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Etoposide is a broadly employed chemotherapeutic and eukaryotic topoisomerase II poison that stabilizes cleaved DNA intermediates to promote DNA breakage and cytotoxicity. How etoposide perturbs topoisomerase dynamics is not known. Here we investigated the action of etoposide on yeast topoisomerase II, human topoisomerase IIα and human topoisomerase IIβ using several sensitive single-molecule detection methods. Unexpectedly, we found that etoposide induces topoisomerase to trap DNA loops, compacting DNA and restructuring DNA topology. Loop trapping occurs after ATP hydrolysis but before strand ejection from the enzyme. Although etoposide decreases the innate stability of topoisomerase dimers, it increases the ability of the enzyme to act as a stable roadblock. Interestingly, the three topoisomerases show similar etoposide-mediated resistance to dimer separation and sliding along DNA but different abilities to compact DNA and chirally relax DNA supercoils. These data provide unique mechanistic insights into the functional consequences of etoposide on topoisomerase II dynamics.

Marine population modeling, which underpins the scientific advice to support fisheries interventions, is an active research field with recent advancements to address modern challenges (e.g., climate change) and enduring issues (e.g., data limitations). Based on discussions during the 'Land of Plenty' session at the 2021 World Fisheries Congress, we synthesize current challenges, recent advances, and interdisciplinary developments in biological fisheries models (i.e., data-limited, stock assessment, spatial, ecosystem, and climate), management strategy evaluation, and the scientific advice that bridges the science-policy interface. Our review demonstrates that proliferation of interdisciplinary research teams and enhanced data collection protocols have enabled increased integration of spatiotemporal, ecosystem, and socioeconomic dimensions in many fisheries models. However, not all management systems have the resources to implement model-based advice, while protocols for sharing confidential data are lacking and impeding research advances. We recommend that management and modeling frameworks continue to adopt participatory co-management approaches that emphasize wider inclusion of local knowledge and stakeholder input to fill knowledge gaps and promote information sharing. Moreover, fisheries management, by which we mean the end-to-end process of data collection, scientific analysis, and implementation of evidence-informed management actions, must integrate improved communication, engagement, and capacity building, while incorporating feedback loops at each stage. Increasing application of management strategy evaluation is viewed as a critical unifying component, which will bridge fisheries modeling disciplines, aid management decision-making, and better incorporate the array of stakeholders, thereby leading to a more proactive, pragmatic, transparent, and inclusive management framework-ensuring better informed decisions in an uncertain world.The online version contains supplementary material available at 10.1007/s11160-022-09726-7.

The antimicrobial resistance crisis requires the introduction of novel antibiotics. The use of conventional broad-spectrum compounds selects for resistance in off-target pathogens and harms the microbiome. This is especially true for Mycobacterium tuberculosis, where treatment requires a 6-month course of antibiotics. Here we show that a novel antimicrobial from Photorhabdus noenieputensis, which we named evybactin, is a potent and selective antibiotic acting against M. tuberculosis. Evybactin targets DNA gyrase and binds to a site overlapping with synthetic thiophene poisons. Given the conserved nature of DNA gyrase, the observed selectivity against M. tuberculosis is puzzling. We found that evybactin is smuggled into the cell by a promiscuous transporter of hydrophilic compounds, BacA. Evybactin is the first, but likely not the only, antimicrobial compound found to employ this unusual mechanism of selectivity.

The determination of the amount of non-intact cells (ANIC) in ground beef products is usually performed using a time-consuming and subjective histometric approach neglecting structural properties, which is why more objective and faster methods including evaluation of quality parameters are needed. To determine, whether the addition of meat batter increases the histologically determined ANIC ground beef samples containing increasing shares of meat batter (non-intact cells) were investigated histologically and results were compared to other methodological approaches, namely lactate dehydrogenase activity (LDH), soluble protein content, metmyoglobin content, drip loss, firmness, and cooking loss. Histological measurements showed that ANIC increased linearly with the addition of meat batter to ground beef. The quality parameters drip loss (r = − 0.834, p r = − 0.499, p r = 0.924, p

With the current COVID-19 pandemic, we all realized how important interactions are. Interactions are everywhere. At the cellular level, protein interactions play a key role and their ensemble, also called interactome, is often referred as the basic building blocks of life. Given its importance, the maintenance of the integrity of the interactome is a real challenge in the cell. Many events during evolution can disrupt interactomes and potentially result in different characteristics for the organisms. However, the molecular underpinnings of changes in interactions at the cellular level are still largely unexplored. Among the perturbations, hybridization puts in contact two different interactomes, which may lead to many changes in the protein interaction network of the hybrid, including gains and losses of interactions. We recently investigated the fate of the interactomes after hybridization between yeast species using a comparative proteomics approach. A large-scale conservation of the interactions was observed in hybrids, but we also noticed the presence of proteostasis-related changes. This suggests that, despite a general robustness, small differences may accumulate in hybrids and perturb their protein physiology. Here, we summarize our work with a broader perspective on the importance of interactions.

To examine if selected demographic (age, gender), clinical (diabetes, coronary artery disease, hyperlipidemia, myocardial infarction, stroke, lung disease, smoking history, alcohol intake), and biomarker [blood pressure (BP), heart rate, body mass index (BMI), neck circumference, Mallampati score] variables are predictors of apnea-hypopnea index (AHI) from polysomnography (PSG). This cross-sectional study recruited a sample of adults (N = 170) who were being evaluated for OSA. Participants completed self-reported demographic and clinical questionnaires, and then completed PSG (n = 142). Multi-collinearity was assessed. Confounding factors, correlations, and potential interactions were explored. The final regression model was performed on 130 participants; 61 (46.9%) had an AHI ≥ 15. Systolic and diastolic BPs were highly correlated. Interactions were tested between gender and other variables (high cholesterol, BMI, neck circumference, systolic BP) and between systolic BP and other variables (high cholesterol, BMI, neck circumference, and lung disease). No interactions occurred between gender or systolic BP and other variables, meaning that the effects of the variables on AHI levels from PSG did not vary depending on gender or systolic BP. BMI, systolic BP, and absence of lung disease were predictors for AHI levels ≥ 15 from PSG. BMI and systolic BP were significant predictors of OSA in this study. The absence of lung disease as a significant predictor was unique and may be due to the small number of participants who self-reported lung disease. To our knowledge, this is the first study to report this combination of variables to predict AHI levels ≥ 15 from PSG.

