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Background: We assessed the relationship between depressive symptoms and perceived COVID-19 risk in the next month. Methods: This analysis used survey data collected during a July 2020 cross-sectional study using a household-based probability sampling design. A total of 615 noninstitutionalized, English- and/or Spanish-speaking adults in Ohio were included. Depressive symptoms screening occurred using the Patient Health Questionnaire-2 (PHQ-2). We applied survey weights so that presented analyses represent the adult population in Ohio. We performed log-risk regression modeling (generalized linear model with binomial distribution and log link) to estimate unadjusted and covariate-adjusted prevalence ratios examining the association between screening positive for depressive symptoms and perceived risk of COVID-19 in the next month. Results: The study population was majority female (59.1%) and White (90.3%). The mean age was 55.9 years (standard deviation (SD)=17.3). About 1 in 20 (4.6%) screened positive for depressive symptoms. A positive depressive symptoms screen was not significantly associated with perceived risk of COVID-19 in the next month (prevalence ratio [PR]=0.75; 95% confidence interval [CI]=0.25–2.24). After confounder adjustment, the adjusted prevalence ratio (aPR) was nearly unchanged (aPR=0.78; 95% CI=0.24–2.55). Conclusion: As depression is often associated with anxiety and pessimism toward the future, the lack of association between depressive symptoms screening and perception of COVID-19 risk in the next month is surprising. Social withdrawal, which is also associated with depression, may have concealed any increased perceived COVID-19 risk, as depressed individuals who remained socially isolated may have had lower perceived COVID-19 risk.

miRNAs are noncoding RNAs with abnormal expression in breast cancer; their expression in high-risk benign breast tissue may relate to breast cancer risk. We examined miRNA profiles in contralateral unaffected breasts (CUB) of patients with breast cancer and validated resulting candidates in two additional sample sets. Expression profiles of 754 mature miRNAs were examined using TaqMan Low Density Arrays in 30 breast cancer samples [15 estrogen receptor (ER)-positive and 15 ER-negative] and paired CUBs and 15 reduction mammoplasty controls. Pairwise comparisons identified miRNAs with significantly differential expression. Seven candidate miRNAs were examined using qRT-PCR in a second CUB sample set (40 cases, 20 ER+, 20 ER−) and 20 reduction mammoplasty controls. Further validation was performed in 80 benign breast biopsy (BBB) samples; 40 from cases who subsequently developed breast cancer and 40 from controls who did not. Logistic regression, using tertiles of miRNA expression, was used to discriminate cases from controls. Seven miRNAs were differentially expressed in tumors and CUBs versus reduction mammoplasty samples. Among them, miR-18a and miR-210 were validated in the second CUB set, showing significantly higher expression in tumor and CUBs than in reduction mammoplasty controls. The expression of miR-18a and miR-210 was also significantly higher in BBB cases than in BBB controls. When both miR-18a and miR-210 were expressed in the upper tertiles in BBB, OR for subsequent cancer was 3.20, P = 0.023. miR-18a and miR-210 are expressed at higher levels in CUBs of patients with breast cancer, and in BBB prior to cancer development, and are therefore candidate breast cancer risk biomarkers. Cancer Prev Res; 10(1); 89–97. ©2016 AACR.

Supplemental Figure 1. Validation of miR-214*, miR-124, miR-193a-3p, miR-485a-3p and miR-671-3p in independent sample set of tumor (ER+T and ER-T) and matching contralateral breast (ER+C, ER-C) compared to reduction mammoplasty controls. Supplemental Figure 2. Expression of ER in (A) CUB validation samples and (B) BBB samples. (A) There is no significant difference between ER+ CUB (ER+C) or ER- CUB (ER-C) and controls. Only the tumor samples (ER+T, ER-T) showed the significant difference vs controls. *** P

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The US Neisseria meningitidis urethritis clade (US_NmUC) harbors gonococcal deoxyribonucleic acid alleles and causes gonorrhea-like urogenital tract disease. A large convenience sample of US_NmUC isolates (N = 122) collected between January 2015 and December 2019 in Columbus, Ohio demonstrated uniform susceptibility to antibiotics recommended for gonorrhea treatment and meningococcal chemoprophylaxis.

Cr phosphine catalysts are uniquely suited for industrial selective ethylene trimerization to 1-hexene. We recently introduced a Cr N-phosphinoamidine catalyst ((P,N)Cr) transition-state model for ...

Objectives The aim of this study was to analyse the course of the canalis sinuosus (CS) until its termination in the anterior maxilla and chart its anatomical relationship with surrounding structures using cone beam computed tomography (CBCT). Methods This study retrospectively analysed 100 CBCT scans (Accuitomo 170, Morita Corp., Kyoto, Japan) of the maxillary sinuses of patients at the Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern. Vertical and horizontal distances between various anatomical structures and the CS were recorded. Results The study included 62 females and 38 males with 45 right‐ and 55 left‐sided CBCTs selected by randomization. The mean age was 55.9 years (range 21–82 years). When comparing right‐ and left‐sided scans, there were statistically significant differences between a number of measurements. These included the most inferior point of the orbital rim and the floor of the nasal cavity (P = 0.04), the origin of the CS and the anterior loop of the descending CS (P = 0.034), and the origin of the CS and floor of the nasal cavity (P = 0.025). Conclusions The use of CBCT allowed investigation of the course of the CS as it progresses across the anterolateral wall of the maxillary sinus to be more accurately defined radiographically than has been previously described. There were some statistically significant differences between vertical measurements comparing left and right side, but none for age or gender. The rate of the identification of the CS using CBCT was 100%.

Quantum-mechanical-based computational design of molecular catalysts requires accurate and fast electronic structure calculations to determine and predict properties of transition-metal complexes. For Zr-based molecular complexes related to polyethylene catalysis, previous evaluation of density functional theory (DFT) and wavefunction methods only examined oxides and halides or select reaction barrier heights. In this work, we evaluate the performance of DFT against experimental redox potentials and bond dissociation enthalpies (BDEs) for zirconocene complexes directly relevant to ethylene polymerization catalysis. We also examined the ability of DFT to compute the fourth atomic ionization potential of zirconium and the effect the basis set selection has on the ionization potential computed with CCSD(T). Generally, the atomic ionization potential and redox potentials are very well reproduced by DFT, but we discovered relatively large deviations of DFT-calculated BDEs compared to experiment. However, evaluation of BDEs with CCSD(T) suggests that experimental values should be revisited, and our CCSD(T) values should be taken as most accurate.

