Miracle-dz/UniFAR-FTUs huggingface dataset:
Detection of secondary binding sites in proteins using fragment screening

Significance The regulation of proteins in biological systems is essential to their function and nature has evolved a diverse array of mechanisms by which to achieve such regulation. Indeed, the primary function of a protein may be regulated by interaction with endogenous ligands or other protein partners binding at secondary sites. In this study, we report that fragment screening using X-ray crystallography can identify such secondary sites that may have a biological function, which in turn implies that the opportunities for modulating protein function with small molecules via such sites are far more widespread than previously assumed. Many of the secondary sites we discovered were previously unknown and therefore offer potential for novel approaches to modulate these protein targets. Proteins need to be tightly regulated as they control biological processes in most normal cellular functions. The precise mechanisms of regulation are rarely completely understood but can involve binding of endogenous ligands and/or partner proteins at specific locations on a protein that can modulate function. Often, these additional secondary binding sites appear separate to the primary binding site, which, for example for an enzyme, may bind a substrate. In previous work, we have uncovered several examples in which secondary binding sites were discovered on proteins using fragment screening approaches. In each case, we were able to establish that the newly identified secondary binding site was biologically relevant as it was able to modulate function by the binding of a small molecule. In this study, we investigate how often secondary binding sites are located on proteins by analyzing 24 protein targets for which we have performed a fragment screen using X-ray crystallography. Our analysis shows that, surprisingly, the majority of proteins contain secondary binding sites based on their ability to bind fragments. Furthermore, sequence analysis of these previously unknown sites indicate high conservation, which suggests that they may have a biological function, perhaps via an allosteric mechanism. Comparing the physicochemical properties of the secondary sites with known primary ligand binding sites also shows broad similarities indicating that many of the secondary sites may be druggable in nature with small molecules that could provide new opportunities to modulate potential therapeutic targets.
Lipoprotein-associated phospholipase A2 and plasma lipids in patients with destructive periodontal disease.

OBJECTIVES Periodontitis is believed to be an independent risk factor of cardiovascular disease (CVD) and to be associated with a moderate systemic inflammatory reaction and hyperlipidaemia. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an enzyme that has been shown to be a risk factor of CVD and that is involved in the degradation of the phospholipid mediator platelet-activating factor (PAF), a potent mediator of inflammation. MATERIAL AND METHODS In the present study, we measured concentrations of plasma lipids and plasma activity of Lp-PLA(2) in 32 patients (mean age 43+/-11 years) with moderate-to-severe periodontitis before and 3 months after local treatment. RESULTS Periodontal therapy resulted in a significant reduction of local inflammation and tissue destruction as reflected in reduced pocket depths and reduced bleeding indices. Pre- and post-treatment plasma lipid levels were (median and range, mmol/l): total cholesterol (C) 5.01 (3.94-7.15) and 4.91 (3.32-8.01); low-density lipoprotein-cholesterol (LDL-C) 3.14 (2.40-4.84) and 2.96 (1.39-5.04); HDL-C 1.27 (0.73-2.17) and 1.25 (0.74-2.55); triglycerides 1.37 (0.48-5.11) and 1.14 (0.38-792). Using the Wilcoxon's rank test, neither parameter showed a significant change. In contrast to the lacking response of plasma lipids, we observed a significant reduction in the activity of Lp-PLA(2). Local treatment lowered the enzyme activity by about 10% from 3.61+/-0.99 to 3.29+/-0.94 micromol/ml/h (mean+/-SD; p<0.001). The pre-treatment values of Lp-PLA(2) and LDL-C significantly correlated with clinical parameters of inflammation and periodontal destruction. CONCLUSION This study indicates that treatment of periodontitis significantly reduces the serum activity of Lp-PLA(2), which is believed to be an independent cardiovascular risk factor.
Automatic Detection of Outliers in Multibeam Echo Sounding Data

