bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrocyclization of Organo‐Peptide Hybrids through a Dual Bio‐orthogonal Ligation: Insights from Structure–Reactivity Studies
Authors: Frost John R. , Vitali Francesca , Jacob Nicholas T. , Brown Micah D. , Fasan Rudi 
Published: November 2012

AbstractMacrocycles constitute an attractive structural class of molecules for targeting biomolecular interfaces with high affinity and specificity. Here, we report systematic studies aimed at exploring the scope and mechanism of a novel chemo‐biosynthetic strategy for generating macrocyclic organo‐peptide hybrids (MOrPHs) through a dual oxime‐/intein‐mediated ligation reaction between a recombinant precursor protein and bifunctional, oxyamino/1,3‐amino‐thiol compounds. An efficient synthetic route was developed to access structurally different synthetic precursors incorporating a 2‐amino‐ mercaptomethyl‐aryl (AMA) moiety previously found to be important for macrocyclization. With these compounds, the impact of the synthetic precursor scaffold and of designed mutations within the genetically encoded precursor peptide sequence on macrocyclization efficiency was investigated. Importantly, the desired MOrPHs were obtained as the only product from all the different synthetic precursors probed in this study and across peptide sequences comprising four to 15 amino acids. Systematic mutagenesis of the “i−1” site at the junction between the target peptide sequence and the intein moiety revealed that the majority of the 20 amino acids are compatible with MOrPH formation; this enables the identification of the most and the least favorable residues for this critical position. Furthermore, interesting trends with respect to the positional effect of conformationally constrained (Pro) and flexible (Gly) residues on the reactivity of randomized hexamer peptide sequences were observed. Finally, mechanistic investigations enabled the relative contributions of the two distinct pathways (side‐chain→C‐end ligation versus C‐end→side‐chain ligation) to the macrocyclization process to be dissected. Altogether, these studies demonstrate the versatility and robustness of the methodology to enable the synthesis and diversification of a new class of organo‐peptide macrocycles and provide valuable structure–reactivity insights to inform the construction of macrocycle libraries through this chemo‐biosynthetic strategy.
A Pan Photoaffinity Probe for Detecting Active Forms of Matrix Metalloproteinases
Authors: Nury Catherine , Czarny Bertrand , Cassar‐Lajeunesse Evelyne , Georgiadis Dimitris , Bregant Sarah , Dive Vincent 
Published: November 2012

AbstractA photoaffinity probe based on the scaffold of a potent broad‐spectrum phosphinic peptide inhibitor of matrix metalloproteinases (MMPs) has been developed. A photolabile diazirine group for covalent modification of MMP active forms was incorporated at the P1′ position, and a tritium radioactive label for the sensitive detection of MMP covalent adducts by radioimaging was attached. The probe was characterized on seven catalytic domains of human MMPs (MMP‐2, ‐3, ‐8, ‐9, ‐12, ‐13 and ‐14) and was found to display nanomolar affinities towards this set of MMPs, covalently modifying them with crosslinking yields varying from 12 to 58 %, thus leading to highly sensitive detection of these MMPs. In a complex proteome complemented with four recombinant MMPs (MMP‐2, ‐9, ‐12 and ‐13), this probe enabled their simultaneous detection with a threshold of few femtomoles and low background labelling. Those properties should make this new pan‐activity‐based MMP probe a valuable tool for the detection of MMP active forms from biological fluids or tissue extracts.
Synthesis of Thermally Stable Energetic 1,2,3‐Triazole Derivatives
Authors: Kumar A. Sudheer , Ghule Vikas D. , Subrahmanyam S. , Sahoo Akhila K. 
Published: November 2012

AbstractVarious thermally stable energetic polynitro‐aryl‐1,2,3‐triazoles have been synthesized through Cu‐catalyzed [3+2] cycloaddition reactions between their corresponding azides and alkynes, followed by nitration. These compounds were characterized by analytical and spectroscopic methods and the solid‐state structures of most of these compounds have been determined by using X‐ray diffraction techniques. Most of the polynitro‐bearing triazole derivatives decomposed within the range 142–319 °C and their heats of formation and crystal densities were determined from computational studies. By using the Kamlet–Jacobs empirical relation, their detonation velocities and pressures were calculated from their heats of formation and crystal densities. Most of these newly synthesized compounds exhibited high positive heats of formation, good thermal stabilities, reasonable densities, and acceptable detonation properties that were comparable to those of TNT.
Bioengineering Parameters for Single‐Use Bioreactors: Overview and Evaluation of Suitable Methods
Authors: Löffelholz Christian , Husemann Ute , Greller Gerhard , Meusel Wolfram , Kauling Jörg , Ay Peter , Kraume Matthias , Eibl Regine , Eibl Dieter 
Published: November 2012