Purpose Ascent to high altitude increases right ventricular (RV) afterload and decreases myocardial energy supply. This study evaluates physiologic variables and comprehensive echocardiographic indices of RV and right atrial (RA) function following rapid ascent to high altitude. Methods Fifty healthy volunteers actively ascended from 1130 to 4559 m in Results sPAP increased from baseline (24 ± 4 mmHg) to the first altitude examination (39 ± 8 mmHg, p p = 0.07) secondary to a significant increase of RA contraction strain (19.2 ± 6.4 vs. 25.4 ± 9.6%, p Conclusion Active and rapid ascent of healthy individuals to 4559 m is associated with an increased contractile performance of the RA that compensates for the increased workload of the RV.

Psychoneurological symptom clusters are co-occurring and interrelated physiological symptoms that may include cancer-related fatigue, pain, depressive symptoms, cognitive disturbances, and sleep disturbances. These symptoms are hypothesized to share a common systemic proinflammatory etiology. Thus, an investigation of systemic immune biomarkers is an important approach to test this hypothesis. Here, we investigated the associations between extracellular vesicle (EV)-associated and soluble cytokines with immune markers and symptom clusters in men with non-metastatic prostate cancer. This observational study included 40 men with non-metastatic prostate cancer at the start (T1) of external beam radiation therapy (EBRT) and 3 months post treatment (T2), as well as 20 men with non-metastatic prostate cancer on active surveillance (AS) seen at one time point. Collected questionnaires assessed patient-reported fatigue, sleep disturbances, depressive symptoms, and cognitive fatigue. In total, 45 soluble and EV-associated biomarkers in plasma were determined by multiplex assays. Principal component analysis (PCA) was used to identify psychoneurological symptom clusters for each study group and their time points. Bivariate correlation analysis was run for each identified PCA cluster with the concentrations of EV-associated and soluble cytokines and immune markers. Both EV-associated and soluble forms of RANTES significantly correlated with the symptom cluster for EBRT at T1, whereas, at T2, soluble IFNα2, IL-9, and IL-17 correlated with the corresponding symptom cluster. For the AS group, soluble survivin correlated with psychoneurological symptoms. Linking specific inflammatory cytokines with psychoneurological symptom clusters in men receiving prostate cancer treatment can enhance understanding of the underlying mechanisms of this phenomenon and aid in developing targeted interventions.

Zusammenfassung Notfallmedikamente kommen an nahezu allen Orten dieser Erde zum Einsatz. Damit werden sie unterschiedlichsten Umweltbedingungen (Kälte, Hitze, direkte Sonneneinstrahlung) ausgesetzt. Sämtliche Daten zur Pharmakokinetik, Pharmakodynamik, Medikamentensicherheit und -haltbarkeit werden jedoch unter standardisierten Bedingungen erhoben, die sich von den Anwendungsbedingungen in der Notfallmedizin erheblich unterscheiden können. Durch die Kälte bei Wintereinsätzen im Gebirge können ebenso wie bei Einsätzen in großer Hitze und bei direkter Sonnenexposition chemische Reaktionen entstehen, welche die Eigenschaften der Medikamente bis hin zur kompletten Wirkungslosigkeit verändern können. Zusätzlich können Unterkühlung oder Überhitzung des Patienten zu einer Zentralisation bzw. Vasodilatation führen und damit das pharmakologische Verteilungsvolumen erheblich verändern, woraus Unter- bzw. Überdosierungen resultieren können. Gleichzeitig kann durch einen temperaturbedingt veränderten Metabolismus die Konjugation und Elimination von Medikamenten beeinflusst sein und zu einer unvorhersehbaren Verlängerung der Medikamentenwirkung führen. Trotz der erheblichen klinischen Relevanz dieser Thematik existieren bisher kaum Daten zu den konkreten Effekten extremer Umweltbedingungen auf die pharmakologischen Eigenschaften von Notfallmedikamenten. Diese Übersicht soll dazu dienen, den aktuellen Kenntnisstand der notfallmedizinischen Pharmakotherapie unter Extrembedingungen darzustellen.

Herein we report the synthesis of new N-4-piperazinyl thiadiazole and oxadiazole ciprofloxacin derivatives and their antibacterial and antimycobacterial activities. Although thiadiazole ciprofloxacin derivatives compound showed broad spectrum antibacterial activity against all the tested strains either Gram-positive or Gram-negative organisms, the oxadiazole derivatives exhibited weaker antibacterial and antimycobacterial activities than thiadiazole derivatives against most of the tested strains compared with the reference ciprofloxacin. Moreover, the antimycobacterial screening revealed that compounds which containing thiadiazole scaffold potently inhibited Mycobacterium smegmatis at MIC of 1.56 and 3.13, respectively, and modestly inhibited the drug-resistant strains. DNA cleavage assay revealed that thiadiazole ciprofloxacin derivatives inhibited supercoil relaxation, albeit to a lesser extent than ciprofloxacin, and it also increased the amount of nicked substrate produced.

