bluuebunny/crossref_metadata_2025_split huggingface dataset:
Confidence from uncertainty - A multi-target drug screening method from robust control theory
Authors: Luni Camilla , Shoemaker Jason E , Sanft Kevin R , Petzold Linda R , Doyle Francis J 
Published: November 2010

Abstract

Background
Robustness is a recognized feature of biological systems that evolved as a defence to environmental variability. Complex diseases such as diabetes, cancer, bacterial and viral infections, exploit the same mechanisms that allow for robust behaviour in healthy conditions to ensure their own continuance. Single drug therapies, while generally potent regulators of their specific protein/gene targets, often fail to counter the robustness of the disease in question. Multi-drug therapies offer a powerful means to restore disrupted biological networks, by targeting the subsystem of interest while preventing the diseased network from reconciling through available, redundant mechanisms. Modelling techniques are needed to manage the high number of combinatorial possibilities arising in multi-drug therapeutic design, and identify synergistic targets that are robust to system uncertainty.

Results
We present the application of a method from robust control theory, Structured Singular Value or μ- analysis, to identify highly effective multi-drug therapies by using robustness in the face of uncertainty as a new means of target discrimination. We illustrate the method by means of a case study of a negative feedback network motif subject to parametric uncertainty.

Conclusions
The paper contributes to the development of effective methods for drug screening in the context of network modelling affected by parametric uncertainty. The results have wide applicability for the analysis of different sources of uncertainty like noise experienced in the data, neglected dynamics, or intrinsic biological variability.
Toll-like receptor 2 agonists inhibit human fibrocyte differentiation
Authors: Maharjan Anu S , Pilling Darrell , Gomer Richard H 
Published: November 2010

AbstractBackgroundIn healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation.ResultsWhen human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF)-α accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC) class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN)-α, IFN-γ, interleukin (IL)-12, aggregated immunoglobulin G (IgG) or serum amyloid P (SAP), factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-α, IFN-γ, granulocyte colony-stimulating factor and tumor growth factor β1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes.ConclusionsOur results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure.
Diagnostic accuracy of existing methods for identifying diabetic foot ulcers from inpatient and outpatient datasets
Authors: Sohn Min‐Woong , Budiman‐Mak Elly , Stuck Rodney M , Siddiqui Farah , Lee Todd A 
Published: November 2010

AbstractBackgroundAs the number of persons with diabetes is projected to double in the next 25 years in the US, an accurate method of identifying diabetic foot ulcers in population‐based data sources are ever more important for disease surveillance and public health purposes. The objectives of this study are to evaluate the accuracy of existing methods and to propose a new method.MethodsFour existing methods were used to identify all patients diagnosed with a foot ulcer in a Department of Veterans Affairs (VA) hospital from the inpatient and outpatient datasets for 2003. Their electronic medical records were reviewed to verify whether the medical records positively indicate presence of a diabetic foot ulcer in diagnoses, medical assessments, or consults. For each method, five measures of accuracy and agreement were evaluated using data from medical records as the gold standard.ResultsOur medical record reviews show that all methods had sensitivity > 92% but their specificity varied substantially between 74% and 91%. A method used in Harrington et al. (2004) was the most accurate with 94% sensitivity and 91% specificity and produced an annual prevalence of 3.3% among VA users with diabetes nationwide. A new and simpler method consisting of two codes (707.1× and 707.9) shows an equally good accuracy with 93% sensitivity and 91% specificity and 3.1% prevalence.ConclusionsOur results indicate that the Harrington and New methods are highly comparable and accurate. We recommend the Harrington method for its accuracy and the New method for its simplicity and comparable accuracy.
Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients
Authors: Krishnan Anand , Ochola Judith , Mundy Julie , Jones Mark , Kruger Peter , Duncan Emma , Venkatesh Bala 
Published: November 2010

Abstract
Introduction
Recent reports have highlighted the prevalence of vitamin D deficiency and suggested an association with excess mortality in critically ill patients. Serum vitamin D concentrations in these studies were measured following resuscitation. It is unclear whether aggressive fluid resuscitation independently influences serum vitamin D.

