•Guiding cyclists in the queue formation process can increase jam density.•Higher jam density coincides with a higher queue discharge rate.•Discharge rate is highest when cyclists queue up in 3-2-3 ...pattern or closely together.•Delay at intersections can be reduced when cyclists queue up closer together.
Congestion in bicycle traffic is a daily occurrence at many urban intersections. It is known that a higher density in the queue leads to a higher discharge rate. In theory, higher jam densities than those currently observed in practice are feasible. This leads to our hypothesis that the delay at intersections can be further reduced when cyclists are encouraged to queue up closer together. To explore this option, we carried out an experiment in which the queue configuration was influenced to increase the jam density. This paper presents ways to increase the queuing density, up to twice the density found without instructions. Results show that increasing the jam density does indeed increase the queue discharge rate; this also holds for jam density values that exceed those observed in normal queuing conditions. The efficiency of the queue discharge process, captured by the discharge rate, was found to increase by 40% when cyclists queue up closely together. Qualitative comparison of the queuing positions and discharge patterns showed that the discharge sequence is largely determined by the queuing position, and that cyclists keep a distance from each other in both time and space during the queue discharge phase. When applied in practice, these findings can be used to update the signal length and green phases for all traffic, thereby reducing congestion in urban areas.
General relativity (GR) extensions based on renormalization group (RG) flows may lead to scale-dependent couplings with nontrivial effects at large distance scales. Here we develop further the ...approach in which RG effects at large distance scales are fully encoded in an effective action and we apply it to cosmology. In order to evaluate the cosmological consequences, our main assumption is the use of a RG scale such that the (infrared) RG effects only appear at perturbative order (not at the background level). The emphasis here is on analytical results and qualitative understanding of the implied cosmology. We employ commonly used parametrizations for describing modified gravity in cosmology (as the slip parameter). From them, we describe the dynamics of the first order perturbations and estimate bounds on the single dimensionless parameter (
ν
) introduced by this framework. Possible impacts on dark matter and dark energy are discussed. It is also shown here that the
ν
parameter effects to
f
σ
8
are stronger at low redshifts (
z
<
1.5
), while different values for
ν
do not appreciably change
f
σ
8
at higher redshifts, thus opening a window to alleviate an issue that is currently faced by
Λ
CDM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To evaluate technical feasibility and oncologic and functional outcomes of three different surgical procedures of nerve-sparing radical cystectomy (NS-RC) for the treatment of ...organ-confined bladder cancer at a single referral centre.
Materials and methods
All consecutive cases of NS-RC carried out between 1997 and 2012 were retrospectively analysed. NS-RC included nerve-sparing cysto-vesicleprostatectomy (NS-CVP), capsule-sparing cystectomy (CS-C) and seminal-sparing cysto-prostatectomy (SS-CP). Peri-operative parameters and post-operative outcomes were analysed.
Results
Overall, 90 patients underwent NS-RC, 35 (38.9 %) of whom received a NS-CVP, while 36 (40 %) and 19 (21.1 %) underwent capsule CS-C and SS-CP, respectively. No difference was registered comparing oncologic outcomes of the three different techniques; however, two local recurrences after CS-C were attributed to the surgical technique. Complete post-operative daytime and night-time urinary continence (UC) at 24 and 48 months was achieved in 94.4 and 74.4 % and in 88.8 and 84.4 % of cases, respectively. CS-C showed both the best UC and sexual function preservation rate at early follow-up (24 months). Overall, a satisfactory post-operative erectile function (IIEF-5 ≥ 22) was proved in 57 (68.6 %) and 54 (65.0 %) patients at 24 and 48 months, respectively. Significant difference was found when comparing sexual function preservation rate of NS-CVP (28.5 %) to that of CS-C (91.6 %) and SS-CP (84.2 %).
Conclusion
NS-RC for male patients accounted for 7.4 % of overall radical cystectomy. To a limited extent of the selected organ-confined bladder cancers treated, the three different procedures analysed showed comparable results in terms of local recurrence and cancer-specific survival. Both CS-C and SS-CP procedures provided excellent functional outcomes when compared to original NS-CVP.
