Pressure-dependent EPANET extension

In water distribution systems (WDSs), the available flow at a demand node is dependent on the pressure at that node. When a network is lacking in pressure, not all consumer demands will be met in full. In this context, the assumption that all demands are fully satisfied regardless of the pressure in the system becomes unreasonable and represents the main limitation of the conventional demand driven analysis (DDA) approach to WDS modelling. A realistic depiction of the network performance can only be attained by considering demands to be pressure dependent. This paper presents an extension of the renowned DDA based hydraulic simulator EPANET 2 to incorporate pressure-dependent demands. This extension is termed “EPANET-PDX” (pressure-dependent extension) herein. The utilization of a continuous nodal pressure-flow function coupled with a line search and backtracking procedure greatly enhance the algorithm’s convergence rate and robustness. Simulations of real life networks consisting of multiple sources, pipes, valves and pumps were successfully executed and results are presented herein. Excellent modelling performance was achieved for analysing both normal and pressure deficient conditions of the WDSs. Detailed computational efficiency results of EPANET-PDX with reference to EPANET 2 are included as well

Faster disease progression in Parkinson's disease with type 2 diabetes is not associated with increased α-synuclein, tau, amyloid-β or vascular pathology

AIMS: Growing evidence suggests a shared pathogenesis between Parkinson's disease and diabetes although the underlying mechanisms remain unknown. The aim of this study is to evaluate the effect of type 2 diabetes on Parkinson's disease progression and to correlate neuropathological findings to elucidate pathogenic mechanisms. METHODS: In this cohort study, medical records were retrospectively reviewed of cases with pathologically-confirmed Parkinson's disease with and without pre-existing type 2 diabetes. Time to disability milestones (recurrent falls, wheelchair dependence, dementia, and care home placement) and survival were compared to assess disease progression and their risk estimated using Cox hazard regression models. Correlation with pathological data was performed, including quantification of α-synuclein in key brain regions and staging of vascular, Lewy and Alzheimer's pathologies. RESULTS: Patients with PD and diabetes (male 76%; age at death 78.6 ± 6.2 years) developed earlier falls (P < 0.001), wheelchair dependence (P = 0.004), dementia (P < 0.001), care home admission (P < 0.001) and had reduced survival (P < 0.001). Predating diabetes was independently associated with a two to three-fold increase in the risk of disability and death. Neuropathological assessment did not show any differences in global or regional vascular pathology, α-synuclein load in key brain areas, staging of Lewy pathology or Alzheimer's disease pathology. CONCLUSIONS: Pre-existing type 2 diabetes contributes to faster disease progression and reduced survival in Parkinson's disease which is not driven by increased vascular, Lewy or Alzheimer's pathologies. Additional non-specific neurodegeneration related to chronic brain insulin resistance may be involved

Women with PCOS have an increased risk for cardiovascular disease regardless of diagnostic criteria - a prospective population-based cohort study

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with many cardiovascular disease (CVD) risk factors, such as obesity, type 2 diabetes mellitus and hypertension. However, it remains debatable whether the presence of multiple CVD risk factors translates to increased CVD events. DESIGN: A prospective, population-based Northern Finland Birth Cohort 1966. METHODS: Individuals with an expected date of birth in 1966 in Northern Finland have been followed from birth. Women in the cohort were classified as having PCOS according to either the National Institute of Health (NIH) criteria (n = 144) or the Rotterdam criteria (n = 386) at age 31, and they were compared to women without any PCOS features. The study population was re-examined at age 46, and the incidence of major adverse cardiovascular events (MACE), including myocardial infarction (MI), stroke, heart failure and cardiovascular mortality, was recorded up to age 53. RESULTS: During the 22-year follow-up, both women with NIH-PCOS and women with Rotterdam-PCOS had a significantly higher risk for cardiovascular events than control women. The BMI-adjusted hazard ratio (HR) for MACE in the Rotterdam-PCOS group and the NIH-PCOS group was 2.33 (1.26-4.30) and 2.47 (1.18-5.17), respectively. The cumulative hazard curves in both diagnostic categories began to diverge at age 35. Regarding the individual CVD endpoints, MI was significantly more prevalent in both women with NIH-PCOS (P = .010) and women with Rotterdam-PCOS (P = .019), when compared to control women. CONCLUSIONS: PCOS should be considered a significant risk factor for CVD. Future follow-up will show how the risk of CVD events develops after menopausal age

Design, Synthesis and Biological Evaluation of N-Sulfonylphenyl glyoxamide-Based Antimicrobial Peptide Mimics as Novel Antimicrobial Agents

