Trauma reactivation under propranolol among traumatized Syrian refugee children: preliminary evidence regarding efficacy.
Background: There is a dearth of therapeutic solutions for traumatized young patients. Trauma reactivation conducted under the influence of the reconsolidation blocker propranolol (Reconsolidation Therapy) is a simple, cost-effective treatment option that has some promising initial results in adults suffering from posttraumatic stress disorder (PTSD). Objective: To explore the usefulness of this novel treatment in children. The primary outcome was the reduction of PTSD symptoms at the end of treatment, while secondary outcomes included reduction in anxiety and in depressive symptoms. Method: An open-label clinical trial was conducted in a refugee camp in Syria, investigating the safety and efficacy of this therapeutic strategy in 117 children suffering from enduring PTSD symptoms. Participants received propranolol 90 minutes before briefly recalling (i.e. reactivating) a single personal traumatic memory, for 5 consecutive days. Self-reported anxiety, depressive, and PTSD symptoms were assessed at baseline, as well as 4 and 13 weeks after treatment. Results: A significant, clinically meaningful symptom reduction was observed at all post-treatment measurement times vs. baseline. More specifically, between baseline and the 13-week follow-up we observed a 64% PTSD symptoms reduction (d = 2.71). In a similar vein, we obtained a 39% symptoms reduction for depressive symptoms (d = 1.01). The general anxiety symptoms improved, but eventually returned to prior level, probably because of the deteriorating living conditions in the camp. Conclusions: This therapy appeared as a potentially safe and useful treatment strategy for children suffering from PTSD symptoms, warranting replication studies using stronger study designs. The social acceptability and ease of implementation of the treatment should also be noted.


Peripheral autonomic impairment in patients newly diagnosed with type II diabetes.
To measure both peripheral and central autonomic function in patients newly diagnosed with type II diabetes. Measurements were made on 49 diabetic patients (8 with long-standing diabetes and neuropathic complications, 41 with newly diagnosed type II diabetes) and on 49 healthy, age- and sex-matched, control subjects. Five of the 41 newly diagnosed type II diabetic patients had retinopathy, and 4 had clinical evidence of neuropathy. No patient or control subject had significant vascular disease. Cardiac autonomic function was investigated by using standard cardiovascular reflex tests. The digital vasoconstrictor responses to deep breathing and body cooling were measured using venous occlusion plethysmography. The vasoconstrictor responses to a deep breath and body cooling were significantly reduced (P < 0.001) in the fingers and toes of the neuropathic patients compared with their matched control subjects, as were the heart rate responses (P < 0.02). The vasoconstrictor responses were significantly reduced in the toes (P < 0.001) and fingers (P < 0.05, P < 0.01) of the newly diagnosed patients compared with the corresponding responses in the control subjects. There was no significant difference in the heart rate or blood pressure responses of these patients and control subjects during standard tests of cardiac autonomic function. Patients with type II diabetes may have impaired peripheral autonomic function at diagnosis.


New approach to weight-of-evidence assessment of ecotoxicological effects in regulatory decision-making.
Ecological risk assessments and risk management decisions are only as sound as the underlying information and processes to integrate them. It is important to develop transparent and reproducible procedures a priori to integrate often-heterogeneous evidence. Current weight-of-evidence (WoE) approaches for effects or hazard assessment tend to conflate aspects of the assessment of the quality of the data with the strength of the body of evidence as a whole. We take forward recent developments in the critical appraisal of the reliability and relevance of individual ecotoxicological studies as part of the effect or hazard assessment of prospective risk assessments and propose a streamlined WoE approach. The aim is to avoid overlap and double accounting of criteria used in reliability and relevance with that used in current WoE methods. The protection goals, problem formulation, and evaluation process need to be clarified at the outset. The data are first integrated according to lines of evidence (LoEs), typically mechanistic insights (e.g., cellular, subcellular, genomic), in vivo experiments, and higher-tiered field or observational studies. Data are then plotted on the basis of both relevance and reliability scores or categories. This graphical approach provides a means to visually assess and communicate the credibility (reliability and relevance of available individual studies), quantity, diversity, and consistency of the evidence. In addition, the external coherence of the body of evidence needs to be considered. The final step in the process is to derive an expression of the confidence in the conclusions of integrating the information considering these 5 aspects in the context of remaining uncertainties. We suggest that this streamlined approach to WoE for the effects or hazard characterization should facilitate reproducible and transparent assessments of data across different regulatory requirements. Integr Environ Assess Manag 2017;13:573-579. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).


Early mucosal sensing of SIV infection by paneth cells induces IL-1β production and initiates gut epithelial disruption.
HIV causes rapid CD4+ T cell depletion in the gut mucosa, resulting in immune deficiency and defects in the intestinal epithelial barrier. Breakdown in gut barrier integrity is linked to chronic inflammation and disease progression. However, the early effects of HIV on the gut epithelium, prior to the CD4+ T cell depletion, are not known. Further, the impact of early viral infection on mucosal responses to pathogenic and commensal microbes has not been investigated. We utilized the SIV model of AIDS to assess the earliest host-virus interactions and mechanisms of inflammation and dysfunction in the gut, prior to CD4+ T cell depletion. An intestinal loop model was used to interrogate the effects of SIV infection on gut mucosal immune sensing and response to pathogens and commensal bacteria in vivo. At 2.5 days post-SIV infection, low viral loads were detected in peripheral blood and gut mucosa without CD4+ T cell loss. However, immunohistological analysis revealed the disruption of the gut epithelium manifested by decreased expression and mislocalization of tight junction proteins. Correlating with epithelial disruption was a significant induction of IL-1β expression by Paneth cells, which were in close proximity to SIV-infected cells in the intestinal crypts. The IL-1β response preceded the induction of the antiviral interferon response. Despite the disruption of the gut epithelium, no aberrant responses to pathogenic or commensal bacteria were observed. In fact, inoculation of commensal Lactobacillus plantarum in intestinal loops led to rapid anti-inflammatory response and epithelial tight junction repair in SIV infected macaques. Thus, intestinal Paneth cells are the earliest responders to viral infection and induce gut inflammation through IL-1β signaling. Reversal of the IL-1β induced gut epithelial damage by Lactobacillus plantarum suggests synergistic host-commensal interactions during early viral infection and identify these mechanisms as potential targets for therapeutic intervention.


Oligoclonal banding in cerebrospinal fluid assessed by electrophoresis on agarose after centrifugal sample concentration through a microconcentrator membrane.
We describe use of a microconcentrator membrane with a 30 000-Da cutoff for treatment of cerebrospinal fluid (CSF) specimens before detection of oligoclonal bands by electrophoresis on agarose. After centrifugation at 2000 X g for 25 min, 0.5-, 1.0-, and 2.0-mL aliquots of CSF were concentrated 15-, 25-, and 40-fold. Analytical recovery of immunoglobulins G and A from the microconcentrators was about 90% (CV 5-8%). We found good correlation between results by this method and by a silver-stain procedure in a study comparing oligoclonal banding in CSF from multiple sclerosis and control patients. After 40-fold concentration of 2 mL of CSF, 2 mg of immunoglobulin G per liter can be detected, because the analytical sensitivity of the electrophoresis is 80 mg/L.


A short food-group-based dietary questionnaire is reliable and valid for assessing toddlers' dietary risk in relatively advantaged samples.
Identifying toddlers at dietary risk is crucial for determining who requires intervention to improve dietary patterns and reduce health consequences. The objectives of the present study were to develop a simple tool that assesses toddlers' dietary risk and investigate its reliability and validity. The nineteen-item Toddler Dietary Questionnaire (TDQ) is informed by dietary patterns observed in Australian children aged 14 (n 552) and 24 (n 493) months and the Australian dietary guidelines. It assesses the intake of 'core' food groups (e.g. fruit, vegetables and dairy products) and 'non-core' food groups (e.g. high-fat, high-sugar and/or high-salt foods and sweetened beverages) over the previous 7 d, which is then scored against a dietary risk criterion (0-100; higher score = higher risk). Parents of toddlers aged 12-36 months (Socio-Economic Index for Areas decile range 5-9) were asked to complete the TDQ for their child (n 111) on two occasions, 3·2 (SD 1·8) weeks apart, to assess test-retest reliability. They were also asked to complete a validated FFQ from which the risk score was calculated and compared with the TDQ-derived risk score (relative validity). Mean scores were highly correlated and not significantly different for reliability (intra-class correlation = 0·90, TDQ1 30·2 (SD 8·6) v. TDQ2 30·9 (SD 8·9); P= 0·14) and validity (r 0·83, average TDQ ((TDQ1+TDQ2)/2) 30·5 (SD 8·4) v. FFQ 31·4 (SD 8·1); P= 0·05). All the participants were classified into the same (reliability 75 %; validity 79 %) or adjacent (reliability 25 %; validity 21 %) risk category (low (0-24), moderate (25-49), high (50-74) and very high (75-100)). Overall, the TDQ is a valid and reliable screening tool for identifying at-risk toddlers in relatively advantaged samples.


Dysfunctional Cognition in Individuals With an Increased Risk for Mania.
There is still a lack of knowledge about attitudes and cognitions that are related to bipolar disorder. Theoretically, it was proposed that exaggerated beliefs about the self, relationships, the need for excitement, and goal-related activities might lead to mania in vulnerable individuals, however, the few studies that examined this hypothesis provided mixed results. One of the unresolved issues is if such a cognitive style is associated with current mood symptoms or with different stages of the illness, i.e. at-risk versus diagnosed bipolar disorder. Therefore, the present study aimed at evaluating depression and mania-related cognitive style in individuals at-risk for mania. In an online survey, we collected data of 255 students of the University of Klagenfurt, Austria. All participants completed the Hypomanic Personality Scale (HPS), the Cognition Checklist for Mania - Revised (CCL-M-R), the Dysfunctional Attitude Scale (DAS), the Beck Depression Inventory (BDI), and the Internal State Scale (ISS). In a hierarchical regression, HPS was positively related to scores of all subscales of the CCL-M-R. The HPS did not significantly predict scores of the DAS. Current manic and depressive symptoms significantly contributed to the models. The present results suggest that a trait-like risk for mania is associated with mania-related but not depression-related cognitions.


