bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia
Authors: Poncet Delphine , Belleville Aurélie , t'Kint de Roodenbeke Claire , Roborel de Climens Aude , Ben Simon Elsa , Merle-Beral Hélène , Callet-Bauchu Evelyne , Salles Gilles , Sabatier Laure , Delic Jozo , Gilson Eric
Published: December 2007

In this study, we explored the telomeric changes that occur in B-chronic lymphocytic leukemia (B-CLL), in which telomere length has recently been demonstrated to be a powerful prognostic marker. We carried out a transcriptomic analysis of telomerase components (hTERT and DYSKERIN), shelterin proteins (TRF1, TRF2, hRAP1, TIN2, POT1, and TPP1), and a set of multifunctional proteins involved in telomere maintenance (hEST1A, MRE11, RAD50, Ku80, and RPA1) in peripheral B cells from 42 B-CLL patients and 20 healthy donors. We found that, in B-CLL cells, the expressions of hTERT, DYSKERIN, TRF1, hRAP1, POT1, hEST1A, MRE11, RAD50, and KU80 were more than 2-fold reduced (P < .001), contrasting with the higher expression of TPP1 and RPA1 (P < .001). This differential expression pattern suggests that both telomerase down-regulation and changes in telomeric proteins composition are involved in the pathogenesis of B-CLL.
Evolution of allostery in the cyclic nucleotide binding module
Authors: Kannan Natarajan , Wu Jian , Anand Ganesh S , Yooseph Shibu , Neuwald Andrew F , Venter J Craig , Taylor Susan S
Published: December 2007

Background

The cyclic nucleotide binding (CNB) domain regulates signaling pathways in both eukaryotes and prokaryotes. In this study, we analyze the evolutionary information embedded in genomic sequences to explore the diversity of signaling through the CNB domain and also how the CNB domain elicits a cellular response upon binding to cAMP.

Results

Identification and classification of CNB domains in Global Ocean Sampling and other protein sequences reveals that they typically are fused to a wide variety of functional domains. CNB domains have undergone major sequence variation during evolution. In particular, the sequence motif that anchors the cAMP phosphate (termed the PBC motif) is strikingly different in some families. This variation may contribute to ligand specificity inasmuch as members of the prokaryotic cooA family, for example, harbor a CNB domain that contains a non-canonical PBC motif and that binds a heme ligand in the cAMP binding pocket. Statistical comparison of the functional constraints imposed on the canonical and non-canonical PBC containing sequences reveals that a key arginine, which coordinates with the cAMP phosphate, has co-evolved with a glycine in a distal β2-β3 loop that allosterically couples cAMP binding to distal regulatory sites.

Conclusion

Our analysis suggests that CNB domains have evolved as a scaffold to sense a wide variety of second messenger signals. Based on sequence, structural and biochemical data, we propose a mechanism for allosteric regulation by CNB domains.
Early Exposure to General Anesthesia Causes Significant Neuronal Deletion in the Developing Rat Brain
Authors: NIKIZAD H. , YON J‐H. , CARTER L. B. , JEVTOVIC‐TODOROVIC V.
Published: December 2007

Frequent exposure of children to general anesthesia is common practice in modern medicine. Although previously unrecognized, recent in vitro and in vivo animal studies suggest that exposure to clinically relevant general anesthetics at the peak of brain development could be detrimental to immature mammalian neurons, as demonstrated by massive and widespread apoptotic neurodegeneration. The survival of the developing neurons presumably depends on proper and timely formation of synapses, for which synaptic proteins (e.g., synaptophysin, synaptobrevin, amphiphysin, synaptosomal‐associated protein 25 [SNAP‐25], and Ca2+/calmodulin‐dependent protein kinase II [CaM kinase II]) are crucially important. Overinhibition of developing neurons impairs synaptic protein function and activity‐induced synaptic plasticity, which could in turn result in permanent neuronal loss. To examine the effects of general anesthesia, the pharmacological agents known to cause extensive neuronal inhibition, on synaptic proteins, and neuronal survival at the peak of synaptogenesis, we exposed 7‐day‐old rat pups to general anesthesia (midazolam, 9 mg/kg of body weight, subcutaneously, followed by 6 h of nitrous oxide 75 vol% and isoflurane 0.75 vol%). We found that this general anesthesia causes permanent neuronal deletion in the most vulnerable brain regions—the cerebral cortex and the thalamus—while transiently modulating protein levels of synaptophysin, synaptobrevin, amphiphysin, SNAP‐25, and CaM kinase II.
Brain‐Derived Neurotrophic Factor in Neuronal Survival and Behavior‐Related Plasticity
Authors: LIPSKY ROBERT H. , MARINI ANN M.
Published: December 2007

Neurotrophins are critical to the development and maintenance of the mammalian central nervous system. Among them is brain‐derived neurotrophic factor (BDNF), whose synthesis and release is targeted by activation of glutamate receptors. Perturbation of this process probably underlies neurodegenerative and psychiatric disorders. A naturally occurring variation in humans, in the form of a common single‐nucleotide polymorphism in the pro region of the polypeptide at codon 66 (Val66→Met), affects processing of the pro‐BDNF polypeptide and its activation‐dependent release. This variant is associated with differences in the volume of the hippocampal formation and with anxiety and depression‐related phenotypes. Convergent findings supporting a role for BDNF in alterations to hippocampal structure and behavior are found in a “humanized” BDNF transgenic mouse. Also, recent human genetic studies have supported a role of BDNF signaling in addictive behaviors by allele‐, genotype‐, and haplotype‐based association of the TrkB gene, which encodes the cognate receptor for BDNF, with alcohol dependence. A better understanding of the influence of BDNF‐mediated pathways in cell survival and plasticity will aid in developing new approaches to restoring normal function in disease states.
Induction of Neurotrophic Factors GDNF and BDNF Associated with the Mechanism of Neurorescue Action of Rasagiline and Ladostigil
Authors: WEINREB ORLY , AMIT TAMAR , BAR‐AM ORIT , YOUDIM MOUSSA B.H.
Published: December 2007

Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common neurodegenerative disorders, although there is no drug or therapeutic treatment to demonstrate disease‐modifying effects. Previous work has proposed that neurodegeneration is linked to a lack of trophic support in those neurons and brain areas associated with PD and AD. Indeed, previous studies have found that neurotrophic factors (NTFs) support neuronal survival in various cellular and animal models of PD and AD. Thus, attention has begun to turn to the possibility of NTF neuroprotective–neurorescue therapies for these diseases, indicating that NTFs may be of significant clinical importance as exogenously supplied or endogenously induced elements that obliterate neuronal deficits and degeneration.
We have recently reported that the anti‐PD drug rasagiline, the anti‐AD drug ladostigil, and their propargyl moiety, propargylamine, enhanced the expression levels of brain‐derived neurotrophic factor and glial cell line–derived neurotrophic factor, endogenous NTFs associated with activation of phosphatidylinositol 3‐kinase, protein kinase, and mitogen‐activated protein kinase cell signaling/survival pathways. These studies indicate that the induction of NTFs by rasagiline and ladostigil might suppress apoptosis and induce neurorescue in neurodegenerative disorders and may support the drugs' possible disease‐modifying mechanism of action.
Effect of Methylene Blue and Related Redox Dyes on Monoamine Oxidase Activity; Rat Pineal Content of N‐Acetylserotonin, Melatonin, and Related Indoles; and Righting Reflex in Melatonin‐Primed Frogs
Authors: OXENKRUG G.F. , SABLIN S.O. , REQUINTINA P.J.
Published: December 2007

The ability of methylene blue (MB) to inhibit the nitric oxide–induced stimulation of N‐methyl‐d‐aspartate receptors has been suggested as a possible mechanism of MB's clinical antidepressant action. This study evaluated the alternative/additional mechanisms of the antidepressant effect of MB on biochemical and behavior levels. Selective inhibition of monoamine oxidase type A (MAO‐A) is widely accepted as a major mechanism of the clinical antidepressant effect. MB and the related redox dyes toluidine blue O (TBO), thionine (TN), brilliant cresyl blue (BCB), and toluylene blue (TB) were reversible competitive inhibitors of both MAO‐A and MAO‐B and were highly selective toward MAO‐A. TBO was the most potent inhibitor, followed by TN, BCB, MB, and TB. The dyes studied increased rat pineal N‐acetylserotonin (NAS) and melatonin content, in accordance with our previous observations of the stimulating effect of selective inhibition of MAO‐A on pineal melatonin biosynthesis. The redox dyes exerted antidepressant‐like activity in frogs; that is, they suppressed the righting reflex in melatonin‐primed frogs. This study's results indicate that selective inhibition of MAO‐A might mediate the clinical antidepressant effect of MB through NAS stimulation and melatonin biosynthesis.
Effect of Luzindole and Other Melatonin Receptor Antagonists on Iron‐ and Lipopolysaccharide‐Induced Lipid Peroxidation in Vitro
Authors: REQUINTINA PURA J. , OXENKRUG GREGORY F.
Published: December 2007

Melatonin and its precursor, N‐acetylserotonin (NAS), have been shown in in vivo and in vitro studies to inhibit iron‐ and lipopolysaccharide (LPS)‐induced lipid peroxidation in rats and mice. Using in vitro studies, we examined whether these effects will be affected by the melatonin receptor antagonists luzindole (a competitive MT1/MT2 antagonist), DH 97 (MT2), prazosin (MT3), and 4‐P‐PDOT (MT2). Lipid peroxidation in the form of malondialdehyde (MDA) was assayed by measuring thiobarbituric acid–reactive substances. The antagonists did not affect the melatonin and NAS effect on iron‐ and LPS‐induced peroxidation. However, luzindole alone, but not the other antagonists, inhibited the iron‐ and LPS‐induced peroxidation in the rat brain and kidney homogenates. At a dose of 50 μM, luzindole reduced iron‐induced MDA levels by 80% in the brain and 84% in the kidney, whereas LPS‐induced MDA levels were reduced by 85% in both brain and kidney. A dose of 800 μM prevented lipid peroxidation, bringing the MDA levels to values of samples untreated by iron or LPS.
Antibodies to Serotonin Attenuate Closed Head Injury Induced Blood–Brain Barrier Disruption and Brain Pathology
Authors: SHARMA H.S. , PATNAIK R. , PATNAIK S. , MOHANTY S. , SHARMA A. , VANNEMREDDY P.
Published: December 2007

