bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of Coenzyme Q10 for Improved Tolerability of Cancer Treatments: A Systematic Review
Authors: Roffe Liz , Schmidt Katja , Ernst Edzard
Published: October 2004

Purpose

The aim of this systematic review was to summarize and evaluate the evidence available for oral supplementation with coenzyme Q10 (CoQ10) to improve the tolerability of cancer treatments.

Materials and Methods

Searches for all published and unpublished controlled trials were carried out on seven databases. Manufacturers of CoQ10 were identified and contacted. Controlled clinical trials of monopreparations of CoQ10 administered orally to cancer patients were included. No language restrictions were imposed. Data were extracted independently by two authors according to predefined criteria.

Results

Six studies were included in the review, including three randomized clinical trials and three nonrandomized clinical trials. Patients in five of six studies received anthracyclines. The results suggested that CoQ10 provides some protection against cardiotoxicity or liver toxicity during cancer treatment. However, because of inadequate reporting and analysis, as well as questionable validity of outcome measures, the results are not conclusive.

Conclusion

Suggestions that CoQ10 might reduce the toxicity of cancer treatments have not been tested by rigorous trials. Further investigations are necessary to determine whether CoQ10 can improve the tolerability of cancer treatments.
Carboplatin/Paclitaxel or Carboplatin/Vinorelbine Followed by Accelerated Hyperfractionated Conformal Radiation Therapy: Report of a Prospective Phase I Dose Escalation Trial From the Carolina Conformal Therapy Consortium
Authors: Marks Lawrence B. , Garst Jennifer , Socinski Mark A. , Sibley Gregory , Blackstock A. William , Herndon James E. , Zhou Sumin , Shafman Timothy , Tisch Andrea , Clough Robert , Yu Xiaoli , Turrisi Andrew , Anscher Mitchell , Crawford Jeffrey , Rosenman Julian
Published: October 2004

Purpose

To prospectively determine the maximum-tolerated dose of accelerated hyperfractionated conformal radiotherapy (RT; 1.6 Gy bid) for unresectable locally advanced lung cancer (IIB to IIIA/B) following induction carboplatin/paclitaxel (C/T) or carboplatin/vinorelbine (C/N).

Methods

Induction chemotherapy, C/T or C/N, was followed by escalating doses of conformally-planned RT (73.6 to 86.4 Gy in 6.4-Gy increments). Concurrent boost methods delivered 1.6 and 1.25 Gy bid to the gross and clinical target volumes, respectively.

Results

Between November 1997 and February 2002, 44 patients were enrolled (median age, 59 years; 59% male; stage III, 98%; median tumor size, 4 cm). Thirty-nine patients completed induction chemotherapy: 19 had a partial response, seven progressed, 15 had no response, and three were not assessable. Chemotherapy-associated toxicities were similar in the two chemotherapy groups. The incidence of grade ≥ 3 RT-induced toxicity was 1/13, 2/14, and 4/12 at 73.6, 80, and 86.4 Gy, respectively, thus defining the maximum tolerated dose at ≈80 Gy. Toxicities were in both lung and esophagus and were similar in the two chemotherapy arms. With a median followup of 34 months in the survivors, the actuarial 2-year survival was 47%, the median survival was 18 months. Fifteen patients had tumor relapse: 5 local failures in the high-dose volume, 2 regional failures outside of the high-dose volume, and 8 distant metastases.

Conclusion

High-dose conformal twice-daily radiation therapy to approximately 80 Gy appears tolerable in well-selected patients with unresectable lung cancer following either C/T or C/N. Dose-limiting toxicities are mainly pulmonary and esophageal.
Induction and Concurrent Chemotherapy With High-Dose Thoracic Conformal Radiation Therapy in Unresectable Stage IIIA and IIIB Non–Small-Cell Lung Cancer: A Dose-Escalation Phase I Trial
Authors: Socinski Mark A. , Morris David E. , Halle Jan S. , Moore Dominic T. , Hensing Thomas A. , Limentani Steven A. , Fraser Robert , Tynan Maureen , Mears Andrea , Rivera M. Patricia , Detterbeck Frank C. , Rosenman Julian G.
Published: October 2004

Purpose

Local control rates at conventional radiotherapy doses (60 to 66 Gy) are poor in stage III non–small-cell lung cancer (NSCLC). Dose escalation using three-dimensional thoracic conformal radiation therapy (TCRT) is one strategy to improve local control and perhaps survival.

Patients and Methods

Stage III NSCLC patients with a good performance status (PS) were treated with induction chemotherapy (carboplatin area under the curve [AUC] 5, irinotecan 100 mg/m2, and paclitaxel 175 mg/m2 days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m2 weekly for 7 to 8 weeks) beginning on day 43. Pre- and postchemotherapy computed tomography scans defined the initial clinical target volume (CTVI) and boost clinical target volume (CTVB), respectively. The CTVI received 40 to 50 Gy; the CTVB received escalating doses of TCRT from 78 Gy to 82, 86, and 90 Gy. The primary objective was to escalate the TCRT dose from 78 to 90 Gy or to the maximum-tolerated dose.