The pathophysiological link between adiposity and blood pressure is not completely understood, and evidence suggests an influence of sex and genetic determinants. We aimed to identify the relationship between adiposity and blood pressure, independent of a robust set of lifestyle and metabolic factors, and to examine the modulating role of sex and Angiotensin-Converting Enzyme (ACE) insertion/deletion (I/D) polymorphisms. In the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) study cohort, 1211 normotensive individuals, aged 30 to 60 years and followed-up after 3.3 years, were characterized for lifestyle and metabolic factors, body composition, and ACE genotype. Body mass index (BMI) and waist circumference (WC) were independently associated with mean arterial pressure, with a stronger relationship in women than men (BMI: r =0.40 versus 0.30; WC: r =0.40 versus 0.30, both P ID and II ACE genotypes in both sexes ( P ACE genotype only in women ( P =0.03). A 5 cm larger WC at baseline increased the risk of developing hypertension at follow-up only in women (odds ratio, 1.56 [95% CI, 1.15–2.10], P =0.004) and in II genotype carriers (odds ratio, 1.87 [95% CI, 1.09–3.20], P =0.023). The hypertensive effect of adiposity is more pronounced in women and in people carrying the II variant of the ACE genotype, a marker of salt sensitivity.

The use of data science tools to provide the emergence of non-trivial chemical features for catalyst design is an important goal in catalysis science. Additionally, there is currently no general strategy for computational homogeneous, molecular catalyst design. Here, we report the unique combination of an experimentally verified DFT-transition-state model with a random forest machine learning model in a campaign to design new molecular Cr phosphine imine (Cr(P,N)) catalysts for selective ethylene oligomerization, specifically to increase 1-octene selectivity. This involved the calculation of 1-hexene : 1-octene transition-state selectivity for 105 (P,N) ligands and the harvesting of 14 descriptors, which were then used to build a random forest regression model. This model showed the emergence of several key design features, such as Cr–N distance, Cr–α distance, and Cr distance out of pocket, which were then used to rapidly design a new generation of Cr(P,N) catalyst ligands that are predicted to give >95% selectivity for 1-octene., The use of data science tools to provide the emergence of non-trivial chemical features for catalyst design is an important goal in catalysis science.

Die Einfuhrung einer elektronischen Patientenakte (EPA) an der Klinik fur Augenheilkunde am Universitatsklinikum des Saarlandes (UKS) im Januar 2016 war eine zeitgemase Antwort auf wachsende Dokumentationspflichten und schnell zunehmende elektronische Diagnostikdaten. Die herstellerseitig ausgelieferte Software ist auf Fachpraxen ausgelegt und kann den Anforderungen von Kliniken nicht „out-of-the-box“ gerecht werden. Wir stellten uns die Frage, welche Funktionen einer digitalen Akte uber die reine Ablosung der Papierakte hinaus den Klinikalltag erleichtern konnen und ob diese im laufenden Betrieb eingefuhrt werden konnen. Die EPA wurde gezielt hinsichtlich der Arbeitsprozesse und Dokumentationsanforderungen der Klinik fur Augenheilkunde am UKS individualisiert. Die Anpassungen umfassten nicht nur die nahtlose Integration in das Klinikinformationssystem (KIS), sondern auch die Struktur und visuelle Darstellung der EPA sowie funktionelle Erweiterungen zur Erstellung von Befundskizzen und zur Verfolgung von Patientenbewegungen innerhalb der Klinik. Uber eine internetbasierte Plattform wurde ein direkter Termin- und Datenaustausch mit Fachpraxen eingerichtet. Durch die Einfuhrung einer sog. „Geisterliste“ kann jederzeit nachvollzogen werden, wo sich die Patienten, die einem Arzt zugeordnet sind, gerade im Hause z. B. zur Diagnostik befinden. Die Erfassung der individuellen Behandlungszeit erlaubt eine Verfolgung der Patientenstrome innerhalb der Klinik, die daraufhin optimiert werden konnen. Bestehende Papierdokumente, insbesondere zur grafischen Erfassung von Befunden, wie z. B. Skizzen, wurden digital abgebildet, wodurch das Einscannen der Dokumente entfallt. Durch das UKS.AUGEN.NETZ wurde eine internetbasierte Moglichkeit geschaffen, durch die Fachpraxen Terminvereinbarungen fur Patienten online vornehmen sowie digitale Untersuchungsdaten und arztliche Korrespondenz austauschen konnen. Durch die bestandig enge Zusammenarbeit von Mitarbeitern der Klinik fur Augenheilkunde am UKS und dem Hersteller der Software kann eine kontinuierliche Optimierung der EPA auch bei laufendem Klinikbetrieb erfolgen und die Zusammenarbeit zwischen Klinik und niedergelassenen Praxen erleichtern.

Groundwater exchanges with most lakes are rarely quantified because there are many technical challenges to quantification. We investigated a lakebed mapping approach to infer the relative areas of groundwater exchange in 12 prairie shallow lakes and five Laurentian mixed forest shallow lakes in Minnesota, USA in 2011. We used a relatively common approach (seepage meters) to provide baseline information on the magnitude and direction of flow at four locations in each lake. To expand from point measurements to the whole-lake scale, we explored use of specific conductivity as a cheaper and more time efficient proxy for groundwater discharge to lakes. We validated the approach at near shore stations in each lake where seepage meter measurements and specific conductivity surveys overlapped. Specific conductivity surveys provided a similar assessment of groundwater discharge compared to seepage meters for 50% of the lake-sampling period combinations. The lakebed mapping approach, when validated for a lake with a limited number of seepage meter (or alternative methods) measurements, offers the advantages of being more time and labor efficient over the use of a similar number of seepage meter monitoring locations; seepage meters (or piezometers, for example) are costlier in terms of equipment and labor, even for single-lake studies. We show the combined approach could provide useful baselines for understanding and mapping groundwater exchange in shallow lakes.

