bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe Mandibuloacral Dysplasia-Associated Lipodystrophy and Progeria in a Young Girl with a Novel Homozygous Arg527Cys LMNA Mutation
Authors: Agarwal Anil K. , Kazachkova Irina , Ten Svetlana , Garg Abhimanyu
Published: September 2008

Context: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24).

Objective: The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy.

Design and Patient: The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3–7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts.

Results: LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase.

Conclusion: Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.
Selective Use of Bilateral Inferior Petrosal Sinus Sampling in Patients with Adrenocorticotropin-Dependent Cushing’s Syndrome Prior to Transsphenoidal Surgery
Authors: Jehle Sigrid , Walsh Jane E. , Freda Pamela U. , Post Kalmon D.
Published: September 2008

Context: Few data are available on the selective use of bilateral inferior petrosal sinus sampling (BIPSS) in the presurgical evaluation of patients with ACTH-dependent Cushing’s syndrome, so we investigated whether its use only in patients without a clear adenoma on magnetic resonance imaging and/or inconsistent biochemical testing affected remission and long-term outcome after surgery in patients with Cushing’s disease (CD).

Setting: This was a retrospective review of patients treated for CD by one pituitary neurosurgeon at tertiary medical centers in New York City.

Patients: A total of 193 consecutive adult patients who underwent initial transsphenoidal surgery (TS) for presumed CD between 1987 and 2005 were included.

Main Outcome Measures: We examined preoperative pituitary imaging and biochemical data, results of BIPSS and surgical pathology, and outcome based on biochemical tests after initial TS and long term after subsequent therapies.

Results: Remission rate after the first TS was 80.8% overall, 79.1% in the BIPSS group (n = 105), and 83.0% in the No-BIPSS group (n = 88). Recurrences occurred in 13.5% after the first TS at a mean of 4.8 ± 3.5 yr (range, 0.7–12.4 yr) with no difference between BIPSS and No-BIPSS groups. Long-term remission was achieved after surgeries and radiotherapy in 85% (86.7% of BIPSS group, 83.0% of No-BIPSS group). CD was ultimately confirmed in all but one patient in each group.

Conclusions: Selective use of BIPSS in the preoperative evaluation of patients with presumed CD did not lead to misdiagnosis in the No-BIPSS group or adversely affect remission rates or long-term outcome.
Novel Inactivating Mutations of the Calcium-Sensing Receptor: The Calcimimetic NPS R-568 Improves Signal Transduction of Mutant Receptors
Authors: Rus Ramona , Haag Christine , Bumke-Vogt Christiane , Bähr Volker , Mayr Bernhard , Möhlig Matthias , Schulze Egbert , Frank-Raue Karin , Raue Friedhelm , Schöfl Christof
Published: September 2008

Context and Objective: Inactivating mutations in the calcium-sensing receptor (CaSR) gene cause neonatal severe hyperparathyroidism and familial hypocalciuric hypercalcemia (FHH). The aims of the present study were the functional characterization of novel mutations of the CaSR found in FHH patients, the comparison of in vitro receptor function with clinical parameters, and the effect of the allosteric calcimimetic NPS R-568 on the signaling of mutant receptors.

Methods: Wild-type and mutant CaSRs (W530G, C568Y, W718X, M734R, L849P, Q926R, and D1005N) were expressed in human embryonic kidney 293 cells. Receptor signaling was studied by measuring intracellular free calcium in response to different concentrations of extracellular calcium ([Ca2+]o).

Results: Four CaSR mutations (C568Y, W718X, M734R, and L849P) demonstrated a complete lack of a [Ca2+]o-induced cytosolic Ca2+ response up to 30 mm [Ca2+]o, whereas the CaSR mutants W530G, Q926R, and D1005N retained some sensitivity to [Ca2+]o. There was no significant relation between the in vitro calcium sensitivity, serum calcium, and intact PTH levels in the patients. Patients with C-terminal CaSR mutations had a calcium to creatine ratio above the established diagnostic threshold of 0.01 for FHH. The calcimimetic NPS R-568 enhanced the responsiveness to [Ca2+]o in CaSR mutants of the extracellular domain (W530G and C568Y) as well as the intracellular C-terminal domain (Q926R and D1005N).

Conclusion: Therefore, calcimimetics might offer medical treatment for symptomatic FHH patients, and more important, for patients with neonatal severe hyperparathyroidism that harbor calcimimetic-sensitive CaSR mutants.
Breast Safety and Efficacy of Genistein Aglycone for Postmenopausal Bone Loss: A Follow-Up Study
Authors: Marini Herbert , Bitto Alessandra , Altavilla Domenica , Burnett Bruce P. , Polito Francesca , Di Stefano Vincenzo , Minutoli Letteria , Atteritano Marco , Levy Robert M. , D'Anna Rosario , Frisina Nicola , Mazzaferro Susanna , Cancellieri Francesco , Cannata Maria Letizia , Corrado Francesco , Frisina Alessia , Adamo Vincenzo , Lubrano Carla , Sansotta Carlo , Marini Rolando , Adamo Elena Bianca , Squadrito Francesco
Published: September 2008

Context: Genistein aglycone improves bone metabolism in women. However, questions about the long-term safety of genistein on breast as well as its continued efficacy still remain.