Closed head injury (CHI) often results in profound brain swelling and instant death of the victims due to compression of the vital centers. However, the neurochemical basis of edema formation in CHI is still obscure. Previous studies from our laboratory show that blockade of serotonin synthesis prior to CHI in a rat model attenuates brain edema, indicating a prominent role for serotonin in head injury. Thus, neutralization of endogenous serotonin activity and/or blocking of its receptors will induce neuroprotection in CHI. Since serotonin has more than 14 receptors and selective serotonin antagonists are still not available, we used serotonin antiserum to neutralize its in vivo effects before or after CHI in a rat model. CHI was produced by an impact of 0.224 N on the right parietal skull bone under Equithesin anesthesia by dropping a weight of 114.6 g from a height of 20 cm through a guide tube. This concussive brain injury resulted in blood–brain barrier (BBB) disruption, brain edema formation, and volume swelling at 5 h that were most pronounced in the contralateral cerebral hemisphere. The plasma and brain serotonin levels were increased several‐fold at this time. Intracerebroventricular administration of serotonin antiserum (1:20, monoclonal) into the left lateral cerebral ventricle (30 μL in PBS) 30 min before or 30 min (but not 60 min) after CHI significantly attenuated BBB disruption, brain edema formation, volume swelling, and brain pathology. The plasma and brain serotonin levels continued to remain high. These observations are the first to suggest that antiserum to serotonin when administered into the CSF during the early phase of CHI are capable of inducing neuroprotection.
Rab‐Mediated Endocytosis
Authors: BASKYS ANDRIUS , BAYAZITOV ILDAR , ZHU ERCHENG , FANG LIWEI , WANG RONG
Published: December 2007

Rab proteins are small GTPases involved in endocytosis and recycling of cell surface molecules. Recently they have been implicated in the etiopathogenesis of several neurodegenerative disorders including Alzheimer's and Lewy body disease. In experiments on organotypic hippocampal cultures, upregulation of Rab protein family member Rab5b after group I metabotropic glutamate receptor (mGluR) stimulation was associated with reduced neuronal vulnerability to excitotoxic injury. This mGluR‐mediated neuroprotection was abolished by antisense‐induced deficiency of Rab5b. Electrophysiological measurements of excitatory synaptic transmission in the Schaffer collateral–CA1 pathway revealed that mGluR activation that induces neuroprotection also induced long‐term depression (LTD) of synaptic transmission. Similar to the neuroprotection, Rab5b deficiency abolished dihydroxyphenylglycine‐induced LTD. Together, these findings support the idea that Rab proteins, and the Rab5b protein in particular, may provide a link between neurodegenerative disease, neuroprotection, and synaptic plasticity, as well as possibly being a useful target for pharmacological interventions.
The Association between Hyperglycemia and Fracture Risk in Middle Age. A Prospective, Population-Based Study of 22,444 Men and 10,902 Women
Authors: Holmberg A. H. , Nilsson P. M. , Nilsson J-Å. , Åkesson K.
Published: December 2007

Aims: Type 1 diabetes mellitus is associated with increased fracture risk, whereas the risk associated with type 2 diabetes is less obvious. Elevated fasting blood glucose and high 2-h glucose during an oral glucose tolerance test indicate impaired glucose tolerance or diabetes. The associations among fasting blood glucose, 2-h glucose, and the risk of fracture were investigated.

Methods: The Malmö Preventive Project consists of 22,444 men (44 ± 6.6 yr) and 10,902 women (50 ±7.4 yr), with a follow-up of 19 yr (±3.9) and 15 yr (±4.5) for incident fractures. Baseline assessment included multiple examinations and lifestyle information. A logistic regression model was used. Adjustments were made for age, body mass index (BMI), and smoking.

Results: Low-energy fractures were recorded in 1246 men and 1236 women. A 2-h glucose measurement between 4.3 and 6.2 mmol/liter in men (second and third quartile), and above 6.5 mmol/liter in women (third and fourth quartile), adjusted for age, BMI, and smoking, was significantly associated with a decreased risk of multiple fractures, in men [odds ratios (ORs) 0.57–0.71] and women (ORs 0.38–0.66). In women, a 2-h glucose measurement above 7.5 mmol/liter was associated with a decreased risk of osteoporotic fractures (OR 0.57, 95% confidence interval 0.44–0.74).

Conclusions: In middle-aged men and women, elevated 2-h glucose levels were associated with decreased risks of multiple and osteoporotic fractures, independent of age, BMI, and smoking. A high 2-h glucose level is characterized by peripheral insulin resistance with a high insulin level. Our findings indirectly suggest a positive effect on bone from hyperglycemia.
Type 2 Deiodinase Polymorphism (Threonine 92 Alanine) Predicts l-Thyroxine Dose to Achieve Target Thyrotropin Levels in Thyroidectomized Patients
Authors: Torlontano Massimo , Durante Cosimo , Torrente Isabella , Crocetti Umberto , Augello Giovanni , Ronga Giuseppe , Montesano Teresa , Travascio Laura , Verrienti Antonella , Bruno Rocco , Santini Stefano , D’Arcangelo Palmina , Dallapiccola Bruno , Filetti Sebastiano , Trischitta Vincenzo
Published: December 2007

Context: Type 2 deiodinase (D2) converts T4 in T3 in several human tissues, including hypothalamus and pituitary, and, therefore, plays a pivotal role in the negative feedback regulation of TSH secretion. A common variant of the gene, threonine (Thr) 92 alanine (Ala), has been identified and associated with decreased D2 enzymatic activity.

Objective: Our objective was to investigate whether this polymorphism predicts the T4 dosage needed to obtain target TSH levels in thyroidectomized patients.

Setting: Ambulatory patients were included in the study.

Patients: A total of 191 consecutive thyroid cancer patients, previously treated by near total thyroidectomy and radioiodine ablation, were studied. They were on stable T4 dose treatment aimed at obtaining either suppressed (supp) (n = 117, < 0.1 mU/liter) or near-supp (n = 74, ≥ 0.1 < 0.5 mU/liter) serum TSH levels.