Results

Twenty-nine patients were enrolled (25 assessable patients; median age, 59 years; 62% male; 45% stage IIIA; 38% PS 0; and 38% ≥ 5% weight loss). Induction CIP was well tolerated (with filgrastim support) and active (partial response rate, 46.2%; stable disease, 53.8%; and early progression, 0%). The TCRT dose was escalated from 78 to 90 Gy without dose-limiting toxicity. The primary acute toxicity was esophagitis (16%, all grade 3). Late toxicity consisted of grade 2 esophageal stricture (n = 3), bronchial stenosis (n = 2), and fatal hemoptysis (n = 2). The overall response rate was 60%, with a median survival time and 1-year survival probability of 24 months and 0.73 (95% CI, 0.55 to 0.89), respectively.

Conclusion

Escalation of the TCRT dose from 78 to 90 Gy in the context of induction and concurrent chemotherapy was accomplished safely in stage III NSCLC patients.
Dose Escalation Studies of Cytarabine, Daunorubicin, and Etoposide With and Without Multidrug Resistance Modulation With PSC-833 in Untreated Adults With Acute Myeloid Leukemia Younger Than 60 Years: Final Induction Results of Cancer and Leukemia Group B Study 9621
Authors: Kolitz Jonathan E. , George Stephen L. , Dodge Richard K. , Hurd David D. , Powell Bayard L. , Allen Steven L. , Velez-Garcia Enrique , Moore Joseph O. , Shea Thomas C. , Hoke Eva , Caligiuri Michael A. , Vardiman James W. , Bloomfield Clara D. , Larson Richard A.
Published: October 2004

Purpose

P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses.

Patients and Methods

A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833.

Results

Doses selected for phase III testing were DNR 90 mg/m2 and ETOP 100 mg/m2 in ADE, and DNR and ETOP each 40 mg/m2 in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients ≤ 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE.

Conclusion

A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients ≤ 45 years old are especially likely to benefit from Pgp inhibition during induction therapy.
Phase II Study of Activated Charcoal to Prevent Irinotecan-Induced Diarrhea
Authors: Michael Michael , Brittain MaryAnne , Nagai Jane , Feld Ronald , Hedley David , Oza Amit , Siu Lillian , Moore Malcolm J.
Published: October 2004

Purpose

The dose-limiting toxicity of irinotecan (CPT-11; Camptosar) is delayed-onset diarrhea, with an incidence at the grade 3 to 4 level of 20% to 35%. SN38, its active moiety, is responsible by a direct effect on mucosal topoisomerase-I. The aim of this study was to assess whether activated charcoal (AC), possibly by adsorbing free lumenal SN38, can reduce irinotecan-induced diarrhea (CID) and optimize its dose-intensity.

Patients and Methods

Patients with advanced colorectal cancer receiving irinotecan 125 mg/m2 intravenously once a week for 4 weeks every 6 weeks were studied. In cycle 1, patients received irinotecan plus AC (5 mL aqueous Charcodote [1,000 mg AC] plus 25 mL water) given the evening before the irinotecan dose and then tid for 48 hours after the dose. In cycle 2, no AC was given. National Cancer Institute Common Toxicity Criteria diarrhea grade, irinotecan dose-intensity, and loperamide consumption were recorded prospectively in both cycles.

Results

Twenty-eight patients had completed cycle 1 with AC; 24 subsequently completed cycle 2 without AC. Grade 3 to 4 diarrhea was 7.1% v 25%, and grade 0 diarrhea was 46.4% v 20.8% in cycles 1 and 2, respectively. Median percent planned dose delivered was 98% v 70% in cycles 1 and 2, respectively. In cycles 1 and 2, respectively, 25% v 54% patients took more than 10 loperamide tablets. AC was well tolerated with excellent compliance.

Conclusion

The administration of AC with irinotecan reduced the incidence of grade 3 to 4 diarrhea and antidiarrheal medication consumption and increased irinotecan dose-intensity. Prophylactic AC may have a role in reducing dose-limiting CID and optimizing irinotecan therapy.
Automated Corneal‐Reflection Eye Tracking in Infancy: Methodological Developments and Applications to Cognition
Authors: Aslin Richard N. , McMurray Bob
Published: October 2004

Since the mid‐1800s, experimental psychologists have been using eye movements and gaze direction to make inferences about perception and cognition in adults (Müller, 1826, cited in Boring, 1942). In the past 175 years, these oculomotor measures have been refined (see Kowler, 1990) and used to address similar questions in infants (see Aslin, 1985, 1987; Branson, 1982; Haith, 1980; Maurer, 1975). The general rationale for relying on these visual behaviors is that where one is looking is closely tied to what one is seeing. This is not to deny the fact that we can detect visual stimuli in the peripheral visual field, but rather that there is a bias to attend to and process information primarily when it is located in the central portion of the retina. Thus, although the direction of gaze is not perfectly correlated with the uptake of visual information (e.g., as in a blank stare or a covert shift of attention), there is a strong presumption that the direction of gaze can provide important information about visual stimuli even in newborn infants (Haith, 1966; Salapatek, 1968; Salapatek & Kessen, 1966).
Evidence of the Face Inversion Effect in 4‐Month‐Old Infants
Authors: Turati Chiara , Sangrigoli Sandy , Ruely Josette , de Schonen Scania
Published: October 2004