Pianp (also known as Leda-1) is a type I transmembrane protein with preferential expression in the mammalian CNS. Its processing is characterized by proteolytic cleavage by a range of proteases including Adam10, Adam17, MMPs, and the γ-secretase complex. Pianp can interact with Pilrα and the GB1a subunit of the GABAB receptor (GBR) complex. A recent case description of a boy with global developmental delay and homozygous nonsense variant in PIANP supports the hypothesis that PIANP is involved in the control of behavioral traits in mammals. To investigate the physiological functions of Pianp, constitutive, global knockout mice were generated and comprehensively analyzed. Broad assessment did not indicate malformation or malfunction of internal organs. In the brain, however, decreased sizes and altered cellular compositions of the dentate gyrus as well as the cerebellum, including a lower number of cerebellar Purkinje cells, were identified. Functionally, loss of Pianp led to impaired presynaptic GBR-mediated inhibition of glutamate release and altered gene expression in the cortex, hippocampus, amygdala, and hypothalamus including downregulation of Erdr1, a gene linked to autism-like behavior. Behavioral phenotyping revealed that Pianp deficiency leads to context-dependent enhanced anxiety and spatial learning deficits, an altered stress response, severely impaired social interaction, and enhanced repetitive behavior, which all represent characteristic features of an autism spectrum disorder-like phenotype. Altogether, Pianp represents a novel candidate gene involved in autism-like behavior, cerebellar and hippocampal pathology, and GBR signaling.

New nitric oxide (NO) donating fluoroquinolones/nitrate ester hybrids were prepared and their structures were characterized by various spectroscopic and analytical tools. The release of NO from the prepared nitrate esters was measured using the modified Griess colorimetric method. Evaluation of antitubercular activity showed that most of tested compounds exhibited comparable or higher activity than the parent fluoroquinolones. Compounds 2b, 3a, 4a, 5a, and 2d showed better activity than ciprofloxacin. Nevertheless, none of the new compounds were superior to the parent fluoroquinolones in terms of DNA cleavage stimulation in mycobacteria. The additional growth inhibition effect that is distinct from gyrase poisoning may be due to release of NO or enhancement of lipophilicity. These data are augmented by docking results where the docked compounds did not exert additional significant bindings over the parent fluoroquinolones.

Throughout the cancer continuum, patients are faced with the cancer- and treatment-related side effects that can have a negative impact on their overall quality of life. Cancer-related fatigue (CRF) and sleep deficiency are among the symptoms that patients and their caregivers most often experience. An increasing body of literature suggests that a strong correlation between CRF and sleep deficiency exists, indicating that they may be reciprocally related and that they may have similar underlying etiology. This paper aims at bringing together the opinions of leading cancer control (i.e., CRF and sleep) and oncology experts in order to increase the understanding of CRF and sleep deficiency's assessment, associated symptom clustering, symptom burden shared by caregivers, and CRF and sleep deficiency management in the cancer care context.

Die chirurgische Therapie analer und rektaler Fistelrezidive mit starren rigiden Narbenhohlen und Exkavationen, entsprechend der Typen 1–4 b und c nach Parks, ist schwierig. Die Idee des korpereigenen perfundierten Gewebes zur Defektfullung ist eine haufig genutzte Therapieoption bei verschiedenen Entitaten und wurde auf die Anwendbarkeit bei der obigen Indikation uberpruft. Geeignet ist der M. gracilis auf Grund seiner raumlichen Verfugbarkeit, und es wird kein funktionelles Defizit hinterlassen. Unter Stomaschutz kann mit einer hohen Erfolgswahrscheinlichkeit ein kompliziertes Analfistelrezidiv versorgt werden.

The bacterial hexameric helicase known as Rho is an archetypal sequence-specific transcription terminator that typically halts the synthesis of a defined set of transcripts, particularly those bearing cytosine-rich 3’ untranslated regions. However, under conditions of translational stress, Rho can also terminate transcription at cytosine-poor sites when assisted by the transcription factor NusG. Recent structural, biochemical, and computational studies of the Rho•NusG interaction in Escherichia coli have helped establish how NusG reprograms Rho activity. NusG is found to be an allosteric activator of Rho that directly binds to the ATPase motor domain of the helicase and facilitates closure of the Rho ring around non-ideal (purine-rich) target RNAs. The manner in which NusG acts on Rho helps to explain how the transcription terminator is excluded from acting on RNA polymerase by exogenous factors, such as the antitermination protein NusE, the NusG paralog RfaH, and RNA polymerase-coupled ribosomes. Collectively, an understanding of the link between NusG and Rho provides new insights into how transcriptional and translational fidelity are maintained during gene expression in bacteria.

Assessment of patient satisfaction following an aesthetic surgery has shown an increasing trend over the past years. To date, there is no prospective and comprehensive study evaluating this aspect after surgical facial and neck rejuvenation. The aim of the current work was to address patient satisfaction after face and neck lift surgery using a validated questionnaire.We present a prospective and multicenter study (five regional centers) involving all patients undergoing face and neck lift surgery between April 2015 and April 2017 in several French centers for aesthetic surgery. All subjects assessed the FACE-Q scales before the procedure, and furtherly at 3-month, 6-month and 12-month follow-ups.Thirty-six patients were included with a median age of 58.5 years old [IQR 54.0-66.0]. The FACE-Q outcomes were significantly higher at 3-month follow-up (p 0.001). Seventy-five percent of the patients underwent an additional surgical procedure associated with face and neck lift. Particularly, a combined blepharoplasty led to a significant increase in the score of global facial appearance. The patients considered themselves a mean of 6 years younger in the third month after surgery. These results remained constant at six and twelve postoperative months.A statistically significant improvement of the FACE-Q scores could be highlighted on every scale, with permanent results at 6 and 12 months postsurgery. We hereby present the first study with evidence that appearance and quality of life outcomes can be reliably assessed after rhytidectomy.This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Rigid work schedules are negatively associated with adults’ sleep. Less is known about whether parents’ work schedule flexibility influences their children’s sleep. We examined associations of mothers’ perceived work schedule flexibility with their children’s sleep over time and whether these associations were mediated by bedtime routine adherence. Two-waves of data were drawn from the Fragile Families and Child Wellbeing Study, a sample of socioeconomically disadvantaged households in large US cities (N = 1040). When the focal children were ages 5 and 9, mothers reported their work schedule flexibility and their child’s bedtime adherence, sleep duration, and difficulty getting to sleep. Cross-sectionally, higher levels of maternal perceived work schedule flexibility were associated with longer child sleep duration and a lower likelihood of having difficulty getting to sleep; these associations were mediated by greater child bedtime adherence. Longitudinally, increases in mothers’ perceived work schedule flexibility from child ages 5 to 9 predicted increases in child bedtime adherence at age 9, which, in turn, predicted increases in child sleep duration at age 9. Increases in perceived work schedule flexibility also predicted a decreased likelihood of children having difficulty getting to sleep, but this association was not mediated by changes in child bedtime adherence. These results suggest that mothers’ perceived work schedule flexibility may be a social determinant of child sleep health, largely through influencing bedtime adherence. Future interventions could consider how to improve bedtime practices in families with working mothers, including by increasing work schedule flexibility perceived by working parents to promote child sleep health.