Endoscopic procedures for removal of foreign bodies of the aerodigestive tract: The Bugando Medical Centre experience.
Foreign bodies in the aerodigestive tract continue to be a common problem that contributes significantly to high morbidity and mortality worldwide. This study was conducted to describe our own experience with endoscopic procedures for removal of foreign bodies in the aerodigestive tract, in our local setting and compare with what is described in literature. This was a prospective descriptive study which was conducted at Bugando Medical Centre between January 2008 and December 2009. Data were collected using a structured questionnaire and analyzed using SPSS computer software version 15. A total of 98 patients were studied. Males outnumbered females by a ratio of 1.1:1. Patients aged 2 years and below were the majority (75.9%). The commonest type of foreign bodies in airways was groundnuts (72.7%) and in esophagus was coins (72.7%). The trachea (52.2%) was the most common site of foreign body's lodgment in the airways, whereas cricopharyngeal sphincter (68.5%) was the commonest site in the esophagus. Rigid endoscopy with forceps removal under general anesthesia was the main treatment modality performed in 87.8% of patients. The foreign bodies were successfully removed without complications in 90.8% of cases. Complication rate was 7.1% and bronchopneumonia was the most common complication accounting for 42.8% of cases. The mean duration of hospital stay was 3.4 days and mortality rate was 4.1%. Aerodigestive tract foreign bodies continue to be a significant cause of childhood morbidity and mortality in our setting. Rigid endoscopic procedures under general anesthesia are the main treatment modalities performed. Prevention is highly recommended whereby parents should be educated to keep a close eye on their children and keep objects which can be foreign bodies away from children's reach.


Neural correlates of language and non-language visuospatial processing in adolescents with reading disability.
Despite anecdotal evidence of relative visuospatial processing strengths in individuals with reading disability (RD), only a few studies have assessed the presence or the extent of these putative strengths. The current study examined the cognitive and neural bases of visuospatial processing abilities in adolescents with RD relative to typically developing (TD) peers. Using both cognitive tasks and functional magnetic resonance imaging (fMRI) we contrasted printed word recognition with non-language visuospatial processing tasks. Behaviorally, lower reading skill was related to a visuospatial processing advantage (shorter latencies and equivalent accuracy) on a geometric figure processing task, similar to findings shown in two published studies. FMRI analyses revealed key group by task interactions in patterns of cortical and subcortical activation, particularly in frontostriatal networks, and in the distributions of right and left hemisphere activation on the two tasks. The results are discussed in terms of a possible neural tradeoff in visuospatial processing in RD.


Insights on the Use of α-Lipoic Acid for Therapeutic Purposes.
α-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants, animals, and humans. It has various properties, among them great antioxidant potential and is widely used as a racemic drug for diabetic polyneuropathy-associated pain and paresthesia. Naturally, ALA is located in mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. Despite its various potentials, ALA therapeutic efficacy is relatively low due to its pharmacokinetic profile. Data suggests that ALA has a short half-life and bioavailability (about 30%) triggered by its hepatic degradation, reduced solubility as well as instability in the stomach. However, the use of various innovative formulations has greatly improved ALA bioavailability. The R enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability as compared to its S enantiomer. Indeed, the use of amphiphilic matrices has capability to improve ALA bioavailability and intestinal absorption. Also, ALA's liquid formulations are associated with greater plasma concentration and bioavailability as compared to its solidified dosage form. Thus, improved formulations can increase both ALA absorption and bioavailability, leading to a raise in therapeutic efficacy. Interestingly, ALA bioavailability will be dependent on age, while no difference has been found for gender. The present review aims to provide an updated on studies from preclinical to clinical trials assessing ALA's usages in diabetic patients with neuropathy, obesity, central nervous system-related diseases and abnormalities in pregnancy.


Predicting the effects of parasite co-infection across species boundaries.
It is normal for hosts to be co-infected by parasites. Interactions among co-infecting species can have profound consequences, including changing parasite transmission dynamics, altering disease severity and confounding attempts at parasite control. Despite the importance of co-infection, there is currently no way to predict how different parasite species may interact with one another, nor the consequences of those interactions. Here, we demonstrate a method that enables such prediction by identifying two nematode parasite groups based on taxonomy and characteristics of the parasitological niche. From an understanding of the interactions between the two defined groups in one host system (wild rabbits), we predict how two different nematode species, from the same defined groups, will interact in co-infections in a different host system (sheep), and then we test this experimentally. We show that, as predicted, in co-infections, the blood-feeding nematode Haemonchus contortus suppresses aspects of the sheep immune response, thereby facilitating the establishment and/or survival of the nematode Trichostrongylus colubriformis; and that the T. colubriformis-induced immune response negatively affects H. contortus This work is, to our knowledge, the first to use empirical data from one host system to successfully predict the specific outcome of a different co-infection in a second host species. The study therefore takes the first step in defining a practical framework for predicting interspecific parasite interactions in other animal systems.


Self-administration and behavioral economics of second-generation synthetic cathinones in male rats.
Synthetic cathinones have become increasingly available as drugs of abuse. Distribution of these drugs is made possible by altering the chemical structures of prohibited cathinones and marketing them under misleading labels. Very little is known about the relative reinforcing effectiveness of new synthetic cathinones relative to known drugs of abuse. We examined self-administration of three second-generation synthetic cathinones: alpha-pyrrolidinopentiophenone (alpha-PVP), 4-methyl-N-ethylcathinone (4-MEC), and 4-methyl-alpha-pyrrolidinopropiophenone (4-MePPP) relative to methamphetamine. Male, Sprague-Dawley rats, implanted with intravenous catheters, were trained to self-administer methamphetamine (0.05 mg/kg/injection) under a fixed-ratio schedule. Following training, various doses of methamphetamine (0.006-0.1 mg/kg/injection), alpha-PVP (0.0015-0.1 mg/kg/injection), 4-MEC (0.1-3.2 mg/kg/injection), or 4-MePPP (0.1-0.8 mg/kg/injection) were available for self-administration in separate groups, followed by a behavioral-economics evaluation of the reinforcing effectiveness of each drug. For all drugs, at least one dose functioned as a reinforcer. Alpha-PVP and 4-MePPP maintained the highest numbers of infusions per session and both were more effective reinforcers relative to methamphetamine. 4-MEC and methamphetamine were not significantly different in terms of infusions per session or reinforcing effectiveness. Emerging synthetic cathinones whose primary pharmacological mechanism is to block dopamine uptake but with little effects on monoamine release or serotonin uptake may have a greater degree of abuse potential compared with known abused stimulants.


Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage.
Background and Purpose- EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods- Subjects were World Federation of Neurological Surgeons grades 2-4, modified Fisher grades 2-4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6-8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results- The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83-1.22], P=0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P=0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3-4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94-1.58], P=0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions- There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02790632.


Adolescents' expectations for the future predict health behaviors in early adulthood.
Health-related behaviors in adolescence establish trajectories of risk for obesity and chronic degenerative diseases, and they represent an important pathway through which socio-economic environments shape patterns of morbidity and mortality. Most behaviors that promote health involve making choices that may not pay off until the future, but the factors that predict an individual's investment in future health are not known. In this paper we consider whether expectations for the future in two domains relevant to adolescents in the U.S.-perceived chances of living to middle age and perceived chances of attending college-are associated with an individual's engagement in behaviors that protect health in the long run. We focus on adolescence as an important life stage during which habits formed may shape trajectories of disease risk later in life. We use data from a large, nationally representative sample of American youth (the US National Longitudinal Study of Adolescent Health) to predict levels of physical activity, fast food consumption, and cigarette smoking in young adulthood in relation to perceived life chances in adolescence, controlling for baseline health behaviors and a wide range of potentially confounding factors. We found that adolescents who rated their chances of attending college more highly exercised more frequently and smoked fewer cigarettes in young adulthood. Adolescents with higher expectations of living to age 35 smoked fewer cigarettes as young adults. Parental education was a significant predictor of perceived life chances, as well as health behaviors, but for each outcome the effects of perceived life chances were independent of, and often stronger than, parental education. Perceived life chances in adolescence may therefore play an important role in establishing individual trajectories of health, and in contributing to social gradients in population health.


Myth busting: does real-world experience lead to better drug choices?
In the era of evidence-based medicine, clinical guidelines, andpersonalized medicine, one would think that convincing clinical trial data would influence clinical practice if disseminated in an appropriate manner. However, it has been estimated that only 50% of current medical practice is evidence-based, clearly demonstrating a compelling need to collect and analyze additional data to better inform practice. Current data are usually gathered from a variety of sources, including clinical trials, observational studies, and meta-analyses. Yet according to Jeff Forringer, CEO of IntrinsiQ, data from oncology practices provide real-world outcomes that give better insight into the efficacy of cancer therapeutics.


Friction forces on atoms after acceleration.
The aim of this paper is to revisit the calculation of atom-surface quantum friction in the quantum field theory formulation put forward by Barton (2010 New J. Phys. 12 113045). We show that the power dissipated into field excitations and the associated friction force depend on how the atom is boosted from being initially at rest to a configuration in which it is moving at constant velocity (v) parallel to the planar interface. In addition, we point out that there is a subtle cancellation between the one-photon and part of the two-photon dissipating power, resulting in a leading order contribution to the frictional power which goes as v(4). These results are also confirmed by an alternative calculation of the average radiation force, which scales as v(3).


