bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells
Authors: Bauer Joshua A , Ye Fei , Marshall Clayton B , Lehmann Brian D , Pendleton Christopher S , Shyr Yu , Arteaga Carlos L , Pietenpol Jennifer A 
Published: July 2010

Abstract
Introduction
Paclitaxel is a widely used drug in the treatment of patients with locally advanced and metastatic breast cancer. However, only a small portion of patients have a complete response to paclitaxel-based chemotherapy, and many patients are resistant. Strategies that increase sensitivity and limit resistance to paclitaxel would be of clinical use, especially for patients with triple-negative breast cancer (TNBC).

Methods
We generated a gene set from overlay of the druggable genome and a collection of genomically deregulated gene transcripts in breast cancer. We used loss-of-function RNA interference (RNAi) to identify gene products in this set that, when targeted, increase paclitaxel sensitivity. Pharmacological agents that targeted the top scoring hits/genes from our RNAi screens were used in combination with paclitaxel, and the effects on the growth of various breast cancer cell lines were determined.

Results
RNAi screens performed herein were validated by identification of genes in pathways that, when previously targeted, enhanced paclitaxel sensitivity in the pre-clinical and clinical settings. When chemical inhibitors, CCT007093 and mithramycin, against two top hits in our screen, PPMID and SP1, respectively, were used in combination with paclitaxel, we observed synergistic growth inhibition in both 2D and 3D breast cancer cell cultures. The transforming growth factor beta (TGFβ) receptor inhibitor, LY2109761, that targets the signaling pathway of another top scoring hit, TGFβ1, was synergistic with paclitaxel when used in combination on select breast cancer cell lines grown in 3D culture. We also determined the relative paclitaxel sensitivity of 22 TNBC cell lines and identified 18 drug-sensitive and four drug-resistant cell lines. Of significance, we found that both CCT007093 and mithramycin, when used in combination with paclitaxel, resulted in synergistic inhibition of the four paclitaxel-resistant TNBC cell lines.

Conclusions
RNAi screening can identify druggable targets and novel drug combinations that can sensitize breast cancer cells to paclitaxel. This genomic-based approach can be applied to a multitude of tumor-derived cell lines and drug treatments to generate requisite pre-clinical data for new drug combination therapies to pursue in clinical investigations.
FK506 causes cellular and functional defects in human natural killer cells
Authors: Kim Tae-Jin , Kim Nayoung , Kang Hyoung Jin , Kim Eun-Ok , Kim Sung Tae , Ahn Hyo Seop , Bluestone Jeffrey A , Lee Kyung-Mi 
Published: July 2010

Abstract
FK506-mediated NK cell defects are associated with impaired IL-2 receptor signaling and selective down-regulation of NK receptors.
The role of NK cells in allogeneic HCT has been increasingly appreciated, particularly in the GVL effect. Although FK506 has been used widely to prevent GVHD, its action was considered to be primarily through activated T cells. In this study, we provide direct evidence for the first time that human NK cells are immediate targets of FK506. Our in vivo data from patients undergoing peripheral blood stem cell transplantation or BMT showed a reduced number of NK cells with down-regulated CD25 expression in their peripheral blood compartment. Likewise, FK506 caused profound inhibition of NK cell proliferation in vitro and suppressed NK cytotoxicity and cytokine secretion in response to IL-2. These defects were accompanied by impaired cell clustering and selective down-regulation of adhesion molecules, ICAM-1, CD2, CD49d, and CD58. Furthermore, FK506 specifically inhibited expression of NKG2D, CD48, and DNAM1 receptors without affecting that of 2B4, NKp30, NKp44, and NKp46. As a result, natural cytotoxicity against K562 tumor targets was impaired, while leaving redirected ADCC via 2B4 intact. Finally, FK506-treated NK cells showed impaired IL-2R signaling and inhibition of STAT3. Collectively, these signaling impairments and selective down-regulation of NK receptors by FK506 may underlie the proliferative and functional defects of NK cells. Thus, our data provide a new insight into the mechanism of immunosuppression by FK506, which should be considered to interpret the outcome of graft transplantation.
‘It's hollow’: the function of pores within myoglobin
Authors: Tomita Ayana , Kreutzer Ulrike , Adachi Shin-ichi , Koshihara Shin-ya , Jue Thomas 
Published: July 2010