Bacterial genomes encode various multidrug efflux pumps (MDR) whose specific conditions for fitness advantage are unknown. We show that the efflux pump MdtEF-TolC, in Escherichia coli, confers a fitness advantage during exposure to extreme acid (pH 2). Our flow cytometry method revealed pH-dependent fitness trade-offs between bile acids (a major pump substrate) and salicylic acid, a membrane-permeant aromatic acid that induces a drug resistance regulon but depletes proton motive force (PMF). The PMF drives MdtEF-TolC and related pumps such as AcrAB-TolC. Deletion of mdtE (with loss of the pump MdtEF-TolC) increased the strain’s relative fitness during growth with or without salicylate or bile acids. However, when the growth cycle included a 2-h incubation at pH 2 (below the pH growth range), MdtEF-TolC conferred a fitness advantage. The fitness advantage required bile salts but was decreased by the presence of salicylate, whose uptake is amplified by acid. For comparison, AcrAB-TolC, the primary efflux pump for bile acids, conferred a PMF-dependent fitness advantage with or without acid exposure in the growth cycle. A different MDR pump, EmrAB-TolC, conferred no selective benefit during growth in the presence of bile acids. Without bile acids, all three MDR pumps incurred a large fitness cost with salicylate when exposed at pH 2. These results are consistent with the increased uptake of salicylate at low pH. Overall, we showed that MdtEF-TolC is an MDR pump adapted for transient extreme-acid exposure and that low pH amplifies the salicylate-dependent fitness cost for drug pumps. IMPORTANCE Antibiotics and other drugs that reach the gut must pass through stomach acid. However, little is known of how extreme acid modulates the effect of drugs on gut bacteria. We find that extreme-acid exposure leads to a fitness advantage for a multidrug pump that otherwise incurs a fitness cost. At the same time, extreme acid amplifies the effect of salicylate selection against multidrug pumps. Thus, organic acids and stomach acid could play important roles in regulating multidrug resistance in the gut microbiome. Our flow cytometry assay provides a way to measure the fitness effects of extreme-acid exposure to various membrane-soluble organic acids, including plant-derived nutrients and pharmaceutical agents. Therapeutic acids might be devised to control the prevalence of multidrug pumps in environmental and host-associated habitats.

The aspirin derivative salicylate selects against bacterial multidrug efflux pumps of Escherichia coli K-12 such as MdtEF-TolC and EmrAB-TolC, and acid stress regulators such as GadE. Salicylate uptake is driven by the transmembrane pH gradient (ΔpH) and the proton motive force (PMF) which drives many efflux pumps. We used flow cytometry to measure the fitness tradeoffs of salicylate, bile acids, and extreme low pH for E. coli cultured with pump deletants. The AcrAB-TolC efflux pump conferred a fitness advantage in the presence of bile acids, an efflux substrate. Without bile acids, AcrA incurred a small fitness cost. The fitness advantage with bile acids was eliminated by the PMF uncoupler CCCP. The Gad acid fitness island encodes components of MdtEF-TolC (an acid-adapted efflux pump) as well as acid regulator GadE. The fitness advantage of E. coli cocultured with a Gad deletant (Δslp-gadX) was lost in the presence of salicylate. Salicylate caused an even larger fitness cost for GadE. MdtE incurred negative or neutral fitness under all media conditions, as did EmrA. But when the competition cycle included two hours at pH 2, MdtE conferred a fitness advantage. The MdtE advantage required the presence of bile acids. Thus, the MdtEF-TolC pump is useful to E. coli for transient extreme acid exposure comparable to passage through the acidic stomach. Salicylate selects against some multidrug efflux pumps, whereas bile acids selects for them; and these fitness tradeoffs are amplified by extreme acid.IMPORTANCEControl of drug resistance in gut microbial communities is a compelling problem for human health. Growth of gut bacteria is limited by host-produced acids such as bile acids, and may be modulated by plant-derived acids such as salicylic acid. Membrane-soluble organic acids can control bacterial growth by disrupting membranes, decreasing cell pH, and depleting PMF. Our flow cytometry assay measures the fitness effects of exposure to membrane-soluble organic acids, with growth cycles that may include a period of extreme acid. We find that extreme-acid exposure leads to a fitness advantage for a multidrug pump, MdtEF-TolC, which otherwise incurs a large fitness cost. Thus, organic acids and stomach acid may play important roles in controlling multidrug resistance in the gut microbiome. Therapeutic acids might be developed to limit the prevalence of multidrug resistance pumps in environmental and host-associated communities.

The use of data science tools to provide the emergence of nontrivial chemical features for catalyst design is an important goal in catalysis science. Additionally, there is currently no general strategy for computational homogeneous, molecular catalyst design. Here we report the unique combination of an experimentally verified DFT-transition-state model with a random forest machine learning model in a campaign to design new molecular Cr phosphine imine (Cr(P,N)) catalysts for selective ethylene oligomerization, specifically to increase 1-octene selectivity. This involved the calculation of 1-hexene:1- octene transition-state selectivity for 105 (P,N) ligands and the harvesting of 14 descriptors, which were then used to build a random forest regression model. This model showed the emergence of several key design features, such as Cr–N distance, Cr–α distance, and Cr distance out of pocket, which were then used to rapidly design a new generation of Cr(P,N) catalyst ligands that are predicted to give >95% selectivity for 1-octene

Molecular, Fe-catalyzed ethylene oligomerization provides access to a range of linear α-olefins (LAOs) that are used to produce polyethylene, lubricants, surfactants, and other commercial products. This work provides an experimental example of an Fe pendant donor diimine ((PDD)Fe) catalyzed ethylene oligomerization that showcases very high olefin oligomer purity without branching and provides K (propagation/(propagation + termination)) values of LAOs fractions, which show larger K values as a function of carbon chain length. This experimental example provided an anchor point to try to identify a practical density functional theory (DFT) protocol to model ethylene oligomerization branching, propagation/termination, and K values. Using M06-L DFT calculations, we successfully modeled the very high oligomerization purity for the (PDD)Fe catalyst, compared to the lower purity for the Fe tridentate pyridine bisimine (PBI)Fe catalyst, which showed enhanced regioselectivity for migratory insertion between Fe–H in...