Cluster carbonyls of the [Re(6)(mu(3)-Se)(8)](2+) core: synthesis, structural characterization, and computational analysis.
The reactions of the previously reported cluster complexes [Re(6)(mu(3)-Se)(8)(PEt(3))(5)I]I, trans-[Re(6)(mu(3)-Se)(8)(PEt(3))(4)I(2)], and cis-[Re(6)(mu(3)-Se)(8)(PEt(3))(4)I(2)] with the [Re(6)(mu(3)-Se)(8)](2+) core with CO in the presence of AgSbF(6) afforded the corresponding cluster carbonyls [Re(6)(mu(3)-Se)(8)(PEt(3))(5)(CO)][SbF(6)](2) (), trans-[Re(6)(mu(3)-Se)(8)(PEt(3))(4)(CO)(2)][SbF(6)](2) (), and cis-[Re(6)(mu(3)-Se)(8)(PEt(3))(4)(CO)(2)][SbF(6)](2) (). Infrared spectroscopy indicated weakening of the bond in CO, suggesting the existence of backbonding between the cluster core and the CO ligand(s). Electrochemical studies focusing on the reversible, one-electron oxidation of the cluster core revealed a large increase in the oxidation potential upon going from the acetonitrile derivatives to their carbonyl analogs, consistent with the depleted electron density of the cluster core upon CO ligation. Disparities between the IR spectra and oxidation potential between and indicate that electronic differences exist between sites trans and cis to the location of a ligand of interest. The active role played by the Se atoms in influencing the cluster-to-CO bonding interactions is suggested through this result and density functional (DF) computational analysis. The computations indicate that molecular orbitals near the HOMO account for backbonding interactions with a high percentage of participation of Se orbitals.


The analysis of regional patterns in health data. I. Distributional considerations.
Regional patterns of health data such as cancer incidence rates are often examined for evidence of environmental effects. In this paper, three measures of spatial clustering are evaluated for use with epidemiologic data. In particular, the effects of variation in regional population structure on the distribution of these measures is considered. It is shown that substantial bias occurs if variation in regional population size is ignored (as has occurred in previous analyses). On the other hand, the methods are robust to small case frequencies and to variation in the regional age distribution. It is recommended that these regional differences be routinely taken into account, which can be done with relatively little additional computation. A companion paper (Walter SD. The analysis of regional patterns in health data. II. The power to detect environmental effects.


Extendable blocking probe in reverse transcription for analysis of RNA variants with superior selectivity.
Here we provide the first strategy to use a competitive Extendable Blocking Probe (ExBP) for allele-specific priming with superior selectivity at the stage of reverse transcription. In order to analyze highly similar RNA variants, a reverse-transcriptase primer whose sequence matches a specific variant selectively primes only that variant, whereas mismatch priming to the alternative variant is suppressed by virtue of hybridization and subsequent extension of the perfectly matched ExBP on that alternative variant template to form a cDNA-RNA hybrid. This hybrid will render the alternative RNA template unavailable for mismatch priming initiated by the specific primer in a hot-start protocol of reverse transcription when the temperature decreases to a level where such mismatch priming could occur. The ExBP-based reverse transcription assay detected BRAF and KRAS mutations in at least 1000-fold excess of wild-type RNA and detection was linear over a 4-log dynamic range. This novel strategy not only reveals the presence or absence of rare mutations with an exceptionally high selectivity, but also provides a convenient tool for accurate determination of RNA variants in different settings, such as quantification of allele-specific expression.


Epigenetic regulation of muscle development.
In eukaryote cells, chromatin appears in several forms and is composed of genomic DNA, protein and RNA. The protein content of chromatin is composed primarily of core histones that are packaged into nucleosomes resulting in the condensation of the DNA. Several epigenetic mechanisms regulate the stability of the nucleosomes and the protein-protein interactions that modify the transcriptional activity of the DNA. Interestingly, epigenetic control of gene expression has recently emerged as a relevant mechanism involved in the regulation of many different biological processes including that of muscle development, muscle mass maintenance, function, and phenotype in health and disease. Recent investigations have shed light into the epigenetic control of biological mechanisms that are key regulators of embryonic muscle development and postnatal myogenesis. In the present review article, we provide a summary of the contents discussed in session 08, titled "Epigenetics of muscle regeneration", during the course of the 45th European Muscle Conference, which was celebrated in Montpellier (France) in September 2016. The main theme of that session was to highlight the most recent progress on the role of epigenetics in the regulation of muscle development and regeneration. The current mini-review has been divided into two major sections. On the one hand, a brief introduction on the topic of myogenesis is offered for the non-specialized reader. On the other, a brief overview of the most relevant epigenetic players that have been shown to control muscle development and regeneration is given.


The complex between simian virus 40 T antigen and a specific host protein.
The small DNA tumour virus simian virus 40 (SV40) expresses only two proteins in the cells that it has transformed, large-T and small-t. Large-T has an apparent molecular mass of 94 000 and genetic evidence indicates that it is necessary both for the induction and maintenance of the transformed state. In the lytic cycle of the virus the large-T protein acts to initiate viral DNA replication and appears to regulatea its own transcription. These properties imply that the protein must interact with existing host cell mechanisms in a specific way and that an understanding of these interactions may be important in discovering how the protein acts in 'transforming' non-permissive cells. To identify these interaction structures in the host cell an immunochemical approach has been adopted, and has shown that a fraction of the large-T protein in transformed cells exists in a specific complex with a host-coded phosphoprotein. The host protein has an apparent molecular mass of 53 000. The physiological role of this host protein-T antigen complex has been examined by studying the nature of the complex in a wide variety of different SV40 transformed cell lines. Although in SV40-transformed cells of rodent origin all the host protein present in the cell is complexed to large-T, it was found that in human cells transformed by SV40 only a fraction of the host protein is present in a complex and these cells contain large-T and the host protein in both the free and the complexed state. In SV40-transformed mouse cells that have been selected for loss of the transformed phenotype the complex was still present and in apparently normal amounts. This would indicate that no simple causal relation exists between the presence of the complex and the phenotype of the cell containing it.


Geometric isomerization of doxepin during its N-demethylation in humans.
The N-demethylation of the individual Z-(cis) and E-(trans) isomers of the tricyclic antidepressant doxepin was studied by examining the 0-8 hr serum concentration-time and the 0-72 hr urinary excretion profiles of parent drug and metabolite in eight healthy males who had received a single oral dose consisting of 25 mg each of Z-[2H0]- and E-[2H4]-labeled drug as the hydrochloride salt. Interconversion of doxepin's isomers was not observed but stereoselective excretion was present. Significant amounts of Z-N-desmethyldoxepin were formed and excreted after dosing with E-doxepin, the urinary Z/E ratio ranging from 0.08 to 3.06. A small amount of nondeuterated E-N-desmethyldoxepin was formed from Z-doxepin in most, but not all, subjects. These findings indicate that isomerization occurs during the N-demethylation of doxepin, possibly involving the formation of an intermediate in which the exocyclic double bond is hydrated and then subseqently dehydrated. This novel biotransformation process accounts for the observation that the Z/E plasma concentration ratio of N-desmethyldoxepin is often greater than that of the administered doxepin in patients receiving the drug therapeutically.


Effect of sperm DNA fragmentation on the clinical outcomes for in vitro fertilization and intracytoplasmic sperm injection in women with different ovarian reserves.
To investigate effect of sperm DNA fragmentation (SDF) on clinical outcomes of assisted reproductive technology in women with normal ovarian reserve (NOR) versus reduced ovarian reserve (ROR). Retrospective clinical study. University-affiliated tertiary teaching hospital. A total of 2,865 consecutive couples undergoing their first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle. SDF assessed using sperm chromatin dispersion in sperm samples 1-2 months before treatment. SDF, IVF, and ICSI outcomes. The grouping criteria were [1] basal follicle stimulating hormone >10 IU/L, [2] antral follicle count <6, and [3] female age ≥38 years. Women fulfilling two of the three criteria were considered to have ROR, and those not meeting any criteria were considered to have NOR. The area under the receiver operating characteristic curve was 0.594 (0.539-0.648) for the ROR group and 0.510 (0.491-0.530) for the NOR group. A cutoff value for SDF to predict the clinical pregnancy rate (CPR) in the ROR group was 27.3%. When the SDF exceeded 27.3%, the live-birth and implantation rates in the ROR group were statistically significantly decreased, but the clinical pregnancy, live-birth, and implantation rates were not affected in the NOR group. The risk of early abortion increased significantly in the NOR group when the SDF exceeded 27.3%. Sperm DNA fragmentation has a greater impact on IVF and ICSI outcomes among women with ROR, so SDF testing may be of particular clinical significance for these couples.


Higher urine 1-hydroxy pyrene glucuronide (1-OHPG) is associated with tobacco smoke exposure and drinking maté in healthy subjects from Rio Grande do Sul, Brazil.
The highest rates of esophageal squamous cell carcinoma (ESCC) in Brazil occur in Rio Grande do Sul, the most southern state, which has incidence rates of 20.4/100,000/year for men and 6.5/100,000/year for women. Exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs) through tobacco smoke and other sources may increase the risk of ESCC. The aims of the current study were to investigate the degree and sources of PAH exposure of the inhabitants of this region of southern Brazil. Two hundred healthy adults (half smokers, half non smokers, half male and half female) were recruited, given a standardized questionnaire, and asked to provide a urine sample for measurement of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite). Urine 1-OHPG concentrations were measured using immunoaffinity chromatography and synchronous fluorescence spectroscopy and urine cotinine was measured using a dipstick test. We examined factors associated with 1-OHPG concentration using Wilcoxon tests and multiple linear regression. Urine 1-hydroxypyrene glucuronide (1-OHPG) was successfully measured on 199 subjects. The median (interquartile range) of urine 1-OHPG in the 199 participants was 2.09 pmol/mL (0.51, 5.84). Tobacco smoke exposure and maté drinking were statistically significantly associated with higher urine 1-OHPG concentrations in the multivariate linear regression model. Tobacco smoke and maté both contribute to high levels of benzo[a]pyrene exposure in the people of southern Brazil. This high PAH exposure may contribute to the high rates of ESCC observed in this population. The increased urine 1-OHPG concentrations associated with maté suggest that contaminants, not just thermal injury, may help explain the increased risk of ESCC previously reported for maté consumption.