The Midwest Geological Sequestration Consortium is conducting the Illinois Basin-Decatur Project (IBDP), a large-scale demonstration of carbon sequestration that injected the CO2 from an ethanol plant into the Mt. Simon Sandstone. Using site-specific data and samples, batch experiments were conducted at reservoir conditions and the reactive transport code TOUGHREACT was used to model the CO2 migration and interactions in the injection formation. In the model, most of the mineral alteration occurred after the injection was completed and brine displaced the CO2 at the base of the plume. K-feldspar dissolution led to a nearly 10% increase in porosity which is a maximum estimate of alteration because, the model omits mineral transformations and may underestimate clay precipitation and the effects of grain coatings. The batch experiments recreated these conditions and showed a little alteration. In both the model and experiments, the bulk of the mineralogy remained inert. Calcite precipitated within the modeled plume where the transformation of K-feldspar to clays buffered the pH, though this process only produced minor mineral sequestration. Less-permeable layers in the model baffled the ascent of the CO2 plume and caused it to spread laterally. The plume did not reach the upper third of the Mt. Simon Sandstone. Both the model and the batch experiments show that the bulk of the Mt. Simon Sandstone will undergo little change due to CO2 injection, and the batch experiments show the feldspar dissolution in the model is likely limited.

Das Biomonitoring-Auskunftssystem der Bundesanstalt fur Arbeitsschutz und Arbeitsmedizin (BAuA) erlaubt Recherchen nach Biomonitoring-Informationen zu einzelnen Gefahrstoffen und Gefahrstoffgruppen. Systemnutzer konnen u. a. klaren, welche Parameter in welchem Probenmaterial bei einer bestimmten Gefahrstoffexposition messbar sind und welche aktuellen Beurteilungswerte fur diese vorliegen. Der Zugriff auf das System erfolgt uber die Internetseiten der BAuA unter www.baua.de/Biomonitoring . Die Datenbasis des Systems wird stetig aktualisiert und erweitert. So wurden zuletzt neue Daten zur Hintergrundbelastung der Bevolkerung der USA und Kanadas, die Blutblei-Bewertungsstufen der Technischen Regel fur Gefahrstoffe 505 „Blei“ des Ausschusses fur Gefahrstoffe (Deutschland) sowie die Ringversuchsangebote des Centre de toxicologie du Quebec (Kanada) eingepflegt. Seit 2017 werden in den Rechercheergebnissen des Auskunftssystems gefahrstoffbezogene Links zur GESTIS-Stoffdatenbank der Deutsche Gesetzlichen Unfallversicherung angeboten.

Geologic carbon sequestration (GCS) projects in the USA are required to monitor groundwater quality for geochemical changes above the injection area that may be a result of CO2 or brine leakage from the storage reservoir. Should CO2 migrate into the groundwater around the compliance wells monitoring the shallower hydrologic units, each compliance parameter could react differently depending on its sensitivity to CO2. Statistically determined limits (SDLs) for detection of CO2 leakage into groundwater were calculated using background water quality data from the Illinois Basin Decatur Project (IBDP) sequestration site and prediction and tolerance intervals for specific compliance parameters. If the parameter concentrations varied outside of these ranges during the injection and post injection periods of a GCS project, then additional actions would be required to determine the reason for the changes in groundwater concentrations. Geochemical modeling can simulate the amount of CO2 needed to alter water quality parameters a statistically significant amount. This information can then inform GCS operators and regulators as to which compliance parameters are relevant (sensitive) to CO2 leakage for a given setting. For the system studied in here, Fe, Ca, K, Mg, CO2, and pH were sensitive to CO2 addition while Al, Cl, Na, and Si were not.

Gyrase is an essential bacterial molecular motor that supercoils DNA using a conformational cycle in which chiral wrapping of > 100 base pairs confers directionality on topoisomerization. To understand the mechanism of this nucleoprotein machine, global structural transitions must be mapped onto the nucleotide cycle of ATP binding, hydrolysis and product release. Here we investigate coupling mechanisms using single-molecule tracking of DNA rotation and contraction during Escherichia coli gyrase activity under varying nucleotide conditions. We find that ADP must be exchanged for ATP to drive the rate-limiting remodeling transition that generates the chiral wrap. ATP hydrolysis accelerates subsequent duplex strand passage and is required for resetting the enzyme and recapturing transiently released DNA. Our measurements suggest how gyrase coordinates DNA rearrangements with the dynamics of its ATP-driven protein gate, how the motor minimizes futile cycles of ATP hydrolysis and how gyrase may respond to changing cellular energy levels to link gene expression with metabolism. Single-molecule measurements of DNA gyrase activity reveal conformational dynamics coupling ATP consumption to DNA supercoiling.