Halobacterium sp. NRC-1 (NRC-1) is an extremely halophilic archaeon that is adapted to multiple stressors such as UV, ionizing radiation and arsenic exposure; it is considered a model organism for the feasibility of microbial life in iron-rich brine on Mars. We conducted experimental evolution of NRC-1 under acid and iron stress. NRC-1 was serially cultured in CM+ medium modified by four conditions: optimal pH (pH 7.5), acid stress (pH 6.3), iron amendment (600 μM ferrous sulfate, pH 7.5), and acid plus iron (pH 6.3, with 600 μM ferrous sulfate). For each condition, four independent lineages of evolving populations were propagated. After 500 generations, 16 clones were isolated for phenotypic characterization and genomic sequencing. Genome sequences of all 16 clones revealed 378 mutations, of which 90% were haloarchaeal insertion sequences (ISH) and ISH-mediated large deletions. This proportion of ISH events in NRC-1 was five-fold greater than that reported for comparable evolution of Escherichia coli. One acid-evolved clone had increased fitness compared to the ancestral strain when cultured at low pH. Seven of eight acid-evolved clones had a mutation within or upstream of arcD, which encodes an arginine-ornithine antiporter; no non-acid adapted strains had arcD mutations. Mutations also affected the arcR regulator of arginine catabolism, which protects bacteria from acid stress by release of ammonia. Two acid-adapted strains shared a common mutation in bop, which encodes bacterio-opsin, apoprotein for the bacteriorhodopsin light-driven proton pump. Thus, in the haloarchaeon NRC-1, as in bacteria, pH adaptation was associated with genes involved in arginine catabolism and proton transport. Our study is among the first to report experimental evolution with multiple resequenced genomes of an archaeon. Haloarchaea are polyextremophiles capable of growth under environmental conditions such as concentrated NaCl and desiccation, but little is known about pH stress. Interesting parallels appear between the molecular basis of pH adaptation in NRC-1 and in bacteria, particularly the acid-responsive arginine-ornithine system found in oral streptococci.

MAGEL2 encodes the L2 member of the MAGE (melanoma antigen) protein family. Protein truncating mutations in MAGEL2 cause Schaaf-Yang syndrome, and MAGEL2 is one of a small set of genes deleted in Prader-Willi syndrome. Excessive daytime sleepiness, night-time or early morning waking, and narcoleptic symptoms are seen in people with Prader-Willi syndrome and Schaaf-Yang syndrome, while mice carrying a gene-targeted Magel2 deletion have disrupted circadian rhythms. These phenotypes suggest that MAGEL2 is important for the robustness of the circadian rhythm. However, a cellular role for MAGEL2 has yet to be elucidated. MAGEL2 influences the ubiquitination of substrate proteins to target them for further modification or to alter their stability through proteasomal degradation pathways. Here, we characterized relationships among MAGEL2 and proteins that regulate circadian rhythm. The effect of MAGEL2 on the key circadian rhythm protein cryptochrome 1 (CRY1) was assessed using in vivo proximity labelling (BioID), immunofluorescence microscopy and ubiquitination assays. We demonstrate that MAGEL2 modulates the ubiquitination of CRY1. Further studies will clarify the cellular role MAGEL2 normally plays in circadian rhythm, in part through ubiquitination and regulation of stability of the CRY1 protein.

We describe the results of our combined experimental and computational investigation of structurally analogous (N-phosphinoamidinate)metal(N(SiMe3)2) precatalysts ((PN)M; M = Mn2+, Fe2+, Co2+, and Ni2+; d5–d8) in the isomerization–hydroboration of 1-octene, cis-4-octene, or trans-4-octene (1a–c) with HBPin. As part of this investigation, the synthesis and crystallographic characterization of diamagnetic (PN)Ni, ((PN)NiH)2, (PN)NiH(L) (L = pyridine or DMAP), and (PN)Ni(NHdipp) (dipp = 2,6-iPr2C6H3) are reported. Divergent catalytic reactivity and selectivity was noted for members of the (PN)M series; (PN)Mn and (PN)Ni afforded poor hydroboration yields, whereas the use of (PN)Fe or (PN)Co afforded high conversion and selectivity for the terminal borylation product, (n-octyl)BPin (2a). DFT calculations involving (PN)M as well as stoichiometric reactivity studies featuring (PN)Ni confirmed that (PN)MH intermediates generated upon reaction of (PN)M with HBPin represent viable catalytic species whereby formati...

Excess fat mass is a cardinal feature of Prader-Willi syndrome (PWS) that is recapitulated in the Magel2-null mouse model of this genetic disorder. There is a pressing need for drugs that can prevent or treat obesity in children with PWS. Recently, a clinical study of a controlled release form of the benzothiadiazine derivative diazoxide demonstrated improved metabolic parameters and decreased fat mass in obese children and adults with PWS. We tested whether chronic diazoxide administration can reduce fat mass and improve metabolism in mice lacking MAGEL2, a gene inactivated in PWS. Magel2-null and wild-type control mice were rendered obese by high fat diet feeding, then provided diazoxide while being maintained on a high fat diet. Treatment of obese mice with diazoxide reduced weight and body fat, lowered blood glucose and improved endurance capacity. Treatment with diazoxide partially normalizes obesity in children and adults with PWS and in a PWS mouse model, demonstrating that the biological pathways impacted by diazoxide may be rational pharmacological targets in PWS and other disorders diseases associated with obesity.

Computational design of molecular homogeneous organometallic catalysts followed by experimental realization remains a significant challenge. Here, we report the development and use of a density functional theory transition-state model that provided quantitative prediction of molecular Cr catalysts for controllable selective ethylene trimerization and tetramerization. This computational model identified a general class of phosphine monocyclic imine (P,N)-ligand Cr catalysts where changes in the ligand structure control 1-hexene versus 1-octene selectivity. Experimental ligand and catalyst synthesis as well as reaction testing quantitatively confirmed predictions.

