Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI

Uropathogenic E. coli (UPEC) employ the mannose‐binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half‐life in vivo. In a rational design strategy, we obtained an X‐ray structure of lead mannosides and then designed mannosides with improved drug‐like properties. We show that cyclizing the carboxamide onto the biphenyl B‐ring aglycone of biphenyl mannosides into a fused heterocyclic ring, generates new biaryl mannosides such as isoquinolone 22 (2‐methyl‐4‐(1‐oxo‐1,2‐dihydroisoquinolin‐7‐yl)phenyl α‐d ‐mannopyranoside) with enhanced potency and in vivo efficacy resulting from increased oral bioavailability. N‐Substitution of the isoquinolone aglycone with various functionalities produced a new potent subseries of FimH antagonists. All analogues of the subseries have higher FimH binding affinity than unsubstituted lead 22 , as determined by thermal shift differential scanning fluorimetry assay. Mannosides with pyridyl substitution on the isoquinolone group inhibit bacteria‐mediated hemagglutination and prevent biofilm formation by UPEC with single‐digit nanomolar potency, which is unprecedented for any FimH antagonists or any other antivirulence compounds reported to date.     

Coproduction of acetic acid and hydrogen/power from natural gas with zero carbon dioxide emissions

A process plant flow sheet that coproduces acetic acid and hydrogen/power from natural gas with zero carbon dioxide emissions is developed. Two cases are explored: the production of acetic acid and hydrogen (Case 1) and the production of acetic acid and power (Case 2). This is realized by the selection of an appropriate reaction cluster whose sum results in the overall reaction that coproduces acetic acid and hydrogen/power. The concept of energetic self‐sufficiency is introduced and it imposes constraints on the system defined in terms of the ratio of oxygen feed to acetic acid produced. Heat and power integration of the converged flow sheet reveals an operating range for each case that guarantees energetic self‐sufficiency. Operating points are chosen to conduct a preliminary economic analysis and a carbon dioxide cost and performance metric calculation to quantify profitability and carbon capture potential of the overall process. © 2017 American Institute of Chemical Engineers AIChE J, 64: 860–876, 2018     

On constrained infinite-time nonlinear optimal control

In this work, we consider the infinite-time optimal control of input affine nonlinear systems subject to point-wise in time inequality constraints on both the process inputs and outputs. Fundamental to solving this constrained infinite-time nonlinear optimal control (CITNOC) problem is the ability to calculate the value function of it's unconstrained counterpart, the infinite-time nonlinear optimal control (ITNOC) problem. Unfortunately, the traditional ITNOC solution procedure of specifying an objective function and then solving for the optimal control policy and corresponding value function is computationally intractable in all but the simplest of examples. However, in many cases one can easily identify a stabilizing feedback for near operating point regulation. Building from this local policy, the proposed method is to construct a meaningful optimal control objective function as well as its corresponding value function. These functions are then used to analyze the closed-loop stability of the proposed policy. Upon return to the constrained case the constructed objective and value functions are again used to develop a self-consistent constrained finite-time scheme that will, for the first time, provide an exact solution to the CITNOC problem. The mechanics of the proposed method are then illustrated by an example from chemical reactor control.     

Small High-Density Lipoprotein (HDL) Subclasses are Increased with Decreased Activity of HDL-Associated Phospholipase A2 in Subjects with Prediabetes

Alterations in high-density lipoprotein (HDL) subclass distribution, as well as in the activities of HDL-associated enzymes, have been associated with increased cardiovascular disease (CVD) risk. HDL subclass distribution and the activities of HDL-associated enzymes remain unknown in prediabetic patients, a condition also associated with increased CVD risk. The aim of the present study was to assess any differences in HDL subclass distribution (using polyacrylamide gel electrophoresis) and in activities of HDL-associated enzymes between prediabetic (impaired fasting glucose, IFG, n = 80) and non-prediabetic subjects (n = 105). Subjects with prediabetes had significantly increased waist circumference, blood pressure and triacylglycerol (TAG) levels compared with subjects with fasting glucose levels <100 mg/dL (all p < 0.05). The proportion of small HDL3 over HDL cholesterol (HDL-C) was significantly increased in prediabetic subjects compared with their controls (p < 0.05). The activity of the anti-atherogenic HDL-associated lipoprotein-associated phospholipase A₂ (HDL-LpPLA₂) was significantly lower in subjects with prediabetes (p < 0.05), whereas the activity of paraoxonase 1 (using both paraoxon and phenyl acetate as substrates) did not significantly differ between subjects with or without prediabetes. In a stepwise linear regression analysis, the proportion of small HDL3 over HDL-C concentration was independently associated with the presence of prediabetes and with total cholesterol and TAG concentration (positively), as well as with HDL-C levels (negatively). We also observed a trend of increased small dense low-density lipoprotein cholesterol levels in prediabetic subjects compared with their controls. Subjects with IFG exhibit increased proportion of small HDL3 particles combined with decreased activity of the anti-atherogenic HDL-LpPLA₂.     