Objective: We assessed the continued safety profile of genistein aglycone on breast and endometrium and its effects on bone after 3 yr of therapy.

Design: The parent study was a randomized, double-blind, placebo-controlled trial involving 389 osteopenic, postmenopausal women for 24-months. Subsequently, a subcohort (138 patients) continued therapy for an additional year.

Patients and Interventions: Participants received 54 mg of genistein aglycone daily (n = 71) or placebo (n = 67). Both treatment arms received calcium and vitamin D3 in therapeutic doses.

Main Outcomes: Mammographic density was assessed at baseline, 24 and 36 months by visual classification scale and digitized quantification. BRCA1 and BRCA2, sister chromatid exchange, and endometrial thickness were also evaluated. Lumbar spine and femoral neck bone mineral density were also assessed. Secondary outcomes were biochemical levels of bone markers.

Results: After 36 months, genistein did not significantly change mammographic breast density or endometrial thickness, BRCA1 and BRCA2 expression was preserved, whereas sister chromatid exchange was reduced compared with placebo. Bone mineral density increases were greater with genistein for both femoral neck and lumbar spine compared to placebo. Genistein also significantly reduced pyridinoline, as well as serum carboxy-terminal cross-linking telopeptide and soluble receptor activator of NF-κB ligand while increasing bone-specific alkaline phosphatase, IGF-I, and osteoprotegerin levels. There were no differences in discomfort or adverse events between groups.

Conclusions: After 3 yr of treatment, genistein exhibited a promising safety profile with positive effects on bone formation in a cohort of osteopenic, postmenopausal women.
Insulin-Like Growth Factor Binding Protein 1 as a Novel Specific Marker of Hepatic Insulin Sensitivity
Authors: Kotronen Anna , Lewitt Moira , Hall Kerstin , Brismar Kerstin , Yki-Järvinen Hannele
Published: September 2008

Background and Aims: The liver is the main source and insulin the main regulator of IGF binding protein 1 (IGFBP-1) in humans. Here we examined how serum IGFBP-1 concentrations are related to directly measured hepatic insulin sensitivity and liver fat content in humans.

Methods: We measured fasting serum (fS) IGFBP-1 concentrations and liver fat content by proton magnetic resonance spectroscopy in 113 nondiabetic subjects. In addition, hepatic insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp (insulin 0.3 mU/kg·min) technique in combination with the infusion of [3-(3)H]glucose in 78 subjects.

Results: fS-IGFBP-1 concentrations were inversely related to liver fat content (r = −0.38, P < 0.0001). Of circulating parameters, fS-IGFBP-1 was better correlated to hepatic insulin sensitivity (r = 0.48, P < 0.0001) than fS-insulin (r = −0.42, P = 0.0001), fS-C-peptide (r = −0.41, P = 0.0002), fS-triglyceride (r = −0.33, P = 0.003), or fS-high-density lipoprotein cholesterol (r = 0.30, P = 0.007). In multiple linear regression analyses, body mass index (P < 0.0001) and fS-IGFBP-1 (P = 0.008), but neither age nor gender, were independently associated with hepatic insulin sensitivity (P < 0.0001 for ANOVA). Neither fS-insulin nor fS-C-peptide were independent determinants of hepatic insulin sensitivity after adjusting for age, gender, and body mass index.

Conclusions: fS-IGFBP-1 is inversely correlated with liver fat and is an obesity-independent and liver-specific circulating marker of hepatic insulin sensitivity.
Cross-Subsidies and Payment for Hospital Care
Authors: Sloan Frank A. , Becker Edmund R.
Published: September 2008

This study uses hospital data from the 1979 American Hospital Association Reimbursement Survey in a multivariate framework to assess the impact of discounts and third-party reimbursement on hospital costs and profitability. Three central issues are addressed: (1) Is a differential payment justified for Medicare, Medicaid, and/or Blue Cross on the basis of differential costs? (2) Have the cost-containment efforts of the dominant payers reduced total payments to hospitals? and (3) What part of the overall savings in payments to hospitals is in the form of reduced costs rather than reduced profits? On the basis of the evidence in this study, we find (1) that the differential payment is not justified; (2) that the cost-containment efforts of the dominant payers have reduced total payments to hospitals somewhat, but a substantial amount of cost-shifting remains; and (3) that the savings is in profits, rather than in costs.
Congressional Voting Behavior on Hospital Legislation: An Exploratory Study
Authors: Feldstein Paul J. , Melnick Glenn
Published: September 2008

This paper analyzes Congressional voting behavior on the Gephardt Amendment to President Carter's hospital cost containment legislation. The impact of opposing interest groups is examined: on one side were hospital and medical interest groups; on the other was the Carter Administration and its political party, as well as states with large Medicaid expenditures. The effect of political contributions from MEDPACs is evaluated, and the relative importance of various factors affecting the vote's outcome is analyzed.
The Growth of Technology and Corporate Profit-Making in the Clinical Laboratories
Authors: Levitt Jane
Published: September 2008