Zwischen 1991 und 2003 fielen bei ehemals gegenuber 1,3-Butadien exponierten Industriearbeitern einige Falle kolorektaler Karzinome auf. Ein entsprechendes Risikopotenzial wurde auch in der relevanten Fachliteratur diskutiert. Folglich wurden eine retrospektive und eine prospektive Kohortenstudie zur weiteren Untersuchung veranlasst. Das Risiko kolorektaler Karzinome wurde in einer Kohorte mit gesichertem Expositionsstatus gegenuber 1,3-Butadien im Vergleich zur Normalbevolkerung untersucht. Die Inzidenz kolorektaler Karzinome wurde in einer Kohorte von 700 Industriearbeitern uber einen Zeitraum von 24 Jahren mit umgerechnet 10.570 Personenjahren untersucht. Ein Vergleich mit einer entsprechenden Normalbevolkerung erfolgte standardisiert nach Alter, Geschlecht und Kalenderjahr fur die gesamte Kohorte und fur Subgruppen exponierter und nicht exponierter Arbeiter. Die initiale Beobachtung in den Jahren 1991 bis 2003 wurde in einem zweiten Untersuchungszeitraum zwischen 2004 und 2015 validiert. Das standardisierte Risikoverhaltnis der Kohorte zur Normalbevolkerung betrug 1,89 (p = 0,009) insgesamt und 1,86 (p = 0,073) in der Validierung. Bei exponierten Arbeitern sind die entsprechenden Risikoverhaltnisse 1,23 (p = 0,684) und 0,63 (p = 0,641), bei nichtexponierten Arbeitern 2,31 (p = 0,003) und 2,59 (p = 0,009). Die Studienergebnisse weisen auf eine Risikoerhohung in der untersuchten Kohorte hin. Ein eindeutiger Schluss ist aufgrund fehlender statistischer Signifikanz in der Validierung jedoch nicht moglich. Insbesondere in der Subgruppe exponierter Arbeiter gab es in der Validierung keinen Hinweis auf eine Risikoerhohung.

Background For more than 60 years patient records of the Department of Ophthalmology at the Saarland Medical Center in Homburg were documented on handwritten paper documents and filed in archives. Increasing requirements for medical documentation, exploding volumes of diagnostic data, overcrowded archives and unavailable files when needed, were the essential rationales for the implementation of an electronic patient archive (EPA). Methods The EPA has been specifically adapted to the requirements of the Department of Ophthalmology in order to guarantee a standardized unobstructed documentation and patient care across all sections of the department. Seamless integration into the clinic information system (KIS) and network-compatible diagnostic software were essential as well as a timely digitization of existing paper charts. Decisive factors for using FIDUS (Arztservice Wente GmbH, Darmstadt, Germany) as the EPA software were the visual layout of the EPA, user friendliness and reference installations of the software in other ophthalmology departments. Results After one and a half years of meticulous preparation with specific adaptations to the requirements of our department, the EPA was finally implemented in January 2016 and since then we have been working on improvements. The EPA software retrieves basic patient data from the KIS and diagnostic data from electronic devices via various interfaces. Expenses for printers could be reduced but computer workplaces had to be expanded or newly created. For previous patients paper files are digitized externally and stored in an electronic archive directly accessible from the EPA. Discussion Successful reorganization and implementation of electronic documentation during clinical routine is feasible with careful preparation and timely involvement of information technology experts, motivated physicians, nurses, research departments and the administration.

One of the remaining “grand challenges” in chemistry is the development of a next generation, less expensive, cleaner process that can allow the vast reserves of methane from natural gas to augment or replace oil as the source of fuels and chemicals. Homogeneous (gas/liquid) systems that convert methane to functionalized products with emphasis on reports after 1995 are reviewed. Gas/solid, bioinorganic, biological, and reaction systems that do not specifically involve methane functionalization are excluded. The various reports are grouped under the main element involved in the direct reactions with methane. Central to the review is classification of the various reports into 12 categories based on both practical considerations and the mechanisms of the elementary reactions with methane. Practical considerations are based on whether or not the system reported can directly or indirectly utilize O2 as the only net coreactant based only on thermodynamic potentials. Mechanistic classifications are based on whet...

The first examples of stoichiometric dehydrogenative B-H/C(sp3 )-H benzylic borylation reactions, which are of relevance to catalytic methylarene (di)borylation, are reported. These unusual transformations involving a (κ2 -P,N)Pt(η3 -benzyl) complex, and either pinacolborane or catecholborane, proceed cleanly at room temperature. Density functional calculations suggest that borylation occurs via successive σ-bond metathesis steps, whereby a PtII -H intermediate engages in C(sp3 )-H bond activation-induced dehydrogenation.

Purpose: miRNAs are non-coding RNAs that are abnormally expressed in breast cancer, with critical roles in cancer due to their regulation of large gene networks. miRNA expression in benign high-risk breast tissue has never been evaluated, but it may provide information about early dysregulation events that contribute to breast cancer risk. The contralateral unaffected breast (CUB) of women with unilateral breast cancer is in high-risk for the second primary cancer. Thus, we examined miRNA expression profiles in tumor and the matching CUBs to seek potential miRNA biomarkers for breast cancer risk. Methods: FFPE tissues of breast cancer and their matching CUB tissues were sectioned. The areas of tumor and normal ductal epithelium were outlined and then dissected using laser microdissection system. Total RNA was extracted for miRNA profiling studies. Expression profiles of 754 mature miRNAs were examined using TaqMan Low Density Arrays assays in 30 paired breast cancer and CUB samples (15 with ER+ tumors, 15 with ER- tumors) and 15 reduction mammoplasty (RM) controls, matched by age, race and menopausal status. ANOVA test was performed to examine the differential expression among groups and pairwise comparison with Sidak adjustment was used for multiple comparison. Seven candidate miRNAs were then examined in an independent CUB sample set (20 with ER+ tumors, 20 with ER- tumors) and 20 RM controls. Further independent validation was performed using qRT-PCR in 80 benign breast biopsy (BBB) samples: 40 from women who subsequently developed breast cancer (cases) and 40 from those who did not (controls). Logistic regression analysis and receiver operating characteristic (ROC) analysis were performed using combinations of the expression of multiple miRNAs to establish models discriminating cases from controls. Results: Seven miRNAs (miR-18a, miR-210, miR-214*, miR-124, miR-193a-3p, miR485-3p and miR-671-3p) were found to be differentially expressed in breast cancer and CUB samples vs. RM samples in the discovery sample set. Among them, miR-18a and miR-210 were validated in a second, independent CUB sample set. The expression of miR-18a and miR-210 were significantly higher in tumor (regardless ER status) compared to CUBs and RM controls. The expression levels in CUBs were significantly higher than in RM. We then examined miR expression in case BBB samples, and confirmed that expression of miR-18a and miR-210 were increased compared with controls. ROC analysis using miR-18a and miR-210 discriminated high-risk cases from standard-risk controls with OR 2.44, P = 0.022. Conclusion: The expression of miR-18a and miR-210 were elevated in breast cancer, in matched CUBs, and in BBB predating cancer diagnosis. These data provide strong support for the hypothesis that miR-18a and miR-210 expression in BBB is an indicator of increased risk of breast cancer. Given the high expression in tumors, they are also potential cancer detection biomarkers. Citation Format: Wang J, Shidfar A, Costa FF, Scholtens D, Bischof JM, Sullivan ME, Ivancic D, Soares MB, Khan SA. Expression of miR-18a and miR-210 in normal breast tissue as candidate markers of breast cancer risk [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-07-02.

