatment persisted at least 6 days after treatment, highlighting the importance of removing such treatment well before evaluating dynamics of the enterohepatic circulation in humans.

Background: Natural antibodies specific for phosphorylcholine (anti-PC) have been implicated as protective factors in atherosclerosis. We herein determined the relationship between IgM anti-PC and incidence of cardiovascular disease (CVD). Methods: We studied 349 incident cases (200 men) of first events of CVD (coronary heart disease (CHD; n = 203 or ischemic stroke; n = 146) and 693 age- and sex-matched controls identified through 12 years of follow-up (1991-2003) of subjects from the cardiovascular cohort within the Malmo Diet and Cancer Study. Relative risks (RR) of CVD with 95% confidence intervals (CI) of incident CVD with adjustments for age, smoking, total cholesterol and blood pressure were determined. Anti-PC-levels were measured using ELISA (Athera CVDefine (TM)). Results: As determined using Athera CVDefine (TM), significant associations were attained with values of anti-PC below 17 U/ml (corresponding to the lowest 9th percentile), which remained after taking confounders into account (RR: 1.79, 95% CI: 1.09-2.94, p=0.021). If men were studied separately, significance was evident at values below 17U/ml (RR: 2.01, 95% Cl: 1.11-3.67, p=0.022), which was not the case among women. Furthermore, values below 17 U/ml were also associated with ischemic stroke (RR = 3.67, 95% Cl: 1.34-10.1, p=0.01), but not with CHD. Conclusion: Low IgM anti-PC could be a novel risk marker for development of ischemic stroke in men. Further studies are needed to establish gender and subgroup differences. (C) 2008 Elsevier Ireland Ltd. All rights reserved. (Less)

Objective To determine levels of athero-protective IgM antibodies against phosphorylcholine in mothers and term-born normal or low birth weight infants. Approach Twenty three mother-infant pairs were studied, of whom 16 infants were within the normal weight range for gestational age (NGA; 3652[504] g) and 7 were small for gestational age (SGA; birth weight: 2715[255] g), the latter 75th percentile) was larger in mothers of NGA-infants (43%) vs. those of SGA-infants (0%, p = 0.032). Conclusions IgM anti-PC levels are low at birth, which suggests that these antibodies do not play a “housekeeping” role in immune function during fetal life/development, but arise predominately on exposure to external antigens after birth. Furthermore, low maternal IgM anti-PC levels may play a role in placental insufficiency, contributing to poor fetal growth and a small-for-date baby. This preliminary observation may have implications for the future risk of atherosclerosis/cardiovascular disease development in pregnant women and their offspring.

Objective— To gain insight into the function of proprotein convertase subtilisin kexin type 9 (PCSK9) in humans by establishing whether circulating levels are influenced by diurnal, dietary, and hormonal changes. Methods and Results— We monitored circulating PCSK9 in a set of dynamic human experiments and could show that serum PCSK9 levels display a diurnal rhythm that closely parallels that of cholesterol synthesis, measured as serum lathosterol. In contrast to these marked diurnal changes in cholesterol metabolism, serum low-density lipoprotein (LDL) cholesterol levels remained stable during the diurnal cycle. Depletion of liver cholesterol by treatment with the bile acid–binding resin, cholestyramine, abolished the diurnal rhythms of both PCSK9 and lathosterol. Fasting (>18 hours) strongly reduced circulating PCSK9 and lathosterol levels, whereas serum LDL levels remained unchanged. Growth hormone, known to be increased during fasting in humans, reduced circulating PCSK9 in parallel to LDL cholesterol levels. Conclusion— Throughout the day, and in response to fasting and cholesterol depletion, circulating PCSK9 displays marked variation, presumably related to oscillations in hepatic cholesterol that modify its activity in parallel with cholesterol synthesis. In addition to this sterol-mediated regulation, additional effects on LDL receptors may be mediated by hormones directly influencing PCSK9.