The data volumes produced by new generation multibeam systems are very large, especially for shallow water systems. Results from recent multibeam surveys indicate that the ratio of the field survey time, to the time used in interactive editing through graphical editing tools, is about 1:1. An important reason for the large amount of processing time is that users subjectively decide which soundings are outliers. There is an apparent need for an automated approach for detecting outliers that would reduce the extensive labor and obtain consistent results from the multibeam data cleaning process, independent of the individual that has processed the data. The proposed automated algorithm for cleaning multibeam soundings was tested using the SAX-99 (Destin FL) multibeam survey data [2]. Eight days of survey data (6.9 Gigabyte) were cleaned in 2.5 hours on an SGI platform. A comparison of the automatically cleaned data with the subjective, interactively cleaned data indicates that the proposed method is, if not better, at least equivalent to interactive editing as used on the SAX-99 multibeam data. Furthermore, the ratio of acquisition to processing time is considerably improved since the time required for cleaning the data was decreased from 192 hours to 2.5 hours (an improvement by a factor of 77).
Extending mobility to publish/subscribe systems using a pro-active caching approach

The publish/subscribe communication paradigm has many characteristics that lend themselves well to mobile wireless networks. Our research investigates the extension of current publish/subscribe systems to support subscriber mobility in such networks. We present a novel mobility management scheme based on a pro-active caching approach to overcome the challenges and the performance concerns of disconnected operations in publish/subscribe systems. We discuss the mechanism of our proposed scheme and present a comprehensive experimental evaluation of our approach and alternative state-of-the-art solutions based on reactive approaches and durable subscriptions. The obtained results illustrate significant performance benefits of our proposed scheme across a range of scenarios. We conclude our work by discussing a modeling approach that can be used to extrapolate the performance of our approach in a near-size environment (in terms of broker network and/or subscriber population) to our experimental testbed.
A novel cadherin cell adhesion molecule: its expression patterns associated with implantation and organogenesis of mouse embryos

The Ca2+-dependent cell adhesion molecules, termed cadherins, were previously divided into two subclasses, E- and N-types, with different adhesive specificity. In this study, we identified a novel class of cadherin, termed P-cadherin, using a visceral endoderm cell line PSA5- E. This cadherin was a 118,000-D glycoprotein and distinct from E- and N-cadherins in immunological specificity and molecular mass. In accord with these findings, cells with P-cadherin did not cross-adhere with cells with E-cadherin. P-Cadherin first appeared in developing mouse embryos in the extraembryonic ectoderm and the visceral endoderm at the egg cylinder stage and later was expressed in various tissues. The placenta and the uterine decidua most abundantly expressed this cadherin. The expression of P-cadherin was transient in many tissues, and its permanent expression was limited to certain tissues such as the epidermis, the mesothelium, and the corneal endothelium. When the tissue distribution of P-cadherin was compared with that of E-cadherin, we found that: each cadherin displayed a unique spatio-temporal pattern of expression; P-cadherin was co-expressed with E-cadherin in local regions of various tissues; and onset or termination of expression of P- cadherin was closely associated with connection or segregation of cell layers, as found with other cadherins. These results suggested that differential expression of multiple classes of cadherins play a role in implantation and morphogenesis of embryos by providing cells with heterogenous adhesive specificity.
The ZMET Technique: A New Paradigm for Improving Marketing and Marketing Research

For decades, marketing and marketing research have been based on a concept of consumer behaviour that is deeply embedded in a linear notion of marketing activities. With increasing regularity, key organising frameworks for marketing and marketing activities are being challenged by academics and practitioners alike. In turn, this has led to the search for new approaches and tools that will help marketers understand the interaction among attitudes, emotions and product/brand choice. More recently, the approach developed by Harvard Professor, Gerald Zaltman, referred to as the Zaltman Metaphor Elicitation Technique (ZMET) has gained considerable interest. This paper seeks to demonstrate the effectiveness of this alternative qualitative method, using a non-conventional approach, thus providing a useful contribution to the qualitative research area.
The Role of Transporters in the Toxicity of Chemotherapeutic Drugs: Focus on Transporters for Organic Cations

