bluuebunny/crossref_metadata_2025 huggingface dataset:
Contracts made manifest
Authors: Greenberg Michael , Pierce Benjamin C. , Weirich Stephanie
Published: January 2010

Since Findler and Felleisen introduced
higher-order contracts
, many variants have been proposed. Broadly, these fall into two groups: some follow Findler and Felleisen in using
latent
contracts, purely dynamic checks that are transparent to the type system; others use
manifest
contracts, where
refinement
types record the most recent check that has been applied to each value. These two approaches are commonly assumed to be equivalent---different ways of implementing the same idea, one retaining a simple type system, and the other providing more static information. Our goal is to formalize and clarify this folklore understanding.

Our work extends that of Gronski and Flanagan, who defined a latent calculus λ
C
and a manifest calculus λ
H
, gave a translation φ from λ
C
to λ
H
, and proved that, if a λ
C
term reduces to a constant, then so does its φ-image. We enrich their account with a translation Ψ from λ
H
to λ
C
and prove an analogous theorem.

We then generalize the whole framework to
dependent contracts
, whose predicates can mention free variables. This extension is both pragmatically crucial, supporting a much more interesting range of contracts, and theoretically challenging. We define dependent versions of λ
H
and two dialects ("lax" and "picky") of λ
C
, establish type soundness---a substantial result in itself, for λ
H
---and extend φ and Ψ accordingly. Surprisingly, the intuition that the latent and manifest systems are equivalent now breaks down: the extended translations preserve behavior in one direction but, in the other, sometimes yield terms that blame more.
Threesomes, with and without blame
Authors: Siek Jeremy G. , Wadler Philip
Published: January 2010

How to integrate static and dynamic types? Recent work focuses on casts to mediate between the two. However, adding casts may degrade tail calls into a non-tail calls, increasing space consumption from constant to linear in the depth of calls.

We present a new solution to this old problem, based on the notion of a threesome. A cast is specified by a source and a target type--a twosome. Any twosome factors into a downcast from the source to an intermediate type, followed by an upcast from the intermediate to the target---a threesome. Any chain of threesomes collapses to a single threesome, calculated by taking the greatest lower bound of the intermediate types. We augment this solution with blame labels to map any failure of a threesome back to the offending twosome in the source program.

Herman, Tomb, and Flanagan (2007) solve the space problem by representing casts with the coercion calculus of Henglein (1994). While they provide a theoretical limit on the space overhead, there remains the practical question of how best to implement coercion reduction. The threesomes presented in this paper provide a streamlined data structure and algorithm for representing and normalizing coercions. Furthermore, threesomes provide a typed-based explanation of coercion reduction.
Myocardial Fatty Acid Metabolism in Health and Disease
Authors: Lopaschuk Gary D. , Ussher John R. , Folmes Clifford D. L. , Jaswal Jagdip S. , Stanley William C.
Published: January 2010

There is a constant high demand for energy to sustain the continuous contractile activity of the heart, which is met primarily by the β-oxidation of long-chain fatty acids. The control of fatty acid β-oxidation is complex and is aimed at ensuring that the supply and oxidation of the fatty acids is sufficient to meet the energy demands of the heart. The metabolism of fatty acids via β-oxidation is not regulated in isolation; rather, it occurs in response to alterations in contractile work, the presence of competing substrates (i.e., glucose, lactate, ketones, amino acids), changes in hormonal milieu, and limitations in oxygen supply. Alterations in fatty acid metabolism can contribute to cardiac pathology. For instance, the excessive uptake and β-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. Furthermore, alterations in fatty acid β-oxidation both during and after ischemia and in the failing heart can also contribute to cardiac pathology. This paper reviews the regulation of myocardial fatty acid β-oxidation and how alterations in fatty acid β-oxidation can contribute to heart disease. The implications of inhibiting fatty acid β-oxidation as a potential novel therapeutic approach for the treatment of various forms of heart disease are also discussed.
Lens Gap Junctions in Growth, Differentiation, and Homeostasis
Authors: Mathias Richard T. , White Thomas W. , Gong Xiaohua
Published: January 2010

The cells of most mammalian organs are connected by groups of cell-to-cell channels called gap junctions. Gap junction channels are made from the connexin (Cx) family of proteins. There are at least 20 isoforms of connexins, and most tissues express more than 1 isoform. The lens is no exception, as it expresses three isoforms: Cx43, Cx46, and Cx50. A common role for all gap junctions, regardless of their Cx composition, is to provide a conduit for ion flow between cells, thus creating a syncytial tissue with regard to intracellular voltage and ion concentrations. Given this rather simple role of gap junctions, a persistent question has been: Why are there so many Cx isoforms and why do tissues express more than one isoform? Recent studies of lens Cx knockout (KO) and knock in (KI) lenses have begun to answer these questions. To understand these roles, one must first understand the physiological requirements of the lens. We therefore first review the development and structure of the lens, its numerous transport systems, how these systems are integrated to generate the lens circulation, the roles of the circulation in lens homeostasis, and finally the roles of lens connexins in growth, development, and the lens circulation.
PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells
Authors: Rivera-Del Valle Nilsa , Gao Shan , Miller Claudia P. , Fulbright Joy , Gonzales Carolina , Sirisawad Mint , Steggerda Susanne , Wheler Jennifer , Balasubramanian Sriram , Chandra Joya
Published: January 2010