Methods
Nineteen patients undergoing cardiopulmonary bypass were studied. Serum 25(OH)D3, 1α,25(OH)2D3, parathyroid hormone, C-reactive protein (CRP), and ionised calcium were measured at five defined timepoints: T1 - baseline, T2 - 5 minutes after onset of cardiopulmonary bypass (CPB) (time of maximal fluid effect), T3 - on return to the intensive care unit, T4 - 24 hrs after surgery and T5 - 5 days after surgery. Linear mixed models were used to compare measures at T2-T5 with baseline measures.

Results
Acute fluid loading resulted in a 35% reduction in 25(OH)D3 (59 ± 16 to 38 ± 14 nmol/L, P < 0.0001) and a 45% reduction in 1α,25(OH)2D3 (99 ± 40 to 54 ± 22 pmol/L P < 0.0001) and i(Ca) (P < 0.01), with elevation in parathyroid hormone (P < 0.0001). Serum 25(OH)D3 returned to baseline only at T5 while 1α,25(OH)2D3 demonstrated an overshoot above baseline at T5 (P < 0.0001). There was a delayed rise in CRP at T4 and T5; this was not associated with a reduction in vitamin D levels at these time points.

Conclusions
Hemodilution significantly lowers serum 25(OH)D3 and 1α,25(OH)2D3, which may take up to 24 hours to resolve. Moreover, delayed overshoot of 1α,25(OH)2D3 needs consideration. We urge caution in interpreting serum vitamin D in critically ill patients in the context of major resuscitation, and would advocate repeating the measurement once the effects of the resuscitation have abated.
Mechanics and energetics of step-to-step transitions isolated from human walking
Authors: Soo Caroline H. , Donelan J. Maxwell 
Published: November 2010

SUMMARYWe isolated step-to-step transitions from other contributors to walking mechanics using a cyclical rocking task and then examined the contribution of individual joints to the total work required to redirect the velocity of the center of mass (COM). Nine participants were instructed to rock backward and forward in the sagittal plane, eliminating the need to swing the legs and progress forward. To systematically increase the required work, we increased step length from 60 to 100% of leg length, keeping rocking frequency constant. The individual limbs method quantified the COM work and the joint power method apportioned the COM work among its various sources. As predicted by a physics-based model, we found that work in rocking was performed mainly during the step-to-step transitions and increased strongly with step length. We also found that increases in the average COM work rate exacted a proportional metabolic cost. The similar patterns of COM work and COM work rate during rocking and walking support the use of rocking to isolate the mechanics of step-to-step transitions. We found that the ankle was the main joint contributing to the positive work required to redirect the COM velocity during forward rocking. At the longest length, it accounted for 88% of the work performed by the trailing leg joints. Interestingly, the summed contribution of ankle, knee and hip joint work accounted for only 39% of the front leg negative COM work during the forward transition, suggesting that most of the collision work is performed by passive tissue.
Presynaptic Ca2+ stores contribute to odor-induced responses in Drosophila olfactory receptor neurons
Authors: Murmu Meena Sriti , Stinnakre Jacques , Martin Jean-René 
Published: November 2010

SUMMARY
In both vertebrates and invertebrates, olfactory receptor neurons (ORNs) respond to several odors. They also adapt to stimulus variations, and this is considered to be a simple form of non-associative learning and neuronal plasticity. Different mechanisms have been described to support neuronal and/or synaptic plasticity. For example in vertebrates, presynaptic Ca2+ stores relying on either the ryanodine receptor (RyR) or the inositol (1,4,5)-trisphosphate receptor (InsP3R) have been reported to participate in synaptic transmission, in hippocampal pyramidal neurons, and in basket cell–Purkinje cell synapses. However, in invertebrates, especially in sensory neurons such as ORNs, similar mechanisms have not yet been detected. In this study, using Drosophila and taking advantage of an in vivo bioluminescence Ca2+-imaging technique in combination with genetic and pharmacological tools, first we show that the GFP–aequorin Ca2+ sensor is sensitive enough to detect odor-induced responses of various durations. Second, we show that for a relatively long (5 s) odor application, odor-induced Ca2+ responses occurring in the axon terminals of ORNs involve intracellular Ca2+ stores. This response is decreased by specifically targeting InsP3R or RyR by RNAi, or application of the specific blockers thapsigargin or ryanodine, suggesting that Ca2+ stores serve to amplify the presynaptic signal. Furthermore, we show that disrupting the intracellular Ca2+ stores in the ORNs has functional consequences since InsP3R- or RyR-RNAi expressing flies were defective in olfactory behavior. Altogether, our results indicate that for long odor applications in Drosophila, the olfactory response depends on intracellular Ca2+ stores within the axon terminals of the ORNs.
Particle size of apoB-48 carrying lipoproteins in remnant lipoproteins isolated from postprandial plasma
Authors: Nakano Takamitsu , Tanaka Akira , Okazaki Mitsuyo , Tokita Yoshiharu , Nagamine Takeaki , Nakajima Katsuyuki 
Published: November 2010

