Overview of Genetically Engineered Mouse Models of Papillary and Anaplastic Thyroid Cancers: Enabling Translational Biology for Patient Care Improvement.

The prognosis from thyroid cancer subtypes in humans covers a spectrum from "cured at almost 90%" to "100% lethal." Invasive and poorly differentiated forms of thyroid cancer are among the most aggressive human cancers, and there are few effective therapeutic options. Genetically engineered mice, based on mutations observed in patients, can accurately recapitulate the human disease and its progression, providing invaluable tools for the preclinical evaluation of novel therapeutic approaches. This overview details models developed to date as well as their uses for identifying novel anticancer agents. © 2015 by John Wiley & Sons, Inc.

Protective effect of a germline, IL-17-neutralizing antibody in murine models of autoimmune inflammatory disease.

Monoclonal antibodies (mAbs) inhibiting cytokines have recently emerged as new drug modalities for the treatment of chronic inflammatory diseases. Interleukin-17 (IL-17) is a T-cell-derived central mediator of autoimmunity. Immunization with Qβ-IL-17, a virus-like particle based vaccine, has been shown to produce autoantibodies in mice and was effective in ameliorating disease symptoms in animal models of autoimmunity. To characterize autoantibodies induced by vaccination at the molecular level, we generated mouse mAbs specific for IL-17 and compared them to germline Ig sequences. The variable regions of a selected hypermutated high-affinity anti-IL-17 antibody differed in only three amino acid residues compared to the likely germline progenitor. An antibody, which was backmutated to germline, maintained a surprisingly high affinity (0.5 nM). The ability of the parental hypermutated antibody and the derived germline antibody to block inflammation was subsequently tested in murine models of multiple sclerosis (experimental autoimmune encephalomyelitis), arthritis (collagen-induced arthritis), and psoriasis (imiquimod-induced skin inflammation). Both antibodies were able to delay disease onset and significantly reduced disease severity. Thus, the mouse genome unexpectedly encodes for antibodies with the ability to functionally neutralize IL-17 in vivo.

Theoretical models of planetary system formation II. Post-formation evolution

Aims. We extend the results of planetary formation synthesis by computing the long-term evolution of synthetic systems from the clearing of the gas disk into the dynamical evolution phase. Methods. We use the symplectic integrator SyMBA to numerically integrate the orbits of planets for 100 Myr, using populations from previous studies as initial conditions. Results. We show that within the populations studied, mass and semimajor axis distributions experience only minor changes from post-formation evolution. We also show that, depending upon their initial distribution, planetary eccentricities can statistically increase or decrease as a result of gravitational interactions. We find that planetary masses and orbital spacings provided by planet formation models do not result in eccentricity distributions comparable to observed exoplanet eccentricities, requiring other phenomena, such as stellar fly-bys, to account for observed eccentricities.

Global models of planet formation and evolution

Despite the strong increase in observational data on extrasolar planets, the processes that led to the formation of these planets are still not well understood. However, thanks to the high number of extrasolar planets that have been discovered, it is now possible to look at the planets as a population that puts statistical constraints on theoretical formation models. A method that uses these constraints is planetary population synthesis where synthetic planetary populations are generated and compared to the actual population. The key element of the population synthesis method is a global model of planet formation and evolution. These models directly predict observable planetary properties based on properties of the natal protoplanetary disc, linking two important classes of astrophysical objects. To do so, global models build on the simplified results of many specialized models that address one specific physical mechanism. We thoroughly review the physics of the sub-models included in global formation models. The sub-models can be classified as models describing the protoplanetary disc (of gas and solids), those that describe one (proto)planet (its solid core, gaseous envelope and atmosphere), and finally those that describe the interactions (orbital migration and N-body interaction). We compare the approaches taken in different global models, discuss the links between specialized and global models, and identify physical processes that require improved descriptions in future work. We then shortly address important results of planetary population synthesis like the planetary mass function or the mass-radius relationship. With these statistical results, the global effects of physical mechanisms occurring during planet formation and evolution become apparent, and specialized models describing them can be put to the observational test. Owing to their nature as meta models, global models depend on the results of specialized models, and therefore on the development of the field of planet formation theory as a whole. Because there are important uncertainties in this theory, it is likely that the global models will in future undergo significant modifications. Despite these limitations, global models can already now yield many testable predictions. With future global models addressing the geophysical characteristics of the synthetic planets, it should eventually become possible to make predictions about the habitability of planets based on their formation and evolution.