This study tested the presence of the face inversion effect in 4‐month‐old infants using habituation to criterion followed by a novelty preference paradigm. Results of Experiment 1 confirmed previous findings, showing that when 1 single photograph of a face is presented in the habituation phase and when infants are required to recognize the same photograph, no differences in recognition performance with upright and inverted faces are found. However, Experiment 2 showed that, when infants are habituated to a face shown in a variety of poses and are required to recognize a new pose of the same face, infants' recognition performances were higher for upright than for inverted faces. Overall, results indicate that, under some experimental conditions, 4‐month‐olds process faces differently according to whether faces are presented upright or inverted.
Expanding the Boundaries of Scholarship in Psychology through Teaching, Research, Service, and Administration
Authors: Mathie Virginia Andreoli , Carlson Janet F. , Johnson David E. , Buskist William , Davis Stephen F. , Smith Randolph A.
Published: October 2004

The Society for the Teaching of Psychology formed a task force in 2000 on Uniting Scholarship and Teaching to develop suggestions for how the Society might facilitate Boyer's (1990) and Halpern et al.'s (1998) expanded views of traditional scholarship with respect to the teaching of psychology. This article represents a partial fulfillment of that charge. Specifically, we explore the scholarly dimensions of teaching, research, service, and administration and consider models for undertaking and documenting scholarship in each of these realms of academic life.
In-vitro transcutaneous delivery of tamoxifen and γ-linolenic acid from borage oil containing ethanol and 1,8-cineole
Authors: Ho Suzanna , Calder Richard J , Thomas Christopher P , Heard Charles M
Published: October 2004

The objective of this study was to examine the effects of ethanol and 1,8-cineole on the transcutaneous delivery of tamoxifen and γ-linolenic acid (GLA) as a two-pronged anti-breast cancer therapy. Formulations containing tamoxifen and varying concentrations of borage oil (∼25% GLA), 1,8-cineole and ethanol were prepared and the simultaneous permeation of tamoxifen and GLA determined across full-thickness pig skin using Franz-type diffusion cells over 48 h. Analysis of tamoxifen and GLA (as methyl ester) were by reverse-phase HPLC. The highest flux of tamoxifen of 488.2 ± 191 times 10−3 μg cm−2 h−1 was observed with a formulation containing 20% 1,8-cineole and 20% ethanol. The same formulation also provided the greatest flux of GLA, 830.6 times 10−3 μg cm−2 h−1. The findings from this work demonstrate the ability of 1,8-cineole and ethanol to enhance the in-vitro permeation of tamoxifen and GLA across the skin and support the plausibility of simultaneously delivering tamoxifen and GLA transcutaneously as a two-pronged anti-breast cancer system.
Antihyperglycaemic and antioxidant effect of hyponidd, an ayurvedic herbomineral formulation in streptozotocin-induced diabetic rats
Authors: Babu P Subash , Prince P Stanely Mainzen
Published: October 2004

Hyponidd is a herbomineral formulation composed of the extracts of ten medicinal plants (Momordica charantia, Melia azadirachta, Pterocarpus marsupium, Tinospora cordifolia, Gymnema sylvestre, Enicostemma littorale, Emblica officinalis, Eugenia jambolana, Cassia auriculata and Curcuma longa). We have investigated hyponidd for its possible antihyperglycaemic and antioxidant effect in diabetic rats. Rats were rendered diabetic by streptozotocin (STZ) (45 mg kg−1 body weight). Oral administration of hyponidd (100 mg kg−1 and 200 mg kg−1) for 45 days resulted in significant lowered levels of blood glucose and significant increased levels of hepatic glycogen and total haemoglobin. An oral glucose tolerance test was also performed in experimental diabetic rats in which there was a significant improvement in blood glucose tolerance in the rats treated with hyponidd. Hyponidd administration also decreased levels of glycosylated haemoglobin, plasma thiobarbituric acid reactive substances, hydroperoxides, ceruloplasmin and α-tocopherol in diabetic rats. Plasma reduced glutathione and vitamin C were significantly elevated by oral administration of hyponidd. The effect of hyponidd at a dose of 200 mg kg−1 was more effective than glibenclamide (600 μg kg−1) in restoring the values to near normal. The results showed that hyponidd exhibits antihyperglycaemic and antioxidant activity in STZ-induced diabetic rats.
Evaluation of khaya gum as a directly compressible matrix system for controlled release
Authors: Odeku Oluwatoyin A , Fell John T
Published: October 2004

Khaya gum has been evaluated as a controlled release agent in modified release matrices in comparison with hydroxypropylmethylcellulose (HPMC) using paracetamol (water soluble) and indometacin (water insoluble) as model drugs. Tablets were produced by direct compression and the in-vitro drug release was assessed in conditions mimicking the gastrointestinal system. Khaya gum matrices provided a controlled release of paracetamol for up to 5 h. The release of paracetamol from khaya gum matrices followed time-independent kinetics (n = 1.042) and release rates were dependent on the concentration of the drug present in the matrix. The addition of tablet excipients not only improved the mechanical properties of the tablet, but also altered the dissolution profile, except for dicalcium phosphate where the profile remained unchanged. HPMC could be used to control the drug release rates from khaya gum matrices and a combination of khaya gum and HPMC gave zero-order time-independent release kinetics. Indometacin exhibited a lag time in excess of 2 h, due to its insolubility at low pH, before the zero-order release was observed. Thus khaya gum matrices could be useful in the formulation of sustained release tablets for up to 5 h and the appropriate combination of khaya gum and HPMC could be used to provide a time-independent release for longer periods.
Preventing restenosis in early drug-eluting stent era: recent developments and future perspectives
Authors: Birkenhauer Peter , Yang Zhihong , Gander Bruno
Published: October 2004