Background Particle size of apoB-48 carrying lipoproteins in remnant-like lipoprotein particles (RLP) in postprandial plasma has not been well characterized. Methods Plasma lipids, lipoproteins and apolipoproteins in 12 healthy subjects were analysed after an oral fat load. RLP isolated by immunoaffinity gel from plasma of a normolipidaemic and a hyperlipidaemic subject in four hours after an oral fat load was fractionated by high-performance liquid chromatography (HPLC) and monitored by total cholesterol (TC), triglycerides (TG), apoB-48 and apoB-100. Results TC, low-density lipoprotein (LDL)-C and apoB did not change after an oral fat load, while TG, RLP-C, RLP-TG and apoB-48 increased significantly in postprandial plasma. HPLC profiles monitored by TC and TG revealed that major lipoproteins increased in RLP after an oral fat load was VLDL size particles. The percentage of RLP-TG in total TG and the ratio of RLP-TG/RLP-C were significantly increased in four hours after an oral fat load compared with the fasting state ( P < 0.01). RLP in four hours after an oral fat load fractionated by HPLC and monitored by TC, TG, apoB-48 and apoB-100 revealed that VLDL size or smaller particles were the major lipoproteins. Conclusions ApoB-48 carrying lipoproteins in RLP isolated from a normolipidaemic and a hyperlipidaemic subject after an oral fat load showed a similar particle size with apoB-100 carrying VLDL remnants. Therefore, the most apoB-48 carrying particles found in postprandial RLP can be classified as CM remnants. The majority of remnants in the postprandial state were not CM remnants, but VLDL remnants.
Analysis of Pharmaceutical Safety-Related Regulatory Actions in Japan: Do Tradeoffs Exist Between Safer Drugs and Launch Delay?
Authors: Yamada Toru , Kusama Makiko , Hirai Yuka , Arnold Frank , Sugiyama Yuichi , Ono Shunsuke 
Published: November 2010

Background: Prediction and management of drug safety is a global regulatory issue. Safety-related regulatory actions (SRRAs) are taken mostly when unexpected adverse drug reactions occur. Currently, Japan is reconciled to delayed access to new drugs (ie, launch delay compared to Western countries), but may have been benefiting by free-riding on safety data accumulated in other countries prior to Japanese launch. Objective: To identify factors that are significantly associated with SRRAs, and to discuss the challenges that Japan might have to face with increasing access to new drugs. Methods: The SRRAs of 135 new drugs approved from January 2000 to December 2005 were analyzed to investigate association with launch lag, company and drug characteristics, market size, submission data, and regulatory status. SRRAs were measured in terms of the number of emergency safety information notifications and official safety instructions issued by the Japanese regulatory agency within 3 years after approval. A negative binomial distribution model was used for regression analysis. Results: Longer launch lags and presence of drugs with similar modes of action were associated with fewer SRRAs. Bridging strategy showed increased SRRAs. No significant association was observed between SRRAs and the subject number in clinical data packages. Occurrence of SRRAs was varied among development strategy, preceding products, and regional regulations. Conclusions: The occurrence of SRRAs was associated with the accumulation of both foreign and domestic postmarketing evidence rather than with clinical trial data upon launch. Considering the paradigm shift to simultaneous global drug development and filing for regulatory approval, this study indicates the importance of intensive data collection in the early postmarketing phase and use of safety information in early markets. However, even if we would be sufficiently cautious about safety risks of new drugs, a population that enjoys first-in-class drugs probably has to bear the risks.
First Report of Lamotrigine-Induced Drug Rash with Eosinophilia and Systemic Symptoms Syndrome with Pancreatitis
Authors: Roquin Guillaume , Peres Marine , Lerolle Nicolas , Dib Nina , Mercat Alain , Croue Anne , Augusto Jean-François 
Published: November 2010