There is uncertainty as to the appropriate follow-up of patients who test positive on multimarker stool DNA (sDNA) testing and have a colonoscopy without neoplasia. To determine the prevalence of missed colonic or occult upper gastrointestinal neoplasia in patients with an apparent false positive sDNA. We prospectively identified 30 patients who tested positive with a commercially available sDNA followed by colonoscopy without neoplastic lesions. Patients were invited to undergo repeat sDNA at 11–29 months after the initial test followed by repeat colonoscopy and upper endoscopy. We determined the presence of neoplastic lesions on repeat evaluation stratified by results of repeat sDNA. Twelve patients were restudied. Seven patients had a negative second sDNA test and a normal second colonoscopy and upper endoscopy. In contrast, 5 of 12 subjects had a persistently positive second sDNA test, and 3 had positive findings, including a 3-cm sessile transverse colon adenoma with high-grade dysplasia, a 2-cm right colon sessile serrated adenoma with dysplasia, and a nonadvanced colon adenoma (p = 0.045). These corresponded to a positive predictive value of 0.60 (95% CI 0.17–1.00) and a negative predictive value of 1.00 (95% CI 1.00–1.00) for the second sDNA test. In addition, the medical records of all 30 subjects with apparent false positive testing were reviewed and no documented cases of malignant tumors were recorded. Repeat positive sDNA testing may identify a subset of patients with missed or occult colorectal neoplasia after negative colonoscopy for an initially positive sDNA. High-quality colonoscopy with careful attention to the right colon in patients with positive sDNA is critically important and may avoid false negative colonoscopy.

Purpose Both exercise and hypoxia cause complex changes in acid–base homeostasis. The aim of the present study was to investigate whether during intense physical exercise in normoxia and hypoxia, the modified physicochemical approach offers a better understanding of the changes in acid–base homeostasis than the traditional Henderson–Hasselbalch approach. Methods In this prospective, randomized, crossover trial, 19 healthy males completed an exercise test until voluntary fatigue on a bicycle ergometer on two different study days, once during normoxia and once during normobaric hypoxia (12% oxygen, equivalent to an altitude of 4500 m). Arterial blood gases were sampled during and after the exercise test and analysed according to the modified physicochemical and Henderson–Hasselbalch approach, respectively. Results Peak power output decreased from 287 ± 9 Watts in normoxia to 213 ± 6 Watts in hypoxia (−26%, P

This study introduces the second release of the Tool for the Automatic Analysis of Lexical Sophistication (TAALES 2.0), a freely available and easy-to-use text analysis tool. TAALES 2.0 is housed on a user's hard drive (allowing for secure data processing) and is available on most operating systems (Windows, Mac, and Linux). TAALES 2.0 adds 316 indices to the original tool. These indices are related to word frequency, word range, n-gram frequency, n-gram range, n-gram strength of association, contextual distinctiveness, word recognition norms, semantic network, and word neighbors. In this study, we validated TAALES 2.0 by investigating whether its indices could be used to model both holistic scores of lexical proficiency in free writes and word choice scores in narrative essays. The results indicated that the TAALES 2.0 indices could be used to explain 58% of the variance in lexical proficiency scores and 32% of the variance in word-choice scores. Newly added TAALES 2.0 indices, including those related to n-gram association strength, word neighborhood, and word recognition norms, featured heavily in these predictor models, suggesting that TAALES 2.0 represents a substantial upgrade.

The purpose of this work is to design and develop a type of experiment setup that would enable the direct observation of steady diffusion process in situ. Two different optical methods - shadowgraph and shearing interferometry - were used for the first time to visualise and quantitatively analyse the diffusion around a droplet of organic substance in supercritical carbon dioxide (SCCO2) as well as in its direct vicinity. We constructed and tested a cylindrical high-pressure chamber and an experiment system with a high speed camera. The solute/solvent combination of DL-α-tocopherol/SCCO2 was applied using shadowgraph. The diffusion coefficients at temperatures of 40o C, 50o C and 60o C and pressures between 75 bar and 90 bar were calculated based on the displacement of the droplet contour in the captured images. The shearing interferometry with a Wollaston-prism was then applied not only for the combination of DL-α-tocopherol/SCCO2, but also for other substances in SCCO2, for example for a type of rose oil and lubricant oil as well as for acetone, benzene, toluene and naphthalene. The changes of the refractive index gradient were directly measured and evaluated with the interferograms; afterwards changes of the density gradients and the diffusion coefficients were determined. We propose then a multivariate regression model to capture the relationship between the diffusion coefficient, the pressure and the temperature. To minimize the influence of gravity-driven convections in the solvent during diffusion, the experiments were also carried out under microgravity condition, i.e. in two parabolic flight campaigns.

This study estimates the associations of income with both (self-reported) child protective services (CPS) involvement and parenting behaviors that proxy for child abuse and neglect risk among unmarried families. Our primary strategy follows the instrumental variables (IV) approach employed by Dahl and Lochner (2012), which leverages variation between states and over time in the generosity of the total state and federal Earned Income Tax Credit for which a family is eligible to identify exogenous variation in family income. As a robustness check, we also estimate standard OLS regressions (linear probability models), reduced form OLS regressions, and OLS regressions with the inclusion of a control function (each with and without family-specific fixed effects). Our micro-level data are drawn from the Fragile Families and Child Wellbeing Study, a longitudinal birth-cohort of relatively disadvantaged urban children who have been followed from birth to age nine. Results suggest that an exogenous increase in income is associated with reductions in behaviorally-approximated child neglect and CPS involvement, particularly among low-income single-mother families.