Halobacterium sp. NRC-1 (NRC-1) is an extremely halophilic archaeon that is adapted to multiple stressors such as UV, ionizing radiation and arsenic exposure; it is considered a model organism for the feasibility of microbial life in iron-rich brine on Mars. We conducted experimental evolution of NRC-1 under acid and iron stress. NRC-1 was serially cultured in CM+ medium modified by four conditions: optimal pH (pH 7.5), acid stress (pH 6.3), iron amendment (600 μM ferrous sulfate, pH 7.5), and acid plus iron (pH 6.3, with 600 μM ferrous sulfate). For each condition, four independent lineages of evolving populations were propagated. After 500 generations, 16 clones were isolated for phenotypic characterization and genomic sequencing. Genome sequences of all 16 clones revealed 378 mutations, of which 90% were haloarchaeal insertion sequences (ISH) and ISH-mediated large deletions. This proportion of ISH events in NRC-1 was five-fold greater than that reported for comparable evolution of Escherichia coli. One acid-evolved clone had increased fitness compared to the ancestral strain when cultured at low pH. Seven of eight acid-evolved clones had a mutation within or upstream of arcD, which encodes an arginine-ornithine antiporter; no non-acid adapted strains had arcD mutations. Mutations also affected the arcR regulator of arginine catabolism, which protects bacteria from acid stress by release of ammonia. Two acid-adapted strains shared a common mutation in bop, which encodes bacterio-opsin, apoprotein for the bacteriorhodopsin light-driven proton pump. Thus, in the haloarchaeon NRC-1, as in bacteria, pH adaptation was associated with genes involved in arginine catabolism and proton transport. Our study is among the first to report experimental evolution with multiple resequenced genomes of an archaeon. Haloarchaea are polyextremophiles capable of growth under environmental conditions such as concentrated NaCl and desiccation, but little is known about pH stress. Interesting parallels appear between the molecular basis of pH adaptation in NRC-1 and in bacteria, particularly the acid-responsive arginine-ornithine system found in oral streptococci.

Background Halobacterium sp. NRC-1 (NRC-1) is an extremely halophilic archaeon that is adapted to multiple stressors such as UV, ionizing radiation and arsenic exposure. We conducted experimental evolution of NRC-1 under acid stress. NRC-1 was serially cultured in CM+ medium modified by four conditions: optimal pH (pH 7.5), acid stress (pH 6.3), iron amendment (600 μM ferrous sulfate, pH 7.5), and acid plus iron (pH 6.3, with 600 μM ferrous sulfate). For each condition, four independent lineages of evolving populations were propagated. After 500 generations, 16 clones were isolated for phenotypic characterization and genomic sequencing. Results Genome sequences of all 16 clones revealed 378 mutations, of which 90% were haloarchaeal insertion sequences (ISH) and ISH-mediated large deletions. This proportion of ISH events in NRC-1 was five-fold greater than that reported for comparable evolution of E. coli. One acid-evolved clone had increased fitness compared to the ancestral strain when cultured at low pH. Seven of eight acid-evolved clones had a mutation within or upstream of arcD, which encodes an arginine-ornithine antiporter; no non-acid adapted strains had arcD mutations. Mutations also affected the arcR regulator of arginine catabolism, which protects bacteria from acid stress by release of ammonia. Two acid-adapted strains shared a common mutation in bop, which encodes the bacteriorhodopsin light-driven proton pump. Unrelated to pH, one NRC-1 minichromosome (megaplasmid) pNRC100 had increased copy number, and we observed several mutations that eliminate gas vesicles and arsenic resistance. Thus, in the haloarchaeon NRC-1, as in bacteria, pH adaptation was associated with genes involved in arginine catabolism and proton transport. Conclusions Our study is among the first to report experimental evolution with multiple resequenced genomes of an archaeon. Haloarchaea are polyextremophiles capable of growth under environmental conditions such as concentrated NaCl and desiccation, but little is known about pH stress. Halobacterium sp. NRC-1 (NRC-1) is considered a model organism for the feasibility of microbial life in iron-rich brine on Mars. Interesting parallels appear between the molecular basis of pH adaptation in NRC-1 and in bacteria, particularly the acid-responsive arginine-ornithine system found in oral streptococci.