Main Outcome Measures: DNA genotyping for D2 Thr92Ala variant and evaluation of T4 dose (μg/kg) needed to obtain target TSH levels were determined.

Results: Ala/Ala homozygous patients needed a higher T4 dose as compared with patients carrying the Thr92 variant (X/Thr patients) according to a recessive genetic model (2.08 ± 0.43 vs. 1.90 ± 0.35 μg/kg; P < 0.05). This difference was observable in the near-supp group (P = 0.002), but not in the supp group (P = 0.4).

Conclusions: D2 Thr92Ala polymorphism seems to predict the need for higher T4 intake in thyroidectomized patients. If this finding is confirmed in additional studies, it may predict the T4 requirement to suppress TSH on the basis of the individual genetic background.
The G53D Mutation in Kir6.2 (KCNJ11) Is Associated with Neonatal Diabetes and Motor Dysfunction in Adulthood that Is Improved with Sulfonylurea Therapy
Authors: Koster Joseph C. , Cadario Francesco , Peruzzi Cinzia , Colombo Carlo , Nichols Colin G. , Barbetti Fabrizio
Published: December 2007

Context: Mutations in the Kir6.2 subunit (KCNJ11) of the ATP-sensitive potassium channel (KATP) underlie neonatal diabetes mellitus. In severe cases, Kir6.2 mutations underlie developmental delay, epilepsy, and neonatal diabetes (DEND). All Kir6.2 mutations examined decrease the ATP inhibition of KATP, which is predicted to suppress electrical activity in neurons (peripheral and central), muscle, and pancreas. Inhibitory sulfonylureas (SUs) have been used successfully to treat diabetes in patients with activating Kir6.2 mutations. There are two reports of improved neurological features in SU-treated DEND patients but no report of such improvement in adulthood.

Objective: The objective of the study was to determine the molecular basis of intermediate DEND in a 27-yr-old patient with a KCNJ11 mutation (G53D) and the patient’s response to SU therapy.

Design: The G53D patient was transferred from insulin to gliclazide and then to glibenclamide over a 160-d period. Motor function was assessed throughout. Electrophysiology assessed the effect of the G53D mutation on KATP activity.

Results: The G53D patient demonstrated improved glycemic control and motor coordination with SU treatment, although glibenclamide was more effective than gliclazide. Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. G53D channels coexpressed with SUR1 (the pancreatic and neuronal isoform) exhibit high-affinity block by gliclazide but are insensitive to block when coexpressed with SUR2A (the skeletal muscle isoform). High-affinity block by glibenclamide is present in G53D channels coexpressed with either SUR1 or SUR2A.

Conclusion: The results demonstrate that SUs can resolve motor dysfunction in an adult with intermediate DEND and that this improvement is due to inhibition of the neuronal but not skeletal muscle KATP.
The Increasing Prevalence of Metabolic Syndrome among Finnish Men and Women over a Decade
Authors: Hu Gang , Lindström Jaana , Jousilahti Pekka , Peltonen Markku , Sjöberg Lena , Kaaja Risto , Sundvall Jouko , Tuomilehto Jaakko
Published: December 2007

Objective: Our objective was to assess a 10-yr change in the prevalence of the metabolic syndrome defined by the National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF) among Finnish men and women.

Design and Subjects: Two cross-sectional population surveys were performed in Finland in 1992 and 2002. A total of 3495 participants aged 45–64 yr were included in the analysis.

Results: In both years the metabolic syndrome was more common among men than women. In men the prevalence of the metabolic syndrome tended to increase slightly between 1992 and 2002, from 48.8–52.6% (P = 0.139) based on the NCEP definition, and from 51.4–55.6% based on the IDF definition (P = 0.102). In women the prevalence of the metabolic syndrome increased significantly from 32.2–39.1% based on the NCEP definition (P = 0.003), and from 38.0–45.3% based on the IDF definition (P = 0.002). In both sexes the prevalence of high blood pressure decreased, but the abnormalities in glucose metabolism increased between 1992 and 2002. The prevalence of central obesity increased in women between 1992 and 2002.

Conclusions: In Finland the prevalence of the metabolic syndrome, based both on the NCEP and IDF definitions, is higher in men than women. However, the increase in the prevalence of the metabolic syndrome, from 1992–2002, was significant only among women.
Thyroid Function and Lipid Subparticle Sizes in Patients with Short-Term Hypothyroidism and a Population-Based Cohort
Authors: Pearce Elizabeth N. , Wilson Peter W. F. , Yang Qiong , Vasan Ramachandran S. , Braverman Lewis E.
Published: December 2007

Context: Relations between thyroid function and lipids remain incompletely understood.

Objective: Our objective was to determine whether lipoprotein subparticle concentrations are associated with thyroid status.

Design and Setting: We conducted a prospective clinical study and cross-sectional cohort analysis at a university endocrine clinic and the Framingham Heart Study.

Subjects: Subjects included 28 thyroidectomized patients with short-term overt hypothyroidism and 2944 Framingham Offspring cohort participants.

Main Outcome Measures: Fasting subclass concentrations of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) particles were measured by nuclear magnetic resonance spectroscopy. TSH values were also measured.