Restenosis is the major limitation of the successful therapy of percutaneous coronary intervention (PCI) for patients with coronary artery disease. The problem was appreciated in the late 1970s to early 1980s. Only in recent years, anti-restenotic therapy has achieved a breakthrough with the development of drug-eluting stents. Here, we provide an overview about pathological mechanisms of restenosis after PCI. Present therapeutic approaches to overcome restenosis and recent clinical results are revisited, and some major concerns in the post-drug-eluting stent era are discussed.
The AP1 transcription factor Fra2 is required for efficient cartilage development
Authors: Karreth Florian , Hoebertz Astrid , Scheuch Harald , Eferl Robert , Wagner Erwin F.
Published: October 2004

The Fos-related AP1 transcription factor Fra2 (encoded by Fosl2)is expressed in various epithelial cells as well as in cartilaginous structures. We studied the role of Fra2 in cartilage development. The absence of Fra2 in embryos and newborns leads to reduced zones of hypertrophic chondrocytes and impaired matrix deposition in femoral and tibial growth plates, probably owing to impaired differentiation into hypertrophic chondrocytes. In addition, hypertrophic differentiation and ossification of primordial arches of the developing vertebrae are delayed in Fra2-deficient embryos. Primary Fosl2–/– chondrocytes exhibit decreased hypertrophic differentiation and remain in a proliferative state longer than wild-type cells. As pups lacking Fra2 die shortly after birth, we generated mice carrying `floxed' Fosl2 alleles and crossed them to coll2a1-Cre mice, allowing investigation of postnatal cartilage development. The coll2a1-Cre, Fosl2f/f mice die between 10 and 25 days after birth, are growth retarded and display smaller growth plates similar to Fosl2–/– embryos. In addition, these mice suffer from a kyphosis-like phenotype, an abnormal bending of the spine. Hence, Fra2 is a novel transcription factor important for skeletogenesis by affecting chondrocyte differentiation.
Foxd1 is required for proper formation of the optic chiasm
Authors: Herrera Eloísa , Marcus Riva , Li Suzanne , Williams Scott E. , Erskine Lynda , Lai Eseng , Mason Carol
Published: October 2004

In animals with binocular vision, retinal ganglion cell (RGC) axons from each eye sort in the developing ventral diencephalon to project to ipsi- or contralateral targets, thereby forming the optic chiasm. Ipsilaterally projecting axons arise from the ventrotemporal (VT) retina and contralaterally projecting axons primarily from the other retinal quadrants. The winged helix transcription factor Foxd1 (previously known as BF-2, Brain Factor 2) is expressed in VT retina, as well as in the ventral diencephalon during the formation of the optic chiasm. We report here that in embryos lacking Foxd1,both retinal development and chiasm morphogenesis are disrupted. In the Foxd1 deficient retina, proteins designating the ipsilateral projection, such as Zic2 and EphB1, are missing, and the domain of Foxg1 (BF-1) expands from nasal retina into the VT crescent. In retina-chiasm co-cultures, VT RGCs from Foxd1 deficient retina are not repulsed by chiasm cells, and in vivo many VT RGCs aberrantly project contralaterally. However, even though the ipsilateral program is lost in the retina, a larger than normal uncrossed component develops in Foxd1 deficient embryos. Chiasm defects include axon stalling in the chiasm and a reduction in the total number of RGCs projecting to the optic tract. In addition, in the Foxd1 deficient ventral diencephalon, Foxg1 invades the Foxd1 domain, Zic2 and Islet1 expression are minimized, and Slit2 prematurely expands, changes that could contribute to axon projection errors. Thus, Foxd1 plays a dual role in the establishment of the binocular visual pathways: first, in specification of the VT retina, acting upstream of proteins directing the ipsilateral pathway; and second, in the patterning of the developing ventral diencephalon where the optic chiasm forms.
An essential role for Fgfs in endodermal pouch formation influences later craniofacial skeletal patterning
Authors: Crump Justin Gage , Maves Lisa , Lawson Nathan D. , Weinstein Brant M. , Kimmel Charles B.
Published: October 2004

Fibroblast growth factor (Fgf) proteins are important regulators of pharyngeal arch development. Analyses of Fgf8 function in chick and mouse and Fgf3 function in zebrafish have demonstrated a role for Fgfs in the differentiation and survival of postmigratory neural crest cells (NCC) that give rise to the pharyngeal skeleton. Here we describe, in zebrafish, an earlier, essential function for Fgf8 and Fgf3 in regulating the segmentation of the pharyngeal endoderm into pouches. Using time-lapse microscopy, we show that pharyngeal pouches form by the directed lateral migration of discrete clusters of endodermal cells. In animals doubly reduced for Fgf8 and Fgf3, the migration of pharyngeal endodermal cells is disorganized and pouches fail to form. Transplantation and pharmacological experiments show that Fgf8 and Fgf3 are required in the neural keel and cranial mesoderm during early somite stages to promote first pouch formation. In addition, we show that animals doubly reduced for Fgf8 and Fgf3 have severe reductions in hyoid cartilages and the more posterior branchial cartilages. By examining early pouch and later cartilage phenotypes in individual animals hypomorphic for Fgf function,we find that alterations in pouch structure correlate with later cartilage defects. We present a model in which Fgf signaling in the mesoderm and segmented hindbrain organizes the segmentation of the pharyngeal endoderm into pouches. Moreover, we argue that the Fgf-dependent morphogenesis of the pharyngeal endoderm into pouches is critical for the later patterning of pharyngeal cartilages.
Neural induction requires BMP inhibition only as a late step, and involves signals other than FGF and Wnt antagonists
Authors: Linker Claudia , Stern Claudio D.
Published: October 2004