Histone deacetylase inhibitors (HDACi) have become a promising new avenue for cancer therapy, and many are currently in Phase I/II clinical trials for various tumor types. In the present study, we show that apoptosis induction and histone alterations by PCI-24781, a novel hydroxamic acid-based HDAC inhibitor, require caspase-8 and the adaptor molecule, Fas-associated death domain (FADD), in acute leukemia cells. PCI-24781 treatment also causes an increase in superoxide levels, which has been reported for other HDACi. However, an antioxidant does not reverse histone alterations caused by PCI-24781, indicating that ROS generation is likely downstream of the effects that PCI-24781 exerts on histone H3. Taken together, these results provide insight into the mechanism of apoptosis induction by PCI-24781 in leukemia by highlighting the roles of caspase-8, FADD and increased superoxide levels.
Automated Test Case Prioritization with Reactive GRASP
Authors: Maia Camila Loiola Brito , do Carmo Rafael Augusto Ferreira , de Freitas Fabrício Gomes , de Campos Gustavo Augusto Lima , de Souza Jerffeson Teixeira
Published: January 2010

Modifications in software can affect some functionality that had been working until that point. In order to detect such a problem, the ideal solution would be testing the whole system once again, but there may be insufficient time or resources for this approach. An alternative solution is to order the test cases so that the most beneficial tests are executed first, in such a way only a subset of the test cases can be executed with little lost of effectiveness. Such a technique is known as regression test case prioritization. In this paper, we propose the use of the Reactive GRASP metaheuristic to prioritize test cases. We also compare this metaheuristic with other search-based algorithms previously described in literature. Five programs were used in the experiments. The experimental results demonstrated good coverage performance with some time overhead for the proposed technique. It also demonstrated a high stability of the results generated by the proposed approach.
Large Waist Circumference Is a Risk Factor for Reflux Esophagitis in Japanese Males
Authors: Yasuhara Hisae , Miyake Yasuhiro , Toyokawa Tatsuya , Matsumoto Kazuyuki , Takahara Masahiro , Imada Takayuki , Yagi Satoru , Miyatake Hirokazu , Nakatsu Morihito , Ando Masaharu , Hirohata Mamoru
Published: January 2010

Background/Aims: The prevalence of reflux esophagitis, which might lead to development of Barrett’s esophagus and esophageal adenocarcinoma, has been increasing. The aim of this study was to assess risk factors for reflux esophagitis. Methods: We conducted a cross-sectional study of 1,495 Japanese subjects undergoing health checkups (822 males and 673 females; median age 50 years) at a tertiary care center. Results: One hundred and twenty-seven subjects (8%) had reflux esophagitis and hiatal hernia was observed in 292 subjects (20%). Reflux esophagitis (13 vs. 3%) and hiatal hernia (28 vs. 9%) were more frequent in males than females. Significant differences in clinical backgrounds were observed between females and males. Multivariate logistic regression analyses revealed that hiatal hernia (OR 6.63, 95% CI 2.47–17.8; p = 0.0002) was associated with reflux esophagitis in females. In males, age (per 1-year increment: OR 0.96, 95% CI 0.94–0.99; p = 0.007), hiatal hernia (OR 3.16, 95% CI 2.05–4.87; p < 0.0001) and waist circumference (per 1-cm increase: OR 1.09, 95% CI 1.02–1.15; p = 0.006) were associated with reflux esophagitis. Conclusions: Abdominal obesity may be an important risk factor for reflux esophagitis in males compared with females.
Celecoxib Inhibits CD133-Positive Cell Migration via Reduction of CCR2 in Helicobacter pylori-Infected Mongolian Gerbils
Authors: Futagami Seiji , Hamamoto Tatsuhiko , Shimpuku Mayumi , Nagoya Hiroyuki , Kawagoe Tetsuro , Horie Akane , Shindo Tomotaka , Gudis Katya , Sakamoto Choitsu
Published: January 2010