SUMMARY
Despite a century of research, the cellular function of myoglobin (Mb), the mechanism regulating oxygen (O2) transport in the cell and the structure–function relationship of Mb remain incompletely understood. In particular, the presence and function of pores within Mb have attracted much recent attention. These pores can bind to Xe as well as to other ligands. Indeed, recent cryogenic X-ray crystallographic studies using novel techniques have captured snapshots of carbon monoxide (CO) migrating through these pores. The observed movement of the CO molecule from the heme iron site to the internal cavities and the associated structural changes of the amino acid residues around the cavities confirm the integral role of the pores in forming a ligand migration pathway from the protein surface to the heme. These observations resolve a long-standing controversy – but how these pores affect the physiological function of Mb poses a striking question at the frontier of biology.
Scaling for stress similarity and distorted-shape similarity in bending and torsion under maximal muscle forces concurs with geometric similarity among different-sized animals
Authors: Norberg R. Åke , Aldrin Björn S. Wetterholm 
Published: July 2010

SUMMARYWhen geometric similarity, or isometry, prevails among animals of different sizes their form and proportions are similar. Weight increases as the cube of the length dimension, while cross-sectional areas increase as its square, so in load-bearing structural elements the stress, caused by the body weight, increases in direct proportion to the length dimension, both for pure axial loads and for transverse bending and torsional loads. On this account, large body sizes would be expected to set up compensatory selection on the proportions of supporting structures, making them disproportionately thicker as required to maintain similar, size-independent safety factors against breakage. Most previous scaling theories have assumed that the strength of support elements has evolved with respect to loads due to the body weight. But then, from the arguments above, a scaling principle different from the geometric similarity rule would be required in order for safety factors to remain similar among different-sized animals. Still, most comparable animals of ‘similar kind’ scale in accordance with the geometric similarity rule. Here, we instead argue that muscle forces cause much larger loads on structural support elements during maximum performance events (such as during prey capture or escape from predators) than do loads dictated by the body weight (such as during cruising locomotion), and that structural strength therefore might evolve with respect to maximal muscle forces rather than to the body weight. We explore how the transverse and longitudinal lengths of structural support elements must scale to one another, and to muscle transverse length, in order to satisfy each of the following, functionally based, similarity principles for support elements placed in bending, or in torsion, by maximal muscle forces during locomotion: (1) similarity in axial stress, or (2) in torsional shear stress, and (3) similarity in bent shape, or (4) in twisted shape. A dimensional relationship that satisfies all four conditions actually turns out to be the geometric similarity rule. These functional attributes may therefore help to explain the prevalence of geometric similarity among animals. Conformance of different-sized species with the geometric similarity principle has not been directly selected for as such, of course, but may have arisen as a by-product of adaptation in morphological proportions, following upon selection, in each separate species-lineage, for adequate and similar safety factors against breakage, and similar optimal distorted shapes, of structural support elements placed in bending, or in torsion, by maximal muscle forces.
Cuticular plasticization in the tick,Amblyomma hebraeum(Acari: Ixodidae): possible roles of monoamines and cuticular pH
Authors: Kaufman W. Reuben , Flynn Peter C. , Reynolds Stuart E. 
Published: July 2010