A dominant molecular explanation for neural induction is the `default model', which proposes that the ectoderm is pre-programmed towards a neural fate, but is normally inhibited by endogenous BMPs. Although there is strong evidence favouring this in Xenopus, data from other organisms suggest more complexity, including an involvement of FGF and modulation of Wnt. However, it is generally believed that these additional signals also act by inhibiting BMPs. We have investigated whether BMP inhibition is necessary and/or sufficient for neural induction. In the chick, misexpression of BMP4 in the prospective neural plate inhibits the expression of definitive neural markers (Sox2 and late Sox3), but does not affect the early expression of Sox3, suggesting that BMP inhibition is required only as a late step during neural induction. Inhibition of BMP signalling by the potent antagonist Smad6, either alone or together with a dominant-negative BMP receptor, Chordin and/or Noggin in competent epiblast is not sufficient to induce expression of Sox2 directly, even in combination with FGF2,FGF3, FGF4 or FGF8 and/or antagonists of Wnt signalling. These results strongly suggest that BMP inhibition is not sufficient for neural induction in the chick embryo. To test this in Xenopus, Smad6 mRNA was injected into the A4 blastomere (which reliably contributes to epidermis but not to neural plate or its border) at the 32-cell stage: expression of neural markers (Sox3 and NCAM) is not induced. We propose that neural induction involves additional signalling events that remain to be identified.
Human embryonic stem cells: prospects for development
Authors: Pera Martin F. , Trounson Alan O.
Published: October 2004

It is widely anticipated that human embryonic stem (ES) cells will serve as an experimental model for studying early development in our species, and,conversely, that studies of development in model systems, the mouse in particular, will inform our efforts to manipulate human stem cells in vitro. A comparison of primate and mouse ES cells suggests that a common underlying blueprint for the pluripotent state has undergone significant species-specific modification. As we discuss here, technical advances in the propagation and manipulation of human ES cells have improved our understanding of their growth and differentiation, providing the potential to investigate early human development and to develop new clinical therapies.
Fkh2p and Sep1p regulate mitotic gene transcription in fission yeast
Authors: Buck Vicky , Ng Szu Shien , Ruiz-Garcia Ana Belen , Papadopoulou Kyriaki , Bhatti Saeeda , Samuel Jane M. , Anderson Mark , Millar Jonathan B. A. , McInerny Christopher J.
Published: October 2004

In the fission yeast Schizosaccharomyces pombe, several genes including cdc15+, spo12+, fin1+, slp1+, ace2+ and plo1+ are periodically expressed during M phase. The products of these genes control various aspects of cell cycle progression including sister chromatid separation, septation and cytokinesis. We demonstrate that periodic expression of these genes is regulated by a common promoter sequence element, named a PCB. In a genetic screen for cell cycle regulators we have identified a novel forkhead transcription factor, Fkh2p, which is periodically phosphorylated in M phase. We show that Fhk2p and another forkhead transcription factor, Sep1p, are necessary for PCB-driven M-phase-specific transcription. In a previous report we identified a complex by electrophoretic mobility shift assay, which we termed PBF, that binds to a 150 bp region of the cdc15+ promoter that contains the PCB element. We have identified Mbx1p, a novel MADS box protein, as a component of PBF. However, although Mbx1p is periodically phosphorylated in M phase, Mbx1p is not required for periodic gene transcription in M phase. Moreover, although PBF is absent in strains bearing a C-terminal epitope tag on Fkh2p, simultaneous deletion of fkh2+ and sep1+ does not abolish PBF binding activity. This suggests that Mbx1p binds to gene promoters, but is not required for transcriptional activation. Together these results suggest that the activation of the Fkh2p and Sep1p forkhead transcription factors triggers mitotic gene transcription in fission yeast.
The dynamic kinetochore-microtubule interface
Authors: Maiato Helder , DeLuca Jennifer , Salmon E. D. , Earnshaw William C.
Published: October 2004

The kinetochore is a control module that both powers and regulates chromosome segregation in mitosis and meiosis. The kinetochore-microtubule interface is remarkably fluid, with the microtubules growing and shrinking at their point of attachment to the kinetochore. Furthermore, the kinetochore itself is highly dynamic, its makeup changing as cells enter mitosis and as it encounters microtubules. Active kinetochores have yet to be isolated or reconstituted, and so the structure remains enigmatic. Nonetheless, recent advances in genetic, bioinformatic and imaging technology mean we are now beginning to understand how kinetochores assemble, bind to microtubules and release them when the connections made are inappropriate, and also how they influence microtubule behaviour. Recent work has begun to elucidate a pathway of kinetochore assembly in animal cells; the work has revealed that many kinetochore components are highly dynamic and that some cycle between kinetochores and spindle poles along microtubules. Further studies of the kinetochore-microtubule interface are illuminating: (1) the role of the Ndc80 complex and components of the Ran-GTPase system in microtubule attachment, force generation and microtubule-dependent inactivation of kinetochore spindle checkpoint activity; (2) the role of chromosomal passenger proteins in the correction of kinetochore attachment errors; and (3) the function of microtubule plus-end tracking proteins, motor depolymerases and other proteins in kinetochore movement on microtubules and movement coupled to microtubule poleward flux.
The AMP-activated protein kinase pathway – new players upstream and downstream
Authors: Hardie D. Grahame
Published: October 2004