Objective: To report a case of lamotrigine-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome with pancreatitis as the initial visceral involvement. Case Summary: A 75-year-old man was admitted to the local hospital for generalized tonic-clonic seizures. Results of the clinical examination and neurologic investigations were unremarkable. Lamotrigine treatment was initiated and the patient was discharged a few days later. Forty days after lamotrigine initiation, he developed an exanthematous maculopapular rash with fever, peripheral lymphadenopathies, and hypereosinophilia. Lamotrigine hypersensitivity was suspected and the drug was suspended on day 45. On day 47, the patient presented with acute abdominal pain with an elevated lipase level. Acute pancreatitis was confirmed on computed tomography scan. The patient's condition worsened and he was transferred to the intensive care unit with multiorgan failure. The diagnosis of lamotrigine-induced DRESS syndrome was confirmed by a compatible skin histology and concomitant human herpesvirus-6 infection. Discussion: This observation has 2 points of interest. First, pancreatic toxicity of lamotrigine has been rarely reported in the literature. Secondly, pancreatitis is uncommon at the early stage of DRESS syndrome. Only 1 other case of DRESS syndrome, secondary to allopurinol, reports pancreatitis along with an Epstein-Barr virus infection. The Naranjo probability scale indicated a probable causality between lamotrigine and DRESS syndrome in this patient. Conclusions: This is the first reported case of lamotrigine-induced DRESS syndrome with pancreatitis as the initial visceral involvement. Clinicians should be aware of this mode of presentation of DRESS syndrome.
Die Rolle der lokalen Eliten abhängiger griechischer Städte vor dem Hintergrund der Entwicklung königlicher Administration und städtischer Politik im 2. Jh. v. Chr.
Authors: Dreyer Boris 
Published: November 2010

Zusammenfassung
Die vorliegende Untersuchung geht von der Rolle der Eliten griechischer Städte im attalidischen Reich aus. Die Koordinaten des politischen Raums, den die Attaliden für die abhängigen Städte schufen, bestimmten auf lange Sicht die Position lokaler Eliten ungleich weniger als die Rahmenbedingungen in den Städten selbst, und zwar relativ unabhängig davon, ob die Städte abhängig waren oder nicht: Im Laufe des 3. und 2. Jh.s wurden die formal nach athenischem Vorbild geprägten städtischen Demokratien immer stärker von Gruppen reicher Mitbürger dominiert. Ihre ab der Mitte des 2. Jh.s immer deutlicher angesprochenen Privilegien sind Ergebnis eines langen Prozesses, in den auch die Entwicklung des Institutionengefüges eingebunden war. Diese Privilegien rechtfertigen ein neues Selbstverständnis der Eliten, das auf die Perpetuierung des eigenen Einflusses und die dauerhafte Etablierung der Position der eigenen Familie in den Städten ausgerichtet war. Nach Bedeutung der Stadt, je nach Region und abhängig von der politischen ,Großwetterlage konnten die Etappen der zunehmenden Elitisierung zwar unterschiedlich einsetzen, aber schließlich führten sie um die Mitte des 2. Jh.s zu demselben Ergebnis. Eine Zäsur bildete am Ende die römische Vorherrschaft, die zu unterschiedlichen Zeiten begann und im Sinne einer Konzentration wirkte: Die Eliten bewährten sich unter den Attaliden auf einer immer stärker normierten Ebene des Austauschs zwischen lokaler Ebene und Reichszentrale. Dieser ,Mittelbau fiel mit Beginn der direkten römischen Herrschaft ab 133 zunächst weg, weswegen die Eliten ihre Bewährungsfelder verloren – ein Feld für Konfliktstoff, denn nur wenige konnten nunmehr noch dauerhaft Kontakt zu Vertretern der Vormacht knüpfen.
El impacto de las guerras mitridáticas en la creación de una nueva clase dirigente. Evergetas y evergetismo en Asia Menor
Authors: Morales Isaías Arrayás 
Published: November 2010

