Development and comparison of an esophageal Doppler monitoring-based treatment algorithm with a heart rate and blood pressure-based treatment algorithm for goal-directed fluid therapy in anesthetized dogs: A pilot study

The objective of this pilot study was to determine the feasibility of a study comparing the efficacy of an esophageal Doppler monitor (EDM)-based fluid therapy algorithm with a heart rate (HR)- and mean arterial blood pressure (MAP)-based algorithm in reducing hypotension and fluid load in anesthetized dogs. Client-owned dogs undergoing general anesthesia for surgical procedures were randomized to two groups. An EDM probe for monitoring blood flow in the descending aorta was placed in each dog before receiving a crystalloid bolus (5 mL/kg) over 5 min. Fluids were repeated in case of fluid responsiveness defined by increasing Velocity Time Integral (VTI) ≥ 10% in group EDM and by decreasing HR ≥ 5 beats/min and/or increasing MAP ≥ 3 mmHg in group standard. The feasibility outcomes included the proportion of dogs completing the study and the clinical applicability of the algorithms. The clinical outcomes were the total administered fluid volume and the duration of hypotension defined as MAP < 60 mmHg. Data was compared between groups with Mann-Whitney U-test. p < 0.05 were deemed significant. Of 25 dogs screened, 14 completed the study (56%). There were no differences in the proportion of recorded time spent in hypotension in group standard [2 (0–39)% (median (range))] and EDM [0 (0–63) %, p = 1], or the total volume of fluids [standard 8 (5–14) mL/kg/h, EDM 11 (4–20) mL/kg/h, p = 0.3]. This study declined the feasibility of a study comparing the impact of two newly developed fluid therapy algorithms on hypotension and fluid load in their current form. Clinical outcome analyses were underpowered and no differences in treatment efficacy between the groups could be determined. The conclusions drawn from this pilot study provide important information for future study designs

Deliberate control over facial expressions in motherhood. Evidence from a Stroop-like task.

The deliberate control of facial expressions is an important ability in human interactions, in particular for mothers with prelinguistic infants. Because research on this topic is still scarce, we investigated the control over facial expressions in a Stroop-like paradigm. Mothers of 2-6 months old infants and nullipara women produced smiles and frowns in response to verbal commands written on distractor faces of adults or infants showing expressions of happiness or anger/distress. Analyses of video recordings with a machine classifier for facial expression revealed pronounced effects of congruency between the expressions required by the participants and those displayed by the face stimuli on the onset latencies of the deliberate facial expressions. With adult distractor faces this Stroop effect was similar whether participants smiled or frowned. With infant distractor faces mothers and non-mothers showed indistinguishable Stroop effects on smile responses; however, for frown responses, the Stroop effect in mothers was smaller than in non-mothers. We suggest that for frown responses in mothers when facing infants, the effect of mimicry or stimulus response compatibility, leading to the Stroop effect, is offset by a caregiving response or empathy

Can BioSAXS detect ultrastructural changes of antifungal compounds in Candida albicans?–an exploratory study

The opportunistic yeast Candida albicans is the most common cause of candidiasis. With only four classes of antifungal drugs on the market, resistance is becoming a problem in the treatment of fungal infections, especially in immunocompromised patients. The development of novel antifungal drugs with different modes of action is urgent. In 2016, we developed a groundbreaking new medium-throughput method to distinguish the effects of antibacterial agents. Using small-angle X-ray scattering for biological samples (BioSAXS), it is now possible to screen hundreds of new antibacterial compounds and select those with the highest probability for a novel mode of action. However, yeast (eukaryotic) cells are highly structured compared to bacteria. The fundamental question to answer was if the ultrastructural changes induced by the action of an antifungal drug can be detected even when most structures in the cell stay unchanged. In this exploratory work, BioSAXS was used to measure the ultrastructural changes of C. albicans that were directly or indirectly induced by antifungal compounds. For this, the well-characterized antifungal drug Flucytosine was used. BioSAXS measurements were performed on the synchrotron P12 BioSAXS beamline, EMBL (DESY, Hamburg) on treated and untreated yeast C. albicans. BioSAXS curves were analysed using principal component analysis (PCA). The PCA showed that Flucytosine-treated and untreated yeast were separated. Based on that success further measurements were performed on five antifungal peptides {1. Cecropin A-melittin hybrid [CA (1–7) M (2–9)], KWKLFKKIGAVLKVL; 2. Lasioglossin LL-III, VNWKKILGKIIKVVK; 3. Mastoparan M, INLKAIAALAKKLL; 4. Bmkn2, FIGAIARLLSKIFGKR; and 5. optP7, KRRVRWIIW}. The ultrastructural changes of C. albicans indicate that the peptides may have different modes of action compared to Flucytosine as well as to each other, except for the Cecropin A-melittin hybrid [CA (1–7) M (2–9)] and optP7, showing very similar effects on C. albicans. This very first study demonstrates that BioSAXS shows promise to be used for antifungal drug development. However, this first study has limitations and further experiments are necessary to establish this application