Phosphorylcholine (PC) may play an important role in the atherogenic and pro-inflammatory effects of oxidized low density lipoproteins. We recently demonstrated that low levels of IgM antibodies against PC (anti-PC) are associated with development of myocardial infarction and stroke. We here evaluate the association between anti-PC and dementia and Alzheimer's disease (AD). We conducted a nested case-control study of 182 incident dementia cases (serum collected before onset of dementia) matched to 366 controls and a case-control study of 97 prevalent dementia cases (serum collected after dementia onset) matched to 205 controls. Controls were matched on gender and age at blood draw (+/- 1 year). Participants were from the Swedish Twin Registry. Anti-PC levels were measured by ELISA. The odds ratio (OR) of dementia was modeled using conditional logistic regression. Patients with dementia had significantly lower mean anti-PC levels than controls (39.1 versus 49.5 U/ml). The likelihood of having dementia or AD was doubled for individuals with the lowest 25% anti-PC levels (OR=2.04 and 2.70, respectively). The results were similar after adjustments for potential confounders. There was no association between anti-PC levels and incident dementia. Low levels of atheroprotective anti-PC could play a role in AD and dementia. Potential mechanisms include decreased anti-inflammatory potential and effects on the vasculature. Further attention is merited to elucidate the role of anti-PC in AD development and the usefulness of anti-PC as a part of risk prediction, prognosis, diagnosis, or treatment.

A permanent transgenic mouse line was generated carrying 40 copies of the human Hox3.3 gene. The resulting mice express large amounts of Hox3.3 protein in posterior regions of the embryo where this homeodomain protein is normally not expressed. The transgene causes homeotic transformations of the skeleton, in particular the appearance of an extra pair of ribs in the lumbar region, transformation of the shape of posterior ribs into that of more anterior ones, and the joining of an additional pair of ribs to the sternum. The phenotype of this line resembles that obtained by the targeted loss-of-function mutation of Hox3.1 (Le Mouellic et al., 1992). In transient assays, the human Hox3.3 transgene leads to the formation of additional ribs in more posterior vertebrae as well.

Homeo box-containing genes (Hox) are expressed in restricted regions of vertebrate embryos and may specify positional information. The organization and expression patterns of these genes are highly conserved among different species, suggesting that their regulation may also have been conserved. We developed a transient expression system, using mosaically transgenic zebrafish, which allows rapid analysis of transgene expression, and examined the activities of two mammalian Hox genes, mouse Hox-1.1 and human HOX-3.3. We found that these Hox promoters are activated in specific regions and tissues of developing zebrafish embryos and that this specificity depends upon the same regulatory elements within the promoters that specify the spatial expression of these genes in mice. Our results suggest that the promoter activities have been remarkably conserved from fish to mammals. To study the regulation of Hox expression in the developing nervous system, we analyzed the promoter activities in spt-1 mutants that have a mesodermal deficiency. Our results suggest that interactions, probably with the paraxial mesoderm, differentially regulate the activities of Hox promoters in the developing nervous system.

HIPOLIDE, D. C., L. L. LOBO, R. DE MEDEIROS, B. NEUMANN, AND S. TUFIK. Treatment with dexamethasone alters yawning behavior induced by cholinergic but not dopaminergic agonist. PHYSIOL BEHAV 65 (4/5) 829–832, 1999.—Because stressful manipulations have been reported to modify drug-induced yawning, the present study investigated the effects of single and repeated treatment with a synthetic glucocorticoid, dexamethasone (DEXA) on apomorphine- and pilocarpine-induced yawning in male rats. Neither single nor repeated treatment with DEXA altered apomorphine-induced yawning. Single administration of DEXA, however, resulted in an increased number of yawns induced by pilocarpine. Conversely, repeated administration of DEXA led to a decreased number of yawns induced by pilocarpine. In conclusion, the present findings show that dopaminergic and cholinergic are distinctly altered by DEXA, in terms of yawning behavior when animals received DEXA.