Results: Total cholesterol and LDL-C were increased during short-term overt hypothyroidism. Large LDL subparticle concentrations increased during hypothyroidism (917 ± 294 vs. 491 ± 183 nmol/liter; P < 0.001), but more atherogenic small LDL was unchanged. Triglycerides marginally increased during hypothyroidism, small VLDL particles significantly increased (P < 0.001), whereas more atherogenic large VLDL was unchanged. Total HDL-C increased during hypothyroidism (76 ± 13 mg/dl vs. 58 ± 15 mg/dl; P < 0.001). There was no change in large HDL-C particle concentrations, whereas small (P < 0.001) and medium (P = 0.002) HDL-C particle concentrations decreased. Among Framingham women, adjusted total cholesterol and LDL-C were positively related to TSH categories (P ≤ 0.003). This was due to a positive correlation between adjusted large LDL subparticle concentrations and log-TSH (P < 0.0001); log small LDL subparticle concentrations decreased slightly as log-TSH increased (P = 0.045). Among Framingham men, the only significant association was a positive association between log-TSH and log large HDL subparticle concentrations (P = 0.04).

Conclusions: There is a shift toward less atherogenic large LDL, small VLDL, and large HDL subparticle sizes in hypothyroid women.
Protein Kinase A-Independent Inhibition of Proliferation and Induction of Apoptosis in Human Thyroid Cancer Cells by 8-Cl-Adenosine
Authors: Robinson-White Audrey J. , Hsiao Hui-Pin , Leitner Wolfgang W. , Greene Elizabeth , Bauer Andrew , Krett Nancy L. , Nesterova Maria , Stratakis Constantine A.
Published: December 2007

Purpose: Protein kinase A (PKA) affects cell proliferation in many cell types and is a potential target for cancer treatment. PKA activity is stimulated by cAMP and cAMP analogs. One such substance, 8-Cl-cAMP, and its metabolite 8-Cl-adenosine (8-Cl-ADO) are known inhibitors of cancer cell proliferation; however, their mechanism of action is controversial. We have investigated the antiproliferative effects of 8-Cl-cAMP and 8-CL-ADO on human thyroid cancer cells and determined PKA’s involvement.

Experimental Design: We employed proliferation and apoptosis assays and PKA activity and cell cycle analysis to understand the effect of 8-Cl-ADO and 8-Cl-cAMP on human thyroid cancer and HeLa cell lines.

Results: 8-Cl-ADO inhibited proliferation of all cells, an effect that lasted for at least 4 d. Proliferation was also inhibited by 8-Cl-cAMP, but this inhibition was reduced by 3-isobutyl-1-methylxanthine; both drugs stimulated apoptosis, and 3-isobutyl-1-methylxanthine drastically reduced 8-Cl-cAMP-induced cell death. 8-Cl-ADO induced cell accumulation in G1/S or G2/M cell cycle phases and differentially altered PKA activity and subunit levels. PKA stimulation or inhibition and adenosine receptor agonists or antagonists did not significantly affect proliferation.

Conclusions: 8-Cl-ADO and 8-Cl-cAMP inhibit proliferation, induce cell cycle phase accumulation, and stimulate apoptosis in thyroid cancer cells. The effect of 8-Cl-cAMP is likely due to its metabolite 8-Cl-ADO, and PKA does not appear to have direct involvement in the inhibition of proliferation by 8-Cl-ADO. 8-Cl-ADO may be a useful therapeutic agent to be explored in aggressive thyroid cancer.
Divine and Human Happiness inNicomachean Ethics
Authors: Bush Stephen S.
Published: December 2007

Nicomachean Ethics presents a puzzle as to whether Aristotle views morally virtuous activity as happiness, as book 1 seems to indicate, or philosophical contemplation as happiness, as book 10 seems to indicate. The most influential attempts to resolve this issue have been either monistic or inclusivist. According to the monists, happiness consists exclusively of contemplation. According to the inclusivists, contemplation is one constituent of happiness, but morally virtuous activity is another. In this essay I will examine influential defenses of monism. Finding these accounts superior to inclusivism, but still deficient, I will present and defend a dualistic account of happiness in which two different types of happiness, one divine and one human, are present in Nicomachean Ethics. When Aristotle commends contemplation as a happiness that humans can attain, he is careful to specify that this activity corresponds to a capacity (nous) that is not, properly speaking, human, even though humans can exercise it. Contemplation, the divine good, is the highest good that humans can obtain, but it is not the characteristic human good. The characteristic human good corresponds to the specifically and merely human function, which is an activity of the compound of human reason and emotions.
CIA Leaks
Authors: von Fintel Kai , Gillies Anthony S.
Published: December 2007

Epistemic modals are standardly taken to be context-dependent quantifiers over possibilities. Thus sentences containing them get truth-values with respect to both a context and an index. But some insist that this relativization is not relative enough: `might'-claims, they say, only get truth-values with respect to contexts, indices, and—the new wrinkle—points of assessment (hence, cia). Here we argue against such “relativist” semantics. We begin with a sketch of the motivation for such theories and a generic formulation of them. Then we catalogue central problems that any such theory faces. We end by outlining an alternative story.
Complex Demonstratives, QI Uses, and Direct Reference
Authors: King Jeffrey C.
Published: December 2007

Complex demonstratives (in the singular) are noun phrases that result from combining the determiners `this' or `that' with syntactically simple or complex common noun phrases such as `woman' or `woman who is taking her skis off'. Thus, `this woman', and `that woman who is taking her skis off' are complex demonstratives. There are also plural complex demonstratives such as `these skis' and `those snowboarders smoking by the gondola'.