Eine fachgerechte Befundung von Messergebnissen im arbeitsmedizinischen Biomonitoring erfordert aktuelle Kenntnisse geeigneter Beurteilungswerte. Da solche Werte von verschiedenen Fachgremien in unterschiedlichen Medien und meist unregelmasig veroffentlicht werden, ergibt sich fur Biomonitoring-Anwender ein nicht unerheblicher Rechercheaufwand.

Das Erfassen von Fehlern und kritischen Zwischenfallen ist eine Voraussetzung fur eine lernorientierte Sicherheitskultur. Viele Krankenhauser haben ein Meldesystem fur kritische Zwischenfalle („critical incident reporting system“, CIRS) implementiert. Anwendung, Nutzen und Einfluss des CIRS auf die Patientensicherheit sind jedoch haufig unbefriedigend geblieben. Wir stellen die Frage, was man in den letzten 10 Jahren gelernt hat, um ein CIRS moglichst optimal zu nutzen. Dem „Yorkshire Contributory Factors Framework“ folgend wird der Nutzen eines CIRS durch konkrete Beispiele aus der neonatologischen und padiatrischen Intensivpflegestation des Kinderspitals Luzern illustriert. Anschliesend werden, basierend auf einer Literatursuche in PubMed (von Januar 2000 bis Dezember 2014) die notwendigen Faktoren und Konzepte fur die erfolgreiche Nutzung eines CIRS definiert. Eine positive Grundhaltung gegenuber Fehlern, eine hohe psychologische Sicherheit und die Uberzeugung, dass ein CIRS nutzlich ist, sind Voraussetzungen vonseiten des Mitarbeiters, damit Vorfalle gemeldet werden und ein Lernen aus Fehlern moglich ist. Eine systematische Analyse der gemeldeten Vorfalle, personelle Ressourcen sowie eine entsprechende Verbreitung der Resultate und Umsetzung daraus abgeleiteter Verbesserungen sind wichtige Faktoren vonseiten der Organisation. Mithilfe des CIRS sollen alle sicherheitsrelevanten Ereignisse erfasst werden. Deren Kategorisierung erleichtert die Identifikation, die Analyse und das Formulieren entsprechender Schlussfolgerungen. Fur eine lernorientierte Sicherheitskultur mussen wir sowohl aus Fehlern als auch aus Erfolgen lernen. Sowohl Faktoren vonseiten des individuellen Mitarbeiters als auch vonseiten der Organisation sind entscheidend, um ein CIRS optimal zu nutzen.

© The Author(s)., [Background]: Dendritic messenger RNA (mRNA) localization and subsequent local translation in dendrites critically contributes to synaptic plasticity and learning and memory. Little is known, however, about the contribution of RNA-binding proteins (RBPs) to these processes in vivo. [Results]: To delineate the role of the double-stranded RBP Staufen2 (Stau2), we generate a transgenic rat model, in which Stau2 expression is conditionally silenced by Cre-inducible expression of a microRNA (miRNA) targeting Stau2 mRNA in adult forebrain neurons. Known physiological mRNA targets for Stau2, such as RhoA, Complexin 1, and Rgs4 mRNAs, are found to be dysregulated in brains of Stau2-deficient rats. In vivo electrophysiological recordings reveal synaptic strengthening upon stimulation, showing a shift in the frequency-response function of hippocampal synaptic plasticity to favor long-term potentiation and impair long-term depression in Stau2-deficient rats. These observations are accompanied by deficits in hippocampal spatial working memory, spatial novelty detection, and in tasks investigating associative learning and memory. [Conclusions]: Together, these experiments reveal a critical contribution of Stau2 to various forms of synaptic plasticity including spatial working memory and cognitive management of new environmental information. These findings might contribute to the development of treatments for conditions associated with learning and memory deficits., This study was supported by grants from the Spanish Ministry of Science and Competitiveness (BFU2014-56692-R to AG and JMD-G) and the Junta de Andalucía (Spain; BIO-122, CVI-02487, and P07-CVI-02686 to AG and JMD-G), from the European Community’s Seventh Framework Program (FP7/2007- 2013 to AG and DB) under grant agreement number 201714 (DEVANX), from the Austrian Science Fund (SFB-F43 to MAK) and the DFG (FOR2333 to MAK; SPP-1738 to MAK and DB). RS is a Boehringer Ingelheim Fonds fellow.

The influence of transverse concentration gradients on detonation propagation in $$\hbox {H}_2$$ –air mixtures is investigated experimentally in a wide parameter range. Detonation fronts are characterized by means of high-speed shadowgraphy, OH* imaging, pressure measurements, and soot foils. Steep concentration gradients at low average $$\hbox {H}_2$$ concentrations lead to single-headed detonations. A maximum velocity deficit compared to the Chapman–Jouguet velocity of 9 % is observed. Significant amounts of mixture seem to be consumed by turbulent deflagration behind the leading detonation. Wall pressure measurements show high local pressure peaks due to strong transverse waves caused by the concentration gradients. Higher average $$\hbox {H}_2$$ concentrations or weaker gradients allow for multi-headed detonation propagation.

This study used data from Waves 1 (1987–1989) and 2 (1992–1994) of the National Survey of Families and Households in the United States and a series of regression models, some of which included individual-specific fixed effects, to estimate associations of particular types and levels of debt with adult depressive symptoms. Results suggest that household debt is positively associated with greater depressive symptoms. However, this association appears to be driven by short-term (unsecured) debt; we found little evidence of associations with depressive symptoms for mid- or long-term debt. The link between short-term debt and depressive symptoms persisted with alternative estimation strategies, including defining debt in absolute and relative terms. Furthermore, this association was particularly concentrated among 51–64 year-old adults, those with a high school education or less, and those who were not stably married throughout the observation period. These findings suggest that short-term debt may have an adverse influence on psychological wellbeing, particularly for those who are less educated, approaching retirement age, or unmarried.

Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1(5-HT-/-) mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while α1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1(5-HT-/-) mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior.