SUMMARYThe degree of plasticization of the alloscutal cuticle of a ‘hard’ (ixodid) tick, Amblyomma hebraeum, and a ‘soft’ (argasid) tick, Ornithodoros moubata, was assessed throughout the blood-feeding period. Cuticle viscosity was calculated from rate of creep of cuticle under constant load using a Maxwell model. Feeding-related plasticization (i.e. increased rate of extension under a constant load) occurred in A. hebraeum but not in O. moubata. Maxwell viscosity of unfed A. hebraeum cuticle was relatively high (~720 GPa s) but was significantly lower in feeding ticks. Small partially fed ticks displayed a viscosity of ~108 GPa s. Still lower values (42 GPa s) were observed in the largest of the engorged ticks. Following cessation of feeding, there was a significant but limited reversal in viscosity back to ~100 GPa s. The water content of cuticle of unfed A. hebraeum (23.4% of wet mass) rose sharply after the onset of feeding and reached a plateau value of 34.0% at a fed/unfed weight ratio of 3 and beyond. Ixodid ticks lay down new endocuticle during the feeding period. The observed increase in cuticle hydration suggests that both old and new cuticles are hydrated during feeding. Monoamines may play an important role in controlling cuticle viscosity. Dopamine (DA) injected into partially fed A. hebraeum caused plasticization. 5-Hydroxytryptamine (serotonin, 5-HT), which induces plasticization in the blood-sucking insect Rhodnius prolixus, had no statistically significant effect on tick cuticle. Octopamine (OA) and tyramine both caused cuticle stiffening (i.e. opposed plasticization). This suggests a possible inhibitory effect but co-injection of OA with DA did not reduce DA-induced plasticization. The mechanism leading to plasticization of tick cuticle may involve a change in cuticular pH. The viscosity of tick cuticle loops was highest at pH 8.0 (389 GPa s) and fell precipitously in the acidic range to a low value of 2.2 GPa s at pH 5.5–5.7. A cuticular pH of ~6.5 would account for the lowest viscosity observed under physiological conditions (42.4 GPa s for large, day 0, engorged ticks). The V-ATPase inhibitor, concanamycin A, was a potent inhibitor of DA-induced plasticization. These results are consistent with a model in which DA acts to cause plasticization through transport of H+ ions into the cuticle. Measurement of cuticular ion (Na+, K+, Ca2+, Mg2+) content did not suggest that plasticization is caused by any of these ions. Taken together, our results suggest that the mechanism of cuticular plasticization in feeding A. hebraeum is related to hydration, and involves the transport of H+ ions into the sub-cuticular space by cells in the hypodermis. Feeding-induced plasticization was not observed in the rapid feeding tick, O. moubata.
Sound transmission and the recognition of temporally degraded sexual advertisement signals in Cope's gray treefrog (Hyla chrysoscelis)
Authors: Kuczynski Michael C. , Vélez Alejandro , Schwartz Joshua J. , Bee Mark A. 
Published: July 2010

SUMMARY
Acoustic communication signals degrade as they propagate between signalers and receivers. While we generally understand the degrading effects of sound propagation on the structure of acoustic signals, we know considerably less about how receivers make behavioral decisions based on the perception of degraded signals in sonically and structurally complex habitats where communication occurs. In this study of acoustic mate recognition in Cope's gray treefrog, Hyla chrysoscelis (Cope 1880), we investigated how the temporal structure of male advertisement calls was compromised by propagation in a natural habitat and how females responded to stimuli mimicking various levels of temporal degradation. In a sound transmission experiment, we quantified changes in the pulsed structure of signals by broadcasting synthetic calls during active choruses from positions where we typically encountered signalers, and re-recording the signals from positions where we typically encountered potential receivers. Our main finding was that the silent gaps between pulses become increasingly ‘filled in’ by background noise and reverberations as a function of increasing propagation distance. We also conducted female phonotaxis experiments to determine the threshold modulation depth required to elicit recognition of the pulsatile structure of the call. Females were surprisingly tolerant of degraded temporal structure, and there was a tendency for greater permissiveness at lower playback levels. We discuss these results in terms of presumed mechanisms of call recognition in complex environments and the acoustic adaptation hypothesis.
Fatigue and Stiffness Evaluations of Reclaimed Asphalt Pavement in Hot Mix Asphalt Mixtures
Authors: Xiao Feipeng , Amirkhanian Serji N. , Wu Boli 
Published: July 2010

Abstract
The recycling of existing asphalt pavement materials produces new pavements with considerable savings in material, money, and energy. Understanding the ability of an asphalt pavement containing reclaimed asphalt pavement (RAP) to resist fracture from repeated loads is essential for the design of hot mix asphalt (HMA) mixtures. However, reaching a better understanding of fatigue behaviors of these pavements continues to challenge researchers all over the world, particularly, as recycled materials with more complex properties are being used in HMA pavements. This study explores the utilization of the conventional fatigue analysis approach in investigating the fatigue life of asphalt mixtures containing RAP. The fatigue beams were made with two asphalt binders, two aggregate sources, four RAP contents (0 %, 15 %, 25 %, and 30 %), and tested at 5 and 20°C. A total of eight mixtures was evaluated and 64 fatigue beams were tested in this study. The test results indicated that the addition of RAP, as expected, increased the viscosity, G∗sinδ, and creep stiffness values while reducing the m-values. However, no obvious trends were found for stiffness and fatigue life of mixtures as the RAP content increased. Statistical analysis results indicated that for binders and mixtures containing 30 % RAP, the utilization of softer binder significantly decreased the viscosity, G∗sinδ, and creep stiffness values; however, there were no significant differences in the stiffness and fatigue life values of these mixtures.
Urine Proteome Analysis May Allow Noninvasive Differential Diagnosis of Diabetic Nephropathy
Authors: Papale Massimo , Di Paolo Salvatore , Magistroni Riccardo , Lamacchia Olga , Di Palma Anna Maria , De Mattia Angela , Teresa Rocchetti Maria , Furci Luciana , Pasquali Sonia , De Cosmo Salvatore , Cignarelli Mauro , Gesualdo Loreto 
Published: July 2010