The introduction of chemotherapy in the treatment of cancer is one of the most important achievements of modern medicine, even allowing the cure of some lethal diseases such as testicular cancer and other malignant neoplasms. The number and type of chemotherapeutic agents available have steadily increased and have developed until the introduction of targeted tumor therapy. It is now evident that transporters play an important role for determining toxicity of chemotherapeutic drugs not only against target but also against nontarget cells. This is of special importance for intracellularly active hydrophilic drugs, which cannot freely penetrate the plasma membrane. Because many important chemotherapeutic agents are substrates of transporters for organic cations, this review discusses the known interaction of these substances with these transporters. A particular focus is given to the role of transporters for organic cations in the development of side effects of chemotherapy with platinum derivatives and in the efficacy of recently developed tyrosine kinase inhibitors to specifically target cancer cells. It is evident that specific inhibition of uptake transporters may be a possible strategy to protect against undesired side effects of platinum derivatives without compromising their antitumor efficacy. These transporters are also important for efficient targeting of tyrosine kinase inhibitors to cancer cells. However, in order to achieve the aims of protecting from undesired toxicities and improving the specificity of uptake by tumor cells, an exact knowledge of transporter expression, function, regulation under normal and pathologic conditions, and of genetically and epigenetically regulation is mandatory.
Comparison of open-label, 8-week trials of olanzapine monotherapy and topiramate augmentation of olanzapine for the treatment of pediatric bipolar disorder.

BACKGROUND The aim of this study was to test the efficacy and safety of olanzapine + topiramate versus olanzapine monotherapy in the treatment of bipolar disorder (BPD) and treatment-attendant weight gain in children and adolescents. METHOD Subjects (N = 40) were outpatients of both sexes, 6-17 years of age, with a Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) diagnosis of BPD (manic, hypomanic, or mixed) and Young Mania Rating Scale (YMRS) total score of >15 treated over 8-week periods in two partially concurrent open-label trials with olanzapine (n = 17) or olanzapine + topiramate (n = 23). RESULTS Subjects in both groups experienced a statistically significant reduction in YMRS scores after 8-week, open-label treatment with olanzapine (baseline YMRS = 26.7 +/- 9.5; end-point YMRS = 18.2 +/- 12.5, p = 0.04) and olanzapine +topiramate (baseline YMRS = 31.3 +/- 7.9; end-point YMRS = 20.4 +/- 11.4, p = 0.04). There was no difference in response between the two groups based on YMRS or Clinical Global Impressions-Improvement (CGI-I) scores. Adverse events were few and mild and similar between the two groups, with the exception of weight gain. The weight gain in the olanzapine group was 5.3 +/- 2.1 kg and the weight gain in the olanzapine + topiramate group was statistically significantly lower, 2.6 +/- 3.6 kg. CONCLUSIONS Augmentation of olanzapine with topiramate resulted in a reduced weight gain over the course of an 8-week, open-label trial when compared with olanzapine treatment alone, but did not lead to greater reduction in symptoms of mania.
HALWPE: Hardware-assisted light weight performance estimation for GPUs

This paper presents a predictive modeling framework for GPU performance. The key innovation underlying this approach is that performance statistics collected from representative workloads running on current generation GPUs can effectively predict the performance of next-generation GPUs. This is useful when simulators are available for the next-generation device, but simulation times are exorbitant, rendering early design space exploration of microarchitectural parameters and other features infeasible. When predicting performance across three Intel GPU generations (Haswell, Broadwell, Skylake), our models achieved low out-of-sample-errors ranging from 7.45% to 8.91%, while running 30,000–45,000 times faster than cycle-accurate simulation.
Multilayer Virtualized Systems Analysis with Kernel Tracing

This paper studies interactions between virtual machines and their host through the sharing of resources like physical CPUs. We present an analysis based on kernel tracing that erases the bounds between virtual machines and their host to reduce the multilayer system into a single layer. For this analysis we developed a view that displays a time line for each host's CPU, showing across time which process is running, even if it is from a virtual machine. By using a system of filters, we added the possibility to highlight in this view either traced machines, virtual CPUs or specific processes. This last feature grants the possibility to precisely see on the host where and when a virtual machine's thread is running.
REMOTE SENSING AND MODELING IN REGIONAL LAND COVER CHANGE STUDY