This article examines private industry's involvement in the area of clinical laboratory testing, as an example of the relationship between the increased cost of medical care and increased involvement of private industry in the health care sector. After tracing the history of corporate and technological development in the clinical laboratory field, and particularly in the area of blood chemistry analysis, the article suggests some implications for public policy of the current state of affairs.
HMO Enrollment: A Study of Market Forces and Regulations
Authors: Welch W. P.
Published: September 2008

This paper investigates the influence of market forces and state regulations on enrollment in prepaid group practices (PGPs)—the dominant form of HMO. Using data at the metropolitan-area level, the paper estimates a lagged-adjustment model in two stages. The first stage estimates the determinants of the existence of a PGP of viable size. Using a technique appropriate for censored samples, the second stage estimates the determinants of enrollment given viability. The result of greatest relevance for policymakers is that restrictions on corporate employment of physicians hinder the growth of PGPs.
The Forgotten Fear of Excrement
Authors: Kuriyama Shigehisa
Published: September 2008

Many patients in Europe and America today think it perfectly plausible that a cure for their insomnia or headaches, say, might be found in the Yellow Emperor's Classic of Medicine of Han dynasty China, that approaches to the body conceived in a distant culture, more than two thousand years ago, might solve their suffering here and now. Yet they wouldn't dream of seeking succor in the works of Galen. Why? How have the beliefs and practices that guided Western medicine up through the eighteenth century come to seem, paradoxically, more alien and distant than ancient Chinese notions of qi? To understand this strange forgetfulness about the Western past, we must linger on a defining feature of traditional humoralism, often slighted in modern synopses: the haunting fear of excrement.
Place, Health, and Disease: The Airs, Waters, Places Tradition in Early Modern England and North America
Authors: Wear Andrew
Published: September 2008

In the early modern era, physical place, health, and disease were integrally linked in a geographical and climatological theory of the environment. The Hippocratic treatise Airs, Waters, Places served as a template for viewing the relationships between places, health, disease, and the physical and mental constitutional nature of people and nations up to the early twentieth century. Central to this conception of the body and its environment is the perception of causal connections between a place, including its climate, season, water, and food, and the people born into it. This essay discusses some of the characteristics of the Airs, Waters, Places tradition and the way this conception of nature was embedded, especially in the discourse of colonial settlement, in the early modern period and beyond.
Stories of Disease Written by Patients and Lay Mediators in the Spanish Republic of Letters (1680–1720)
Authors: Pardo-Tomás José , Martínez-Vidal Àlvar
Published: September 2008

Consultation by mail had been common in medical practice more or less since the time of its consolidation in Europe in the twelfth and thirteenth centuries, but this mode of communication vastly expanded in the seventeenth and eighteenth centuries. Analyzing a group of letters sent to the Spanish court physician Juan Muñoz y Peralta (1665–1746) by his patients, this article shows how these patients, far from being passive, were actively involved in elaborating medical knowledge and in making decisions about therapeutic strategies for their own treatment. Our main aim is to focus attention on these nonprofessional voices, on the words of patients themselves or those who, like them, were not trained in medicine. Approaching our subject through this interpretative framework, we provide an example of medical-cultural analysis that documents voices belonging to patients who were active in considering, interpreting, and treating disease in an effort to have control over their own bodies. Their voices should be taken into account when writing a cultural history of early modern medicine.
The Body Debated: Bodies and Rights in Seventeenth and Eighteenth-Century Germany
Authors: Lindemann Mary
Published: September 2008

Scholars of medical history have discovered that the notion of “monstrous births” presented challenging legal issues in the early modern world. Were such offspring–often conjoined twins– “monsters” in the civil sense? Were they, for example, able to make a will, inherit, contract, and perform other civil actions? While the question of the “civil rights” of conjoined twins in the early modern period usually remained truly academic (as few such births survived), a whole series of other conditions–some unusual, some very common–raised similar medico-legal issues. Pregnancy, mental retardation, epilepsy, deformity, disputed sexuality (hermaphroditism, intersexuality, or castration), deafness, blindness, and even more fleeting circumstances such as fever, could call into question an individual's ability to perform normal legal actions or to be allowed to inherit an estate, serve as a guardian, or give testimony in court. This article examines how competence imperatives worked out in quotidian practice. While there are numerous points at which a “body” became problematic (in a medico-legal sense), this study uses two particular situations–baptism and marriage–to probe how practices were shaped not only by “experts” (physicians, theologians, and jurists) but also by what may be called local knowledge.
Leprosy in the Medieval Imaginary
Authors: Zimmerman Susan
Published: September 2008