The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy status. Whenever the cellular ATP:ADP ratio falls, owing to a stress that inhibits ATP production or increases ATP consumption, this is amplified by adenylate kinase into a much larger increase in the AMP:ATP ratio. AMP activates the system by binding to two tandem domains on the γ subunits of AMPK, and this is antagonized by high concentrations of ATP. AMP binding causes activation by a sensitive mechanism involving phosphorylation of AMPK by the tumour suppressor LKB1. Once activated, AMPK switches on catabolic pathways that generate ATP while switching off ATP-consuming processes. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of hormones and cytokines such as leptin, adiponectin and ghrelin. A particularly interesting downstream target recently identified is TSC2 (tuberin). The LKB1→AMPK→TSC2 pathway negatively regulates the target of rapamycin (TOR), and this appears to be responsible for limiting protein synthesis and cell growth, and protecting against apoptosis, during cellular stresses such as glucose starvation.
Electrothermal Atomic Absorption Spectrometric Determination of Gold by Vapor Formation and in situ Trapping in Graphite Tubes
Authors: Ertaş Gülay , Ataman O. Yavuz
Published: October 2004

Gold was determined in ore samples following generation, separation, collection on a graphite cuvette inner wall, and atomization of its volatile species formed by combining an acidified sample solution with an aqueous sodium tetrahydroborate solution at room temperature. A detection limit of 2.6 μg L−1 (3σ) was obtained with a 5.0 mL sample volume. Precision of replicate measurements was typically 10% RSD. The overall efficiency of the volatile species generation, transport, and trapping process was 0.4%. Atomization of gold from Pd, Ir, Cu, Ag, and W coated graphite cuvettes, following by trapping of the gaseous volatile gold species on these surfaces, has been investigated. Pd coating was found to decrease the sensitivity. Five μg of Ir, 20 μg of Cu, 20 μg of Ag, and 5 μg of W were chosen as optimum masses. W treatment was the best one for sensitivity enhancement, having an improvement factor of 2.4. Silanization of glass surfaces significantly decreased memory effects; improved peak shapes were thus obtained for flow injection vapor generation atomic absorption spectrometry (FI-VGAAS). The method described in this study was used for the determination of gold in an ore reference material, Gold Ore (MA-1b), Canadian Reference Materials Program.
Quantifying Ethanol Content of Beer Using Interpretive Near-Infrared Spectroscopy
Authors: Engelhard Sonja , Löhmannsröben Hans-Gerd , Schael Frank
Published: October 2004

On the basis of absorption measurements in the near-infrared (NIR) spectral range, a new method for the quantification of the ethanol content of beer is presented. Instead of the multivariate calibration models most commonly employed in NIR spectroscopic works, we use interpretive difference spectroscopy: Two wavelengths are selected according to the assignment of the absorption bands of the main substances of content of beer in the NIR region, and the difference between the absorbances at these wavelengths is used for ethanol quantification. Absorption spectra of the dominating beer ingredients are discussed and the calibration procedure with ethanol/water mixtures is shown. Robustness against the carbohydrate content of beer samples was demonstrated by analyzing solutions of ethanol and maltose in water. Validation of the method was performed with various beer samples with an ethanol concentration range between 0.5 and 7.7 vol %. The pertinent advantage of the procedure developed in this work is the indication that the results are independent from seasonal variations of the ingredients, which is of high interest for products with natural ingredients such as beer.
Determination of Spectrometer-Detector Parameters from Calibration Spectra and the Use of the Parameters in Spectrometer Calibrations
Authors: Holy John A.
Published: October 2004

The grating equation is used to generate quadratic calibration equations for multichannel detectors with perpendicular and tilted focal planes. The quadratic coefficients are not independent and contain terms that are used to solve for spectrometer-detector parameters. The parameters can be calculated from a quadratic fit at one spectrometer position, but more accurate values can be obtained from quadratic fits at two spectrometer positions. The calculations show that the detector focal plane is tilted by about two degrees. Once values for the spectrometer-detector parameters are obtained from calibrations using at least three lines at one or two spectrometer positions, only one calibration line at any spectrometer position is required to obtain accuracies on the order of 0.1 cm−1 over a several thousand wavenumber range. The main cause of spectrometer drift is a change in the diffraction angle and/or the spectrometer included angle. This drift is almost totally compensated by the one-line calibration, which adjusts the diffraction angle. A neon pen lamp is used to generate the calibration spectra. Using standard air wavelengths compared to true wavelengths can produce calibration errors of 0.1 to 0.6 cm−1; the magnitude depends on local conditions and how the laser wavelength is treated.
Factors Affecting the Sorption of Model Environmental Pollutants onto Silver Polydimethylsiloxane Nanocomposite Raman Substrates
Authors: De Jesús M. A. , Giesfeldt K. S. , Sepaniak M. J.
Published: October 2004