This paper summarises the general pattern of urban land-cover change in the Northeastern Illinois between 1972 and 1997 using Landsat acquired remotely sensed images. The region, centred by the city of Chicago, experienced dramatic land cover change in the past decades. Accompanying the redistribution of population and decentralisation of metropolitan functions are the tremendous growth and development of outlying suburban areas. Comparison of classified land cover data of 1972, 1985, and 1997 demonstrates that urban land expansion dominated the regional pattern of land cover change. Between 1972 and 1985, urban land increased by 14.5%. Urban land increase and suburban sprawl accelerated to about 30% between 1985 and 1997. Within the 25 years between 1972 and 1997, urban land increased about 49%. Most of the suburban land expansion occurred by consumption of agricultural land in the outer-ring and collar counties. About 22% and 20% of agricultural land were converted into other land use in the time periods between 1972 and 1985, and 1985 and 1997, respectively. A 37% decrease of agricultural land was observed from 1972 to 1997. Natural areas, on the other hand, declined 7.6% from 1972 to 1985, and 14.5% from 1985 to 1997. In total, 21% of natural areas were converted into other types of land covers. Many municipalities, particularly in the collar counties of Chicago, have expanded their territory by annexation. The expansion of the municipalities partially reflects the extent and potential of urbanization in the suburban areas.
Wiring through tunneling nanotubes – from electrical signals to organelle transfer

Tunneling nanotubes (TNTs) represent a subset of F-actin-based transient tubular connections that allow direct communication between distant cells. Recent studies have provided new insights into the existence of TNTs in vivo, and this novel mechanism of intercellular communication is implicated in various essential processes, such as development, immunity, tissue regeneration and transmission of electrical signals. TNTs are versatile structures known to facilitate the transfer of various cargos, such as organelles, plasma membrane components, pathogens and Ca2+. Recently, a new function of TNTs in the long-range transfer of electrical signals that involves gap junctions has been suggested. This indicates that different types of TNTs might exist, and supports the notion that TNTs might not be just passive open conduits but rather are regulated by gating mechanisms. Furthermore, TNTs have been found in different cell lines and are characterized by their diversity in terms of morphology. Here we discuss these novel findings in the context of the two models that have been proposed for TNT formation, and focus on putative proteins that could represent TNT specific markers. We also shed some light on the molecular mechanisms used by TNTs to transfer cargos, as well as chemical and electrical signals.
2009 Executive Summary

Web applications are ubiquitous nowadays. Consequently, the field of Web application security is of ever rising significance. This Dagstuhl seminar was conducted to assemble researchers active in the domain to gain a first comprehensive overview of this young discipline in security research. From a content perspective, the topic was explored in a great variety of directions, including for instance Web browser-based security measures, language-based techniques, software engineering centric methods, run-time enforcement, static analysis, or formal approaches.
Enhanced Basal Activity of a Cardiac Ca2+ Release Channel (Ryanodine Receptor) Mutant Associated With Ventricular Tachycardia and Sudden Death

Abstract— Mutations in the human cardiac Ca2+ release channel (ryanodine receptor, RyR2) gene have recently been shown to cause effort-induced ventricular arrhythmias. However, the consequences of these disease-causing mutations in RyR2 channel function are unknown. In the present study, we characterized the properties of mutation R4496C of mouse RyR2, which is equivalent to a disease-causing human RyR2 mutation R4497C, by heterologous expression of the mutant in HEK293 cells. [3H]ryanodine binding studies revealed that the R4496C mutation resulted in an increase in RyR2 channel activity in particular at low Ca2+ concentrations. This increased basal channel activity remained sensitive to modulation by caffeine, ATP, Mg2+, and ruthenium red. In addition, the R4496C mutation enhanced the sensitivity of RyR2 to activation by Ca2+ and by caffeine. Single-channel analysis showed that single R4496C mutant channels exhibited considerable channel openings at low Ca2+ concentrations. HEK293 cells transfected with mutant R4496C displayed spontaneous Ca2+ oscillations more frequently than cells transfected with wild-type RyR2. Substitution of a negatively charged glutamate for the positively charged R4496 (R4496E) further enhanced the basal channel activity, whereas replacement of R4496 by a positively charged lysine (R4496K) had no significant effect on the basal activity. These observations indicate that the charge and polarity at residue 4496 plays an essential role in RyR2 channel gating. Enhanced basal activity of RyR2 may underlie an arrhythmogenic mechanism for effort-induced ventricular tachycardia.
Integrating robotics software