Background/Aims: To see whether celecoxib prevents gastric cancer occurrence by disrupting the progression of chronic gastritis into gastric carcinoma through its inhibition of the migration of CD133-positive cells, one of the surface markers of bone marrow-derived cells, in Helicobacter pylori-infected gerbils. Methods: 70 gerbils were divided into six groups. Group 1 gerbils served as control (n = 6). 10 gerbils were given N-methyl-N-nitrosourea (MNU), 30 ppm (group 2). 6 short-term Helicobacter pylori-infected gerbils (group 3) were sacrificed after 8 weeks of H. pylori infection and 6 long-term H. pylori-infected gerbils were sacrificed after 42 weeks of H. pylori infection (group 4). 20 gerbils were given MNU pretreatment and long-term H. pylori infection (group 5). In addition, after H. pylori inoculation, 22 gerbils also received a celecoxib in their diet (group 6). CD133 and CCR2 expression in gastric tissues was evaluated by Western blot analysis and immunostaining. Results: CD133-positive cells were mainly localized in the bottom of the gastric epithelial cells. CD133-positive cells also migrated into gastric cancer tissues in this model. CD133-positive cells in MNU-pretreated H. pylori-infected gerbils were significantly increased compared to those in H. pylori short-term infected gerbils. Celecoxib treatment significantly reduced CD133-positive cell migration and CCR2 expression levels. CD133- and CCR2-positive cells were colocalized in H. pylori-infected gastritis and gastric cancer tissues. Celecoxib treatment significantly reduced the number of CD133- and CCR2-positive cells. Conclusions: Celecoxib inhibits CD133-positive cell migration via the reduction of CCR2 in this model. Further studies are needed to clarify the precise mechanisms driving H. pylori infection-induced CD133-positive cell migration and its link to the progression of chronic gastritis into gastric cancer.
Inhibition of Caries Progression by Resin Infiltration in situ
Authors: Paris S. , Meyer-Lueckel H.
Published: January 2010

The infiltration of caries lesions with low-viscosity light-curing resins (infiltrants) has been shown to inhibit further demineralization in vitro. The aim of the present study was to assess the efficacy of resin infiltration in preventing lesion progression in situ. In each of 104 bovine enamel specimens, 2 artificial enamel caries lesions were created. The specimens were randomly allocated to 2 groups: in the test group, 1 of the lesions was etched for 5 s (37% H3PO4) and subsequently infiltrated twice with a preproduct infiltrant, each time for 60 s. As a positive control, 1 lesion was superficially sealed with a fissure sealant. The second lesion in each specimen served as an untreated control. The specimens were inserted into intraoral appliances and worn by 11 volunteers in the mandibular buccal sulcus for 100 days. Plaque accumulation was promoted by a mesh, and the appliances were stored in 10% sucrose solution (2 × 30 min/day). The specimens were analyzed using transversal microradiography and wavelength-independent microradiography. The specimens of 2 participants were excluded from analysis. The baseline integrated mineral losses (transversal microradiography values; mean ± SD: 2474 ± 549 vol% × µm) and lesion depths (98 ± 20 µm) did not differ significantly between the various groups (p > 0.05; paired t test). After the in situ phase, the infiltrated and positive control lesions showed significantly less progression compared to the untreated controls (p < 0.05). It can be concluded that resin infiltration is efficacious in preventing further demineralization of artificial enamel caries lesions under cariogenic conditions in situ.
No Major Differences in 30-Day Outcomes in High-Risk Patients Randomized to Off-Pump Versus On-Pump Coronary Bypass Surgery
Authors: Møller Christian H. , Perko Mario J. , Lund Jens T. , Andersen Lars W. , Kelbæk Henning , Madsen Jan K. , Winkel Per , Gluud Christian , Steinbrüchel Daniel A.
Published: January 2010

Background—

Off-pump coronary artery bypass grafting compared with coronary revascularization with cardiopulmonary bypass seems safe and results in about the same outcome in low-risk patients. Observational studies indicate that off-pump surgery may provide more benefit in high-risk patients. Our objective was to compare 30-day outcomes in high-risk patients randomized to coronary artery bypass grafting without or with cardiopulmonary bypass.

Methods and Results—

We randomly assigned 341 patients with a EuroSCORE ≥5 and 3-vessel coronary disease to undergo coronary artery bypass grafting without or with cardiopulmonary bypass. Patients were followed through the Danish National Patient Registry. The primary outcome was a composite of adverse cardiac and cerebrovascular events (ie, all-cause mortality, acute myocardial infarction, cardiac arrest with successful resuscitation, low cardiac output syndrome/cardiogenic shock, stroke, and coronary reintervention). An independent adjudication committee blinded to treatment allocation assessed the outcomes. Baseline characteristics were well balanced between groups. The mean number of grafts per patient did not differ significantly between groups (3.22 in off-pump group and 3.34 in on-pump group;
P
=0.11). Fewer grafts were performed to the lateral part of the left ventricle territory during off-pump surgery (0.97 versus 1.14 after on-pump surgery;
P
=0.01). No significant differences in the composite primary outcome (15% versus 17%;
P
=0.48) or the individual components were found at 30-day follow-up.

Conclusions—

Both off- and on-pump coronary artery bypass grafting can be performed in high-risk patients with low short-term complications.

Clinical Trial Registration—

clinicaltrials.gov. Identifier: NCT00120991.
Nox Activator 1
Authors: Niu Xi-Lin , Madamanchi Nageswara R. , Vendrov Aleksandr E. , Tchivilev Igor , Rojas Mauricio , Madamanchi Chaitanya , Brandes Ralph P. , Krause Karl-Heinz , Humphries Julia , Smith Alberto , Burnand Kevin G. , Runge Marschall S.
Published: January 2010

Background—

Despite a concerted effort by many laboratories, the critical subunits that participate in vascular smooth muscle cell (VSMC) NADPH oxidase function have yet to be elucidated. Given the potential therapeutic importance of cell-specific inhibition of NADPH oxidase, we investigated the role of Nox activator 1 (NoxA1), a homolog of p67phox, in VSMC NADPH oxidase function and atherosclerosis.