My book Complex Demonstratives: A Quantificational Account argues against what I call the direct reference account of complex demonstratives (henceforth DRCD) and defends a quantificational account of complex demonstratives. In two recent papers, Nathan Salmon has criticized one of the book's arguments against DRCD. In this essay I show that Salmon's criticism fails. I also show that the version of DRCD that Salmon ends up endorsing is false.
Spectrin-anchored phosphodiesterase 4D4 restricts cAMP from disrupting microtubules and inducing endothelial cell gap formation
Authors: Creighton Judy , Zhu Bing , Alexeyev Mikhail , Stevens Troy
Published: December 2007

Dynamic cAMP fluctuations that are restricted to a sub-plasma-membrane domain strengthen endothelial barrier integrity. Phosphodiesterases (PDEs) localize within this domain where they limit cAMP diffusion into the bulk cytosolic compartment; however, the molecular identity of PDEs responsible for endothelial cell membrane cAMP compartmentation remain poorly understood. Our present findings reveal that the D4 splice variant of the PDE4 phosphodiesterase family – PDE4D4 – is expressed in pulmonary microvascular endothelial cells, and is found in plasma membrane fractions. PDE4D4 interacts with αII spectrin within this membrane domain. Although constitutive PDE4D4 activity limits cAMP access to the bulk cytosol, inhibiting its activity permits cAMP to access a cytosolic domain that is rich in microtubules, where it promotes protein kinase A (PKA) phosphorylation of tau at Ser214. Such phosphorylation reorganizes microtubules and induces interendothelial cell gap formation. Thus, spectrin-anchored PDE4D4 shapes the physiological response to cAMP by directing it to barrier-enhancing effectors while limiting PKA-mediated microtubule reorganization.
Conservation of the pro-apoptotic nuclease activity of endonuclease G in unicellular trypanosomatid parasites
Authors: Gannavaram Sreenivas , Vedvyas Chetan , Debrabant Alain
Published: December 2007

Endonuclease G is a mitochondrial protein implicated in DNA fragmentation during apoptosis in cell types ranging from fungi to mammals. Features of programmed cell death have been reported in a number of single-celled organisms, including the human trypanosomatid parasites Leishmania and Trypanosoma. However, the protozoan cell death pathways and the effector molecules involved in such processes remain to be identified. In this report, we describe the pro-apoptotic function of endonuclease G in trypanosomatid parasites. Similar to metazoans, trypanosome endoG showed intrinsic nuclease activity, is localized in mitochondria and is released from this organelle when cell death is triggered. Overexpression of endoG strongly promoted apoptotic cell death under oxidant or differentiation-related stress in Leishmania and, conversely, loss of endoG expression conferred robust resistance to oxidant-induced cell death in T. brucei. These data demonstrate the conservation of the pro-apoptotic endonuclease activity of endoG in these evolutionarily ancient eukaryotic organisms. Furthermore, nuclear DNA degradation by endoG upon release from mitochondria might represent a caspase-independent cell death mechanism in trypanosomatid parasites as genes encoding caspase-like proteins have not been identified in their genomes.
`Quantal' Ca2+ release at the cytoplasmic aspect of the Ins(1,4,5)P3R channel in smooth muscle
Authors: McCarron John G. , Chalmers Susan , Muir Thomas C.
Published: December 2007

Smooth muscle responds to activation of the inositol (1,4,5)-trisphosphate receptor [Ins(1,4,5)P3R] with a graded concentration-dependent (`quantal') Ca2+ release from the sarcoplasmic reticulum (SR) store. Graded release seems incompatible both with the finite capacity of the store and the Ca2+-induced Ca2+ release (CICR)-like facility, at Ins(1,4,5)P3Rs, that, once activated, should release the entire content of SR Ca2+. The structural organization of the SR and the regulation of Ins(1,4,5)P3R activity by inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] and Ca2+ have each been proposed to explain `quantal' Ca2+ release. Here, we propose that regulation of Ins(1,4,5)P3R activity by lumenal Ca2+ acting at the cytoplasmic aspect of the receptor might explain `quantal' Ca2+ release in smooth muscle. The entire SR store was found to be lumenally continuous and Ca2+ could diffuse freely throughout: peculiarities of SR structure are unlikely to account for `quantal' release. While Ca2+ release was regulated by [Ca2+] within the SR, the velocity of release increased (accelerated) during the release process. The extent of acceleration of release determined the peak cytoplasmic [Ca2+] and was attenuated by a reduction in SR [Ca2+] or an increase in cytoplasmic Ca2+ buffering. Positive feedback by released Ca2+ acting at the cytoplasmic aspect of Ins(1,4,5)P3Rs (i.e. CICR-like) might (a) account for the acceleration, (b) provide the regulation of release by SR [Ca2+] and (c) explain the `quantal' release process itself. During Ca2+ release, SR [Ca2+] and thus unitary Ins(1,4,5)P3R currents decline, CICR reduces and stops. With increasing [Ins(1,4,5)P3], coincidental activation of several neighbouring Ins(1,4,5)P3Rs offsets the reduced Ins(1,4,5)P3R current to renew CICR and Ca2+ release.
A Parallel Genetic Algorithm for the Multilevel Unconstrained Lot-Sizing Problem
Authors: Homberger Jörg
Published: December 2007