The derogation of leprosy in medieval culture was disproportionate to its medical threat, presumably influenced by the spectacle of a disintegrative process akin to putrefaction. In the medieval imaginary, leprous blood was linked to menstrual blood, supposedly discharged by both impure women and Jewish men, and believed to be a carrier of the disease. The perceived threat of leprous blood to Christian bodily integrity was played out in atropaic social rituals and in widespread defamations against lepers, women, and Jews as devourers or cannibals. This study claims that such practices worked to displace fundamental anxieties generated by the “sacramental cannibalism” of the eucharistic feast, in which the body and blood of Christ were fused with those of communicants through the process of ingestion. The medieval counternarrative mythologizing lepers, women, and Jews as would-be devourers served to insulate the sacramental status of the Eucharist, to distinguish pure from impure blood, and to displace the archaic fear of physical obliteration. However, of the three demonized groups it was the leper alone who was subject to a kind of double jeopardy: as a visible emblem of the instability of bodily boundaries, the leper served as both agent and illustration of the fearsomeness of physical dissolution.
Integrin-linked kinase – essential roles in physiology and cancer biology
Authors: McDonald Paul C. , Fielding Andrew B. , Dedhar Shoukat
Published: September 2008

Integrin-linked kinase (ILK) is a multifunctional intracellular effector of cell-matrix interactions and regulates many cellular processes, including growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. The use of recently developed Cre-lox-driven recombination and RNA-interference technologies has enabled the evaluation of the physiological roles of ILK in several major organ systems. Significant developmental and tissue-homeostasis defects occur when the gene that encodes ILK is deleted, whereas the expression of ILK is often elevated in human malignancies. Although the cause(s) of ILK overexpression remain to be fully elucidated, accumulating evidence suggests that its oncogenic capacity derives from its regulation of several downstream targets that provide cells with signals that promote proliferation, survival and migration, supporting the concept that ILK is a relevant therapeutic target in human cancer. Furthermore, a global analysis of the ILK `interactome' has yielded several novel interactions, and has revealed exciting and unexpected cellular functions of ILK that might have important implications for the development of effective therapeutic agents.
Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells
Authors: Kokudo Takashi , Suzuki Yuka , Yoshimatsu Yasuhiro , Yamazaki Tomoko , Watabe Tetsuro , Miyazono Kohei
Published: September 2008

Epithelial-mesenchymal transition (EMT) plays important roles in various physiological and pathological processes, and is regulated by signaling pathways mediated by cytokines, including transforming growth factor β (TGFβ). Embryonic endothelial cells also undergo differentiation into mesenchymal cells during heart valve formation and aortic maturation. However, the molecular mechanisms that regulate such endothelial-mesenchymal transition (EndMT) remain to be elucidated. Here we show that TGFβ plays important roles during mural differentiation of mouse embryonic stem cell-derived endothelial cells (MESECs). TGFβ2 induced the differentiation of MESECs into mural cells, with a decrease in the expression of the endothelial marker claudin 5, and an increase in expression of the mural markers smooth muscle α-actin, SM22α and calponin, whereas a TGFβ type I receptor kinase inhibitor inhibited EndMT. Among the transcription factors involved in EMT, Snail was induced by TGFβ2 in MESECs. Tetracycline-regulated expression of Snail induced the differentiation of MESECs into mural cells, whereas knockdown of Snail expression abrogated TGFβ2-induced mural differentiation of MESECs. These results indicate that Snail mediates the actions of endogenous TGFβ signals that induce EndMT.
Loss of ATAC-specific acetylation of histone H4 at Lys12 reduces binding of JIL-1 to chromatin and phosphorylation of histone H3 at Ser10
Authors: Ciurciu Anita , Komonyi Orban , Boros Imre M.
Published: September 2008

Various combinations of post-translational modifications of the N-terminal tails of nucleosomal histones serve as signals to govern chromatin-related processes. The relationship, however, among different types of histone modifications – most frequently acetylation, phosphorylation and methylation – and the order of their establishment has been explored only in a few cases. Here we show that a reduced level of histone H4 acetylated at Lys12 by the ATAC-HAT complex leads to a decrease in the histone H3 phosphorylation at Ser10 by the kinase JIL-1. As JIL-1 activity antagonizes histone H3 dimethylation at Lys9 by SU(VAR)3-9, our observations demonstrate the interdependent actions of an acetyltransferase, a kinase and a methyltransferase. We demonstrate that, in accord with the steps of modifications, mutations that affect ATAC subunits (such as dGcn5, dAda2a and dAda3) (1) decrease the level histone H3 phosphorylation at Ser10, (2) can be rescued partially by JIL-1 overproduction, (3) enhance the spread of histone H3 dimethylation at Lys9 and (4) are suppressed by mutations of Su(var)3-9. We propose that a reduced level of histone H4 acetylated at Lys12 by ATAC attenuates histone H3 phosphorylation at Ser10 by JIL-1 owing to reduced binding of JIL-1 to hypoacetylated chromatin.
TM9SF4 is required forDrosophilacellular immunity via cell adhesion and phagocytosis
Authors: Bergeret Evelyne , Perrin Jackie , Williams Michael , Grunwald Didier , Engel Elodie , Thevenon Dominique , Taillebourg Emmanuel , Bruckert Franz , Cosson Pierre , Fauvarque Marie-Odile
Published: September 2008