Methods and Results—

The presence of NoxA1 in mouse aortic VSMCs was confirmed by reverse-transcription polymerase chain reaction and sequencing. NoxA1/p47phox interaction after thrombin treatment was observed by immunoprecipitation/Western analysis of lysates from p47phox
−/−
VSMCs transfected with adenoviral HA-NoxA1 and Myc-p47phox. Infection with adenoviral NoxA1 significantly enhanced thrombin-induced reactive oxygen species generation in wild-type but not in p47phox
−/−
and Nox1
−/−
VSMCs. Thrombin-induced reactive oxygen species production and VSMC proliferation were significantly reduced after downregulation of NoxA1 with shRNA. Infection with NoxA1 shRNA but not scrambled shRNA significantly decreased thrombin-induced activation of the redox-sensitive protein kinases (Janus kinase 2, Akt, and p38 mitogen-activated protein kinase) in VSMCs. Adenovirus-mediated overexpression of NoxA1 in guidewire-injured mouse carotid arteries significantly increased superoxide production in medial VSMCs and enhanced neointimal hyperplasia. NoxA1 expression was significantly increased in aortas and atherosclerotic lesions of ApoE
−/−
mice compared with age-matched wild-type mice. Furthermore, in contrast to p67phox, immunoreactive NoxA1 is present in intimal and medial SMCs of human early carotid atherosclerotic lesions.

Conclusions—

NoxA1 is the functional homolog of p67phox in VSMCs that regulates redox signaling and VSMC phenotype. These findings support the potential for modulation of NoxA1 expression as a viable approach for the treatment of vascular diseases.
Influence of Changes in Blood Pressure on Cerebral Perfusion and Oxygenation
Authors: Lucas Samuel J.E. , Tzeng Yu Chieh , Galvin Sean D. , Thomas Kate N. , Ogoh Shigehiko , Ainslie Philip N.
Published: January 2010

Cerebral autoregulation (CA) is a critical process for the maintenance of cerebral blood flow and oxygenation. Assessment of CA is frequently used for experimental research and in the diagnosis, monitoring, or prognosis of cerebrovascular disease; however, despite the extensive use and reference to static CA, a valid quantification of “normal” CA has not been clearly identified. While controlling for the influence of arterial P
co
2
, we provide the first clear examination of static CA in healthy humans over a wide range of blood pressure. In 11 healthy humans, beat-to-beat blood pressure (radial arterial), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), end-tidal P
co
2
, and cerebral oxygenation (near infrared spectroscopy) were recorded continuously during pharmacological-induced changes in mean blood pressure. In a randomized order, steady-state decreases and increases in mean blood pressure (8 to 14 levels; range: ≈40 to ≈125 mm Hg) were achieved using intravenous infusions of sodium nitroprusside or phenylephrine, respectively. MCAv
mean
was altered by 0.82±0.35% per millimeter of mercury change in mean blood pressure (
R
2
=0.82). Changes in cortical oxygenation index were inversely related to changes in mean blood pressure (slope=−0.18%/mm Hg;
R
2
=0.60) and MCAv
mean
(slope=−0.26%/cm · s
−1
;
R
2
=0.54). There was a progressive increase in MCAv pulsatility with hypotension. These findings indicate that cerebral blood flow closely follows pharmacological-induced changes in blood pressure in otherwise healthy humans. Thus, a finite slope of the plateau region does not necessarily imply a defective CA. Moreover, with progressive hypotension and hypertension there are differential changes in cerebral oxygenation and MCAv
mean
.
Ecstatic display calls of the Adélie penguin honestly predict male condition and breeding success
Authors: Brunton Dianne , Rodrigo Allen , Marks Emma
Published: January 2010

The Adélie penguin (Pygoscelis adeliae) breeds in large, noisy Antarctic colonies and has evolved a communication system of complex intra- and inter-sexual visual and vocal behaviours. The Ecstatic Display Call (EDC) given by males whilst at the breeding colony is composed of introductory beats, short repeated syllables and a climactic long syllable. Here, we show that spectral qualities of the short syllables of the EDC can predict body condition and breeding success and suggest that in addition to its role in territory defence, the EDC may function as an honest signal of male quality for female mate choice. In the short repeated syllables frequency modulation, mean frequency, and pitch were all significantly lower in birds of better condition, with frequency modulation changing concomitantly with changing condition during the breeding season. Furthermore, during the period of mate attraction, a male's frequency modulation predicted both his latency to pair and likelihood of successfully breeding. Due to the long incubation fasts in this species we propose that female Adélie penguins may reliably use frequency modulation of the EDC as a potentially honest signal of early season male condition and the likelihood of a successful breeding outcome.
Self-grooming by male meadow voles differs across copulation but is not affected by the risk and intensity of sperm competition
Authors: Ferkin Michael , delBarco-Trillo Javier , Vaughn Ashlee
Published: January 2010

