Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis

Systemic sclerosis (SSc) is characterised by progressive multiple organ fibrosis leading to morbidity and mortality. Lysyl oxidases play a vital role in the cross-linking of collagens and subsequent build-up of fibrosis in the extracellular matrix. As such, their inhibition provides a novel treatment paradigm for SSc. A novel small molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical development for myelofibrosis treatment was evaluated using in vivo rodent models resembling the fibrotic conditions in SSc. Both lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression were elevated in the skin and lung of SSc patients. The oral application of PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin mouse model, reducing dermal thickness and α-smooth muscle actin. Similarly, in the bleomycin-induced mouse lung model, PXS-5505 reduced pulmonary fibrosis toward normal levels, mediated by its ability to normalise collagen/elastin crosslink formation. PXS-5505 also reduced fibrotic extent in models of the ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney, and the CCl4-induced fibrotic liver. PXS-5505 consistently demonstrates potent anti-fibrotic efficacy in multiple models of organ fibrosis relevant to the pathogenesis of SSc, suggesting that it may be efficacious as a novel approach for treating SSc.     

Photothermal self-oscillation and laser cooling of graphene optomechanical systems

By virtue of their low mass and stiffness, atomically thin mechanical resonators are attractive candidates for use in optomechanics. Here, we demonstrate photothermal back-action in a graphene mechanical resonator comprising one end of a Fabry-Perot cavity. As a demonstration of the utility of this effect, we show that a continuous wave laser can be used to cool a graphene vibrational mode or to power a graphene-based tunable frequency oscillator. Owing to graphene's high thermal conductivity and optical absorption, photothermal optomechanics is efficient in graphene and could ultimately enable laser cooling to the quantum ground state or applications such as photonic signal processing.     

The Role of Polymorphisms at the Interleukin-1, Interleukin-4, GATA-3 and Cyclooxygenase-2 Genes in Non-Surgical Periodontal Therapy

Periodontitis is a multifactorial disease. The aim of this explorative study was to investigate the role of Interleukin-(IL)-1, IL-4, GATA-3 and Cyclooxygenase-(COX)-2 polymorphisms after non-surgical periodontal therapy with adjunctive systemic antibiotics (amoxicillin/metronidazole) and subsequent maintenance in a Caucasian population. Analyses were performed using blood samples from periodontitis patients of a multi-center trial (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00707369","term_id":"NCT00707369"}}NCT00707369=ABPARO-study). Polymorphisms were analyzed using quantitative real-time PCR. Clinical attachment levels (CAL), percentage of sites showing further attachment loss (PSAL) ≥1.3 mm, bleeding on probing (BOP) and plaque score were assessed. Exploratory statistical analysis was performed. A total of 209 samples were genotyped. Patients carrying heterozygous genotypes and single-nucleotide-polymorphisms (SNP) on the GATA-3-IVS4 +1468 gene locus showed less CAL loss than patients carrying wild type. Heterozygous genotypes and SNPs on the IL-1A-889, IL-1B +3954, IL-4-34, IL-4-590, GATA-3-IVS4 +1468 and COX-2-1195 gene loci did not influence CAL. In multivariate analysis, CAL was lower in patients carrying GATA-3 heterozygous genotypes and SNPs than those carrying wild-types. For the first time, effects of different genotypes were analyzed in periodontitis progression after periodontal therapy and during supportive treatment using systemic antibiotics demonstrating a slight association of GATA-3 gene locus with CAL. This result suggests that GATA-3 genotypes are a contributory but non-essential risk factor for periodontal disease progression.     

A multi-dimensional scheduling scheme in a Grid computing environment

In this paper, we propose a novel distributed resource-scheduling algorithm capable of handling multiple resource requirements for jobs that arrive in a Grid computing environment. In our proposed algorithm, referred to as multiple resource scheduling (MRS) algorithm, we take into account both the site capabilities and the resource requirements of jobs. The main objective of the algorithm is to obtain a minimal execution schedule through efficient management of available Grid resources. We first propose a model in which the job and site resource characteristics can be captured together and used in the scheduling algorithm. To do so, we introduce the concept of a n-dimensional virtual map and resource potential. Based on the proposed model, we conduct rigorous simulation experiments with real-life workload traces reported in the literature to quantify the performance. We compare our strategy with most of the commonly used algorithms in place on performance metrics such as job wait times, queue completion times, and average resource utilization. Our combined consideration of job and resource characteristics is shown to render high-performance with respect to above-mentioned metrics in the environment. Our study also reveals the fact that MRS scheme has a capability to adapt to both serial and parallel job requirements, especially when job fragmentation occurs. Our experimental results clearly show that MRS outperforms other strategies and we highlight the impact and importance of our strategy.     