Nonaspanins are characterised by a large N-terminal extracellular domain and nine putative transmembrane domains. This evolutionarily conserved family comprises three members in Dictyostelium discoideum (Phg1A, Phg1B and Phg1C) and Drosophila melanogaster, and four in mammals (TM9SF1-TM9SF4), the function of which is essentially unknown. Genetic studies in Dictyostelium demonstrated that Phg1A is required for cell adhesion and phagocytosis. We created Phg1A/TM9SF4-null mutant flies and showed that they were sensitive to pathogenic Gram-negative, but not Gram-positive, bacteria. This increased sensitivity was not due to impaired Toll or Imd signalling, but rather to a defective cellular immune response. TM9SF4-null larval macrophages phagocytosed Gram-negative E. coli inefficiently, although Gram-positive S. aureus were phagocytosed normally. Mutant larvae also had a decreased wasp egg encapsulation rate, a process requiring haemocyte-dependent adhesion to parasitoids. Defective cellular immunity was coupled to morphological and adhesion defects in mutant larval haemocytes, which had an abnormal actin cytoskeleton. TM9SF4, and its closest paralogue TM9SF2, were both required for bacterial internalisation in S2 cells, where they displayed partial redundancy. Our study highlights the contribution of phagocytes to host defence in an organism possessing a complex innate immune response and suggests an evolutionarily conserved function of TM9SF4 in eukaryotic phagocytes.
Zinc as a translation regulator in neurons: implications for P-body aggregation
Authors: Blumenthal Jacob , Ginzburg Irith
Published: September 2008

Post-transcriptional mechanisms of gene expression in neuronal cells include mRNA transport and local protein synthesis, which play a vital role in the control of polarity, synaptic plasticity and growth cone motility. RNA-binding proteins, which form the transported ribonucleoparticle (RNP), control mRNA stability and local translation. Recently, the existence of processing bodies (P-bodies), in which mRNA decapping and degradation take place, was revealed in neurons. It was suggested that P-bodies serve as a transient storage compartment for mRNAs, which can be released and, upon stimulation, resume translation. In this study, we focused on the localization of the Dcp1a protein, which serves as a P-body marker, in PC12 growth cones and P19 neuronal cells and its association with the tau mRNA-binding protein HuD. We found that stimulation of neurons by zinc, which is stored and released from synaptic vesicles, caused a disruption of polysomes into monosomes, whereas HuD protein distribution in sucrose gradient fractions remained unaffected. In addition, zinc application caused an aggregation of Dcp1a protein in an RNA-dependent manner. These findings suggest a role for zinc in translation regulation via disruption of polysomes, aggregation of P-bodies in neurons and impairment of the RNP-polysome interaction.
Cyclin E-dependent localization of MCM5 regulates centrosome duplication
Authors: Ferguson Rebecca L. , Maller James L.
Published: September 2008

Centrosomes are the primary microtubule-organizing centers in animal cells and are required for bipolar spindle assembly during mitosis. Amplification of centrosome number is commonly observed in human cancer cells and might contribute to genomic instability. Cyclin E–Cdk2 has been implicated in regulating centrosome duplication both in Xenopus embryos and extracts and in mammalian cells. Localization of cyclin E on centrosomes is mediated by a 20-amino acid domain termed the centrosomal localization sequence (CLS). In this paper, cyclin E is shown to directly interact with and colocalize on centrosomes with the DNA replication factor MCM5 in a CLS-dependent but Cdk2-independent manner. The domain in MCM5 that is responsible for interaction with cyclin E is distinct from any previously described for MCM5 function and is highly conserved in MCM5 proteins from yeast to mammals. Expression of MCM5 or its cyclin E-interacting domain, but not MCM2, significantly inhibits over-duplication of centrosomes in CHO cells arrested in S-phase. These results indicate that proteins involved in DNA replication might also regulate centrosome duplication.
STRA8-deficient spermatocytes initiate, but fail to complete, meiosis and undergo premature chromosome condensation
Authors: Mark Manuel , Jacobs Hugues , Oulad-Abdelghani Mustapha , Dennefeld Christine , Féret Betty , Vernet Nadège , Codreanu Carmen-Alina , Chambon Pierre , Ghyselinck Norbert B.
Published: September 2008

We analysed the phenotypic outcome of a Stra8-null mutation on male meiosis. Because the mutant spermatocytes (1) underwent premeiotic DNA replication, (2) displayed cytological features attesting initiation of recombination and of axial-element assembly, and (3) expressed Spo11 and numerous other meiotic genes, it was concluded that STRA8 is dispensable for meiotic initiation. The few mutant spermatocytes that progressed beyond leptonema showed a prolonged bouquet-stage configuration, asynapsis and heterosynapsis, suggesting function(s) of STRA8 in chromosome pairing. Most importantly, a large number of mutant leptotene spermatocytes underwent premature chromosome condensation, within 24 hours following the meiotic S phase. This phenomenon yielded aberrant metaphase-like cells with 40 univalent chromosomes, similar to normal mitotic metaphases. From these latter observations and from the wild-type pattern of Stra8 expression, we propose that, in preleptotene spermatocytes, STRA8 is involved in the process that leads to stable commitment to the meiotic cell cycle.
The molecular logic of Notch signaling – a structural and biochemical perspective
Authors: Gordon Wendy R. , Arnett Kelly L. , Blacklow Stephen C.
Published: September 2008