Meadow voles, Microtus pennsylvanicus, self-groom before, during and after copulation, which may convey olfactory information to nearby conspecifics. Since males who self-groom at high rates were found to be attractive to females, it is possible that the copulating male may attempt to increase his attractiveness over that of other males who are present or nearby. In that the presence of other males affects sperm investment and can be used by males as an indicator of sperm competition, we tested the hypothesis that the presence of scent marks of other males near a sexually receptive female affects the self-grooming behaviour of males that encounter them. We did so by pairing a male and a female vole in the presence of the odours of one male conspecific, five male conspecifics, or no male conspecifics. The amount of time male voles self-groomed was not affected by the risk or intensity of sperm competition. We also tested the hypothesis that self-grooming behaviour of males differed depending on whether it was performed before, during, or after copulation. Male voles differed in the amount of time and the location on their body that they self-groomed before, during, and after copulation.
Exit bos frisica, The Tolsum tablet and Roman law
Authors: Zwalve W.J.
Published: January 2010

The text of the Tolsum tablet, discovered in a Frisian mound in or about 1905, was first published by C.W. Vollgraff in 1917. His reading became the standard text for all subsequent editions of the tablet, for example in Arangio-Ruiz's edition of Roman legal documents in FIRA. Thanks to the efforts of A.K. Bowman, R.S.O. Tomlin and K.A. Worp (and the Frisian Museum in Leeuwarden), we now have a new (and totally different) reading, indicating a money loan, rather than the sale of a Frisian ox. This article contains a first assessment of the value of the new reading for the discipline of Roman law. It is contended that the standard clause vel ei ad quem ea res pertinebit in documents like this relates to a possible assignment of the debt, since in Roman commercial practice money debts were assigned by transferring the cautio representing the debt.
Jesuit freedom of contract
Authors: Decock Wim
Published: January 2010

This paper describes and explains the central role of the principle of contractual liberty with the Jesuits of the early modern period. Designed as a diptych, it intends to clarify how the legal and the moral philosophical tradition mutually enriched each other at the threshold of modernity. The 'ius commune' helped the Jesuits in formulating the idea of negative freedom, only for that 'ius commune' to undergo a transformation itself under the influence of the scientific account of contract law that the Jesuits were to develop on its basis. First it will be shown how the Jesuits arrived at a moral problem-solving method capable of freeing man from unduely burdensome obligations before the court of conscience through the application of the law of property and procedure. Secondly, this paper will highlight the turn towards positive freedom through the Jesuits' elaboration of a general doctrine of contract as a mutually accepted promise centered around the notions of liberty, consensualism, and the image of the will as a private legislator.
Genesis of Pre–Hurricane Felix (2007). Part II: Warm Core Formation, Precipitation Evolution, and Predictability
Authors: Wang Zhuo , Montgomery M. T. , Dunkerton T. J.
Published: January 2010

This is the second of a two-part study examining the simulated formation of Atlantic Hurricane Felix (2007) in a cloud-representing framework. Here several open issues are addressed concerning the formation of the storm’s warm core, the evolution and respective contribution of stratiform versus convective precipitation within the parent wave’s pouch, and the sensitivity of the development pathway reported in Part I to different model physics options and initial conditions. All but one of the experiments include ice microphysics as represented by one of several parameterizations, and the partition of convective versus stratiform precipitation is accomplished using a standard numerical technique based on the high-resolution control experiment.

The transition to a warm-core tropical cyclone from an initially cold-core, lower tropospheric wave disturbance is analyzed first. As part of this transformation process, it is shown that deep moist convection is sustained near the pouch center. Both convective and stratiform precipitation rates increase with time. While stratiform precipitation occupies a larger area even at the tropical storm stage, deep moist convection makes a comparable contribution to the total rain rate at the pregenesis stage, and a larger contribution than stratiform processes at the storm stage. The convergence profile averaged near the pouch center is found to become dominantly convective with increasing deep moist convective activity there. Low-level convergence forced by interior diabatic heating plays a key role in forming and intensifying the near-surface closed circulation, while the midlevel convergence associated with stratiform precipitation helps to increase the midlevel circulation and thereby contributes to the formation and upward extension of a tropospheric-deep cyclonic vortex.

Sensitivity tests with different model physics options and initial conditions demonstrate a similar pregenesis evolution. These tests suggest that the genesis location of a tropical storm is largely controlled by the parent wave’s critical layer, whereas the genesis time and intensity of the protovortex depend on the details of the mesoscale organization, which is less predictable. Some implications of the findings are discussed.
Flow and Hydraulics near the Sill of Hood Canal, a Strongly Sheared, Continuously Stratified Fjord
Authors: Gregg M. C. , Pratt L. J.
Published: January 2010