[Foot-and-mouth disease and its differential diagnoses].
Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals, which leads to the formation of vesicles, erosions und ulcerations in the mouth and hairless parts of the skin, in particular on the feet. Due to its dramatic economic consequences, FMD is considered to be one of the most important diseases of animals. There is a permanent risk of introduction of the virus into Europe due to travel and illegal importation of agricultural products. Cloven-hoofed animals (cattle, sheep, goats, pigs and related game animals) are the typical hosts of the FMD virus. However, some zoo and wild animals belonging to other taxonomical groups, such as giraffes, elephants and camels, are also susceptible. Stomatitis and infections of the feet in livestock occur quite frequently, and often the causes of these conditions remain obscure. Sometimes, a differentiation from FMD is not possible on the basis of clinical signs and gross lesions, necessitating further laboratory investigations. This applies in particular to cases caused by the agents of vesicular stomatitis (VS) and swine vesicular disease (SVD). Additionally, other infectious agents can cause stomatitis, e.g. the viruses of mucosal disease (MD), malignant catarrhal fever (MCF), rinderpest, peste des petits ruminants (PPR), papular stomatitis, orf, blue tongue (BT) and epizootic haemorrhagic disease (EHD). In sheep, a stomatitis of unclear etiology was described as "OMAGOD". Furthermore, bacteria, chemicals and mechanical trauma can cause stomatitis and pododermatitis.


Beetroot juice versus chard gel: A pharmacokinetic and pharmacodynamic comparison of nitrate bioavailability.
Dietary supplementation with inorganic nitrate (NO3-) has been shown to induce a multitude of advantageous cardiovascular and metabolic responses during rest and exercise. While there is some suggestion that pharmacokinetics may differ depending on the NO3- source ingested, to the best of our knowledge this has yet to be determined experimentally. Here, we compare the plasma pharmacokinetics of NO3-, nitrite (NO2-), and total nitroso species (RXNO) following oral ingestion of either NO3- rich beetroot juice (BR) or chard gels (GEL) with the associated changes in blood pressure (BP). Repeated samples of venous blood and measurements of BP were collected from nine healthy human volunteers before and after ingestion of the supplements using a cross-over design. Plasma concentrations of RXNO and NO2- were quantified using reductive gas-phase chemiluminescence and NO3- using high pressure liquid ion chromatography. We report that, [NO3-] and [NO2-] were increased and systolic BP reduced to a similar extent in each experimental arm, with considerable inter-individual variation. Intriguingly, there was a greater increase in [RXNO] following ingestion of BR in comparison to GEL, which may be a consequence of its higher polyphenol content. In conclusion, our data suggests that while differences in circulating NO2- and NO3- concentrations after oral administration of distinct NO3--rich supplementation sources are moderate, concentrations of metabolic by-products may show greater-than-expected variability; the significance of the latter observation for the biological effects under study remains to be investigated.


Hypertension with diabetes mellitus complications.
Chronic diabetic complications are classified as microvascular or macrovascular and contribute to mortality and loss of quality of life. Hyperglycemia plays a critical role in the pathogenesis of microvascular complications, such as diabetic retinopathy, incipient nephropathy, and neuropathy, while atherosclerosis contributes to the pathogenesis of macrovascular complications. Diabetes mellitus and hypertension are frequently present together. Among many microvascular diabetic complications, hypertension plays a predominant role in the progression of diabetic nephropathy by glomerular hyperfiltration. Hypertension also induces atherosclerosis in diabetes. Thus, hypertension is a high-risk factor for both microvascular and macrovascular chronic diabetic complications. In this review, we summarize the current knowledge on the pathophysiological mechanisms of microvascular and macrovascular chronic diabetic complications with particular emphasis on the contribution of hypertension. We also briefly discuss various options available for the treatment of each diabetic complication.


Nonparametric Transfer Function Models.
In this paper a class of nonparametric transfer function models is proposed to model nonlinear relationships between 'input' and 'output' time series. The transfer function is smooth with unknown functional forms, and the noise is assumed to be a stationary autoregressive-moving average (ARMA) process. The nonparametric transfer function is estimated jointly with the ARMA parameters. By modeling the correlation in the noise, the transfer function can be estimated more efficiently. The parsimonious ARMA structure improves the estimation efficiency in finite samples. The asymptotic properties of the estimators are investigated. The finite-sample properties are illustrated through simulations and one empirical example.


Prevention of dystrophic pathology in severely affected dystrophin/utrophin-deficient mice by morpholino-oligomer-mediated exon-skipping.
Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional protein. Antisense-mediated exon-skipping is one of the most promising approaches for the treatment of DMD because of its capacity to correct the reading frame and restore dystrophin expression, which has been demonstrated in vitro and in vivo. In particular, peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) have recently been shown to induce widespread high levels of dystrophin expression in the mdx mouse model. Here, we report the efficiency of the PPMO-mediated exon-skipping approach in the utrophin/dystrophin double-knockout mouse (dKO) mouse, which is a much more severe and progressive mouse model of DMD. Repeated intraperitoneal (i.p.) injections of a PPMO targeted to exon 23 of dystrophin pre-mRNA in dKO mice induce a near-normal level of dystrophin expression in all muscles examined, except for the cardiac muscle, resulting in a considerable improvement of their muscle function and dystrophic pathology. These findings suggest great potential for PPMOs in systemic treatment of the DMD phenotype.


Excited-State Dynamics in Borylated Arylisoquinoline Complexes in Solution and in cellulo.
Two four-coordinate organoboron N,C-chelate complexes with different functional terminals on the PEG chains are studied with respect to their photophysical properties within human MCF-7 cells. Their excited-state properties are characterized by time-resolved pump-probe spectroscopy and fluorescence lifetime microscopy. The excited-state relaxation dynamics of the two complexes are similar when studied in DMSO. Aggregation of the complexes with the carboxylate terminal group is observed in water. When studying the light-driven excited-state dynamics of both complexes in cellulo, i. e., after being taken up into human MCF-7 cells, both complexes show different features depending on the nature of the anchoring PEG chains. The lifetime of a characteristic intramolecular charge-transfer state is significantly shorter when studied in cellulo (360±170 ps) as compared to in DMSO (∼960 ps) at 600 nm for the complexes with an amino group. However, the kinetics of the complexes with the carboxylate group are in line with those recorded in DMSO. On the other hand, the lifetimes of the fluorescent state are almost identical for both complexes in cellulo. These findings underline the importance to evaluate the excited-state properties of fluorophores in a complex biological environment in order to fully account for intra- and intermolecular effects governing the light-induced processes in functional dyes.


Fibro-adipose vascular anomaly (FAVA): three case reports with an emphasis on the mammalian target of rapamycin (mTOR) pathway.
Fibro-adipose vascular anomaly (FAVA) is a new entity of vascular anomalies with somatic and mosaic gain-of-function mutations of the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). PIK3CA mutation excessively activates mammalian target of rapamycin (mTOR) pathway, which promotes angiogenesis and lymphangiogenesis. Histologically, FAVA is composed of intramuscular fibrous and adipose tissues with venous malformation (VM). Although sirolimus known as a mTOR inhibitor has good response to FAVA, expression pattern of the mTOR pathway was still unclear. Herein, we immunohistochemically investigated three novel FAVA patients with an emphasis on the mTOR pathway (p-S6K1, p-4EBP1 and p-AKT). Case 1: A 10-year-old female had complained of pain in the left thigh since she was 6-year-old. Under the clinical diagnosis of VM, she underwent surgical resection for the lesion. Case 2: A 29-year-old female patient had complained of discomfort and mild pain in the left shoulder since she was 18-year-old. After childbirth, she had severe ongoing pain and contracture of the shoulder. Under clinical diagnosis of VM, surgical resection was performed. Case 3: A 53-year-old female had complained of pain and knee restriction after surgical treatment of a knee tumor at the age of 31. Under the clinical diagnosis of atypical lipomatous tumor or high grade liposarcoma, surgical resection was performed. Histologically, all three patients presented with characteristic features of fibrous and adipose tissues with abnormal vessels within the skeletal muscle, leading to diagnosis of FAVA. Although VM has been reported as an important finding in FAVA, immunohistological findings demonstrated that abnormal vessels comprised complex of VM and lymphatic malformation (LM) in all cases. Furthermore, besides vascular malformation, abnormal fibrous and adipose tissues of FAVA expressed mTOR pathway components. We presented three new cases of FAVA. Histological and immunohistochemical analyses revealed that VM and LM complex was an important finding in FAVA, and that the mTOR pathway components were expressed in abnormal fibrous tissue, adipose tissue and vascular malformation. These findings suggested that FAVA might be a mesenchymal malformation caused by PI3K/AKT/mTOR pathway.


Disentangling scene content from spatial boundary: complementary roles for the parahippocampal place area and lateral occipital complex in representing real-world scenes.
Behavioral and computational studies suggest that visual scene analysis rapidly produces a rich description of both the objects and the spatial layout of surfaces in a scene. However, there is still a large gap in our understanding of how the human brain accomplishes these diverse functions of scene understanding. Here we probe the nature of real-world scene representations using multivoxel functional magnetic resonance imaging pattern analysis. We show that natural scenes are analyzed in a distributed and complementary manner by the parahippocampal place area (PPA) and the lateral occipital complex (LOC) in particular, as well as other regions in the ventral stream. Specifically, we study the classification performance of different scene-selective regions using images that vary in spatial boundary and naturalness content. We discover that, whereas both the PPA and LOC can accurately classify scenes, they make different errors: the PPA more often confuses scenes that have the same spatial boundaries, whereas the LOC more often confuses scenes that have the same content. By demonstrating that visual scene analysis recruits distinct and complementary high-level representations, our results testify to distinct neural pathways for representing the spatial boundaries and content of a visual scene.