OBJECTIVE
Chronic renal insufficiency and/or proteinuria in type 2 diabetes may stem from chronic renal diseases (CKD) other than classic diabetic nephropathy in more than one-third of patients. We interrogated urine proteomic profiles generated by surface-enhanced laser desorption/ionization-time of flight/mass spectrometry with the aim of isolating a set of biomarkers able to reliably identify biopsy-proven diabetic nephropathy and to establish a stringent correlation with the different patterns of renal injury.

RESEARCH DESIGN AND METHODS
Ten micrograms of urine proteins from 190 subjects (20 healthy subjects, 20 normoalbuminuric, and 18 microalbuminuric diabetic patients and 132 patients with biopsy-proven nephropathy: 65 diabetic nephropathy, 10 diabetic with nondiabetic CKD [nd-CKD], and 57 nondiabetic with CKD) were run using a CM10 ProteinChip array and analyzed by supervised learning methods (Classification and Regression Tree analysis).

RESULTS
The classification model correctly identified 75% of patients with normoalbuminuria, 87.5% of those with microalbuminuria, and 87.5% of those with diabetic nephropathy when applied to a blinded testing set. Most importantly, it was able to reliably differentiate diabetic nephropathy from nd-CKD in both diabetic and nondiabetic patients. Among the best predictors of the classification model, we identified and validated two proteins, ubiquitin and β2-microglobulin.

CONCLUSIONS
Our data suggest the presence of a specific urine proteomic signature able to reliably identify type 2 diabetic patients with diabetic glomerulosclerosis.
How does one conceive time? Measurement by means of Time Metaphors Questionnaire
Authors: Sobol-Kwapinska Malgorzata , Nosal Czeslaw 
Published: July 2010

How does one conceive time? Measurement by means of Time Metaphors Questionnaire
Attitude towards time are usually expressed by means of metaphors. This paper presents phases of construction and validation of the Time Metaphors Questionnaire. This is a method for testing conceiving of time. An exploratory factor analyses yielded seven factor scales: Friendly Time, Hostile Time, Rapid Passage of Time, Significance of the Moment, Subtle Time, Wild Time and Empty Time. Results of correlations between scales of the Time Metaphors Questionnaire and with selected methods (Temporal Orientation Scale AION-2000, NEO-Five Factor Inventory) indicate, among other things, an ambivalence of psychological time and an importance of positive evaluation of current moment.
The effects of different saddle pads on forces and pressure distribution beneath a fitting saddle
Authors: KOTSCHWAR A. B. , BALTACIS A. , PEHAM C. 
Published: July 2010

SummaryReason for performing study:Saddle pads are widely used in riding sports but their influence on saddle pressures is poorly understood.Objective:To evaluate the forces acting on the horse's back, and the eventual pressure distribution by using different saddle pads underneath a fitting saddle.Methods:Sixteen sound horses of different breeds and ages were ridden on a treadmill at walk and sitting trot. The horses were wearing a dressage saddle with a fitting saddle tree and 4 different saddle pads (gel, leather, foam and reindeer fur) successively. For comparison, measurements were made without any saddle pad. Right forelimb motion was used to synchronise the pressure data with the stride cycles. A pressure mat was used under the saddle pad to collect the kinetic data. Maximum overall force (MOF) and the pressure distribution in longitudinal and transversal direction were calculated to identify differences between the measurements with and without saddle pads.Results:A significant decrease in MOF was interpreted as improved saddle fit, and a significant increase as worsened saddle fit. Only the reindeer fur pad significantly decreased the MOF from 1005 N to 796 N at walk and from 1650 N to 1437 N at trot compared to without pad measurements. None of the saddle pads increased the MOF significantly when compared to the data without saddle pad. The pressure distribution in longitudinal and transversal direction was also improved significantly only by the reindeer fur pad at trot compared to no pad.Conclusion:This study demonstrated that a well chosen saddle pad can reduce the load on the horse's back and therefore improve the suitability of a fitting saddle.
Real‐time RT‐PCR for the detection and quantitative analysis of equine rhinitis viruses
Authors: QUINLIVAN M. , MAXWELL G. , LYONS P. , ARKINS S. , CULLINANE A. 
Published: July 2010