The Notch signaling pathway constitutes an ancient and conserved mechanism for cell-cell communication in metazoan organisms, and has a central role both in development and in adult tissue homeostasis. Here, we summarize structural and biochemical advances that contribute new insights into three central facets of canonical Notch signal transduction: (1) ligand recognition, (2) autoinhibition and the switch from protease resistance to protease sensitivity, and (3) the mechanism of nuclear-complex assembly and the induction of target-gene transcription. These advances set the stage for future mechanistic studies investigating ligand-dependent activation of Notch receptors, and serve as a foundation for the development of mechanism-based inhibitors of signaling in the treatment of cancer and other diseases.
Overexpressed mitochondrial leucyl-tRNA synthetase suppresses the A3243G mutation in the mitochondrial tRNALeu(UUR) gene
Authors: Park Hyejeong , Davidson Edgar , King Michael P.
Published: September 2008

The A3243G mutation in the human mitochondrial tRNALeu(UUR) gene causes a number of human diseases. This mutation reduces the level and fraction of aminoacylated tRNALeu(UUR) and eliminates nucleotide modification at the wobble position of the anticodon. These deficiencies are associated with mitochondrial translation defects that result in decreased levels of mitochondrial translation products and respiratory chain enzyme activities. We have suppressed the respiratory chain defects in A3243G mutant cells by overexpressing human mitochondrial leucyl-tRNA synthetase. The rates of oxygen consumption in suppressed cells were directly proportional to the levels of leucyl-tRNA synthetase. Fifteenfold higher levels of leucyl-tRNA synthetase resulted in wild-type respiratory chain function. The suppressed cells had increased steady-state levels of tRNALeu(UUR) and up to threefold higher steady-state levels of mitochondrial translation products, but did not have rates of protein synthesis above those in parental mutant cells. These data suggest that suppression of the A3243G mutation occurred by increasing protein stability. This suppression of a tRNA gene mutation by increasing the steady-state levels of its cognate aminoacyl-tRNA synthetase is a model for potential therapies for human pathogenic tRNA mutations.
Value-of-Information Analysis for Nuclear Waste Storage Tanks
Authors: Eppel Thomas , von Winterfeldt Detlof
Published: September 2008

This article describes an application of a value-of-information (VOI) analysis to a problem involving information collection and sampling costs of millions of dollars and ultimate consequences of decisions ranging in the hundreds of millions of dollars. The context of this VOI analysis was the determination of the chemical and radiological composition of nuclear waste in 177 storage tanks at the Department of Energy's (DOE) Hanford Site in southeastern Washington State. These tanks include different types of waste and knowing their composition affects important decisions about how to treat these wastes for purposes of processing, stabilization, and ultimate storage. This analysis was conducted as part of a larger “proof-in-principle” study of how VOI concepts could be used to improve the collection of data for the purpose of identifying the composition of nuclear tank wastes and for subsequent decisions about tank-waste management. The analysis showed that a VOI analysis can be very useful and it can also provide specific guidance on the problem at hand. In particular, the analysis showed that it was worth while to collect additional information for only four of 15 tanks in question and eventually, the DOE decided to act on these tanks without the additional information. At the same time the DOE decided to focus on another set of tanks, which involved more imminent risks of flammable gas explosions and focused its effort on collecting information and stabilizing these tanks.
Promised Lead-Time Contracts Under Asymmetric Information
Authors: Lutze Holly , Özer Özalp
Published: September 2008

We study the important problem of how a supplier should optimally share the consequences of demand uncertainty (i.e., the cost of inventory excesses and shortages) with a retailer in a two-level supply chain facing a finite planning horizon. In particular, we characterize a multiperiod contract form, the promised lead-time contract, that reduces the supplier's risk from demand uncertainty and the retailer's risk from uncertain inventory availability. Under the contract terms, the supplier guarantees on-time delivery of complete orders of any size after the promised lead time. We characterize the optimal promised lead time and the corresponding payments that the supplier should offer to minimize her expected inventory cost, while ensuring the retailer's participation. In such a supply chain, the retailer often holds private information about his shortage cost (or his service level to end customers). Hence, to understand the impact of the promised lead-time contract on the supplier's and the retailer's performance, we study the system under local control with full information and local control with asymmetric information. By comparing the results under these information scenarios to those under a centrally controlled system, we provide insights into stock positioning and inventory risk sharing. We quantify, for example, how much and when the supplier and the retailer overinvest in inventory as compared to the centrally controlled supply chain. We show that the supplier faces more inventory risk when the retailer has private service-level information. We also show that a supplier located closer to the retailer is affected less by information asymmetry. Next, we characterize when the supplier should optimally choose not to sign a promised lead-time contract and consider doing business under other settings. In particular, we establish the optimality of a cutoff level policy. Finally, under both full and asymmetric service-level information, we characterize conditions when optimal promised lead times take extreme values of the feasible set, yielding the supplier to assume all or none of the inventory risk—hence the name all-or-nothing solution. We conclude with numerical examples demonstrating our results.
Optimal Joint Inventory and Transshipment Control Under Uncertain Capacity
Authors: Hu Xinxin , Duenyas Izak , Kapuscinski Roman
Published: September 2008