AbstractDuring the past five years, the number of single‐use bioreactors used in biopharmaceutical research and production has increased tremendously. This increase has been particularly associated with mammalian cell culture processes from small‐ to medium‐scale volumes. Even though nowadays customers can choose from a multitude of 2nd and 3rd generation single‐use bioreactors, ranging from mL‐ up to m3‐scale, there is a lack of knowledge of their engineering parameters. Different approaches have been applied to characterization investigations, resulting in an inability to compare different single‐use bioreactors with each other and their reusable counterparts, creating an obstacle to a systematic approach to scaling‐up the process. This article describes parametric, experimental and computer‐based numeric methods for biochemical engineering characterization of single‐use bioreactors, which have already been used successfully for the characterization of their reusable counterparts. For the first time, these methods have been evaluated in terms of their practical application.
Highly Ligand Efficient and Selective N‐2‐(Thioethyl)picolinamide Histone Deacetylase Inhibitors Inspired by the Natural Product Psammaplin A
Authors: Baud Matthias G. J. , Haus Patricia , Leiser Thomas , Meyer‐Almes Franz‐Josef , Fuchter Matthew J. 
Published: November 2012

AbstractNovel picolinamide‐based histone deacetylase (HDAC) inhibitors were developed, drawing inspiration from the natural product psammaplin A. We found that the HDAC potency and isoform selectivity provided by the oxime unit of psammaplin A could be reproduced by using carefully chosen heterocyclic frameworks. The resulting (hetero)aromatic amide based compounds displayed very high potency and isoform selectivity among the HDAC family, in addition to excellent ligand efficiency relative to previously reported HDAC inhibitors. In particular, the high HDAC1 isoform selectivity provided by the chloropyridine motif represents a valuable design criterion for the development of new lead compounds and chemical probes that target HDAC1.
Long‐term regional control and survival in patients with “low‐risk,” early stage oral tongue cancer managed by partial glossectomy and neck dissection without postoperative radiation
Authors: Ganly Ian , Goldstein David , Carlson Diane L. , Patel Snehal G. , O'Sullivan Brian , Lee Nancy , Gullane Patrick , Shah Jatin P. 
Published: November 2012

AbstractBACKGROUND:The objectives of this study were to determine the incidence of locoregional failure in patients with low‐risk, early stage oral tongue squamous cell cancer (OTSCC) who undergo partial glossectomy and ipsilateral elective neck dissection without receiving postoperative radiation.METHODS:A combined database of patients with OTSCC who received treatment at Memorial Sloan‐Kettering Cancer Center and Princess Margaret Cancer Center from 1985 to 2005 was established. In total, 164 patients with pathologic T1‐T2N0 OTSCC who underwent partial glossectomy and ipsilateral elective neck dissection without postoperative radiation were identified. Patient‐related, tumor‐related, and treatment‐related characteristics were recorded. Local recurrence‐free survival, regional recurrence‐free survival, and disease‐specific survival were calculated by the Kaplan‐Meier method. Predictors of outcome were analyzed by univariate and multivariate analysis.RESULTS:At a median follow‐up of 66 months (range 1‐171 months), the 5‐year rates of local recurrence‐free survival, regional recurrence‐free survival, and disease‐specific survival were 89%, 79.9%, and 85.6%, respectively. Regional recurrence was ipsilateral in 61% of patients and contralateral in 39% of patients. The regional recurrence rate was 5.7% for tumors <4 mm and 24% for tumors ≥4 mm. Multivariate analysis indicated that tumor thickness was the only independent predictor of neck failure (regional recurrence‐free survival, 94% vs 72% [P = .02] for tumors <4 mm vs ≥4 mm, respectively). Patients who developed recurrence in the neck had a significantly poorer disease‐specific survival compared with those who did not (33% vs 97%; P < .0001).CONCLUSIONS:Patients with low‐risk, pathologic T1‐T2N0 OTSCC had a greater than expected rate of neck failure, with contralateral recurrence accounting for close to 40% of recurrences. Failure occurred predominantly in patients who had primary tumors that were ≥4 mm thick. Cancer 2013. © 2013 American Cancer Society.
Effect of including cancer‐specific variables on models examining short‐term outcomes
Authors: Merkow Ryan P. , Kmiecik Thomas E. , Bentrem David J. , Winchester David P. , Stewart Andrew K. , Ko Clifford Y. , Bilimoria Karl Y. 
Published: November 2012