Engineering anisotropic cardiac monolayers on microelectrode arrays for non-invasive analyses of electrophysiological properties.
A standard culture of cardiac cells as unorganized monolayers on tissue culture plastic or glass does not recapitulate the architectural or the mechanical properties of native myocardium. We investigated the physical and protein cues from the extracellular matrix to engineer anisotropic cardiac tissues as highly aligned monolayers on top of the microelectrode array (MEA). The MEA platform allows non-invasive measurement of beating rate and conduction velocity. The effect of different extracellular proteins was tested by using the most common extracellular matrix proteins in the heart, fibronectin and gelatin, after aligning myocytes using a microcontact (μC) printing technique. Both proteins showed similar electrophysiological results before the monolayer began to delaminate after the sixth day of culture. Additionally, there were no significant differences on day 4 between the two microcontact printed proteins in terms of sarcomere alignment and gap junction expression. To test the effect of substrate stiffness, a micromolded (μM) gelatin hydrogel was fabricated in different concentrations (20% and 2%), corresponding to the elastic moduli of approximately 33 kPa and 0.7 kPa, respectively, to cover both spectra of the in vivo range of myocardium. Cardiac monolayers under micromolded conditions beat in a much more synchronized fashion, and exhibited conduction velocity that was close to the physiological value. Both concentrations of gelatin hydrogel conditions yielded similar sarcomere alignment and gap junction expression on day 4 of culture. Ultimately, the 3D micromolded gelatin hydrogel that recapitulated myocardial stiffness improved the synchronicity and conduction velocity of neonatal rat ventricular myocytes (NRVM) without any stimulation. Identifying such microenvironmental factors will lead to future efforts to design heart on a chip platforms that mimic in vivo environment and predict potential cardiotoxicity when testing new drugs.


Passive music listening spontaneously engages limbic and paralimbic systems.
In this PET study, non-musicians passively listened to unfamiliar instrumental music revealed afterward to elicit strongly pleasant feelings. Activations were observed in the subcallosal cingulate gyrus, prefrontal anterior cingulate, retrosplenial cortex, hippocampus, anterior insula, and nucleus accumbens. This is the first observation of spontaneous responses in such limbic and paralimbic areas during passive listening to unfamiliar although liked music. Activations were also seen in primary auditory, secondary auditory, and temporal polar areas known to respond to music. Our findings complement neuroimaging studies of aesthetic responses to music that have used stimuli selected by subjects or designed by experimenters. The observed pattern of activity is discussed in terms of a model synthesizing emotional and cognitive responses to music.


Harnessing subcellular-resolved organ distribution of cationic copolymer-functionalized fluorescent nanodiamonds for optimal delivery of active siRNA to a xenografted tumor in mice.
Diamond nanoparticles (nanodiamonds) can transport active drugs in cultured cells as well as in vivo. However, in the latter case, methods allowing the determination of their bioavailability accurately are still lacking. A nanodiamond can be made fluorescent with a perfectly stable emission and a lifetime ten times longer than that of tissue autofluorescence. Taking advantage of these properties, we present an automated quantification method of fluorescent nanodiamonds (FND) in histological sections of mouse organs and tumors, after systemic injection. We use a home-made time-delayed fluorescence microscope comprising a custom pulsed laser source synchronized on the master clock of a gated intensified array detector. This setup allows ultra-high-resolution images (120 Mpixels in size) of whole mouse organ sections to be obtained, with subcellular resolution and single-particle sensitivity. As a proof-of-principle experiment, we quantified the biodistribution and aggregation state of new cationic FNDs capable of transporting small interfering RNA inhibiting the oncogene responsible for Ewing sarcoma. Image analysis showed a low yield of nanodiamonds in the tumor after intravenous injection. Thus, for the in vivo efficacy assay, we injected the nanomedicine into the tumor. We achieved a 28-fold inhibition of the oncogene. This method can readily be applied to other nanoemitters with ≈100 ns lifetime.


CA 125: the past and the future.
Over the last 15 years, substantial progress has been made in understanding the potential and the limitations of the CA 125 assay. More than 2000 papers have been published concerning laboratory and clinical studies of CA 125. The original CA 125 assay utilized the OC 125 antibody that recognizes the CA 125 epitope on a high molecular weight glycoprotein. Despite repeated attempts, the gene encoding the peptide component has not yet been cloned. Monoclonal antibodies have been raised against other epitopes expressed by this molecule, leading to the development of the CA 125-II assay that exhibits less day-to-day variation. Using either assay, elevated levels of CA 125 are detected in a number of benign conditions, including endometriosis. CA 125 is most consistently elevated in epithelial ovarian cancer, but can be expressed in a number of gynecologic (endometrial, fallopian tube) and non-gynecologic (pancreatic, breast, colon and lung) cancers. The best established application of the CA 125 assay is in monitoring ovarian cancer. The rate of decline in CA 125 during primary chemotherapy has been an important independent prognostic factor in several multivariate analyses. Persistent elevation of CA 125 at the time of a second look surgical surveillance procedure predicts residual disease with > 95% specificity. Rising CA 125 values have preceded clinical detection of recurrent disease by at least 3 months in most, but not all studies. Given the modest activity of salvage chemotherapy, this information has not yet impacted on survival. Rising CA 125 during subsequent chemotherapy has been associated with progressive disease in more than 90% of cases. CA 125 may serve as an effective surrogate marker for clinical response in phase II trials of new drugs. CA 125 levels can aid in distinguishing malignant from benign pelvic masses, permitting effective triage of patients for primary surgery. Early detection of ovarian cancer remains the most promising application of CA 125. An algorithm has been developed that estimates the risk of ovarian cancer (ROC) based upon the level and trend of CA 125 values. A major trial has been initiated that uses the ROC algorithm to trigger transvaginal sonography and/or subsequent laparotomy. Such a trial could demonstrate improvement in survival through early detection. This strategy should provide adequate specificity, but sensitivity for early stage disease may not be optimal. In the future, improved sensitivity may be attained using multiple markers and neural network analysis. Most serum tumor markers have been proteins or carbohydrates, but lipid markers such as lysophosphatidic acid deserve evaluation. Genomic and proteonomic technologies should identify additional novel markers.


Antibody-based proteomics for discovery and exploration of proteins expressed in pancreatic islets.
Abnormal glucose tolerance and deviant blood glucose levels are late stage clinical parameters that signify diabetes mellitus. To be able to diagnose the disease at an earlier stage and develop new tools for beta cell imaging, new molecular markers are needed. In the present study, five proteins highly expressed in pancreatic islets with no expression in the surrounding exocrine glandular cells of pancreas, and one protein with the opposite expression pattern, were identified by searches in the Human Protein Atlas (www.proteinatlas.org). The proteins were analyzed immunohistochemically on a specially designed tissue microarray, containing isolated human islets and pancreatic tissues with different characteristics, and compared to the expression of previously known markers of endocrine and exocrine pancreatic cells. Of the five novel endocrine markers, tetraspanin-7 was identified as a membrane-bound protein with exclusive positivity in islet cells. Also beta-2-microglobulin and ubiquitin carboxyl-terminal hydrolase isozyme L1 were expressed in a majority of islet cells, whereas sad1/unc-84 domain-containing protein 1 and beta-1,3-glucuronyltransferase 1 were positive in a smaller subset of islet cells. The potential exocrine marker galectin-2 was expressed in both exocrine acinary cells and pancreatic ductal cells, with no or low positivity in islet cells. In conclusion, antibody-based proteomics and specially designed tissue microarrays enable identification and exploration of novel proteins with differential expression in pancreatic islets. Here we describe 5 candidate proteins for further investigation of their physiological role and potential involvement in the pathogenesis of diabetes. One of these proteins, tetraspanin-7, is expressed on the cell membrane and could thus be a potential candidate for future development of tracers for beta cell imaging.


Enterococcus faecalis hemolysin-bacteriocin plasmids belong to the same incompatibility group.
Plasmid pair coexistence was studied both among nine Enterococcus faecalis hemolysin-bacteriocin (Hly-Bcn) plasmids, including pJH2, pAD1, pAM gamma 1, and pIP964, and between pIP964 and five R plasmids. Some of the Hly-Bcn plasmids used were derivatives encoding resistance to erythromycin or tetracycline. The Hly-Bcn plasmids were incompatible with each other; 40 to 100% displacement was observed bilaterally for eight pairs and unilaterally for one pair. In contrast, pIP964 stably coexisted with each of the R plasmids. Entry exclusion was associated with incompatibility for most of the Hly-Bcn plasmids. The nine Hly-Bcn plasmids harbored by E. faecalis form a distinct incompatibility (Inc) group, designated IncHly.


Assessing the recovery of an Antarctic predator from historical exploitation.
The recovery of whale populations from centuries of exploitation will have important management and ecological implications due to greater exposure to anthropogenic activities and increasing prey consumption. Here, a Bayesian population model integrates catch data, estimates of abundance, and information on genetics and biology to assess the recovery of western South Atlantic (WSA) humpback whales (Megaptera novaeangliae). Modelling scenarios evaluated the sensitivity of model outputs resulting from the use of different data, different model assumptions and uncertainty in catch allocation and in accounting for whales killed but not landed. A long period of exploitation drove WSA humpback whales to the brink of extinction. They declined from nearly 27 000 (95% PI = 22 800-33 000) individuals in 1830 to only 450 (95% PI = 200-1400) whales in the mid-1950s. Protection led to a strong recovery and the current population is estimated to be at 93% (95% PI = 73-100%) of its pre-exploitation size. The recovery of WSA humpback whales may result in large removals of their primary prey, the Antarctic krill (Euphausia superba), and has the potential to modify the community structure in their feeding grounds. Continued monitoring is needed to understand how these whales will respond to modern threats and to climate-driven changes to their habitats.