The dolphin proline-rich antimicrobial peptide Tur1A inhibits protein synthesis by targeting the bacterial ribosome

Proline-rich antimicrobial peptides (PrAMPs) internalize into susceptible bacteria using specific transporters and interfere with protein synthesis and folding. To date, mammalian PrAMPs have so far only been identified in artiodactyls. Since cetaceans are co-phyletic with artiodactyls, we mined the genome of the bottlenose dolphin Tursiops truncates, leading to the identification of two PrAMPs, Tur1A and Tur1B. Tur1A, which is orthologous to the bovine PrAMP Bac7, is internalized into E. coli without damaging the membranes using the inner membrane transporters SbmA and YjiL/MdM. Furthermore, like Bac7, Tur1A also inhibits bacterial protein synthesis by binding to the ribosome and blocking the transition from the initiation to the elongation phase. By contrast, Tur1B is a poor inhibitor of protein synthesis and may utilize another mechanism of action. An X-ray structure of Tur1A bound within the ribosomal exit tunnel provides a basis to develop these peptides as novel antimicrobial agents

Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS

Antimicrobial peptides (AMPs) are a promising class of compounds being developed against multi-drug resistant bacteria. Hybridization has been reported to increase antimicrobial activity. Here, two proline-rich peptides (consP1: VRKPPYLPRPRPRPL-CONH2 and Bac5-v291: RWRRPIRRRPIRPPFWR-CONH2) were combined with two arginine-isoleucine-rich peptides (optP1: KIILRIRWR-CONH2 and optP7: KRRVRWIIW-CONH2). Proline-rich antimicrobial peptides (PrAMPs) are known to inhibit the bacterial ribosome, shown also for Bac5-v291, whereas it is hypothesized a "dirty drug" model for the arginine-isoleucine-rich peptides. That hypothesis was underpinned by transmission electron microscopy and biological small-angle X-ray scattering (BioSAXS). The strength of BioSAXS is the power to detect ultrastructural changes in millions of cells in a short time (seconds) in a high-throughput manner. This information can be used to classify antimicrobial compounds into groups according to the ultrastructural changes they inflict on bacteria and how the bacteria react towards that assault. Based on previous studies, this correlates very well with different modes of action. Due to the novelty of this approach direct identification of the target of the antimicrobial compound is not yet fully established, more research is needed. More research is needed to address this limitation. The hybrid peptides showed a stronger antimicrobial activity compared to the proline-rich peptides, except when compared to Bac5-v291 against E. coli. The increase in activity compared to the arginine-isoleucine-rich peptides was up to 6-fold, however, it was not a general increase but was dependent on the combination of peptides and bacteria. BioSAXS experiments revealed that proline-rich peptides and arginine-isoleucine-rich peptides induce very different ultrastructural changes in E. coli, whereas a hybrid peptide (hyP7B5GK) shows changes, different to both parental peptides and the untreated control. These different ultrastructural changes indicated that the mode of action of the parental peptides might be different from each other as well as from the hybrid peptide hyP7B5GK. All peptides showed very low haemolytic activity, some of them showed a 100-fold or larger therapeutic window, demonstrating the potential for further drug development

Vector Meson Photoproduction with an Effective Lagrangian in the Quark Model

A quark model approach to the photoproduction of vector mesons off nucleons is proposed. Its starting point is an effective Lagrangian of the interaction between the vector meson and the quarks inside the baryon, which generates the non-diffractive s- and u- channel resonance contributions. Additional t-channel $\pi^0$ and $\sigma$ exchanges are included for the $\omega$ and $\rho^0$ production respectively to account for the large diffractive behavior in the small $t$ region as suggested by Friman and Soyeur. The numerical results are presented for the $\omega$ and $\rho$ productions in four isospin channels with the same set of parameters, and they are in good agreement with the available data not only in $\omega$ and $\rho^0$ productions but also in the charged $\rho$ productions where the additional t-channel $\sigma$ exchange does not contribute so that it provides an important test to this approach. The investigation is also extended to the $\phi$ photoproduction, and the initial results show that the non-diffractive behavior of the $\phi$ productions in the large $t$ region can be described by the s- and u- channel contributions with significantly smaller coupling constants, which is consistent with the findings in the similar studies in the QHD framework. The numerical investigation has also shown that polarization observables are essential for identifying so-called "missing resonances".Comment: 36 pages, 10 PS figures, extended version of nucl-th/9711061 and nucl-th/9803021, submitted to PR

Pore-scale Modeling of Viscous Flow and Induced Forces in Dense Sphere Packings

We propose a method for effectively upscaling incompressible viscous flow in large random polydispersed sphere packings: the emphasis of this method is on the determination of the forces applied on the solid particles by the fluid. Pore bodies and their connections are defined locally through a regular Delaunay triangulation of the packings. Viscous flow equations are upscaled at the pore level, and approximated with a finite volume numerical scheme. We compare numerical simulations of the proposed method to detailed finite element (FEM) simulations of the Stokes equations for assemblies of 8 to 200 spheres. A good agreement is found both in terms of forces exerted on the solid particles and effective permeability coefficients