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Antibiotic resistance is a major global health concern. There is an urgent need for the development of novel antimicrobials. Recently, phenylglyoxamide-based small molecular antimicrobial peptide mimics have been identified as potential new leads to treat bacterial infections. Here, we describe the synthesis of novel phenylglyoxamide derivatives via the ring-opening reaction of N-sulfonylisatins with primary amines, followed by conversion into hydrochloride, quaternary ammonium iodide or gunidinium salts. The antibacterial activity of the compounds against Staphylococcus aureus was evaluated by in vitro assays. Structure-activity relationship studies revealed that 5-bromo-substituent at the phenyl ring, octyl group appended to the ortho sulfonamide group or guanidine hydrochloride salt as the terminal group significantly contributed to potency. The most potent compound, the gunidinium salt 35 d, exhibited a minimum inhibitory concentration value of 12 μM and a therapeutic index of 15. It also demonstrated its potential to act as antimicrobial pore-forming agent. Overall, the results identified 35 d as a new lead antimicrobial compound

Interplay of Mre11 Nuclease with Dna2 plus Sgs1 in Rad51-Dependent Recombinational Repair

The Mre11/Rad50/Xrs2 complex initiates IR repair by binding to the end of a double-strand break, resulting in 5′ to 3′ exonuclease degradation creating a single-stranded 3′ overhang competent for strand invasion into the unbroken chromosome. The nuclease(s) involved are not well understood. Mre11 encodes a nuclease, but it has 3′ to 5′, rather than 5′ to 3′ activity. Furthermore, mutations that inactivate only the nuclease activity of Mre11 but not its other repair functions, mre11-D56N and mre11-H125N, are resistant to IR. This suggests that another nuclease can catalyze 5′ to 3′ degradation. One candidate nuclease that has not been tested to date because it is encoded by an essential gene is the Dna2 helicase/nuclease. We recently reported the ability to suppress the lethality of a dna2Δ with a pif1Δ. The dna2Δ pif1Δ mutant is IR-resistant. We have determined that dna2Δ pif1Δ mre11-D56N and dna2Δ pif1Δ mre11-H125N strains are equally as sensitive to IR as mre11Δ strains, suggesting that in the absence of Dna2, Mre11 nuclease carries out repair. The dna2Δ pif1Δ mre11-D56N triple mutant is complemented by plasmids expressing Mre11, Dna2 or dna2K1080E, a mutant with defective helicase and functional nuclease, demonstrating that the nuclease of Dna2 compensates for the absence of Mre11 nuclease in IR repair, presumably in 5′ to 3′ degradation at DSB ends. We further show that sgs1Δ mre11-H125N, but not sgs1Δ, is very sensitive to IR, implicating the Sgs1 helicase in the Dna2-mediated pathway

Exploring Curved Superspace

We systematically analyze Riemannian manifolds M that admit rigid supersymmetry, focusing on four-dimensional N=1 theories with a U(1)_R symmetry. We find that M admits a single supercharge, if and only if it is a Hermitian manifold. The supercharge transforms as a scalar on M. We then consider the restrictions imposed by the presence of additional supercharges. Two supercharges of opposite R-charge exist on certain fibrations of a two-torus over a Riemann surface. Upon dimensional reduction, these give rise to an interesting class of supersymmetric geometries in three dimensions. We further show that compact manifolds admitting two supercharges of equal R-charge must be hyperhermitian. Finally, four supercharges imply that M is locally isometric to M_3 x R, where M_3 is a maximally symmetric space.Comment: 39 pages; minor change

Supergravity for Effective Theories

Higher-derivative operators are central elements of any effective field theory. In supersymmetric theories, these operators include terms with derivatives in the K\"ahler potential. We develop a toolkit for coupling such supersymmetric effective field theories to supergravity. We explain how to write the action for minimal supergravity coupled to chiral superfields with arbitrary numbers of derivatives and curvature couplings. We discuss two examples in detail, showing how the component actions agree with the expectations from the linearized description in terms of a Ferrara-Zumino multiplet. In a companion paper, we apply the formalism to the effective theory of inflation.Comment: 26 page

Effects of oxidized low density lipoprotein, lipid mediators and statins on vascular cell interactions

The integrin heterodimer CD11b/CD18 (alpha M beta 2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive! and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet alpha llb beta 3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endothelium ex vivo was increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac,mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDL in vitro,indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs

Tame D-tadpoles in gauge mediation

We revisit models of gauge mediated supersymmetry breaking where messenger parity is violated. Such a symmetry is usually invoked in order to set to zero potentially dangerous hypercharge D-term tadpoles. A milder hypothesis is that the D-tadpole vanishes only at the first order in the gauge coupling constant. Then the next order leads to a contribution to the sfermion masses which is of the same magnitude as the usual radiative one. This enlarges the parameter space of gauge mediated models. We first give a completely general characterization of this contribution, in terms of particular three-point functions of hidden sector current multiplet operators. We then explore the parameter space by means of two simple weakly coupled models, where the D-tadpole arising at two-loops has actually a mild logarithmic divergence.Comment: 13 pages + 9 pages of appendix, 1 figure; v2: some clarifying comments added, version to appear in JHE