In this paper, we address the optimal joint control of inventory and transshipment for a firm that produces in two locations and faces capacity uncertainty. Capacity uncertainty (e.g., due to downtime, quality problems, yield, etc.) is a common feature of many production systems, but its effects have not been explored in the context of a firm that has multiple production facilities. We first characterize the optimal production and transshipment policies and show that uncertain capacity leads the firm to ration the inventory that is available for transshipment to the other location and characterize the structure of this rationing policy. Then, we characterize the optimal production policies at both locations, which are defined by state-dependent produce-up-to thresholds. We also describe sensitivity of the optimal production and transshipment policies to problem parameters and, in particular, explain how uncertain capacity can lead to counterintuitive behavior, such as produce-up-to limits decreasing for locations that face stochastically higher demand. We finally explore, through a numerical study, when the optimal policy is most likely to yield significant benefits compared to simple policies.
The Pseudoflow Algorithm: A New Algorithm for the Maximum-Flow Problem
Authors: Hochbaum Dorit S.
Published: September 2008

We introduce the pseudoflow algorithm for the maximum-flow problem that employs only pseudoflows and does not generate flows explicitly. The algorithm solves directly a problem equivalent to the minimum-cut problem—the maximum blocking-cut problem. Once the maximum blocking-cut solution is available, the additional complexity required to find the respective maximum-flow is O(m log n). A variant of the algorithm is a new parametric maximum-flow algorithm generating all breakpoints in the same complexity required to solve the constant capacities maximum-flow problem. The pseudoflow algorithm has also a simplex variant, pseudoflow-simplex, that can be implemented to solve the maximum-flow problem. One feature of the pseudoflow algorithm is that it can initialize with any pseudoflow. This feature allows it to reach an optimal solution quickly when the initial pseudoflow is “close” to an optimal solution. The complexities of the pseudoflow algorithm, the pseudoflow-simplex, and the parametric variants of pseudoflow and pseudoflow-simplex algorithms are all O(mn log n) on a graph with n nodes and m arcs. Therefore, the pseudoflow-simplex algorithm is the fastest simplex algorithm known for the parametric maximum-flow problem. The pseudoflow algorithm is also shown to solve the maximum-flow problem on s, t-tree networks in linear time, where s, t-tree networks are formed by joining a forest of capacitated arcs, with nodes s and t adjacent to any subset of the nodes.
Multitask and Multistage Production Planning and Scheduling for Process Industries
Authors: Gaglioppa Francesco , Miller Lisa A. , Benjaafar Saif
Published: September 2008

We consider the planning and scheduling of production in a multitask/multistage batch manufacturing process typical of industries such as chemical manufacturing, food processing, and oil refining. We allow instances in which multiple sequences of tasks may be used to produce end products. We formulate the problem as a mixed-integer linear program and show that the linear programming relaxation has a large integrality gap and requires significant computational effort to solve to optimality for large instances. Using echelon inventory, we construct a new family of valid inequalities for this problem. The formulation with the additional constraints leads to a significantly tighter linear programming relaxation and to greatly reduced solution times for the mixed-integer linear program.
Service Competition with General Queueing Facilities
Authors: Allon Gad , Federgruen Awi
Published: September 2008

In many service industries, companies compete with each other on the basis of the waiting time their customers experience, along with the price they charge for their service. A firm's waiting-time standard may either be defined in terms of the expected value or a given, for example 95%, percentile of the steady state waiting-time distribution. We investigate how a service industry's competitive behavior depends on the characteristics of the service providers' queueing systems. We provide a unifying approach to investigate various standard single-stage systems covering the spectrum from M/M/1 to general G/GI/s systems, along with open Jackson networks to represent multistage service systems. Assuming that the capacity cost is proportional with the service rates, we refer to its dependence on (i) the firm's demand rate, and (ii) the waiting-time standard as the capacity cost function. We show that across the above broad spectrum of queueing models, the capacity cost function belongs to a specific four-parameter class of function, either exactly or as a close approximation. We then characterize how this capacity cost function impacts the equilibrium behavior in the industry. We give separate treatments to the case where the firms compete in terms of (i) prices (only), (ii) their service level or waiting-time standard (only), and (iii) simultaneously in terms of both prices and service levels. The firms' demand rates are given by a general system of equations of the prices and waiting-time standards in the industry.
Note: A Simple Heuristic for Serial Inventory Systems with Fixed Order Costs
Authors: Shang Kevin H.
Published: September 2008

We propose a heuristic for finding base order quantities for stochastic inventory models. The heuristic includes two steps. The first clusters the stages according to cost parameters. The second solves a single-stage problem for each cluster with the original problem data. In a numerical study, we show that the heuristic is near optimal.
An Exact Approach to the One-Dimensional Facility Layout Problem
Authors: Amaral André R. S.
Published: September 2008