BackgroundHalobacterium sp. NRC-1 (NRC-1) is an extremely halophilic archaeon that is adapted to multiple stressors such as UV, ionizing radiation and arsenic exposure. We conducted experimental evolution of NRC-1 under acid stress. NRC-1 was serially cultured in CM+ medium modified by four conditions: optimal pH (pH 7.5), acid stress (pH 6.3), iron amendment (600 μM ferrous sulfate, pH 7.5), and acid plus iron (pH 6.3, with 600 μM ferrous sulfate). For each condition, four independent lineages of evolving populations were propagated. After 500 generations, 16 clones were isolated for phenotypic characterization and genomic sequencing.ResultsGenome sequences of all 16 clones revealed 378 mutations, of which 90% were haloarchaeal insertion sequences (ISH) and ISH-mediated large deletions. This proportion of ISH events in NRC-1 was five-fold greater than that reported for comparable evolution of E. coli. One acid-evolved clone had increased fitness compared to the ancestral strain when cultured at low pH. Seven of eight acid-evolved clones had a mutation within or upstream of arcD, which encodes an arginine-ornithine antiporter; no non-acid adapted strains had arcD mutations. Mutations also affected the arcR regulator of arginine catabolism, which protects bacteria from acid stress by release of ammonia. Two acid-adapted strains shared a common mutation in bop, which encodes the bacteriorhodopsin light-driven proton pump. Unrelated to pH, one NRC-1 minichromosome (megaplasmid) pNRC100 had increased copy number, and we observed several mutations that eliminate gas vesicles and arsenic resistance. Thus, in the haloarchaeon NRC-1, as in bacteria, pH adaptation was associated with genes involved in arginine catabolism and proton transport.ConclusionsOur study is among the first to report experimental evolution with multiple resequenced genomes of an archaeon. Haloarchaea are polyextremophiles capable of growth under environmental conditions such as concentrated NaCl and desiccation, but little is known about pH stress. Halobacterium sp. NRC-1 (NRC-1) is considered a model organism for the feasibility of microbial life in iron-rich brine on Mars. Interesting parallels appear between the molecular basis of pH adaptation in NRC-1 and in bacteria, particularly the acid-responsive arginine-ornithine system found in oral streptococci.

Introduction Apical surgery is frequently indicated in maxillary first molars. Occasionally, a vascular anastomosis in the lateral maxillary sinus wall can be observed during surgery. The aim of this study was to examine the distance between the vascular bone channel (VBC) and the root apices of maxillary first molars using cone-beam computed tomographic imaging. Methods Cone-beam computed tomographic images of 104 maxillary first molars were oriented in the coronal plane to evaluate the distance between the roots and the VBC. The measurements were only recorded in relation to the buccal roots. In addition, demographic parameters and further measurements such as the diameter of the VBC and the proximity to the periapical pathology were evaluated. Results A total of 210 VBCs were assessed. The mean distance from the VBC to the apices of the buccal roots of the maxillary first molars was 6.18 mm ± 3.84 mm. The VBC was mostly located intrasinusally (74.3%) and only rarely superficially (0.5%). The diameter of the VBC was on average 0.88 ± 0.32 mm. Conclusions In this study, the VBC was usually found closer to the mesiobuccal than to the distobuccal root apex. During preparation of the access window, the existence of the VBC should be kept in mind because the mesiobuccal roots of maxillary first molars undergo apical surgery to the buccally positioned roots only.

Benzoic acid, a partial uncoupler of the proton motive force (PMF), selects for sensitivity to chloramphenicol and tetracycline during the experimental evolution of Escherichia coli K-12. Transcriptomes of E. coli isolates evolved with benzoate showed the reversal of benzoate-dependent regulation, including the downregulation of multidrug efflux pump genes, the gene for the Gad acid resistance regulon, the nitrate reductase genes narHJ, and the gene for the acid-consuming hydrogenase Hyd-3. However, the benzoate-evolved strains had increased expression of OmpF and other large-hole porins that admit fermentable substrates and antibiotics. Candidate genes identified from benzoate-evolved strains were tested for their roles in benzoate tolerance and in chloramphenicol sensitivity. Benzoate or salicylate tolerance was increased by deletion of the Gad activator ariR or of the acid fitness island from slp to the end of the gadX gene encoding Gad regulators and the multidrug pump genes mdtEF. Benzoate tolerance was also increased by deletion of multidrug component gene emrA, RpoS posttranscriptional regulator gene cspC, adenosine deaminase gene add, hydrogenase gene hyc (Hyd-3), and the RNA chaperone/DNA-binding regulator gene hfq. Chloramphenicol resistance was decreased by mutations in genes for global regulators, such as RNA polymerase alpha subunit gene rpoA, the Mar activator gene rob, and hfq. Deletion of lipopolysaccharide biosynthetic kinase gene rfaY decreased the rate of growth in chloramphenicol. Isolates from experimental evolution with benzoate had many mutations affecting aromatic biosynthesis and catabolism, such as aroF (encoding tyrosine biosynthesis) and apt (encoding adenine phosphoribosyltransferase). Overall, benzoate or salicylate exposure selects for the loss of multidrug efflux pumps and of hydrogenases that generate a futile cycle of PMF and upregulates porins that admit fermentable nutrients and antibiotics. IMPORTANCE Benzoic acid is a common food preservative, and salicylic acid (2-hydroxybenzoic acid) is the active form of aspirin. At high concentrations, benzoic acid conducts a proton across the membrane, depleting the proton motive force. In the absence of antibiotics, benzoate exposure selects against proton-driven multidrug efflux pumps and upregulates porins that admit fermentable substrates but that also allow the entry of antibiotics. Thus, evolution with benzoate and related molecules, such as salicylates, requires a trade-off for antibiotic sensitivity, a trade-off that could help define a stable gut microbiome. Benzoate and salicylate are naturally occurring plant signal molecules that may modulate the microbiomes of plants and animal digestive tracts so as to favor fermenters and exclude drug-resistant pathogens.

The implementation of electronic medical records (EMR) in the Department of Ophthalmology at the Saarland University Medical Center (UKS) in January 2016 was a timely response to growing documentation requirements and rapidly increasing electronic diagnostic data. The software system was primarily developed for private practices and cannot therefore meet the different requirements of various clinics out of the box. The purpose of this study was to identify features of the EMR beyond purely paper replacement that can assist in the clinical workflow and whether these features can be implemented in a running system.The EMR was specifically individualized with respect to the work processes and documentation requirements of the Department of Ophthalmology at the UKS. In addition to a seamless integration into the hospital information system (HIS) the modifications included changes in the structure and visual presentation of the EMR as well as functional extensions. An internet-based platform was set up to enable a direct exchange of appointments and patient data with specialist practices.Due to the introduction of a so-called ghost list the position of patients within the hospital who are allocated to a physician, e.g. for diagnostics, can be reconstructed at any point in time. The logging of the individual treatment times enables tracking of patient flow within the clinic and a reduction of waiting times. Existing paper documents particularly for the graphic recording of findings, such as sketches, are digitalized eliminating the need to scan documents. The UKS.AUGEN.NETZ is an internet-based portal to facilitate direct organization of appointments with specialist practitioners and for the exchange of digital examination data and medical correspondence.The permanent close cooperation between employees of the Department of Ophthalmology at the UKS and the manufacturer of the software enables a continuous optimization of the EMR in a fully operational clinical workflow. In addition, the web-based interface improves the cooperation between the hospital and private practices.