Study on the Effect of Mn,Zn, and Sb on Undercooling Behavior of Sn-Ag-Cu Alloys Using Differential Thermal Analysis

Differential thermal analysis (DTA) has been conducted on directionally solidified near-eutectic Sn-3.0 wt.%Ag-0.5 wt.%Cu (SAC), SAC \(+\) 0.2 wt.%Sb, SAC \(+\) 0.2 wt.%Mn, and SAC \(+\) 0.2 wt.%Zn. Laser ablation inductively coupled plasma mass spectroscopy was used to study element partitioning behavior and estimate DTA sample compositions. Mn and Zn additives reduced the undercooling of SAC from 20.4\(^\circ \hbox {C}\) to \(4.9^\circ \hbox {C}\) and \(2^\circ \hbox {C}\), respectively. Measurements were performed at cooling rate of \(10^\circ \hbox {C}\) per minute. After introducing 200 ppm \(\hbox {O}_2\) into the DTA, this undercooling reduction ceased for SAC \(+\) Mn but persisted for SAC \(+\) Zn.     

Ruthenium complex-cored dendrimers: Shedding light on efficiency trade-offs in dye-sensitised solar cells

A series of first generation dendrimers provide important insight into the performance of dye-sensitised solar cells (DSSCs). The dendrimers are comprised of a substituted [cis-di(thiocyanato)-bis(2,2′-bipyridyl)ruthenium(II) complex, first generation biphenyl-based dendrons, and either four, eight, or twelve 2-ethylhexyloxy surface groups. The dendrimers were bound to the titanium dioxide of the DSSCs via carboxylate groups on one of the bipyridyl moieties in a similar manner to the ‘gold standard’ [cis-di(thiocyanato)-bis(4,4′-dicarboxylate-2,2′-bipyridyl)]ruthenium(II) 1 (N3). Exchanging one pair of the carboxylate groups on one bipyridyl ligand of N3 with styryl units to give [cis-di(thiocyanato)-(4,4′-dicarboxylate-2,2′-bipyridyl)-(4,4′-distyryl-2,2′-bipyridyl]ruthenium(II) 2 resulted in an improvement in device performance (7.19% ± 0.11% for 2 versus 6.94% ± 0.12% for N3). Devices containing the dendrimers also had good efficiencies but the performance was found to decrease with the increasing number of surface groups, which gives rise to an increase in the molecular volume of the dye. The device containing the dendrimer with four surface groups, 3, had a global efficiency of 6.32% ± 0.13%, which was comparable to N3 (6.94% ± 0.12%) in the same device configuration. In contrast, the dendrimer with twelve surface groups, 5, had an efficiency of 3.69% ± 0.19%. Complex 2 and all three dendrimers have the same core chromophore, which absorbs more light than N3. The decrease in efficiency with increasing molecular volume was therefore determined to be due to less dye being adsorbed. Hence molecular volume and molar extinction coefficient are both first order parameters in achieving high conversion efficiencies and must be taken into account when designing new dyes for DSSCs.     

GD&T-Based Characterization of Short-Range Non-contact 3D Imaging Systems

We present a series of test metrics, artifacts, and procedures for characterizing and verifying the operating limits of a short-range non-contact three-dimensional imaging system. These metrics have been designed to correspond to dimensioning and tolerancing metrics that are widely used in industry (e.g. automotive, aerospace, etc.). We introduce operating limit metrics that correspond with the geometric dimensioning and tolerancing (GD&T) metrics of Form (Flatness and Circularity), Orientation (Angularity), Location (Sphere, Corner, and Hole Position Errors), and Size (Diameter, Sphere-spacing, Plane-spacing and Angle Errors). An example is presented to illustrate how these metrics, artifacts, and associated test procedures can be used in practice.     

Evolutionary functional black-box testing in an industrial setting

During the past years, evolutionary testing research has reported encouraging results for automated functional (i.e. black-box) testing. However, despite promising results, these techniques have hardly been applied to complex, real-world systems and as such, little is known about their scalability, applicability, and acceptability in industry. In this paper, we describe the empirical setup used to study the use of evolutionary functional testing in industry through two case studies, drawn from serial production development environments at Daimler and Berner & Mattner Systemtechnik, respectively. Results of the case studies are presented, and research questions are assessed based on them. In summary, the results indicate that evolutionary functional testing in an industrial setting is both scalable and applicable. However, the creation of fitness functions is time-consuming. Although in some cases, this is compensated by the results, it is still a significant factor preventing functional evolutionary testing from more widespread use in industry.     

Growing a list

It is easy to find expert knowledge on the Internet on almost any topic, but obtaining a complete overview of a given topic is not always easy: information can be scattered across many sources and must be aggregated to be useful. We introduce a method for intelligently growing a list of relevant items, starting from a small seed of examples. Our algorithm takes advantage of the wisdom of the crowd, in the sense that there are many experts who post lists of things on the Internet. We use a collection of simple machine learning components to find these experts and aggregate their lists to produce a single complete and meaningful list. We use experiments with gold standards and open-ended experiments without gold standards to show that our method significantly outperforms the state of the art. Our method uses the ranking algorithm Bayesian Sets even when its underlying independence assumption is violated, and we provide a theoretical generalization bound to motivate its use.     

Plowing with precedence: A variant of the windy postman problem

In winter, a common problem is to determine the route that a snowplow should take in order to minimize the distance traveled. We propose a variant of this arc routing problem that is motivated by the fact that deadhead travel over streets that have already been plowed is significantly faster than the time it takes to plow the street. This problem differs from most arc routing problems because the cost of traversing a street changes depending on the order of the streets on a route. We develop a method that generates near-optimal solutions to instances as large as 200 nodes.