SummaryReasons for performing study: Equine rhinitis viruses (ERV) cause respiratory disease and loss of performance in horses. It has been suggested that the economic significance of these viruses may have been underestimated due to insensitive methods of detection.Objectives: To develop a sensitive, rapid, real‐time RT‐PCR (rRT‐PCR) assay suitable for the routine diagnosis and epidemiological surveillance of the A and B variants of ERV.Methods: TaqMan primer probe sets for ERAV and ERBV were designed from conserved regions of the 5′ UTR of the ERV genome. Over 400 samples from both clinically affected and asymptomatic horses were employed for validation of the assays. ERAV samples positive by rRT‐PCR were verified by virus isolation and ERBV positive samples were verified by rRT‐PCR using a different set of primers.Results: The detection limit of the rRT‐PCR for both viruses was 10–100 genome copies. Of 250 archival nasal swabs submitted for diagnostic testing over a 7 year period, 29 were ERAV positive and 3 were ERBV positive with an average incidence rate per year of 10 and 1.5%, respectively. There was evidence of co‐circulation of ERAV and ERBV with equine influenza virus (EIV). Of 100 post race urine samples tested, 29 were ERAV positive by rRT‐PCR. Partial sequencing of 2 ERBV positive samples demonstrated that one was 100% identical to ERBV1 from a 270 bp sequence and the other was more closely related to ERBV2 than ERBV1 (95% compared to 90% nucleotide identity in 178 bp).Conclusions: The rRT‐PCR assays described here are specific and more sensitive than virus isolation. They have good reproducibility and are suitable for the routine diagnosis of ERAV and ERBV.Potential relevance: These assays should be useful for investigating the temporal association between clinical signs and rhinitis virus shedding.
Biportal thoracoscopic sympathectomy for palmar hyperhidrosis in adolescents
Authors: Wait Scott D. , Killory Brendan D. , Lekovic Gregory P. , Dickman Curtis A. 
Published: July 2010

Object
Palmar, axillary, and plantar hyperhidrosis is often socially, emotionally, and physically disabling for adolescents. The authors report surgical outcomes in all adolescents treated for palmar hyperhidrosis via bilateral thoracoscopic sympathectomy at the Barrow Neurological Institute by the senior author.

Methods
A prospectively maintained database of all adolescent patients undergoing bilateral thoracoscopic sympathectomy between 1998 and 2006 (inclusive) was reviewed. Additional follow-up was obtained as needed in clinic or by phone or written questionnaire.

Results
Fifty-four patients (40 females) undergoing bilateral procedures were identified. Their mean age was 15.4 years (range 10–17 years). Average follow-up was 42 weeks (range 0.2–143 weeks). Hyperhidrosis involved the palms alone in 10 patients; the palms and axilla in 6 patients; the palms and plantar surfaces in 17 patients; and the palms, axilla, and plantar surfaces in 21 patients. Palmar hyperhidrosis resolved completely in 98.1% of the patients. Resolution or improvement of symptoms was seen in 96.3% of patients with axillary and 71.1% of those with plantar hyperhidrosis. Hospital stay averaged 0.37 days with 68.5% of patients discharged the day of surgery. One patient experienced brief intraoperative asystole that resolved with medications and had no long-term sequelae. Otherwise, no serious intraoperative complications occurred. No patient required chest tube drainage. The percentage of patients who reported satisfaction and willingness to undergo the procedure again was 98.1%.

Conclusions
Biportal, bilateral thoracoscopic sympathectomy is an effective and low-morbidity treatment for severe palmar, axillary, and plantar hyperhidrosis.