Band Structure of Wurtzite GaBiAs Nanowires.
We report on the first successful growth of wurtzite (WZ) GaBiAs nanowires (NWs) and reveal the effects of Bi incorporation on the electronic band structure by using polarization-resolved optical spectroscopies performed on individual NWs. Experimental evidence of a decrease in the band-gap energy and an upward shift of the topmost three valence subbands upon the incorporation of Bi atoms is provided, whereas the symmetry and ordering of the valence band states remain unchanged, that is, Γ9, Γ7, and Γ7 within the current range of Bi compositions. The extraordinary valence band structure of WZ GaBiAs NWs is explained by anisotropic hybridization and anticrossing between p-like Bi states and the extended valence band states of host WZ GaAs. Moreover, the incorporation of Bi into GaAs is found to significantly reduce the temperature sensitivity of the band-gap energy in WZ GaBiAs NWs. Our work therefore demonstrates that utilizing dilute bismide alloys provides new avenues for band-gap engineering and thus photonic engineering with NWs.


OLEDs as models for bird magnetoception: detecting electron spin resonance in geomagnetic fields.
Certain species of living creatures are known to orientate themselves in the geomagnetic field. Given the small magnitude of approximately 48 μT, the underlying quantum mechanical phenomena are expected to exhibit coherence times in the microsecond regime. In this contribution, we show the sensitivity of organic light-emitting diodes (OLEDs) to magnetic fields far below Earth's magnetic field, suggesting that coherence times of the spins of charge-carrier pairs in these devices can be similarly long. By electron paramagnetic resonance (EPR) experiments, a lower bound for the coherence time can be assessed directly. Moreover, this technique offers the possibility to determine the distribution of hyperfine fields within the organic semiconductor layer. We extend this technique to a material system exhibiting both fluorescence and phosphorescence, demonstrating stable anticorrelation between optically detected magnetic resonance (ODMR) spectra in the singlet (fluorescence) and triplet (phosphorescence) channels. The experiments demonstrate the extreme sensitivity of OLEDs to both static as well as dynamic magnetic fields and suggest that coherent spin precession processes of coulombically bound electron-spin pairs may play a crucial role in the magnetoreceptive ability of living creatures.


Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication.
SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.


Graphical Overlays: Using Layered Elements to Aid Chart Reading.
Reading a visualization can involve a number of tasks such as extracting, comparing or aggregating numerical values. Yet, most of the charts that are published in newspapers, reports, books, and on the Web only support a subset of these tasks. In this paper we introduce graphical overlays-visual elements that are layered onto charts to facilitate a larger set of chart reading tasks. These overlays directly support the lower-level perceptual and cognitive processes that viewers must perform to read a chart. We identify five main types of overlays that support these processes; the overlays can provide (1) reference structures such as gridlines, (2) highlights such as outlines around important marks, (3) redundant encodings such as numerical data labels, (4) summary statistics such as the mean or max and (5) annotations such as descriptive text for context. We then present an automated system that applies user-chosen graphical overlays to existing chart bitmaps. Our approach is based on the insight that generating most of these graphical overlays only requires knowing the properties of the visual marks and axes that encode the data, but does not require access to the underlying data values. Thus, our system analyzes the chart bitmap to extract only the properties necessary to generate the desired overlay. We also discuss techniques for generating interactive overlays that provide additional controls to viewers. We demonstrate several examples of each overlay type for bar, pie and line charts.


Vagus Nerve Stimulation Paired With Rehabilitative Training Enhances Motor Recovery After Bilateral Spinal Cord Injury to Cervical Forelimb Motor Pools.
Closed-loop vagus nerve stimulation (VNS) paired with rehabilitative training has emerged as a strategy to enhance recovery after neurological injury. Previous studies demonstrate that brief bursts of closed-loop VNS paired with rehabilitative training substantially improve recovery of forelimb motor function in models of unilateral and bilateral contusive spinal cord injury (SCI) at spinal level C5/6. While these findings provide initial evidence of the utility of VNS for SCI, the injury model used in these studies spares the majority of alpha motor neurons originating in C7-T1 that innervate distal forelimb muscles. Because the clinical manifestation of SCI in many patients involves damage at these levels, it is important to define whether damage to the distal forelimb motor neuron pools limits VNS-dependent recovery. In this study, we assessed recovery of forelimb function in rats that received a bilateral incomplete contusive SCI at C7/8 and underwent extensive rehabilitative training with or without paired VNS. The study design, including planned sample size, assessments, and statistical comparisons, was preregistered prior to beginning data collection ( https://osf.io/ysvgf/ ). VNS paired with rehabilitative training significantly improved recovery of volitional forelimb strength compared to equivalent rehabilitative training without VNS. Additionally, VNS-dependent enhancement of recovery generalized to 2 similar, but untrained, forelimb tasks. These findings indicate that damage to alpha motor neurons does not prevent VNS-dependent enhancement of recovery and provides additional evidence to support the evaluation of closed-loop VNS paired with rehabilitation in patients with incomplete cervical SCI.


Cardioprotective roles of aged garlic extract, grape seed proanthocyanidin, and hazelnut on doxorubicin-induced cardiotoxicity.
Doxorubicin (DXR) is a chemotherapeutic agent used effectively in the treatment of several childhood malignancies. During treatment, cardiotoxicity caused by cell damage due to the free oxygen radicals that are generated is a major limiting factor. This study was undertaken to determine whether DXR-induced cardiotoxicity could be prevented by natural foods with antioxidant properties such as aged garlic extract (AGEX), grape seed proanthocyanidin (PA), and hazelnut. Wistar albino male rats were assigned randomly to 9 groups each consisting of 15 rats. AGEX, PA, and hazelnut groups received these antioxidants in addition to their standard rat diet. They were also treated with cumulative intraperitoneal (i.p.) injections according to 2 different regimens: either a high-dose of 15 mg/kg DXR (3.75 mg/kg per week for 4 weeks) or a low-dose of 7.5 mg/kg DXR (1.875 mg/kg per week for 4 weeks). The control group received i.p. 0.9% saline. AGEX, PA, or hazelnut supplements were given orally to the groups for a 6-week period starting 1 week before the DXR treatment and ending 1 week after the treatment. One week after the last DXR injection, heart tissue samples were analyzed to determine malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and xanthine oxidase (XO) levels, and serum samples were taken for creatine kinase (CK). There were no significant changes in MDA levels among the control, DXR-treated groups, or supplemented groups that received additional natural antioxidant foods. SOD enzyme levels were decreased in rats treated with DXR. PA prevented the decrease at low doses of DXR. DXR treatment decreased CAT enzyme levels, but additional PA and hazelnut consumption increased these levels at low cumulative doses. XO enzyme levels were decreased in AGEX and hazelnut groups, but PA prevented the decrease. CK levels were elevated after DXR administration, indicating myocardial injury, but PA significantly reversed this. Although there were no differences histopathologically between AGEX, PA, and hazelnut groups, the protective effects of AGEX and PA were evident in electron microscopy. In conclusion, the positive effects of natural antioxidant foods on the prevention of DXR-induced cardiac injury could not be clearly shown on the basis of antioxidant enzymes. However, the electron microscopic changes clearly demonstrated the protective effects of AGEX and PA. The supplementation of these antioxidant foods over longer periods may show more definitive results. Human studies with different doses are needed to evaluate the effects of these foods on the human heart.


Injection-induced earthquakes.
Earthquakes in unusual locations have become an important topic of discussion in both North America and Europe, owing to the concern that industrial activity could cause damaging earthquakes. It has long been understood that earthquakes can be induced by impoundment of reservoirs, surface and underground mining, withdrawal of fluids and gas from the subsurface, and injection of fluids into underground formations. Injection-induced earthquakes have, in particular, become a focus of discussion as the application of hydraulic fracturing to tight shale formations is enabling the production of oil and gas from previously unproductive formations. Earthquakes can be induced as part of the process to stimulate the production from tight shale formations, or by disposal of wastewater associated with stimulation and production. Here, I review recent seismic activity that may be associated with industrial activity, with a focus on the disposal of wastewater by injection in deep wells; assess the scientific understanding of induced earthquakes; and discuss the key scientific challenges to be met for assessing this hazard.


Inductive reasoning.
Inductive reasoning entails using existing knowledge or observations to make predictions about novel cases. We review recent findings in research on category-based induction as well as theoretical models of these results, including similarity-based models, connectionist networks, an account based on relevance theory, Bayesian models, and other mathematical models. A number of touchstone empirical phenomena that involve taxonomic similarity are described. We also examine phenomena involving more complex background knowledge about premises and conclusions of inductive arguments and the properties referenced. Earlier models are shown to give a good account of similarity-based phenomena but not knowledge-based phenomena. Recent models that aim to account for both similarity-based and knowledge-based phenomena are reviewed and evaluated. Among the most important new directions in induction research are a focus on induction with uncertain premise categories, the modeling of the relationship between inductive and deductive reasoning, and examination of the neural substrates of induction. A common theme in both the well-established and emerging lines of induction research is the need to develop well-articulated and empirically testable formal models of induction. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.