The presence of aromatic compounds in water is an important topic in environmental sciences. Silver-polydimethylsiloxane nanocomposites (Ag-PDMS) have recently been demonstrated as promising substrates for the detection of model environmental pollutants via surface-enhanced Raman spectroscopy (SERS). This work discusses how different variables such as pH and matrix composition can affect the sorption and SERS activity of these chemicals. The results show that the conjugate base of weak acids can interact more efficiently with the substrate, leading to an increased signal at higher pH, while amino-aromatic compounds interact more efficiently at a lower pH. The sorption of these chemicals is an essential step in the process and has been attributed to the absorption of the analyte into the PDMS followed by its adsorption to the metallic surface. In addition, the presence of moderate concentrations (1 × 10−4 M) of a supporting electrolyte such as nitrate or fluoride can improve the sorption of 4-hydroxybenzoic acid to the Ag-PDMS nanoparticles. Other ions such as phosphate and chloride cause rapid oxidation of the substrates even at concentrations as low as 1 × 10−5 M. The effect of these variables in the analysis of real samples is presented. The potential use of liquid chromatography for isolating the model pollutants from detrimental matrix components in natural waters is also shown.
Adsorption of S—S Containing Proteins on a Colloidal Silver Surface Studied by Surface-Enhanced Raman Spectroscopy
Authors: Podstawka Edyta , Ozaki Yukihiro , Proniewicz Leonard M.
Published: October 2004

We present a Raman and surface-enhanced Raman scattering (SERS) study of the following proteins containing S–S group(s): α-chymotrypsin (α-CHT), insulin, lysozyme, oxytocin (OXT), Streptomyces subtilisin inhibitor (SSI), and trypsin inhibitor (STI). The SERS study is performed in order to understand the adsorption mechanism of the above-mentioned proteins on a colloidal silver surface. The SERS spectra presented here show bands associated mainly with aromatic amino acid vibrations. In addition, two distinct vibrations of the –C–S–S–C– fragment are observed in the Raman and SERS spectra, i.e., v(SS) and v(CS). The enhancement of the v(SS) vibration in the SERS spectra yields evidence that the intact disulfide bridge(s) is (are) located near the silver surface. This finding is supported by the presence of the v(CS) mode(s). The presence of vs(COO−) and v(C–COO−) in the SERS spectra in the 1384–1399 cm−1 and 909–939 cm−1 regions, respectively, indicate that the negatively charged COO− groups (aspartic and glutamic acids) assist in the binding on the positively charged silver surface. The Raman amide I and III bands observed in the 1621–1633 and 1261–1289 cm−1 ranges, respectively, indicate that the α-helical conformation is favored for binding to the surface over the random coil or β-sheet conformations. In addition, the presence of the imino group of Trp and/or His indicates that these amino acid residues may also bind to the silver sol.
Quantitative Analysis of Raman Signal Enhancement from Aqueous Samples in Liquid Core Optical Fibers
Authors: Qi Dahu , Berger Andrew J.
Published: October 2004

Raman scattering from aqueous liquids can be collected with high efficiency by enclosing the liquid within a suitable waveguide, as several groups have reported. Here, we present a quantitative model that predicts the relative strength of signals collected from (a) a tubular waveguide and (b) a flat-walled cuvette. Experimental measurements of Raman scattering from aqueous ethanol are made using two geometries, a Teflon®-AF waveguide and a standard quartz cuvette. The model correctly predicts the enhancements in several ethanol Raman bands provided by the waveguide geometry. This model should be useful in aligning and characterizing liquid core waveguides, whose manufacture is still undergoing refinements. In particular, the model shows that absorption and scattering losses affect the enhancement factor in different ways.
Fourier Transform Infrared-Probed O(3P) Microreactor: Demonstration with Ethylene Reactions in Argon Matrix
Authors: Gossage John L. , Gomes Jewel A. G. , Cocke David L. , Li Kuyen , Lin Che-Jen , Tadmor Rafael , Basu Abir , Bhat Shagun , Tandel Satish , Jayabalu Prashanth , Balu Harimadhav
Published: October 2004

To demonstrate the development of an oxygen atom microreactor in the form of liquid-helium-cooled solid argon matrix deposited on an infrared (IR) window, the oxidation of ethylene by mobile O atoms has been investigated. O atom diffusion through the argon matrix is confirmed and used to examine ethylene–oxygen atom reactions. In a bench-scale matrix isolation system probed with a Fourier transform infrared (FT-IR) spectrometer, matrices of solid Ar at 8–10 K doped with NO2 and ethylene have been prepared on a ZnSe window within an evacuated cryostat. The matrices have been photolyzed using 350–450 nm photons, and the reaction products resulting from the reaction of O(3P), one of the photolysis products of NO2, with ethylene have been identified using FT-IR and a Gaussian 98W simulation program. These products include oxirane, acetaldehyde, ethyl nitrite radical, and ketene. The temperature effect in the range of 10–30 K on the products formed has also been investigated. The reaction mechanisms are discussed and the viability of the solid Ar matrix being a low temperature microreactor to examine reaction mechanisms of mobile oxygen atoms is elaborated.
Molar Absorptivities of Glucose and other Biological Molecules in Aqueous Solutions over the First Overtone and Combination Regions of the Near-Infrared Spectrum
Authors: Amerov Airat K. , Chen Jun , Arnold Mark A.
Published: October 2004