The one-dimensional facility layout problem is concerned with arranging n departments of given lengths on a line, while minimizing the weighted sum of the distances between all pairs of departments. The problem is NP-hard because it is a generalization of the minimum linear arrangement problem. In this paper, a 0-1 quadratic programming model consisting of only O(n2) 0-1 variables is proposed for the problem. Subsequently, this model is cast as an equivalent mixed-integer program and then reduced by preprocessing. Next, additional redundant constraints are introduced and linearized in a higher space to achieve an equivalent mixed 0-1 linear program, whose continuous relaxation provides an approximation of the convex hull of solutions to the quadratic program. It is shown that the resulting mixed 0-1 linear program is more efficient than previously published mixed-integer formulations. In the computational results, several problem instances taken from the literature were efficiently solved to optimality. Moreover, it is now possible to efficiently solve problems of a larger size.
Selecting a Portfolio of Suppliers Under Demand and Supply Risks
Authors: Federgruen Awi , Yang Nan
Published: September 2008

We analyze a planning model for a firm or public organization that needs to cover uncertain demand for a given item by procuring supplies from multiple sources. Each source faces a random yield factor with a general probability distribution. The model considers a single demand season. All supplies need to be ordered before the start of the season. The planning problem amounts to selecting which of the given set of suppliers to retain, and how much to order from each, so as to minimize total procurement costs while ensuring that the uncertain demand is met with a given probability. The total procurement costs consist of variable costs that are proportional to the total quantity delivered by the suppliers, and a fixed cost for each participating supplier, incurred irrespective of his supply level. Each potential supplier is characterized by a given fixed cost and a given distribution of his random yield factor. The yield factors at different suppliers are assumed to be independent of the season's demand, which is described by a general probability distribution.

Determining the optimal set of suppliers, the aggregate order and its allocation among the suppliers, on the basis of the exact shortfall probability, is prohibitively difficult. We have therefore developed two approximations for the shortfall probability. Although both approximations are shown to be highly accurate, the first, based on a large-deviations technique (LDT), has the advantage of resulting in a rigorous upper bound for the required total order and associated costs. The second approximation is based on a central limit theorem (CLT) and is shown to be asymptotically accurate, whereas the order quantities determined by this method are asymptotically optimal as the number of suppliers grows. Most importantly, this CLT-based approximation permits many important qualitative insights.
Now or Later: A Simple Policy for Effective Dual Sourcing in Capacitated Systems
Authors: Veeraraghavan Senthil , Scheller-Wolf Alan
Published: September 2008

We examine a possibly capacitated, periodically reviewed, single-stage inventory system where replenishment can be obtained either through a regular fixed lead time channel, or, for a premium, via a channel with a smaller fixed lead time. We consider the case when the unsatisfied demands are backordered over an infinite horizon, introducing the easily implementable, yet informationally rich dual-index policy. We show very general separability results for the optimal parameter values, providing a simulation-based optimization procedure that exploits these separability properties to calculate the optimal inventory parameters within seconds. We explore the performance of the dual-index policy under stationary demands as well as capacitated production environments, demonstrating when the dual-sourcing option is most valuable. We find that the optimal dual-index policy mimics the behavior of the complex, globally optimal state-dependent policy found via dynamic programming: the dual-index policy is nearly optimal (within 1% or 2%) for the majority of cases, and significantly outperforms single sourcing (up to 50% better). Our results on optimal dual-index parameters are generic, extending to a variety of complex and realistic scenarios such as nonstationary demand, random yields, demand spikes, and supply disruptions.
Analysis of Perishable-Inventory Systems with Censored Demand Data
Authors: Lu Xiangwen , Song Jing-Sheng , Zhu Kaijie
Published: September 2008

We consider a multiperiod inventory system of a perishable product with unobservable lost sales. Demand distribution parameters are unknown and are updated periodically using the Bayesian approach based on the censored historical sales data. We develop an explicit expression of the first-order condition for optimality that demonstrates the key trade-off of the problem. The result generalizes partial characterizations of this trade-off in the literature. It shows that the myopic solution is a lower bound on the optimal inventory level. It also enables us to quantify the expected marginal value of information.
The Stochastic Knapsack Revisited: Switch-Over Policies and Dynamic Pricing
Authors: Lin Grace Y. , Lu Yingdong , Yao David D.
Published: September 2008

The stochastic knapsack has been used as a model in wide-ranging applications from dynamic resource allocation to admission control in telecommunication. In recent years, a variation of the model has become a basic tool in studying problems that arise in revenue management and dynamic/flexible pricing, and it is in this context that our study is undertaken. Based on a dynamic programming formulation and associated properties of the value function, we study in this paper a class of control that we call switch-over policies—start by accepting only orders of the highest price, and switch to including lower prices as time goes by, with the switch-over times optimally decided via convex programming. We establish the asymptotic optimality of the switch-over policy, and develop pricing models based on this policy to optimize the price reductions over the decision horizon.