Investigating the impact of mindfulness meditation training on working memory: a mathematical modeling approach.
We investigated whether mindfulness training (MT) influences information processing in a working memory task with complex visual stimuli. Participants were tested before (T1) and after (T2) participation in an intensive one-month MT retreat, and their performance was compared with that of an age- and education-matched control group. Accuracy did not differ across groups at either time point. Response times were faster and significantly less variable in the MT versus the control group at T2. Since these results could be due to changes in mnemonic processes, speed-accuracy trade-off, or nondecisional factors (e.g., motor execution), we used a mathematical modeling approach to disentangle these factors. The EZ-diffusion model (Wagenmakers, van der Maas, & Grasman, Psychonomic Bulletin & Review 14:(1), 3-22, 2007) suggested that MT leads to improved information quality and reduced response conservativeness, with no changes in nondecisional factors. The noisy exemplar model further suggested that the increase in information quality reflected a decrease in encoding noise and not an increase in forgetting. Thus, mathematical modeling may help clarify the mechanisms by which MT produces salutary effects on performance.


Bioremediation of cadmium-contaminated water systems using intact and alkaline-treated alga (Hydrodictyon reticulatum) naturally grown in an ecosystem.
Cadmium can enter water, soil, and food chain in amounts harmful to human health by industrial wastes. The use of intact and NaOH-treated dried algal tissues (Hydrodictyon reticulatum), a major ecosystem bio-component, for Cd removal from aqueous solutions was characterized. Cadmium biosorption was found to be dependent on solution pH, bioadsorbent dose, the interaction between pH and dose, contact time, and initial Cd concentration. The experimental results indicated that the biosorption performance of alkaline-treated algal tissues was better than that of intact tissues. The maximum biosorption capacities were 7.40 and 12.74 mg g-1 for intact and alkaline-treated bioadsorbents, respectively, at optimum operating conditions. Biosorption reaches equilibrium after 24 and 240 minutes of contact, respectively, for alkaline-treated and intact bioadsorbents. Cadmium biosorption was best fitted to Langmuir isotherm model (R2 ≈ 0.99) and the kinetic study obeyed the pseudo-second-order kinetic model, which suggests chemisorption as the rate-limiting step in the biosorption process. Alkaline-treated algal tissues can be used as a new material of low-cost bioadsorbent for continuous flow rate treatment systems.


Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats.
Heroin and oxycodone abuse occurs over a wide range of drug doses and by various routes of administration characterized by differing rates of drug absorption. The current study addressed the efficacy of a heroin vaccine [morphine hapten conjugated to keyhole limpet hemocyanin (M-KLH)] or oxycodone vaccine [oxycodone hapten conjugated to keyhole limpet hemocyanin (OXY-KLH)] for reducing drug distribution to brain after intravenous heroin or oxycodone, or subcutaneous oxycodone. Rats immunized with M-KLH or keyhole limpet hemocyanin (KLH) control received an intravenous bolus dose of 0.26 or 2.6 mg/kg heroin. Vaccination with M-KLH increased retention of heroin and its active metabolites 6-acetylmorphine (6-AM) and morphine in plasma compared with KLH controls, and reduced total opioid (heroin + 6-AM + morphine) distribution to brain but only at the lower heroin dose. Immunization also protected against respiratory depression at the lower heroin dose. Rats immunized with OXY-KLH or KLH control received 0.22 or 2.2 mg/kg oxycodone intravenously, the molar equivalent of the heroin doses. Immunization with OXY-KLH significantly reduced oxycodone distribution to brain after either oxycodone dose, although the magnitude of effect of immunization at the higher oxycodone dose was small (12%). By contrast, vaccination with OXY-KLH was more effective when oxycodone was administered subcutaneously rather than intravenously, reducing oxycodone distribution to brain by 44% after an oxycodone dose of 2.3 mg/kg. Vaccination also reduced oxycodone-induced antinociception. These data suggest that the efficacy of OXY-KLH and M-KLH opioid vaccines is highly dependent upon opioid dose and route of administration.


A novel three-dimensional culture system for isolation and clonal propagation of neural stem cells using a thermo-reversible gelation polymer.
In the present study, we examined the possible utility of a three-dimensional culture system using a thermo-reversible gelation polymer to isolate and expand neural stem cells (NSCs). The polymer is a synthetic biologically inert polymer and gelates at temperatures higher than the gel-sol transition point ( approximately 20 degrees C). When fetal mouse brain cells were inoculated into the gel, spherical colonies were formed ( approximately 1% in primary culture and approximately 9% in passage cultures). The spheroid-forming cells were positive for expression of the NSC markers nestin and Musashi. Under conditions facilitating spontaneous neural differentiation, the spheroid-forming cells expressed genes characteristic to astrocytes, oligodendrocytes, and neurons. The cells could be successively propagated at least to 80 poly-D-lysines over a period of 20 weeks in the gel culture with a growth rate higher than that observed in suspension culture. The spheroids formed by fetal mouse brain cells in the gel were shown to be of clonal origin. These results indicate that the spheroid culture system is a convenient and powerful tool for isolation and clonal expansion of NSCs in vitro.


Autism following a history of newborn encephalopathy: more than a coincidence?
Between June 1993 and December 1996, 276 term newborn infants with encephalopathy and 564 randomly selected term controls were enrolled in a population-based study of moderate and severe term newborn encephalopathy (NE) in Western Australia. During comprehensive neurobehavioural and cognitive follow-up of all patients and controls at 3 years and again at 5 years of age we found an unexpected but strong association between NE and autism spectrum disorders (ASDs). A diagnosis of ASD by age 5 years was reached using criteria according of the Diagnostic Statistical Manual, 4th edition. Linking records to the Western Australian Disability Services Commission Register ensured that no child in the study with ASD was missed. By age 5 years, 37 (13.4%) infants with NE and one (0.2%) control had died. Among the 239 survivors of NE, 12 (5%) were diagnosed with an ASD. Of these, 10 (4.2%) met the full criteria for autism, one had pervasive developmental disorder-not otherwise specified, and one had Asperger syndrome. Among the 563 surviving controls, five (0.8%) were diagnosed with an ASD: three with autism, one with autism/possible Asperger syndrome, and one with Asperger syndrome. Compared with the controls, the children who had experienced NE were 5.9 times (95% confidence interval 2.0-16.9) more likely to have been diagnosed with an ASD.


General Assessment of Humoral Activity in Healthy Humans.
The humoral immune system is network of biological molecules designed to maintain a healthy homeostatic equilibrium. Because antibodies are an abundant and highly specific effector of immunological action, they are also an important reservoir of previous host exposures. Antibodies may play a major role in early detection of host challenge. Unfortunately, few practical methods exist for interpreting the information stored in antibody variable regions. Immunosignatures use a microarray of thousands of random sequence peptides to interrogate antibodies in a broad and unbiased fashion. The pattern of binding between antibody and peptide is reproducible. Once the system has been trained on a disease cohort, blinded samples can be reliably predicted. Although immunosignatures of both chronic and infectious disease have been extensively tested, less has been done to demonstrate how healthy immunosignatures change over time or between individuals. Here, we report the results of a study of immunosignatures of healthy persons over brief (12 h sampled once per hour), intermediate (32 days sampled once per day), and long (5 years sampled once every year) time spans. Using this information, we were also able to detect intentional and unintentional immunological perturbations in the form of a vaccine and an infection, respectively. Our findings suggest that, even with the variability inherent in healthy immunosignatures, a single person's immunosignature will remain constant over time. Over this healthy signature, vaccines and infections create subsignatures that are common across multiple people, even subsuming healthy fluctuations. These findings have implications for disease monitoring and early diagnosis.


[Use of immunocytochemical assays in the study of exudates from serous cavities in the practical work of a laboratory].
The clinical introduction of new methods for processing fluid samples and the application of supplementary methods for improving the diagnostic accuracy of the pattern of pleurisy is very important for differential diagnosis. The possibilities of using immunocytochemical assay in the practical work of a clinical diagnostic (cytological) laboratory were studied in 96 patients, including 78 and 18 patients with pleural and ascitic fluids, respectively). A Cytospin-IV centrifuge was used for immunocytochemical assay by the routine procedure. The Streptadivin-biotin LSAB2 and EnVision+ test systems were employed to visualize an antigen/antibody reaction. Diaminobenzidine (DAB) was used as a chromogen. A set of markers, comprising 11 antibodies, was applied to the verification of a neoplasm from serous cavities. Mesothelioma was diagnosed in 65 patients. Epithelial mesothelioma was identified in 62 (95.4%) cases. Mesothelioma cells were positive to vimentin and ceratins, calretinin, mesothelin, and thrombomodulin. In 31 cases, adenogenic carcinoma metastases to the serous cavities were typified by an immunopositive reaction to CEA, Ber-EP4, EMA, and cytokeratins and a negative reaction to calretinin, mesothelin, and thrombomodulin. There was occasionally a positive reaction to CD-15 and vimentin.


Diversity of Active Viral Infections within the Sphagnum Microbiome.
Sphagnum-dominated peatlands play an important role in global carbon storage and represent significant sources of economic and ecological value. While recent efforts to describe microbial diversity and metabolic potential of the Sphagnum microbiome have demonstrated the importance of its microbial community, little is known about the viral constituents. We used metatranscriptomics to describe the diversity and activity of viruses infecting microbes within the Sphagnum peat bog. The vegetative portions of six Sphagnum plants were obtained from a peatland in northern Minnesota, and the total RNA was extracted and sequenced. Metatranscriptomes were assembled and contigs were screened for the presence of conserved virus marker genes. Using bacteriophage capsid protein gp23 as a marker for phage diversity, we identified 33 contigs representing undocumented phages that were active in the community at the time of sampling. Similarly, RNA-dependent RNA polymerase and the nucleocytoplasmic large DNA virus (NCLDV) major capsid protein were used as markers for single-stranded RNA (ssRNA) viruses and NCLDV, respectively. In total, 114 contigs were identified as originating from undescribed ssRNA viruses, 22 of which represent nearly complete genomes. An additional 64 contigs were identified as being from NCLDVs. Finally, 7 contigs were identified as putative virophage or polinton-like viruses. We developed co-occurrence networks with these markers in relation to the expression of potential-host housekeeping gene rpb1 to predict virus-host relationships, identifying 13 groups. Together, our approach offers new tools for the identification of virus diversity and interactions in understudied clades and suggests that viruses may play a considerable role in the ecology of the Sphagnum microbiome.IMPORTANCESphagnum-dominated peatlands play an important role in maintaining atmospheric carbon dioxide levels by modifying conditions in the surrounding soil to favor the growth of Sphagnum over that of other plant species. This lowers the rate of decomposition and facilitates the accumulation of fixed carbon in the form of partially decomposed biomass. The unique environment produced by Sphagnum enriches for the growth of a diverse microbial consortia that benefit from and support the moss's growth, while also maintaining the hostile soil conditions. While a growing body of research has begun to characterize the microbial groups that colonize Sphagnum, little is currently known about the ecological factors that constrain community structure and define ecosystem function. Top-down population control by viruses is almost completely undescribed. This study provides insight into the significant viral influence on the Sphagnum microbiome and identifies new potential model systems to study virus-host interactions in the peatland ecosystem.