Molar absorptivities are measured for water, glucose, alanine, ascorbate, lactate, triacetin, and urea in the near-infrared spectral region at 37 °C. Values are based on the Beer–Lambert law and cover the first overtone (1550–1850 nm; 6450–5400 cm−1) and combination (2000–2500 nm; 4000–5000 cm−1) spectral windows through aqueous media. Accurate calculations demand accounting for the impact of water displacement upon dissolution of solute. In this regard, water displacement coefficients are measured and reported for each solute. First overtone absorptivities range from 2 to 7 × 10−5 mM−1mm−1 for all solutes except urea, for which absorptivity values are below 0.5 × 10−5 mM−1mm−1 across this spectral range. Molar absorptivities over the combination spectral region range from 0.8 to 3.2 × 10−4 mM−1mm−1, which is a factor of four to five greater than the first overtone absorptivities. Accuracy of the measured values is assessed by comparing calculated or modeled spectra with spectra measured from standard solutions. This comparison reveals accurately modeled spectra in terms of magnitude and position of solute absorption bands. Both actual and modeled spectra from glucose solutions reveal positive and negative absorbance values depending on the measurement wavelength. It is shown that the net absorbance of light is controlled by the magnitude of the absorptivity of glucose compared to the product of the absorptivity of water and the water displacement coefficient for glucose.
Sequencing of Genomic DNA by Combined Amplification and Cycle Sequencing Reaction
Authors: Murphy Kathleen M , Berg Karin D , Eshleman James R
Published: October 2004

Background: Despite considerable advances, DNA sequencing has remained somewhat time-consuming and expensive, requiring three separate steps to generate sequencing products from a template: amplification of the target sequence; purification of the amplified product; and a sequencing reaction. Our aim was to develop a method to routinely combine PCR amplification and cycle sequencing into one single reaction, enabling direct sequencing of genomic DNA.

Methods: Combined amplification and sequencing reactions were set up with Big Dye™ sequencing reagents (Applied Biosystems) supplemented with variable amounts of forward and reverse primers, deoxynucleotide triphosphates (dNTPs), and input DNA. Reactions were thermal-cycled for 35 or 45 cycles. Products were analyzed by capillary electrophoresis to detect sequencing products.

Results: Reactions using two oligonucleotide primers at a ratio of 5:1 (500 nM primer 1 and 100 nM primer 2), 125 μM supplemental dNTPs, and 35–45 thermal cycles optimally supported combined amplification and cycle sequencing reactions. Our results suggest that these reactions are dominated by PCR during early cycles and convert to cycle sequencing in later cycles. We used this technique for a variety of sequencing applications, including the identification of germline mutations/polymorphisms in the Factor V and BRCA2 genes, sequencing of tumor DNA to identify somatic mutations in the DPC4/SMADH4 and FLT3 genes, and sequencing of 16S ribosomal DNA for bacterial speciation.

Conclusions: PCR amplification and cycle sequencing can be combined into a single reaction using the conditions described. This technique allows direct sequencing of genomic DNA, decreasing the cost and labor involved in gene sequencing.
(Re)sensing the observer: offering an open order cybernetics
Authors: Gaugusch Andrea , Seaman Bill
Published: October 2004

Instead of presuming the ‘observer’ as given, we are (re)sensing the observer and are thereby offering an ‘open order cybernetics’ (OOC). We are first of all concerned about our acquisition and use of language as the precondition for any meaningful statement. This self-reflexive point of departure distinguishes our project from philosophers who are presuming ‘something’ (‘closure’, ‘selforganization’, ‘self ’, ‘auto-poiesis’, ‘senses’, ‘objects’, ‘subjects’, ‘language’, ‘nervous systems’ etc.) in the first place without being aware of their presumptions i.e. that they are able to already talk meaningfully about ‘something’. We are undertaking a self-reflexive loop towards our already undertaken ‘meaningful’ actions, reflecting inside our concepts on our concepts, trying to find out how our concepts about ‘something’ have come into existence. We are reflecting on our concepts through this ongoing open investigation. We are sketching the ramifications of such a self-reflexive loop for epistemology as well as for the main research areas within cognitive science (i.e. language acquisition, perception, consciousness). We are also pointing towards virtual reality in combination with the arts as an awareness aid, helping us in our self-reflexive endeavours.
On the evolution of artificial consciousness. Re-inventing the wheel, Re: Inventing the wheel
Authors: Jones Stephen
Published: October 2004

In this article I suggest how we might conceptualize some kind of artificial consciousness as an ultimate development of Artificial Life. This entity will be embodied in some sort of constructed (biological or non-biological) body. The contention is that consciousness within self-organized
entities is not only possible but inevitable. The basic sensory and interactive processes by which an organism operates within an environment are such as to be the basic processes that are necessary for consciousness. I then look at likely criteria for consciousness, and point to an architecture
of the cognitive which maps onto the physiological layer, the brain. While evolutionary algorithms and neural nets will be at the heart of the production of artificial intelligences there is a particular architectural organization that may be necessary in the production of conscious artefacts.
This involves the operations of multiple layers of feedback loops in the anatomy of the brain, in the social construction of the contents of consciousness and in particular in the self-regulation necessary for the continued operation of metabolically organized systems. Finally I make some
comments on the ethics of such a procedure.