BioSAXS measurements reveal that two antimicrobial peptides induce similar molecular changes in gram-negative and gram-positive bacteria

Two highly active short broad-spectrum AMPs (14D and 69D) with unknown mode of action have been investigated in regards to their effect against the Gramnegative bacteria Escherichia coli and the Gram-positive bacteria methicillinresistant Staphylococcus aureus (MRSA). Minimal inhibitory concentration (MIC) measurements using a cell density of 108 cfu/ml resulted in values between 16 and 32 μg/ml. Time-kill experiments using 108 cfu/ml revealed complete killing, except for 69D in combination with MRSA, where bacterial load was reduced a million times. Small-angle X-ray scattering of biological samples (BioSAXS) at 108 cfu/ml was applied to investigate the ultrastructural changes in E. coli and MRSA in response to these two broad-spectrum AMPs. In addition, electron microscopy (EM) was performed to visualize the treated and non-treated bacteria. As expected, the scattering curves generated using BioSAXS show the ultrastructure of the Grampositive and Gram-negative bacteria to be very different (BioSAXS is not susceptible to the outer shape). After treatment with either peptide, the scattering curves of E.coli and MRSA cells are much more alike. Whereas in EM, it is notoriously difficult to observe changes for spherical Gram-positives; the BioSAXS results are superior and reveal strongly similar effects for both peptides induced in Gram-positive as well as Gram-negative bacteria. Given the high-throughput possibility and robust statistics, BioSAXS can support and speed up mode of action research in AMPs and other antimicrobial compounds, making a contribution toward the development of urgently needed drugs against resistant bacteria

Correct quantum chemistry in a minimal basis from effective Hamiltonians

We describe how to create ab-initio effective Hamiltonians that qualitatively describe correct chemistry even when used with a minimal basis. The Hamiltonians are obtained by folding correlation down from a large parent basis into a small, or minimal, target basis, using the machinery of canonical transformations. We demonstrate the quality of these effective Hamiltonians to correctly capture a wide range of excited states in water, nitrogen, and ethylene, and to describe ground and excited state bond-breaking in nitrogen and the chromium dimer, all in small or minimal basis sets

Umweltgerechte Prozessführung und Zustandserkennung in Chemieanlagen mit neuronalen Netzen - Teilvorhaben 2: Konzipierung und Erprobung des Zustandserkennungsverfahrens

Im Rahmen des Teilvorhabens wurde ein Online-Monitoring-System für stark exotherme Reaktionen entwickelt, das das Bedienungspersonal bei der optimalen und umweltgerechten Prozessführung von komplexen oder sicherheitstechnisch schwierigen Semibatch-Prozessen in Rührkesselreaktoren (Batch-Reaktoren) unterstützen soll. Das Monitoring-System (MoSys) basiert auf dimensionslosen Stoff- und Wärmebilanzen mit adaptiven Komponenten. MoSys muss zuerst mit den Prozessdaten von normalen und unerwünschten Batch-Verläufen angelernt werden, die im Miniplant unter den Bedingungen des Industrieprozesses durchgeführt wurden. Die Adaption der Bilanzmodelle an die Zielanlage erfolgt durch zweischichtige Perceptron-Netze. Um eine vollständige Maßstabsübertragung zu gewährleisten, sollte MoSys mit Prozessdaten von mindestens einem normalen Batch-Verlauf in der Chemieanlage angepasst und validiert werden. MoSys wurde sowohl für eine homogene exotherme Veresterungsreaktion als auch für einen komplexen heterogenen exothermen Hydrierprozess konzipiert. Experimentelle Tests wurden für die Veresterung in einer Pilotanlage und für die Hydrierung in einer industriellen Chemieanlage durchgeführt. Zur Industrieerprobung wurde MoSys in ein Batch-Informations-Management-System (BIMS) integriert, das auch entwickelt und in das Prozessleitsystem (PLS) einer Mehrzweckanlage im Feinchemie-Werk Radebeul (Degussa AG) implementiert wurde. Dadurch konnten die MoSys-Ausgaben simultan mit wichtigen Prozesssignalen auf den Terminals des PLS visualisiert werden. Zum Beispiel werden der Hydrierungsfortschritt, das vorhergesagte Reaktionsende und die Konzentrationsverläufe des Edukts, Zwischenprodukts und Produkts auf den Terminals der Operatorstationen angezeigt. Wenn unerwünschte Betriebszustände auftreten, wird das Bedienungspersonal frühzeitig alarmiert und Anweisungen für Gegenmaßnahmen, die nur vom Operator ausgeführt werden dürfen, werden auf den Terminals angezeigt. Die Leistungsfähigkeit von MoSys/BIMS konnte während zweier Hydrierungs-Produktionskampagnen nachgewiesen werden