Resumen
El artículo estudia la formación de una nueva oligarquía mixta en las poleis minor-asiáticas, valorando la trascendencia que, en este sentido, tuvieron las secuelas dejadas por las guerras mitrid ticas. Se analiza también el rol jugado por los evergetas locales, que, tras sobrevivir a la crisis global que comportó el conflicto mitridático, se erigieron en salvadores de sus respectivas patrias. Tales evergetas, bien relacionados con las autoridades romanas, protagonizaron una frenética actividad diplomàtica durante el siglo I a. C., encaminada a conseguir o defender los privilegios de sus poleis.
Influence of added and differently attached methyl groups on the crystal structure of 2,6-diphenyl substituted p-nitrophenol
Authors: Kurjatschij Sanrda , Eißmann Diana , Seichter Wilhelm , Weber Edwin 
Published: November 2010

Abstract
In order to find out the consequences of a methyl substitution on the crystalline packing behaviour of the parent compound 2,6-diphenyl-4-nitrophenol, three analogous nitrophenols being substituted at different positions of the lateral phenyl rings were comparatively studied with regard to their crystal structures. While the molecular structures do not suggest marked differences, the network structures do, showing dependency on the presence and positional substitution of the methyl groups. This is revealed by the formation of weakly O—H…π bonded dimers or supramolecular chains, more strongly hold together through interacting OH and nitro groups.
REEAl2.07(B4O10)O0.60 dimetaborates (REE = La, Pr); synthesis and X-ray structural characterization
Authors: Capitelli Francesco , Chita Giuseppe , Leonyuk Nikolay I. , Koporulina Elizaveta V. , Bellatreccia Fabio , Ventura Giancarlo Della 
Published: November 2010

Abstract
Nonstoichiometric REEAl2.07(B4O10)O0.60 (REE = La, Pr) borates have been crystallized and analyzed by means of single crystal X-ray diffraction. The compounds resulted to be isostructural within hexagonal space group P-62m (n. 189), with the following unit cell parameters: a = 4.6170(1) Å, c = 9.3640(3) Å and V = 172.87(1) Å3 (La); a = 4.5990(1) Å; c = 9.3270(2) Å and V = 170.87(1) Å3 (Pr). REE cations make up a trigonal prismatic coordination, by means of six REE-O bonds under 2.5 Å; aluminium cation is five-coordinated, displaying a square pyramidal coordination, while the boron atom forms BO4 tetrahedral units. The present borates belong to the structural type of NdAl2.07(B4O10)O0.60 dimetaborate [1]: thus, the three-dimensional framework can be described as a structure packed down crystallographic axis c, with layers of six-membered rings of B tetrahedra alternated by inter-layers REE cations and layers of Al polyhedra. An intricate network of Al···O and REE···O interactions complete the array.
Control of Germline torso Expression by the BTB/POZ Domain Protein Pipsqueak Is Required for Embryonic Terminal Patterning in Drosophila
Authors: Grillo Marco , Furriols Marc , Casanova Jordi , Luschnig Stefan 
Published: November 2010

Abstract
Early embryogenesis in Drosophila melanogaster is controlled by maternal gene products, which are deposited in the egg during oogenesis. It is not well understood how maternal gene expression is controlled during germline development. pipsqueak (psq) is a complex locus that encodes several nuclear protein variants containing a PSQ DNA-binding domain and a BTB/POZ domain. Psq proteins are thought to regulate germline gene expression through epigenetic silencing. While psq was originally identified as a posterior-group gene, we show here a novel role of psq in embryonic terminal patterning. We characterized a new psq loss-of-function allele, psqrum, which specifically affects signaling by the Torso (Tor) receptor tyrosine kinase (RTK). Using genetic epistasis, gene expression analyses, and rescue experiments, we demonstrate that the sole function impaired by the psqrum mutation in the terminal system is an essential requirement for controlling transcription of the tor gene in the germline. In contrast, the expression of several other maternal genes, including those encoding Tor pathway components, is not affected by the mutation. Rescue of the psqrum terminal phenotype does not require the BTB/POZ domain, suggesting that the PSQ DNA-binding domain can function independently of the BTB/POZ domain. Our finding that tor expression is subject to dedicated transcriptional regulation suggests that different maternal genes may be regulated by multiple distinct mechanisms, rather than by a general program controlling nurse-cell transcription.