Acoarse-grained parallel genetic algorithm (PGA) for the multilevel unconstrained lot-sizing problem (MLULSP) is described and evaluated using 176 benchmark problems from the literature, with problem sizes varying from 5 to 500 products and with simulations ranging from 12 to 52 periods. The parallelization approach consists of concurrently executing several subpopulations (demes) of a genetic algorithm with the occasional migration of individuals between them. The migration is controlled by the migration model of Cantú-Paz [Cantú-Paz, E. 2001. Migration policies, selection pressure, and parallel evolutionary algorithms. J. Heuristics 7 311–334]. The genetic algorithm used is based on a new binary coding for the MLULSP. The PGA, which is the first application of a parallel metaheuristic to the MLULSP, is competitive with the best known solution methods. It was possible with the new method to calculate new best solutions for 34 of the benchmark problems. Furthermore, the migration enables a super-linear speedup. The results indicate that parallel genetic algorithms are suitable for solving large-problem instances of the MLULSP with acceptable computing times.
Leadership and Competition in Network Supply Chains
Authors: Majumder Pranab , Srinivasan Ashok
Published: December 2007

This paper considers network supply chains with price dependent demand by modelling them as large acyclic networks. Such large networks are common in the automobile and apparel industries. We develop a model to analyze the effect of these large-scale problems involving long sequences of contracts, and show that contract leadership, as well as leader position in the network, affect the performance of the entire supply chain. We generalize Spengler (Spengler, J. 1950. Vertical integration and anti-trust policy. J. Political Econom. 58 347–352) to a game on a “contract tree” for a particular supply chain and extend the concept of double marginalization so that it can be applied in the form of a transformation to each contract that is offered by one member to another in the “contract tree.” We construct an algorithm to find the equilibrium solution, and derive the optimal location of the leader (“optimal” being the leader location that maximizes total supply chain profits). Our work formalizes many intuitive insights; for example, member profits are determined by systemwide rather than individual costs. Finally, we model Cournot competition between competing supply chains (both two heterogeneous trees and multiple identical trees) and show the effect of changes in leader position as well as cost structure on the equilibrium.
Optimizing Call Center Staffing Using Simulation and Analytic Center Cutting-Plane Methods
Authors: Atlason Júlíus , Epelman Marina A. , Henderson Shane G.
Published: December 2007

We consider the problem of minimizing staffing costs in an inbound call center, while maintaining an acceptable level of service in multiple time periods. The problem is complicated by the fact that staffing level in one time period can affect the service levels in subsequent periods. Moreover, staff schedules typically take the form of shifts covering several periods. Interactions between staffing levels in different time periods, as well as the impact of shift requirements on the staffing levels and cost, should be considered in the planning. Traditional staffing methods based on stationary queueing formulas do not take this into account. We present a simulation-based analytic center cutting-plane method to solve a sample average approximation of the problem. We establish convergence of the method when the service-level functions are discrete pseudoconcave. An extensive numerical study of a moderately large call center shows that the method is robust and, in most of the test cases, outperforms traditional staffing heuristics that are based on analytical queueing methods.
Structural Properties of Buyback Contracts for Price-Setting Newsvendors
Authors: Song Yuyue , Ray Saibal , Li Shanling
Published: December 2007

This paper studies a buyback contract in the Stackelberg framework of a manufacturer (leader) selling to a price-setting newsvendor retailer (follower). Using an analytical model that focuses on a multiplicative demand form, we generalize previous results and produce new structural insights. A novel transformation technique first enables us to establish the unimodality of the profit functions for both channel partners, under relatively mild assumptions. Further analysis identifies the necessary and sufficient condition under which the optimal contract for the manufacturer (wholesale and buyback prices) is distribution free, i.e., independent of the uncertainty in customer demand. A specific instance of the above condition is also necessary and sufficient for a no-buyback contract to be optimal from the manufacturer's perspective. We then prove that the optimal performance of the decentralized channel for distribution-free buyback contracts depends only on the curvature of the deterministic demand part. In addition, some of the optimal decisions and relevant profit ratios for buyback contracts in our setting are shown to be identical to those for their deterministic price-only counterparts.
Maximum Profit Scheduling
Authors: Chen Zhi-Long , Hall Nicholas G.
Published: December 2007

The classical scheduling literature considers many problems where a given set of jobs must be processed at minimum cost, subject to various resource constraints. The literature only considers the issue of revenue generation in a very limited way, by allowing a job to remain unprocessed and its revenue contribution to be lost. By contrast, we consider three diverse practical situations where efficient scheduling affects revenue in much more general and realistic ways. First, we study two make-to-order environments where efficient scheduling increases customer goodwill, thus stimulating demand in different ways. Second, we study two make-to-stock environments where efficient scheduling creates inventory, thus also stimulating demand in different ways. Third, we study new product markets where efficient scheduling leads to a company becoming the first mover, and thus acquiring a larger market share. In each case, we provide both a computationally efficient algorithm for scheduling and a proof that a much more efficient algorithm is unlikely to exist. For both the make-to-stock and make-to-order problems, we also describe heuristic approaches that are easy to implement, and we study their average performance. The results show that substantial benefits arise from considering the implications of efficient scheduling for revenue and net profit. The practical impact of our work is to demonstrate the importance of efficient scheduling, not only in controlling cost, but also in increasing revenue and net profit.
OM Forum—Managing Customer Experiences: Perspectives on the Temporal Aspects of Service Encounters
Authors: Bitran Gabriel R. , Ferrer Juan-Carlos , Rocha e Oliveira Paulo
Published: December 2007

Aservice encounter is an experience that extends over time. Therefore, its effective management must include the control of the timing of the delivery of each of the service's elements and the enhancement of the customer's experience between and during the delivery of the various elements. This paper provides a conceptual framework that links the duration of a service encounter to behaviors that have been shown to affect profitability. Analysis of the framework reveals a wide gap between the behavioral assumptions typically made in operations research (OR) and operations management (OM) models and the state of the art in the marketing and psychology literature. The central motivations behind this paper are (1) to help the OR and OM community bridge this gap by bringing to its attention recent findings from the behavioral literature that have implications for the design of queueing systems for service firms and (2) to identify opportunities for further research.
Workforce Design with Movement Restrictions Between Workstation Groups
Authors: Bard Jonathan F. , Wan Lin
Published: December 2007