Analysis and Future Prospects for Cross-border Congestion Management Methods for the European Electricity Market

This paper presents an analysis of current and potential cross-border congestion management methods for the EU electricity market. Many currently used techniques are reported and the main aspects of possible future are presented. The main steps of the newly established coordinated auction technique will be reported and an example of a real case for the South European Region will be implemented. Moreover, in order to eliminate loop flows, avoid congestions at the day ahead stage and increase the total transfer capacity of the south UCTE region (countries Greece, Albania and FYROM), it will be shown that Flexible Ac Transmission Systems technology can help market players to get access to more transfer capacity for their transactions, while security margins are being maintained.     

Mass/heat-exchange network representation of distillation networks

This article introduces the “state space” conceptual framework to process synthesis, which is used to provide a novel representation of a distillation network as a composite heat- and mass-exchange network. This representation suggests that distillation network synthesis may best be viewed as an interacting heat- and mass-exchange network synthesis problem. In that regard, familiar tools (such as pinch diagrams) from both heat-exchange network (HEN) and mass-exchange network (MEN) synthesis are shown to be of use in arriving at energy-efficient distillation network designs. Examples of propylene-propane and solvent-water separations are used to illustrate the proposed conceptual framework.     

A framework for designing cloud forensic-enabled services (CFeS)

Requirements Engineering - Cloud computing is used by consumers to access cloud services. Malicious actors exploit vulnerabilities of cloud services to attack consumers. The link between these two...     

Direkte und indirekte Randelementmethoden zur Bestimmung der Lage des Schubmittelpunktes beliebig geformter Stabquerschnitte

Zusammenfassung Die Koordinaten des Schubmittelpunktes eines beliebig berandeten Stabquerschnittes werden in dieser Arbeit aus der Torsionsverw?lbung des Querschnittes berechnet. Zur Bestimmung der Querschnittsverw?lbung wird die Randelementmethode (Boundary-Element-Method) herangezogen. Dabei entstehen durch verschiedene Vorgehensweisen mehrere Fredholmsche Integralgleichungen erster und zweiter Art, von denen jedoch nur bestimmte zur L?sung des genannten Problems geeignet sind. Einige direkte und indirekte Integralgleichungen werden hier für beliebig berandete Stabquerschnitte bezüglich ihrer Einsetzbarkeit untersucht und miteinander verglichen. Es zeigt sich dabei, da? auch eine Integralgleichung erster Art problemlos eingesetzt werden kann. Die Randelemente werden bei der numerischen L?sung der Integralgleichungen durch Polynome dritten Grades und die unbekannten Funktionen durch Polynome zweiten Grades approximiert, um eine glatte Berandung und stetigen Funktionenverlauf zu sichern.—Die Methode ist auf dünnwandige, dickwandige, offene und auf geschlossene Profile anwendbar. Numerische Ergebnisse für verschiedene Querschnittsformen aus den DIN-Normen zeigen die Effektivit?t sowohl der direkten als auch der indirekten Methode.     

Results of transperineal levator-plasty in treatment of symptomatic rectocele

A rectocele is a herniation of the anterior rectal wall through the rectovaginal septum into the vagina. The most important risk factors are a previous hysterectomy, obstetic injuries and the descending perineum syndrome. In some patients the rectocele becomes symptomatical because of defecation disorders. The patients have to give manual vaginal or perineal help during defecation. Radiological parameters like the size of the rectocele or retention of barium only have limited value for the clinical evaluation. In a high percentage we find simultaneous symptoms of fecal incontinence. Transperineal anterior levatorplasty makes it possible to close the rectocele. This procedure has a positive influence on defecation and continence. In a prospective study we performed anterior levatorplasty in 35 female patients having a rectocele in combination with rectal outlet obstruction. Subjective improvement of the defecation disorder was found in 74%. Only 1 patient complained of deterioration. No patient needed manual vaginal help postoperatively. Patients who needed perineal help preoperatively had worse results. Patients who did not need any manual help preoperatively nevertheless reported an improvement postoperatively. Fifteen of 20 patients, who suffered from fecal incontinence preoperatively, reported a better continence postoperatively (75%). Even in patients with incontinence the anterior levatorplasty is a good method for rectocele repair, as it improves rectal emptying and simultaneously provides therapy for fecal incontinence.