AbstractBACKGROUND:The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) generally has not collected cancer‐specific variables. Because increasing numbers of studies are using ACS NSQIP data to study cancer surgery, the objectives of the current study were 1) to examine differences between existing ACS NSQIP variables and cancer registry variables, and 2) to determine whether the addition of cancer‐specific variables improves modeling of short‐term outcomes.METHODS:Data from patients in the ACS NSQIP and National Cancer Data Base (NCDB) who underwent colorectal resection for cancer were linked (2006‐2008). By using regression methods, the relative importance of cancer staging and neoadjuvant therapy variables were assessed along with their effects on morbidity, serious morbidity, and mortality.RESULTS:From 146 hospitals, 11,405 patients were identified who underwent surgery for colorectal cancer (colon, 85%; rectum, 15%). The NCDB metastatic cancer variable and the ACS NSQIP disseminated cancer variables agreed marginally (Cohen kappa coefficient, 0.454). For mortality, only the ACS NSQIP disseminated cancer variable and the NCDB stage IV variable were identified as important predictors; whereas the variables stage I through III, tumor (T)‐classification, and lymph node (N)‐classification were not selected. Cancer stage variables were inconsistently important for serious morbidity (stage IV, T‐classification), superficial surgical site infection (N‐classification), venous thromboembolism (metastatic cancer), and pneumonia (T‐classification). With respect to neoadjuvant therapy, ACS NSQIP and NCDB variables agreed moderately (kappa, 0.570) and predicted superficial surgical site infection, serious morbidity, and organ space surgical site infection. The model fit was similar regardless of the inclusion of stage and neoadjuvant therapy variables.CONCLUSIONS:Although advanced disease stage and neoadjuvant therapy variables were predictors of short‐term outcomes, their inclusion did not improve the models. Cancer 2013. © 2012 American Cancer Society.
Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex
Authors: Agster Kara L. , Mejias‐Aponte Carlos A. , Clark Brian D. , Waterhouse Barry D. 
Published: November 2012

AbstractThe brainstem nucleus locus coeruleus (LC) is the sole source of norepinephrine (NE)‐containing fibers in the mammalian cortex. Previous studies suggest that the density of noradrenergic fibers in rat is relatively uniform across cortical regions and that cells in the nucleus discharge en masse. This implies that activation of the LC results in equivalent release of NE throughout the cortex. However, it is possible that there could be differences in the density of axonal varicosities across regions, and that these differences, rather than a difference in fiber density, may contribute to the regulation of NE efflux. Quantification of dopamine β‐hydroxylase (DβH)‐immunostained varicosities was performed on several cortical regions and in the ventral posterior medial (VPM) thalamus by using unbiased sampling methods. The density of DβH varicosities is greater in the prefrontal cortex than in motor, somatosensory, or piriform cortices, greater in superficial than in deep layers of cortex, and greater in the VPM than in the somatosensory cortex. Our results provide anatomical evidence for non‐uniform release of NE across functionally discrete cortical regions. This morphology may account for a differential, region‐specific, impact of LC output on different cortical areas. J. Comp. Neurol. 521:2195–2207, 2013. © 2012 Wiley Periodicals, Inc.
Diversity of thalamorecipient spine morphology in cat visual cortex and its implication for synaptic plasticity
Authors: da Costa Nuno Maçarico 
Published: November 2012