Hood Canal, a long fjord in Washington State, has strong tides but limited deep-water renewal landward of a complex constriction. Tide-resolving hydrographic and velocity observations at the constriction, with a depth-cycling towed body, varied markedly during three consecutive years, partly because of stratification variations. To determine whether hydraulic control is generally important and to interpret observations of lee waves, blocking, and other features, hydraulic criticality is estimated over full tidal cycles for channel wide internal wave modes 1, 2, and 3, at five cross-channel sections, using mode speeds from the extended Taylor–Goldstein equation. These modes were strongly supercritical during most of ebb and flood on the gentle seaward sill face and for part of flood at the base of the steep landward side. Examining local criticality along the thalweg found repeated changes between mode 1 being critical and supercritical approaching the sill crest during flood, unsurprising given local minima and maxima in the cross-sectional area, with the sill crest near a maximum. Density crossing the sill sometimes resembled an overflow with an internal hydraulic control at the sill, followed by a hydraulic jump or lee wave. Long-wave speeds, however, suggest cross waves, particularly along the shallower gentler side, where flow downstream of a large-amplitude wave was uniformly supercritical. Supercritical approaching the sill, peak ebb was critical to mode 1 and supercritical to modes 2 and 3 at the base while forming a sluggish dome of dense water over the sill. Full interpretation exceeds observations and existing theory.
The INGV–CMCC Seasonal Prediction System: Improved Ocean Initial Conditions
Authors: Alessandri Andrea , Borrelli Andrea , Masina Simona , Cherchi Annalisa , Gualdi Silvio , Navarra Antonio , Di Pietro Pierluigi , Carril Andrea F.
Published: January 2010

The development of the Istituto Nazionale di Geofisica e Vulcanologia (INGV)–Centro Euro-Mediterraneo per i Cambiamenti Climatici (CMCC) Seasonal Prediction System (SPS) is documented. In this SPS the ocean initial-conditions estimation includes a reduced-order optimal interpolation procedure for the assimilation of temperature and salinity profiles at the global scale. Nine-member ensemble forecasts have been produced for the period 1991–2003 for two starting dates per year in order to assess the impact of the subsurface assimilation in the ocean for initialization. Comparing the results with control simulations (i.e., without assimilation of subsurface profiles during ocean initialization), it is shown that the improved ocean initialization increases the skill in the prediction of tropical Pacific sea surface temperatures of the system for boreal winter forecasts. Considering the forecast of the 1997/98 El Niño, the data assimilation in the ocean initial conditions leads to a considerable improvement in the representation of its onset and development. The results presented in this paper indicate a better prediction of global-scale surface climate anomalies for the forecasts started in November, probably because of the improvement in the tropical Pacific. For boreal winter, significant increases in the capability of the system to discriminate above-normal and below-normal temperature anomalies are shown in both the tropics and extratropics.
Data Assimilation: A Fully Nonlinear Approach to Ensemble Formation Using Indistinguishable States
Authors: Khare Shree , Smith Leonard A.
Published: January 2010

Operational forecasting with simulation models involves the melding of observations and model dynamics to determine a set of initial conditions for each forecast. The Kalman filter (KF) provides the optimal closed-form solution to a general linear stochastic (perfect model) case, while the target of the problem has not even been defined in the case of imperfect models. Data assimilation in a nonlinear, perfect-model scenario is considered. It is shown that a new fully nonlinear approach based upon the indistinguishable states (IS) systematically outperforms the ensemble Kalman filter (EnKF). The IS provides an ensemble of initial conditions, consistent with (i) the model dynamics, (ii) the observational noise model, and (iii) the particular observations over a window. It is argued that this is the relevant limit to consider in data assimilation, when the desire is to place high probability density in the vicinity of the target state. The advantages of the IS approach come in part from its ability to provide attractor-balanced ensembles near any attracting manifold the system may evolve on. The use of an EnKF, provides a computationally cheaper alternative that place points in the general vicinity of the target. A low (i.e., 2) dimensional example is used to provide easily visualized evidence for these claims, which are then tested in a higher (i.e., 12) dimensional system. Inasmuch as the IS approach is shown to outperform the EnKF systematically in these perfect-model experiments, it provides an interesting alternative approach when informative ensembles are desired.
‘Striking out’: Shifting labour markets, welfare to work policy and the renegotiation of gender performances
Authors: Smith Katherine E. , Bambra Clare , Joyce Kerry
Published: January 2010

Since 1997, the English government has committed itself to the twin (and inter-linked) policy aims of reducing health inequalities and tackling social exclusion. Welfare to work interventions have formed a key part of the policy response to both of these problems. So far, this approach has been largely supply-side focused and ‘gender-blind’, treating both men and women who are not in employment as discrete entities who, with the right combination of training and support, can be engaged within the formal economy. Drawing on data from qualitative case studies of two such interventions in the North-East of England (one of which offered unemployed parents childcare training and the other of which provided vocational and advisory support to young parents), this paper contributes to a growing literature exploring the gender dimensions of social policy interventions. The findings emphasize the centrality of gender to participants and demonstrate the necessity of gender sensitivity in projects designed to tackle worklessness.
Slouching towards dystopia: the new military futurism
Authors: Carr Matt
Published: January 2010