This paper is concerned with the problem of determining the optimal size and composition of a permanent workforce needed to run a facility when demand is specified by a workstation group (WSG) for up to 24 hours a day, 7 days a week. For full-time employees, a solution is characterized by a bid job, which consists of a five-day-a-week schedule, a lunch break for all shifts, and a set of WSG task assignments for each of the half-hour periods in a shift. In contrast, each part-time employee may be given anywhere from one to six shifts during the week, and each shift may vary from four to eight hours in length. To facilitate supervision, all employees must be assigned to a home WSG, but when idle time exists in their schedules, they can be redeployed to other WSGs for a portion of the day.

One of the complicating and unique factors addressed in this paper is the existence of nonsymmetric movement restrictions between WSGs. For example, an employee whose home base is A may be permitted to perform tasks at B, but not vice versa. Because the full problem could not be reduced to a single model, a multistage solution approach was developed. In the first stage, an extended shift-scheduling problem is solved to determine the optimal number of employees and their shifts. The results are postprocessed in subsequent stages to obtain lunch breaks, days off, and task assignments under WSG movement restrictions.

In the implementation of the multistage approach, two alternatives were explored. The first was based on the idea of partitioning the WSGs into manageable clusters and then solving them in series. The second involved the direct solution of an integer programming formulation of the task assignment problem with home-base restrictions and WSG movement restrictions, but for a fixed workforce. An iterative scheme was used to adjust the size of the workforce until all constraints were satisfied and overall optimality was achieved. Testing was done with data provided by the U.S. Postal Service (USPS) mail processing and distribution center (P&DC) in Dallas. The computations showed that the second alternative always yielded the smaller workforce and was always able to find good solutions within 30 minutes.
Data Set—Real-World Multiechelon Supply Chains Used for Inventory Optimization
Authors: Willems Sean P.
Published: December 2007

This data set describes 38 multiechelon supply chains that have been implemented in practice. These chains exhibit special structure that can be used to inform and test analytical models. Although the data were not collected with the intention of econometric analysis, they may be useful in an empirical study. The data described in this paper are publicly available at the journal's website (http://msom.pubs.informs.org/ecompanion.html).
Hyaline membrane disease of the neonate prolonged intubation in management: Effects on the larynx
Authors: Hawkins Donald B.
Published: December 2007

Hyaline membrane disease, an illness of premature neonates, is associated with 20–30% of all neonatal deaths and 50–70% of premature deaths in the United States. Often related to perinatal hypoxia, its basic pathophysiology consists of surfactant deficiency with diffuse atelectasis, and pulmonary hypoperfusion.

With expanding knowledge of hyaline membrane disease, methods of management evolved to the use of assisted ventilation with endotracheal tubes. One hundred twenty‐two surviving infants with hyaline membrane disease were intubated for periods of four to 112 days at the Los Angeles County‐USC Medical Center over a five‐year period. Their clinical courses, and effects of intubation on their larynges, are discussed.

Autopsy examination of 30 neonatal larynges after intubation revealed a high incidence of ulcerations within the cricoid area. The neonate's tolerance of intubation must be due to resiliency of its cricoid cartilage. Microscopic changes in cartilage with growth are demonstrated. With growth, cartilage matrix increases; it becomes less hydrated, more fibrous, and more rigid.

Neonates with normal larynges can tolerate long periods of intubation with polyvinyl chloride, uniform diameter, endotracheal tubes. With the use of principles successful in neonatal intubation, older patients can tolerate longer periods of intubation than was acceptable in earlier years; however, while intubation of neonates can be measured in weeks, in older patients it should still be measured in days.
Compound frontal sinus injuries with intracranial penetration
Authors: Donald Paul J. , Bernstein Leslie
Published: December 2007

Extensive trauma to the forehead, resulting in large penetrating wounds of the frontal sinus that extend into the frontal lobes of the brain, has traditionally been treated by frontal sinus ablation. Although this operation eliminates dead space, it leaves the patient with a depressed area in the forehead with little protection for the brain.

The success of Nadell and Kline in replacing skull fragments following compound depressed skull fractures yet avoiding infection has spurred us to attempt this technique in penetrating injuries of the frontal sinus. By preserving the anterior frontal sinus wall, we have not only afforded protection for the frontal lobes of the brain, but, at the same time, avoided the cosmetic defect that would be left by an ablation procedure.

This procedure has been performed on two patients at our institution. After a two‐year follow‐up, excellent forehead profile preservation has been achieved and there has been no evidence of bone absorption or infection at any time since surgery.
Place of total thyroidectomy in rhinolaryngologists' surgical treatment of thyroid disease
Authors: White Irving L.
Published: December 2007

Total thyroidectomy is more frequently performed and is becoming more widely accepted as the treatment of choice for more surgical diseases of the thyroid gland. Improvement in anesthesia, presurgical and postoperative care, as well as more meticulous surgical technique, have decreased the complications associated with this operation. As is demonstrated, morbidity and complications of total thyroidectomy are no more frequent nor severe than when subtotal thyroidectomy is performed. This allows boadening of the indications for total thyroidectomy to include more cases which will be better controlled, but for which total thyroidectomy had been withheld because of the fear of increased morbidity.