AbstractA feature of spine synapses is the existence of a neck connecting the synapse on the spine head to the dendritic shaft. As with a cable, spine neck resistance (Rneck) increases with increasing neck length and is inversely proportional to the cross‐sectional area of the neck. A synaptic current entering a spine with a high Rneck will lead to greater local depolarization in the spine head than would a similar input applied to a spine with a lower Rneck. This could make spines with high Rneck more sensitive to plastic changes since voltage sensitive conductances, such as N‐methyl‐D‐aspartic acid (NMDA) channels can be more easily activated. This hypothesis was tested using serial section electron microscopic reconstructions of thalamocortical spine synapses and spine necks located on spiny stellate cells and corticothalamic cells from area 17 of cats. Thalamic axons and corticothalamic neurons were labeled by injections of the tracer biotinylated dextran amine (BDA) in the dorsal lateral geniculate nucleus (dLGN) of anesthetized cats and spiny stellates were filled intracellularly in vivo with horseradish peroxidase. Twenty‐eight labeled spines that formed synapses with dLGN boutons were collected from three spiny stellate and four corticothalamic cells and reconstructed in 3D from serial electron micrographs. Spine length, spine diameter, and the area of the postsynaptic density were measured from the 3D reconstructions and Rneck of the spine was estimated. No correlation was found between the postsynaptic density size and the estimated spine Rneck. This suggests that forms of plasticity that lead to larger synapses are independent of spine neck resistance. J. Comp. Neurol. 521:2058–2066, 2013. © 2012 Wiley Periodicals, Inc.
Membrane microdomain organization, calcium signal, and NFAT activation as an important axis in polarized Th cell function
Authors: Izsepi Emese , Himer Leonora , Szilagyi Orsolya , Hajdu Peter , Panyi György , Laszlo Gloria , Matko Janos 
Published: November 2012

AbstractT helper lymphocytes become polarized upon antigen and cytokine stimuli received after their maturation in the thymus. Since the balance of Th1 and Th2 responses is critical in healthy and pathological immune responses, understanding the molecular base of T cell polarization still remained an important question. Using our Th0/Th1/Th2 hybridoma model system, we performed a comparative study on polarized Th1 and Th2 cells in terms of their membrane raft expression/composition, their TCR mediated activation signaling, and sensitivity to activation‐induced cell death (AICD) using flow and image cytometric methods. We show here that the TCR stimulation induced more intense and sustained Ca2+‐response in Th1 cells compared to Th2 ones correlates well with a shorter nuclear residence time of the Ca2+‐dependent NFAT transcription factor in Th2 cells. In addition, NFAT translocation directly depended on lipid raft integrity/membrane cholesterol level. Expression pattern of raftophilic accessory proteins (CD4, CD59, and CD48) and lipids (GM1, cholesterol) were also different in the Th1 and Th2 hybridomas, similarly to differentiated spleen Th cells. The activation‐induced, remarkably clustered and polarized membrane distribution of TCR/CD3 complex in Th1, but not in Th2 cells, together with an increased raft localization of Kv1.3 ion channels regulating the Ca2+‐response, are consistent with the above properties of NFAT. Finally, the polarized Th cells, especially Th1, were more sensitive to AICD than their unpolarized Th0 precursor. These results suggest that the membrane microdomain organization—Ca2+‐signaling—NFAT activation axis is an important determinant of polarized Th cell effector function and fate. © 2012 International Society for Advancement of Cytometry
Nanoparticles Based Electroanalysis in Diagnostics Applications
Authors: Merkoçi Arben 
Published: November 2012

AbstractNanoparticles with electrochemical properties such as red‐ox changes easy to be followed by stripping analysis or electrocatalysis to be followed by simple amperometric detection represent interesting building blocks in the design and fabrication of novel biosensors with interest for diagnostics applications. Various examples related to DNA, protein and cell detection are shown. Nanoparticles are mostly used as labels in a similar way as enzymes or dyes but offering the advantages of better stability and in general cost efficiency of the devices. The employment of nanoparticles in electrochemical based biosensing systems is simple and the obtained performance seems to fit with the requirements for real applications in detection of various biomarkers with interest for point of care applications and even early detection or during treatment of illnesses such as cancer, beside others.
Amperometric Magnetoimmunosensors for Direct Determination of D‐Dimer in Human Serum
Authors: Gamella María , Campuzano Susana , Conzuelo Felipe , Reviejo A. Julio , Pingarrón José M. 
Published: November 2012