Developing software for controlling robotic systems is costly due to the complexity inherent in these systems. There is a need for tools that permit a reduction in the programming efforts, aiming at the generation of modular and robust applications, and promoting software reuse. The techniques which are of common use today in other areas are not adequate to deal with the complexity associated with these systems. In this work we present CoolBOT, a component oriented framework for programming robotic systems, based on the Port Automata model that fosters controllability and observability of software components. A simple demonstrator outlines the benefits of using the proposed approach in the development of a robotic application.
Snf1 Dependence of Peroxisomal Gene Expression Is Mediated by Adr1*

Eukaryotes utilize fatty acids by β-oxidation, which occurs in the mitochondria and peroxisomes in higher organisms and in the peroxisomes in yeast. The AMP-activated protein kinase regulates this process in mammalian cells, and its homolog Snf1, together with the transcription factors Adr1, Oaf1, and Pip2, regulates peroxisome proliferation and β-oxidation in yeast. A constitutive allele of Adr1 (Adr1c) lacking the glucose- and Snf1-regulated phosphorylation substrate Ser-230 was found to be Snf1-independent for regulation of peroxisomal genes. In addition, it could compensate for and even suppress the requirement for Oaf1 or Pip2 for gene induction. Peroxisomal genes were found to be regulated by oleate in the presence of glucose, as long as Adr1c was expressed, suggesting that the Oaf1/Pip2 heterodimer is Snf1-independent. Consistent with this observation, Oaf1 binding to promoters in the presence of oleate was not reduced in a snf1Δ strain. Exploring the mechanism by which Adr1c permits Snf1-independent peroxisomal gene induction, we found that strength of promoter binding did not correlate with transcription, suggesting that stable binding is not a prerequisite for enhanced transcription. Instead, enhanced transcriptional activation and suppression of Oaf1, Pip2, and Snf1 by Adr1c may be related to the ability of Adr1c to suppress the requirement for and enhance the recruitment of transcriptional coactivators in a promoter- and growth medium-dependent manner.
Modelle des Innovationsprozesses

Sowohl in der Forschung als auch in der Praxis sind Prozessmodelle ein wichtiger Bestandteil des Innovationsmanagements. Hierbei erfullen Prozessmodelle die unterschiedlichsten Aufgaben. In der Praxis werden beispielsweise Prozessmodelle als Managementtool eingesetzt, um real ablaufende Prozesse zu standardisieren. In der Forschung werden Innovationsprozesse empirisch erfasst und in Prozessmodellen moglichst realistisch wiedergegeben. So vielfaltig wie die Einsatzmoglichkeiten von Prozessmodellen sind die Ausgestaltungen der Modelle, die von der jeweiligen Zielsetzung des Unternehmens oder des Forschers abhangen. Somit gibt es nicht das richtige Prozessmodell. Ziel dieses Arbeitspapieres ist es, einen Uberblick uber die verschiedenen Einsatzmoglichkeiten und Ausgestaltungen von Prozessmodellen zu geben. Es wird eine Auswahl von Prozessmodellen aus dem englischsprachigen und deutschsprachigen Raum prasentiert und Besonderheiten herausgearbeitet.
Ethanol: Software defined networking for 802.11 Wireless Networks

Wireless Networks have become ubiquitous and dense to support the growing demand from mobile users. To improve the performance of these networks, new approaches are required, such as context and service aware control algorithms, which are not possible on today's closed proprietary WLAN controllers. In this work, we propose Ethanol, a software-defined networking architecture for 802.11 dense WLANs. This paper describes the benefits of programmable APs, and proposes Ethanol, an architecture for network-wide control of QoS, user mobility, AP virtualization, and security on 802.11 APs. The proposal is evaluated on a prototype using off-the-shelf APs over three use cases.