Experimental evolution of Escherichia coli K-12 with benzoate, a partial uncoupler of the proton motive force (PMF), selects for mutations that decrease antibiotic resistance. We conducted experimental evolution in the presence of carbonyl cyanide m-chlorophenylhydrazone (CCCP), a strong uncoupler. Cultures were serially diluted daily 1:100 in LBK medium containing 20-150 µM CCCP buffered at pH 6.5 or at pH 8.0. After 1,000 generations, the populations tolerated up to 150 µM CCCP. Sequenced isolates had mutations in mprA ( emrR ), which downregulates the EmrAB-TolC pump that exports CCCP. A mprA :: kanR deletion conferred growth at 60 CCCP, though not at the higher levels resisted by evolved strains (150 µM). Some mprA mutant strains also had point mutations affecting emrA , but deletion of emrA abolished the CCCP resistance. Thus, CCCP-evolved isolates contained additional adaptations. One isolate lacked emrA or mprA mutations but had mutations in cecR ( ybiH ) whose product upregulates drug pumps YbhG and YbhFSR; and in gadE , which upregulates multidrug pump mdtEF . A cecR :: kanR deletion conferred partial resistance to CCCP. Other multidrug efflux genes that had mutations include ybhR and acrAB . The acrB isolate was sensitive to AcrAB substrates chloramphenicol and tetracycline. Other mutant genes in CCCP-evolved strains include rng (ribonuclease G) and cyaA (adenylate cyclase). Overall, experimental evolution revealed a CCCP-dependent fitness advantage for mutations increasing CCCP efflux via EmrA; and for mutations that may deactivate proton-driven pumps for drugs not present ( cecR , gadE , acrAB , ybhR ). These results are consistent with our previous report of drug sensitivity associated with evolved benzoate tolerance. IMPORTANCE The genetic responses of bacteria to depletion of proton motive force (PMF), and their effects on drug resistance, are poorly understood. PMF drives export of many antibiotics, but the energy cost may decrease fitness when antibiotics are absent. Our evolution experiment reveals genetic mechanisms of adaptation to the PMF uncoupler CCCP, including selection for increased CCCP efflux, but also against the expression of PMF-driven pumps for drugs not present. The results have implications for our understanding of the gut microbiome, which experiences high levels of organic acids that decrease PMF.

An ongoing challenge in the analysis of document collections is how to summarize content in terms of a set of inferred themes that can be interpreted substantively in terms of topics. The current practice of parameterizing the themes in terms of most frequent words limits interpretability by ignoring the differential use of words across topics. Here, we show that words that are both frequent and exclusive to a theme are more effective at characterizing topical content, and we propose a regularization scheme that leads to better estimates of these quantities. We consider a supervised setting where professional editors have annotated documents to topic categories, organized into a tree, in which leaf-nodes correspond to more specific topics. Each document is annotated to multiple categories, at different levels of the tree. We introduce a hierarchical Poisson convolution model to analyze these annotated documents. A parallelized Hamiltonian Monte Carlo sampler allows the inference to scale to millio...

Background and purpose α- and β-melanocyte-stimulating hormones (MSH) are derived from pro-opiomelanocortin (POMC) and are the natural agonist ligands of the melanocortin 4 receptor, a key regulator of energy homeostasis. Recent rodent and human data have implicated the MAGEL2 gene, which may regulate activation of POMC neurons, as a significant contributor to the metabolic symptoms observed in Prader-Willi Syndrome (PWS). Firstly, patients with protein truncating mutations in MAGEL2 exhibit numerous clinical characteristics of PWS. Secondly, Magel2-null mice may not normally activate MC4 receptors, as they are defective in the activation of their POMC neurons and hence may fail to normally release the POMC-derived MC4 receptor agonist ligands α- and β-MSH. Magel2-null mice represent a tractable animal model for the metabolic and appetitive imbalance seen in patients with PWS. Experimental approach We tested a dose titration of the MC4 receptor agonist setmelanotide, in development for rare monogenic forms of obesity, in Magel2-null mice. Key results We show that Magel2-null mice are hypersensitive to the appetite suppressing and metabolic effects of setmelanotide. Conclusion and implications Setmelanotide may be a useful investigational hormone/neuropeptide replacement therapy for PWS and rare monogenic forms of obesity exhibiting impaired function of POMC neurons.

Prader-Willi syndrome is characterized by severe hypotonia in infancy, with decreased lean mass and increased fat mass in childhood followed by severe hyperphagia and consequent obesity. Scoliosis and other orthopaedic manifestations of hypotonia are common in children with Prader-Willi syndrome and cause significant morbidity. The relationships among hypotonia, reduced muscle mass and scoliosis have been difficult to establish. Inactivating mutations in one Prader-Willi syndrome candidate gene, MAGEL2, cause a Prader-Willi-like syndrome called Schaaf-Yang syndrome, highlighting the importance of loss of MAGEL2 in Prader-Willi syndrome phenotypes. Gene-targeted mice lacking Magel2 have excess fat and decreased muscle, recapitulating altered body composition in Prader-Willi syndrome. We now demonstrate that Magel2 is expressed in the developing musculoskeletal system, and that loss of Magel2 causes muscle-related phenotypes in mice consistent with atrophy caused by altered autophagy. Magel2-null mice serve as a preclinical model for therapies targeting muscle structure and function in children lacking MAGEL2 diagnosed with Prader-Willi or Schaaf-Yang syndrome.