The use of specific activators and inhibitors that penetrate the central nervous system has suggested an essential functional role of L-type calcium channels (LTCC) in several important physiological processes of the brain, including the modulation of the mesoaccumbal dopamine signalling pathway, synaptic transmission of auditory stimuli and synaptic plasticity of neutral and aversive learning and memory processes. However, the lack of selectivity of available pharmacological agents towards the most prominent LTCC isoforms in the brain, namely Cav1.2 and Cav1.3, has hampered the elucidation of the precise contribution made by each specific channel isoform within these specific physiological processes. Modern genetic approaches, both in rodents and in human, have recently enhanced our understanding of the selective functional roles of Cav1.2 and Cav1.3 channels. In rodents, the characterisation of global and conditional isoform-specific knockouts suggests a contribution of Cav1.2 channels in spatial memory formation, whereas Cav1.3 channels seem to be involved in the consolidation of fear memories and in neurodegenerative mechanisms associated with the development of Parkinson's disease. With regard to the molecular mechanisms underlying drug addiction, Cav1.3 channels are necessary for the development and Cav1.2 channels for the expression of cocaine and amphetamine behavioural sensitisation. In humans, both the identification of naturally occurring LTCC variants ("channelopathies") and unbiased genome-wide association studies have linked LTCCs to working memory performance in healthy individuals and schizophrenic patients. Individually, CACNA1C polymorphisms and CACNA1D variants have been linked to a variety of psychiatric diseases and to congenital deafness, respectively. However, the contribution of individual LTCCs and their polymorphisms to human brain function and diseases remains unclear, necessitating the use of isoform-specific pharmacological agents.

Seit uber 5 Jahren unterstutzt das Biomonitoring-Auskunftssystem der Bundesanstalt fur Arbeitsschutz und Arbeitsmedizin (BAuA) Betriebsarzte sowie andere Arbeitsschutzakteure bei ihren Recherchen nach gefahrstoffbezogenen Biomonitoring-Informationen. Das System basiert auf einer im Internet frei zuganglichen relationalen Datenbank und ermoglicht einzelstoff- und stoffgruppenbezogene Recherchen nach Untersuchungsparametern, Analysenverfahren, ihren Qualitatssicherungsmoglichkeiten sowie nach Beurteilungswerten. Das System wird stetig aktualisiert und inhaltlich erweitert. So wurden 2013 folgende Daten neu in das System aufgenommen: Biologische Arbeitsstofftoleranzwerte (BAT) der Schweizerischen Unfallversicherungsanstalt (Suva), gefahrstoffbezogene Biomonitoring-Grenzwerte der osterreichischen Verordnung uber die Gesundheitsuberwachung am Arbeitsplatz (VGU) sowie Analysenverfahren, die zur Ermittlung von Referenzwerten zur Gefahrstoffhintergrundbelastung der Bevolkerung der USA eingesetzt wurden. Zusatzlich konnten eine Vielzahl von Verlinkungen zu den zitierten Datenquellen und zu Fachtexten, z. B. zu den Stoffdossiers der MAK-Collection, in das System eingearbeitet werden. Eine seit 2013 technisch deutlich verbesserte Suchfunktion ermoglicht fehlertolerante Suchprozeduren.

Type IIA topoisomerases control DNA supercoiling and disentangle chromosomes by a complex, ATP-dependent strand passage mechanism. Although a general framework exists for type IIA topoisomerase function, the architecture of the full-length enzyme has remained undefined. Here we present the first structure of a fully-catalytic Saccharomyces cerevisiae topoisomerase II homodimer, complexed with DNA and a nonhydrolyzable ATP analog. The enzyme adopts a domain-swapped configuration wherein the ATPase domain of one protomer sits atop the nucleolytic region of its partner subunit. This organization produces an unexpected interaction between the bound DNA and a conformational transducing element in the ATPase domain, which we show is critical for both DNA-stimulated ATP hydrolysis and global topoisomerase activity. Our data indicate that the ATPase domains pivot about each other to ensure unidirectional strand passage and that this state senses bound DNA to promote ATP turnover and enzyme reset.

Schwerbrandverletzte (mehr als 20% verbrannter Korperoberflache bei Erwachsenen) weisen in der ersten Phase (8–48 h) einen durch das massive Kapillarleck bedingten Verbrennungsschock auf, der einer Infusionstherapie bedarf, um die Hamodynamik wieder herzustellen. Bis in die 80er Jahre stellte eine unzureichende Flussigkeitstherapie (Unterinfusion) die Haupttodesursache von Verbrennungspatienten dar. Seither ist die ubermasige Flussigkeitstherapie (Uberinfusion) zu einer beachtenswerten Quelle von Komplikationen geworden: abdominales Kompartmentsyndrom, Entlastungsschnitte (Escharotomie), Verschlechterung des Gasaustauschs, Verlangerung der kunstlichen Beatmung und des Spitalaufenthalts. Die Uberinfusion hat Ende der 90er Jahre begonnen, wo innerhalb der ersten 24 h Flussigkeitsmengen zugefuhrt wurden, die weit uber den 4 ml/kg/% BSA („burn surface area“) der Parkland-Formel lagen. Dieser Beitrag analysiert die Faktoren, welche zu einer Uberinfusion fuhren konnen und zeigt Moglichkeiten, dem durch eine strikte Kontrolle der praklinischen Infusionstherapie sowie durch eine permissive Hypovolamie vorzubeugen.