We consider an inflationary scenario in the holographic braneworld with a cosmological fluid occupying the 3+1 dimensional brane located at the holographic boundary of an asymptotic ADS5 bulk. The ...contribution of the boundary conformal field can be represented as a modification of Einstein's equations on the boundary. Using these effective Einstein equations we calculate the cosmological perturbations and derive the corresponding power spectra assuming a general k-essence type of inflaton. We find that the braneworld scenario affects the scalar power spectrum only in the speed of sound dependence on the slow-roll parameters whereas there is no change in the tensor power spectrum. This implies that the changes in the spectral indices appear at the second order in the slow-roll parameter expansion.
BACKGROUND AND PURPOSE DF 2156A is a new dual inhibitor of IL‐8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and ...selectivity, and evaluated its therapeutic potential.
EXPERIMENTAL APPROACH The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and 35S‐GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge‐induced angiogenesis) experimental models of inflammation.
KEY RESULTS A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys99 on CXCR1 and the non‐conserved residue Asp293 on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non‐competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2‐mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge‐induced angiogenesis, DF 2156A reduced leucocyte influx, TNF‐α production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary‐like organization of HUVECs in response to human IL‐8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte‐macrophage infiltration and associated hepatocellular injury.
CONCLUSION AND IMPLICATIONS DF 2156A is a non‐competitive allosteric inhibitor of both IL‐8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.
Background and purpose:
Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 ...inhibitor, DF 2162, in adjuvant‐induced polyarthritis (AIA) were investigated.
Experimental approach:
A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti‐TNF or anti‐CINC‐1 antibodies on joint inflammation and local production of cytokines and chemokines.
Key results:
DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg−1, twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL‐1β, CCL2 and CCL5. The effects of DF2162 were similar to those of anti‐TNF, and more effective than those of anti‐CINC‐1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction.
Conclusions and implications:
DF 2162, a novel orally‐active non‐competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti‐TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.
British Journal of Pharmacology (2008) 153, 992–1002; doi:10.1038/sj.bjp.0707462; published online 24 September 2007
Targeting C5a: Recent Advances in Drug Discovery ALLEGRETTI, M; MORICONI, A; BECCARI, A. R ...
Current medicinal chemistry,
2005-January, 2005, 2005-00-00, 2005-01-01, 20050101, Letnik:
12, Številka:
2
Journal Article
Recenzirano
Activation of complement via the innate and adaptive immune system is vital to the bodys defences in fighting infections. Unregulated complement activation is likely to play a crucial role in the ...pathogenesis of several diseases including psoriasis, adult (acute) respiratory distress syndrome (ARDS), bullous pemphigoid (BP), rheumatoid arthritis (RA) and ischemia-reperfusion (I / R) injury. The 74 amino acid peptide C5a is released after complement activation at sites of inflammation and is a potent chemoattractant for neutrophils, basophils, eosinophils, leukocytes, monocytes and macrophages. Recombinant proteins and humanized anti-C5 antibodies have been recently developed for blocking specific proteins of the complement system bringing renewed attention towards complement inhibition. Pharmacological studies have been highlighting the complement fragment C5a as an interesting target for the management of complement mediated diseases. Specific inhibition of C5a biological activity could gain therapeutic benefit without affecting the protective immune response. In the last few years several peptide and non-peptide antagonists of C5a have been discovered and tested in relevant pharmacological models; the availability of orally active compounds is rapidly helping to delineate the precise role of C5a in immunoinflammatory disorders. Moreover, mutagenesis data for the C5a / C5a receptor (C5aR) couple make C5aR a valuable model for mechanistic studies of peptidergic G-protein coupled receptors (GPCRs). The aim of this review is to outline the recent advances in C5a inhibition, especially highlighting the value of a multidisciplinary integrated approach in drug discovery.
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