AbstractTwo different D‐dimer disposable amperometric immunosensing designs based on indirect competitive or sandwich formats and the use of carboxylic acid‐modified magnetic beads (COOH‐MBs) and screen‐printed carbon electrodes (SPCEs) have been developed and compared. In both approaches, the resulting modified MBs were magnetically captured on the surface of a SPCE which was used as the transducer for the electrochemical detection at −0.20 V upon addition of H2O2, and hydroquinone (HQ). Both configurations exhibited linear ranges of clinical usefulness and detection limits quite below the clinical threshold (0.5 µg mL−1 D‐dimer). The sandwich configuration has been successfully tested with serum samples.
Holocene profile changes along a California coastal stream
Authors: Haible William W. 
Published: November 2012

AbstractWalker Creek in Marin County, California is a coastal stream draining to Tomales Bay, which lies in the San Andreas Rift Zone. Its valley contains an alluvial fill with a basal gravel dated at 5000 years BP. In upstream parts of the watershed, channels are incised arroyo‐like in the fill leaving the valley floor standing as a high terrace averaging 5·5 m (18 ft) high. Below this terrace is an inner terrace of historic age that stands 2·4 m (8 ft) above the streambed. The stratigraphy and morphology of this valley are seen in others nearby, and indicate that in the last half of Holocene time in this region a single episode of valley alluviation was followed by two episodes of valley cutting.The second episode of valley cutting is occurring in the present time. During the last 60 years the flow has become seasonal, the stream has incised 1·5 m (5 ft) below the inner terrace in upstream reaches, aggraded 1·2 m (4 ft) in downstream reaches, and extended its estuary. Incision upstream has begun to re‐expose the bedrock valley floor and is associated with aggradation downstream that has caused the flood plain to overtop both terraces. This has decreased the stream's gradient.Using a stream that is currently effecting major changes in its valley and channel morphology, two aspects of hydraulic adjustment in fluvial systems are examined. The changes in the average slope of the longitudinal profile are small but measureable. Profile concavity has not changed measurably. The various profiles that have existed in Holocene time show that stream gradient can be, but is not necessarily, slightly adjusted during valley filling and cutting. Flow measurements at a high discharge show that the channel has begun to assume the hydraulic geometry of an ephemeral channel. Adjustments of depth, velocity, and roughness appear to be hydraulic adjustments in response to changing watershed conditions.
Dementia case management and risk of long‐term care placement: a systematic review and meta‐analysis
Authors: Tam‐Tham Helen , Cepoiu‐Martin Monica , Ronksley Paul E. , Maxwell Colleen J. , Hemmelgarn Brenda R. 
Published: November 2012

ABSTRACTObjectivesThe objective of our study is to evaluate the effectiveness of dementia case management compared with usual care on reducing long‐term care placement, hospitalization, and emergency department visits for adult patients with dementia. We also sought to evaluate the effectiveness of this intervention on delaying time to long‐term care placement and hospitalization.MethodsWe searched electronic databases supplemented by bibliographies and conference proceedings for randomized controlled trials testing the effectiveness of dementia case management in reducing resource utilization in a population of caregiver–care recipient dyads living in the community. We meta‐analyzed the risk ratio (RR) and weighted mean differences of long‐term care placement and the RR of hospital admissions. Pooled estimates were further stratified by study characteristics and measures of study quality.ResultsSeventeen studies were included in the meta‐analysis. The overall pooled RR of long‐term care placement was 0.94 (95% confidence interval [0.85, 1.03]; p = 0.227) for dementia case management compared with usual care. Stratification by follow‐up duration indicated a statistically significant reduction in risk of long‐term care placement when follow‐up duration was less than 18 months (RR 0.61, 95% confidence interval [0.41, 0.91], p = 0.015). There was no effect of dementia case management compared with usual care for the other outcomes.ConclusionDementia case management demonstrated a short‐term positive effect on reducing the risk of long‐term care placement among older people with dementia residing in the community. However, other sources of resource utilization and more extended effects of dementia case management on risk of long‐term care placement warrant further investigation. Copyright © 2012 John Wiley & Sons, Ltd.