In recent years, the military establishments of the US and the UK have produced a series of reports that attempt to ‘think the unthinkable in imagining future threats to the security of the West. A new genre of military futurology has emerged which owes as much to apocalyptic Hollywood movies as it does to the cold war tradition of ‘scenario planning . Often outlandish and bizarre in its prophecies, and always dystopian, this new military futurism sees threats to the western way of life emanating not only from rogue states, weapons of mass destruction and terrorism but also from resurgent nationalism, conflicts over dwindling resources, migration, disease, organised crime, abrupt climate change and the emergence of‘failed cities where social disorder is rife. This article provides a survey of the genre, showing how the grim predictions of the military futurists provide a justification for endless global war against enemies that may never exist.
The continuing debate about urban bias
Authors: Jones Gareth A. , Corbridge Stuart
Published: January 2010

This article reviews the current state of the debate around the concept of ‘urban bias’. It first reviews Michael Lipton’s original formulation of an Urban Bias Thesis (UBT), and the initial debates that took shape in regard to his work and the work of Elliott Berg and Robert Bates. The main body of the article, however, considers a recent reworking of the UBT by Robert Eastwood and Michael Lipton, and four sets of objections that can be raised against it. Central to these objections are new accounts of the importance of mobility in constructing rural-urban livelihoods and claims emanating from the ‘new economic geography’ about the economic advantages of towns and cities. The article concludes with a short review of the implication of the continuing debate on ‘urban bias’ for public policy and Poverty Reduction Strategies.
Telling apart friend from foe: discriminating between commensals and pathogens at mucosal sites
Authors: Srinivasan Naren
Published: January 2010

From the moment we are born, we are exposed to a vast variety of microbes. The intestine in particular is perhaps inhabited by the largest number of microbes, consisting of both established commensals as well as sporadic pathogens. Mucosal surfaces form an important barrier against microbial invasion. Together with the physical barrier that they provide, mucosal surfaces also rely on innate immune functions to sense luminal microbes and signal accordingly to generate protective immune responses. However, since innate immune recognition is microbial specific and antigen-independent, the contact with both beneficial commensals and harmful pathogens creates the need for discrimination between the two. The mechanisms governing the ability of the mucosal immune system to discriminate between commensals and pathogens have long been unclear; however, recent discoveries have shed some light on this distinction. This review will summarize the current theories put forth to explain how the mucosal immune system maintains tolerance towards commensals while retaining the ability to mount inflammatory responses against pathogens.
Learning to predict expression efficacy of vectors in recombinant protein production
Authors: Chan Wen-Ching , Liang Po-Huang , Shih Yan-Ping , Yang Ueng-Cheng , Lin Wen-chang , Hsu Chun-Nan
Published: January 2010

Background

Recombinant protein production is a useful biotechnology to produce a large quantity of highly soluble proteins. Currently, the most widely used production system is to fuse a target protein into different vectors in Escherichia coli (E. coli). However, the production efficacy of different vectors varies for different target proteins. Trial-and-error is still the common practice to find out the efficacy of a vector for a given target protein. Previous studies are limited in that they assumed that proteins would be over-expressed and focused only on the solubility of expressed proteins. In fact, many pairings of vectors and proteins result in no expression.

Results

In this study, we applied machine learning to train prediction models to predict whether a pairing of vector-protein will express or not express in E. coli. For expressed cases, the models further predict whether the expressed proteins would be soluble. We collected a set of real cases from the clients of our recombinant protein production core facility, where six different vectors were designed and studied. This set of cases is used in both training and evaluation of our models. We evaluate three different models based on the support vector machines (SVM) and their ensembles. Unlike many previous works, these models consider the sequence of the target protein as well as the sequence of the whole fusion vector as the features. We show that a model that classifies a case into one of the three classes (no expression, inclusion body and soluble) outperforms a model that considers the nested structure of the three classes, while a model that can take advantage of the hierarchical structure of the three classes performs slight worse but comparably to the best model. Meanwhile, compared to previous works, we show that the prediction accuracy of our best method still performs the best. Lastly, we briefly present two methods to use the trained model in the design of the recombinant protein production systems to improve the chance of high soluble protein production.

Conclusion

In this paper, we show that a machine learning approach to the prediction of the efficacy of a vector for a target protein in a recombinant protein production system is promising and may compliment traditional knowledge-driven study of the efficacy. We will release our program to share with other labs in the public domain when this paper is published.
Reaction graph kernels predict EC numbers of unknown enzymatic reactions in plant secondary metabolism
Authors: Saigo Hiroto , Hattori Masahiro , Kashima Hisashi , Tsuda Koji
Published: January 2010

Background

Understanding of secondary metabolic pathway in plant is essential for finding druggable candidate enzymes. However, there are many enzymes whose functions are not yet discovered in organism-specific metabolic pathways. Towards identifying the functions of those enzymes, assignment of EC numbers to the enzymatic reactions they catalyze plays a key role, since EC numbers represent the categorization of enzymes on one hand, and the categorization of enzymatic reactions on the other hand.

Results

We propose reaction graph kernels for automatically assigning EC numbers to unknown enzymatic reactions in a metabolic network. Reaction graph kernels compute similarity between two chemical reactions considering the similarity of chemical compounds in reaction and their relationships. In computational experiments based on the KEGG/REACTION database, our method successfully predicted the first three digits of the EC number with 83% accuracy. We also exhaustively predicted missing EC numbers in plant's secondary metabolism pathway. The prediction results of reaction graph kernels on 36 unknown enzymatic reactions are compared with an expert's knowledge. Using the same data for evaluation, we compared our method with E-zyme, and showed its ability to assign more number of accurate EC numbers.