Soluble plasma programmed death 1 (PD-1) and Tim-3 in primary HIV infection.
: Soluble forms of the coinhibitory receptors programmed death 1 (PD-1) and Tim-3 exist, but their relationship with T-cell surface expression remains unclear. When measured by an enzyme-linked immunosorbent assay in plasma, soluble PD-1, and soluble Tim-3 were elevated during primary HIV infection, decreased on antiretroviral therapy to levels found in controls, and correlated with cell surface expression. We conclude that soluble PD-1 and soluble Tim-3 are easy to measure biomarkers of immune exhaustion which potentially eliminate the need for flow cytometry.


New antiprogestins with partial agonist activity: potential selective progesterone receptor modulators (SPRMs) and probes for receptor- and coregulator-induced changes in progesterone receptor induction properties.
A pharmacologically relevant property of steroid hormone-regulated gene induction is the partial agonist activity of antisteroid complexes. We now report that dexamethasone-mesylate (Dex-Mes) and dexamethasone-oxetanone (Dex-Ox), each a derivative of the glucocorticoid-selective steroid dexamethasone (Dex), are two new antiprogestins with significant amounts of agonist activity with both the A and B isoforms of progesterone receptor (PR), for different progesterone-responsive elements, and in several cell lines. These compounds continue to display activity under conditions where another partial antiprogestin (RTI-020) is inactive. These new antiprogestins were used to determine whether the partial agonist activity of PR complexes can be modified by changing concentrations of receptor or coregulator, as we have recently demonstrated for glucocorticoid receptors (GRs). Because GR and coregulator concentrations simultaneously altered the position of the physiologically relevant dose-response curve, and associated EC(50), of GR-agonist complexes, we also examined this phenomenon with PR. We find that elevated PR or transcriptional intermediary factor 2 (TIF2) concentrations increase the partial agonist activity of Dex-Mes and Dex-Ox, and the EC(50) of agonists, independently of changes in total gene transactivation. Furthermore, the corepressors SMRT (silencing mediator for retinoid and thyroid receptors) and NCoR (nuclear receptor corepressor) each suppresses gene induction but NCoR acts opposite to SMRT and, like the coactivator TIF2, reduces the EC(50) and increases the partial agonist activity of antiprogestins. These comparable responses of GR and PR suggest that variations in receptor and coregulator concentrations may be a general mechanism for altering the induction properties of other steroid receptors. Finally, the magnitude of coregulator effects on PR induction properties are often not identical for agonists and the new antagonists, suggesting subtle mechanistic differences. These properties of Dex-Mes and Dex-Ox, plus the sensitivity of their activity to cellular differences in PR and coregulator concentrations, make these steroids potential new SPRMs (selective progesterone receptor modulators) that should prove useful as probes of PR induction properties.


Rationality.
This chapter reviews selected findings in research on reasoning, judgment, and choice and considers the systematic ways in which people violate basic requirements of the corresponding normative analyses. Recent objections to the empirical findings are then considered; these objections question the findings' relevance to assumptions about rationality. These objections address the adequacy of the tasks used in the aforementioned research and the appropriateness of the critical interpretation of participants' responses, as well as the justifiability of some of the theoretical assumptions made by experimenters. The objections are each found not to seriously impinge on the general conclusion that people often violate tenets of rationality in inadvisable ways. In the process, relevant psychological constructs, ranging from cognitive ability and need for cognition, to dual process theories and the role of incentives, are discussed. It is proposed that the rationality critique is compelling and rightfully gaining influence in the social sciences in general.


Diverse pathological implications of YKL-40: answers may lie in 'outside-in' signaling.
The developing paradigms about YKL-40, a member of the "mammalian chitinase-like proteins", from across the globe, project it as a vital parameter for the detection of disease onset and progression. It is expressed and secreted by cancer cells of different origins along with a variety of non-malignant cells including inflammatory and structural cells. Numerous studies demonstrate that YKL-40 over-expression is associated with increased patient mortality though the cellular receptors responsible for mediating these effects have not yet been identified. The putative YKL-40 ligands are thought to be carbohydrate structures, since it is capable of binding chitin, chito-oligosaccharides and heparin. Binding of collagen to YKL-40, identified it as the only non-carbohydrate extracellular matrix (ECM) ligand for YKL-40. Our broad understanding of YKL-40 as a versatile biomarker and its involvement in activating several signaling pathways make us anticipate that its specific receptors/binding partners may exist on the cell surface also. The cell surface heparan sulfate (HS) moieties seem to be the potential candidates for this role, suggesting that it could interact with HS-proteoglycans. It is recommended to clearly delineate YKL-40-mediated signaling mechanisms before promoting the YKL-40 know-how for translational research, in both diagnostic and therapeutic applications. The present review provides an overview of YKL-40 as a versatile biomarker, discussing the related pathological mechanisms and aims to reassess and unify the already proposed diverse hypotheses in YKL-40-regulated signaling mechanisms.


Chemical exposures at work and cardiovascular morbidity. Atherosclerosis, ischemic heart disease, hypertension, cardiomyopathy and arrhythmias.
Relatively little systematic research has been directed towards the potential effects, either etiologic or aggravating, of industrial chemicals on cardiovascular diseases. While some evidence indicates that exposure to certain pesticides might affect lipoprotein metabolism in man, there is no consistent documentation to support the view that atherosclerosis is caused in man by chemical exposures in industry. In this respect results from some animal studies are highly interesting, eg, exposure to some carcinogens, but the hypotheses presented have not yet been vigorously tested in man. Exposure to carbon monoxide is detrimental to the myocardium, especially in patients with ischemic heart disease, but there are no reliable data on elevated cardiac mortality due to carbon monoxide exposure in industrial populations. A few studies have reported arrhythmias or sudden deaths among workers exposed to solvents and organic nitrates. The effects of lead and cadmium upon human blood pressure have remained controversial, although the bulk of controlled epidemiologic studies suggests that they, if at all existent, are not strong.


Human immunodeficiency virus type 1 infection of mature CD3hiCD8+ thymocytes.
Although CD4+ cells are the primary targets of human immunodeficiency virus type 1 (HIV-1) infection, earlier reports have suggested that intrathymic infection of CD8+ cells may occur. However, it was unclear whether HIV-1-infected CD8+ thymocytes were truly mature single-positive (SP) cells. In the present study, SCID mice implanted with human fetal thymus and liver tissues (SCID-hu mice) were infected with three primary isolates of HIV-1 and infected thymocytes were analyzed to assess maturational status. After intra-implant or intraperitoneal injection with HIV-1, thymocytes were sorted by three-color flow cytometric analysis into mature populations of CD3hiCD4+ and CD3hiCD8+ SP cells of > 99% purity (< 0.3% CD4-containing cells in the CD8+ population). The presence of HIV-1 provirus in the sorted thymocyte populations was determined by quantitative PCR. A fraction of mature CD3hiCD8+ thymocytes contained HIV-1 proviral DNA, and evidence of viral mRNA transcription in these cells was demonstrated by in situ hybridization. In contrast, when uninfected CD3hiCD8+ thymocytes were cocultured with HIV-1-infected CD4+ thymocytes, no evidence of productive HIV-1 infection was detected. Thus, HIV-1 infection of CD8+ thymocytes in the SCID-hu mouse does not occur by direct contact with the virus. Rather, cell surface CD4 is required; therefore, precursor cells are the likely primary target of HIV-1 infection in the thymus. During ontogeny, some of these infected cells continue their differentiation into mature CD8+ SP thymocytes that contain proviral DNA and express viral RNA.


Pain intensity and quality of life perception in children with hypermobility syndrome.
Hypermobility syndrome (HMS) is a major source of morbidity in children. Impaired quality of life (QoL) has been observed recently in adults with HMS; however, this issue is yet to be investigated in children with this condition. This study compared pain intensity and QoL in children with HMS with healthy controls. It also examined the relationship between pain intensity and QoL in children with HMS. Following ethical approval, 29 children diagnosed with HMS and 37 healthy children aged 8-15 years participated. Informed written consent was obtained from participants and their parents/guardians. Average knee pain over the past week was examined using the Coloured Analogue Scale. QoL was measured via the Pediatric Quality of Life Inventory. Mann-Whitney U tests were performed to compare pain and QoL scores between the two groups. Spearman Rho correlation analysis was performed to examine the relationship between pain and QoL. Overall QoL scores in each domain were significantly lower in children with HMS (all p < 0.001) compared with the controls. Pain intensity was significantly higher in children with HMS compared with their healthy counterparts (p < 0.001). A strong negative correlation was observed between pain intensity and overall QoL and all the domains (r range = -0.614 to -0.717; all p < 0.001). In conclusion, the findings of the present study imply that pain and QoL assessment might form important components of clinical examination for children diagnosed with HMS. These children may benefit from appropriate treatment programmes to alleviate pain intensity and improve QoL.