Bacterial DNA gyrase uses the energy from ATP to introduce negative supercoils into DNA via formation of a chiral wrap intermediate. Now DNA rotation and contraction are simultaneously visualized using a single-molecule setup. The data reveal multiple steps, including a dominant non-chiral intermediate step. DNA gyrase is a molecular motor that harnesses the free energy of ATP hydrolysis to introduce negative supercoils into DNA. A critical step in this reaction is the formation of a chiral DNA wrap. Here we observe gyrase structural dynamics using a single-molecule assay in which gyrase drives the processive, stepwise rotation of a nanosphere attached to the side of a stretched DNA molecule. Analysis of rotational pauses and measurements of DNA contraction reveal multiple ATP-modulated structural transitions. DNA wrapping is coordinated with the ATPase cycle and proceeds by way of an unanticipated structural intermediate that dominates the kinetics of supercoiling. Our findings reveal a conformational landscape of loosely coupled transitions funneling the motor toward productive energy transduction, a feature that may be common to the reaction cycles of other DNA and protein remodeling machines.

Research has been limited in circadian activity rhythms and their relationship with health status in early-stage breast cancer survivors. Maintaining strong circadian parameters may reduce symptoms and improve physical functioning and disease-free survival.This is a descriptive, correlational, secondary analysis of data from a randomized controlled trial collected 1 year after the first chemotherapy treatment; n = 156 cases with 7 days of wrist actigraph data of six circadian activity rhythm parameters; measures of function, fatigue, sleep, and anxiety/depression; and demographic/medical data including body mass index (BMI).In the total sample and three BMI categories, acrophase was the only circadian parameter that reached means established in healthy adults. In the total sample, phase-delayed acrophase was associated with higher depression (r = 0.180, p = 0.025) and lower morning energy (r = -0.194, p = 0.016) and trended for higher fatigue (r = 0.153, p = 0.057). Lower morning energy was also associated with a lower circadian quotient (r = 0.158, p = 0.05). As BMI increased, weaker circadian parameters were recorded consistently. When compared with women in normal BMI categories, obese women's amplitude and 24-h autocorrelation coefficient were significantly weaker (p = 0.011-0.015). In obese women, phase-delayed acrophase was correlated with higher fatigue and anxiety and with lower morning energy and physical functioning.Amplitude and 24-h autocorrelation parameters were significantly weaker, and phase-delayed acrophase was linked to several more intense symptoms and lower physical functioning in obese women.Clinicians need to target high-risk women with phase-delayed rhythms, higher symptoms, and lower physical functioning for intervention.

Compare outcomes with vaginal gel versus intramuscular progesterone replacement in donor oocyte recipients.A single-center retrospective analysis (January 2004-December 2006) evaluated pregnancy outcomes (serum human chorionic gonadotropin, implantation, clinical pregnancy, delivery, total pregnancy loss rates) for 225 recipients of embryos from donor (aged32 years) oocytes. Vaginal progesterone gel (Crinone® 8%; 90 mg twice daily; n = 105) or intramuscular progesterone (50 mg once daily; n = 120) was started the afternoon of oocyte retrieval and continued until a negative pregnancy test or 10 weeks' gestation.There were no statistically significant differences between groups for the five pregnancy outcomes; numerical results favored vaginal progesterone in all cases. Confidence intervals showed vaginal gel was within, or1% from, a noninferiority limit of 10% versus intramuscular progesterone for four of five pregnancy outcomes.Pregnancy outcomes were comparable for progesterone replacement with vaginal gel and intramuscular progesterone in an oocyte donation program.

Environmental compartments of riverine systems are polluted by organic contaminants in particular as a result of industrial activity. Sediments and soils of conjunct floodplains can act as archives for long-term anthropogenic pollution. While some chemicals are prevalent, several compounds show source specificity. Compounds closely related to industrial chemical processes comprise precursors, intermediates, and by- and side-products. To better understand the environmental fate of such contamination in aquatic systems, we examined historic sediments of the Mulde River, a riverine system adjacent to the former industrial area Bitterfeld-Wolfen, Germany. This industrial complex produced a variety of chemical compounds between 1950 and the late 1980s. Comparison with related, more recent soil samples from floodplains revealed the presence of these organic indicators (e.g., halogenated naphthalenes, tetrachlorothiophene, dichlorodiphenylsulfone, 1,1,1,2,2-pentachloroethylbenzene, chlorinated diphenylethers) in the uppermost soil layers even over 20 years after the general shutdown of industrial production. Concentrations of numerous non-source-specific pollutants such as DDT metabolites, chlorinated benzenes, and dinaphthyl sulfones were also elevated in most recent wetland soil layers. Generally, concentration profiles showed the highest concentration of compounds in the uppermost soil layer. With increasing soil depth, concentrations decreased. Therefore, the results suggest a continuous input of source and non-source specific contaminations over secondary pollution pathways. This long-term pollution of the environment poses a threat to the quality of riverine systems.

The general efficacy of psychotherapeutic approaches in the treatment of mental disorders has been demonstrated by meta-analyses. Disorder-specific methods are increasingly dominating the field. In the field of depression psychological interventions have proven to be as equally effective as pharmacotherapy in mild and moderate depressives but with longer lasting effects after termination of treatment. The combination of both methods is particularly relevant for the therapy of severe and chronic depression. The indications should be differentiated beyond the severity and course of the disorder, e.g. according to previous traumatization, comorbidity, patient difficulty and the empirical evidence of the different approaches.

Hintergrunde, Konzeption und vorlaufige Ergebnisse der Freiburger Arbeitsunfallstudie FAUST-II werden vorgestellt. Diese von der Deutschen Gesetzlichen Unfallversicherung (DGUV) geforderte Studie untersucht die psychischen Auswirkungen von schweren Arbeitsunfallen, deren screeningbasierte Fruherkennung und Moglichkeiten der psychologischen Fruhintervention. In 18 unfallchirurgischen Kliniken wird die praktische Anwendung eines screeningbasierten Diagnose- und Behandlungsalgorithmus fur psychische Gesundheitsstorungen unter Routinebedingungen evaluiert. Im Ausblick des vorliegenden Beitrags werden vorlaufige Schlussfolgerungen fur die Praxis und das Vorgehen der 2. Studienphase diskutiert.