Conclusion

Reaction graph kernels are a new metric for comparing enzymatic reactions.
Efficient genome-scale phylogenetic analysis under the duplication-loss and deep coalescence cost models
Authors: Bansal Mukul S , Burleigh J Gordon , Eulenstein Oliver
Published: January 2010

Background

Genomic data provide a wealth of new information for phylogenetic analysis. Yet making use of this data requires phylogenetic methods that can efficiently analyze extremely large data sets and account for processes of gene evolution, such as gene duplication and loss, incomplete lineage sorting (deep coalescence), or horizontal gene transfer, that cause incongruence among gene trees. One such approach is gene tree parsimony, which, given a set of gene trees, seeks a species tree that requires the smallest number of evolutionary events to explain the incongruence of the gene trees. However, the only existing algorithms for gene tree parsimony under the duplication-loss or deep coalescence reconciliation cost are prohibitively slow for large datasets.

Results

We describe novel algorithms for SPR and TBR based local search heuristics under the duplication-loss cost, and we show how they can be adapted for the deep coalescence cost. These algorithms improve upon the best existing algorithms for these problems by a factor of n, where n is the number of species in the collection of gene trees. We implemented our new SPR based local search algorithm for the duplication-loss cost and demonstrate the tremendous improvement in runtime and scalability it provides compared to existing implementations. We also evaluate the performance of our algorithm on three large-scale genomic data sets.

Conclusion

Our new algorithms enable, for the first time, gene tree parsimony analyses of thousands of genes from hundreds of taxa using the duplication-loss and deep coalescence reconciliation costs. Thus, this work expands both the size of data sets and the range of evolutionary models that can be incorporated into genome-scale phylogenetic analyses.
A novel approach for haplotype-based association analysis using family data
Authors: Chen Yixuan , Li Xin , Li Jing
Published: January 2010

Background

Haplotype-based approaches have been extensively studied for case-control association mapping in recent years. It has been shown that haplotype methods can provide more consistent results comparing to single-locus based approaches, especially in cases where causal variants are not typed. Improved power has been observed by clustering similar or rare haplotypes into groups to reduce the degrees of freedom of association tests. For family-based association studies, one commonly used strategy is Transmission Disequilibrium Tests (TDT), which examine the imbalanced transmission of alleles/haplotypes to affected and normal children. Many extensions have been developed to deal with general pedigrees and continuous traits.

Results

In this paper, we propose a new haplotype-based association method for family data that is different from the TDT framework. Our approach (termed F_HapMiner) is based on our previous successful experiences on haplotype inference from pedigree data and haplotype-based association mapping. It first infers diplotype pairs of each individual in each pedigree assuming no recombination within a family. A phenotype score is then defined for each founder haplotype. Finally, F_HapMiner applies a clustering algorithm on those founder haplotypes based on their similarities and identifies haplotype clusters that show significant associations with diseases/traits. We have performed extensive simulations based on realistic assumptions to evaluate the effectiveness of the proposed approach by considering different factors such as allele frequency, linkage disequilibrium (LD) structure, disease model and sample size. Comparisons with single-locus and haplotype-based TDT methods demonstrate that our approach consistently outperforms the TDT-based approaches regardless of disease models, local LD structures or allele/haplotype frequencies.

Conclusion

We present a novel haplotype-based association approach using family data. Experiment results demonstrate that it achieves significantly higher power than TDT-based approaches.
An automated framework for understanding structural variations in the binding grooves of MHC class II molecules
Authors: Yeturu Kalidas , Utriainen Tapani , Kemp Graham JL , Chandra Nagasuma
Published: January 2010

Background

MHC/HLA class II molecules are important components of the immune system and play a critical role in processes such as phagocytosis. Understanding peptide recognition properties of the hundreds of MHC class II alleles is essential to appreciate determinants of antigenicity and ultimately to predict epitopes. While there are several methods for epitope prediction, each differing in their success rates, there are no reports so far in the literature to systematically characterize the binding sites at the structural level and infer recognition profiles from them.

Results

Here we report a new approach to compare the binding sites of MHC class II molecules using their three dimensional structures. We use a specifically tuned version of our recent algorithm, PocketMatch. We show that our methodology is useful for classification of MHC class II molecules based on similarities or differences among their binding sites. A new module has been used to define binding sites in MHC molecules. Comparison of binding sites of 103 MHC molecules, both at the whole groove and individual sub-pocket levels has been carried out, and their clustering patterns analyzed. While clusters largely agree with serotypic classification, deviations from it and several new insights are obtained from our study. We also present how differences in sub-pockets of molecules associated with a pair of autoimmune diseases, narcolepsy and rheumatoid arthritis, were captured by PocketMatch
13.

Conclusion

The systematic framework for understanding structural variations in MHC class II molecules enables large scale comparison of binding grooves and sub-pockets, which is likely to have direct implications towards predicting epitopes and understanding peptide binding preferences.