Effects of stress on drug-induced yawning: Constant vs. intermittent stress. PHYSIOL BEHAV 58(1) 181-184, 1995.--Experiment 1 tested whether chronic exposure to immobilization, foot shock or forced swimming would result in suppression of apomorphine-, pilocarpine-, and physostigmine-induced yawning. Immobilization caused suppression of yawning, whereas foot shock and swimming resulted in increased number of yawns. Since interstressor interval was long in the two latter stressors, animals could have recovered and the increase in yawning could be due to the last (acute) exposure to stress. In Experiment 2 we recorded the number of yawns induced by pilocarpine in animals exposed to 1 h of swimming or foot shock. No differences between control and acutely stressed animals were detected. These results suggest that yawning is differently altered by constant and intermittent stressors (i.e., diminished by constant and increased by intermittent stress).

Introduction The purpose of this study was to investigate the effects of vegan diet in patients with rheumatoid arthritis (RA) on blood lipids oxidized low-density lipoprotein (oxLDL) and natural atheroprotective antibodies against phosphorylcholine (anti-PCs). Methods Sixty-six patients with active RA were randomly assigned to either a vegan diet free of gluten (38 patients) or a well-balanced non-vegan diet (28 patients) for 1 year. Thirty patients in the vegan group completed more than 3 months on the diet regimen. Blood lipids were analyzed by routine methods, and oxLDL and anti-PCs were analyzed by enzyme-linked immunosorbent assay. Data and serum samples were obtained at baseline and after 3 and 12 months. Results Mean ages were 50.0 years for the vegan group and 50.8 years for controls. Gluten-free vegan diet induced lower body mass index (BMI) and low-density lipoprotein (LDL) and higher anti-PC IgM than control diet (p < 0.005). In the vegan group, BMI, LDL, and cholesterol decreased after both 3 and 12 months (p < 0.01) and oxLDL after 3 months (p = 0.021) and trendwise after 12 months (p = 0.090). Triglycerides and high-density lipoprotein did not change. IgA anti-PC levels increased after 3 months (p = 0.027) and IgM anti-PC levels increased trendwise after 12 months (p = 0.057). There was no difference in IgG anti-PC levels. In the control diet group, IgM anti-PC levels decreased both after 3 and 12 months (p < 0.01). When separating vegan patients into clinical responders and non-responders at 12 months, the effects on oxLDL and anti-PC IgA were seen only in responders (p < 0.05). Conclusion A gluten-free vegan diet in RA induces changes that are potentially atheroprotective and anti-inflammatory, including decreased LDL and oxLDL levels and raised anti-PC IgM and IgA levels.

Central administration of ACTH in rats induces yawning and stretching. In order to study the effects of REM sleep deprivation on ACTH-induced yawning, the peptide was injected immediately after the REM sleep deprivation period or 24 h later. REM sleep deprivation impaired ACTH-induced yawning, but after a 24-hour recovery period, rats displayed a number of yawns similar to those in control animals. Implications for an involvement of dopaminergic and mainly cholinergic systems are discussed.

Yawning behavior was used to evaluate the sensitivity of presynaptic dopamine receptors and postsynaptic acetylcholine receptors of normal and REM sleep-deprived (REMSD) rats. The results show a lowering of the dose-response curve obtained with pomorphine and pilocarpine, as well as a shift to the right in the curve obtained with physostigmine. These results suggest that REMSD induced subsensitization of presynaptic dopamine receptors and/or postsynaptic acetylcholine receptors with different characteristics related to the mechanism of action of the cholinomimetic agent employed.

Studies by previous investigators have demonstrated an in vitro binding of vinyl sulfone dyes to the lysine and hydroxylysine groups of collagen. On this basis Remazol brilliant blue B, RH, RV and R, and Remazol black (Hoechst) were tested in several connective tissue procedures. Although selective staining of collagen was observed, the results were not considered a marked improvement over stains currently employed in these methods. Remazol black B in aqueous solutions (pH 7-8) stained elastin, and basement membanes. Red blood cells were deeply stained. This particular sample was also an excellent collagen stain in picric acid mixtures. It is possible that other histologic applications for these new dyes may be found.