Code-switching: a touchstone of models of bilingual language production

The goal of the present thesis was to investigate the production of code-switched utterances in bilinguals’ speech production. This study investigates the availability of grammatical-category information during bilingual language processing. The specific aim is to examine the processes involved in the production of Persian-English bilingual compound verbs (BCVs). A bilingual compound verb is formed when the nominal constituent of a compound verb is replaced by an item from the other language. In the present cases of BCVs the nominal constituents are replaced by a verb from the other language. The main question addressed is how a lexical element corresponding to a verb node can be placed in a slot that corresponds to a noun lemma. This study also investigates how the production of BCVs might be captured within a model of BCVs and how such a model may be integrated within incremental network models of speech production. In the present study, both naturalistic and experimental data were used to investigate the processes involved in the production of BCVs. In the first part of the present study, I collected 2298 minutes of a popular Iranian TV program and found 962 code-switched utterances. In 83 (8%) of the switched cases, insertions occurred within the Persian compound verb structure, hence, resulting in BCVs. As to the second part of my work, a picture-word interference experiment was conducted. This study addressed whether in the case of the production of Persian-English BCVs, English verbs compete with the corresponding Persian compound verbs as a whole, or whether English verbs compete with the nominal constituents of Persian compound verbs only. Persian-English bilinguals named pictures depicting actions in 4 conditions in Persian (L1). In condition 1, participants named pictures of action using the whole Persian compound verb in the context of its English equivalent distractor verb. In condition 2, only the nominal constituent was produced in the presence of the light verb of the target Persian compound verb and in the context of a semantically closely related English distractor verb. In condition 3, the whole Persian compound verb was produced in the context of a semantically unrelated English distractor verb. In condition 4, only the nominal constituent was produced in the presence of the light verb of the target Persian compound verb and in the context of a semantically unrelated English distractor verb. The main effect of linguistic unit was significant by participants and items. Naming latencies were longer in the nominal linguistic unit compared to the compound verb (CV) linguistic unit. That is, participants were slower to produce the nominal constituent of compound verbs in the context of a semantically closely related English distractor verb compared to producing the whole compound verbs in the context of a semantically closely related English distractor verb. The three-way interaction between version of the experiment (CV and nominal versions), linguistic unit (nominal and CV linguistic units), and relation (semantically related and unrelated distractor words) was significant by participants. In both versions, naming latencies were longer in the semantically related nominal linguistic unit compared to the response latencies in the semantically related CV linguistic unit. In both versions, naming latencies were longer in the semantically related nominal linguistic unit compared to response latencies in the semantically unrelated nominal linguistic unit. Both the analysis of the naturalistic data and the results of the experiment revealed that in the case of the production of the nominal constituent of BCVs, a verb from the other language may compete with a noun from the base language, suggesting that grammatical category does not necessarily provide a constraint on lexical access during the production of the nominal constituent of BCVs. There was a minimal context in condition 2 (the nominal linguistic unit) in which the nominal constituent was produced in the presence of its corresponding light verb. The results suggest that generating words within a context may not guarantee that the effect of grammatical class becomes available. A model is proposed in order to characterize the processes involved in the production of BCVs. Implications for models of bilingual language production are discussed.

Calibrating a CGE model with NTBs that Incorporates Standard Models of Modern Trade Theory

We propose a way to incorporate NTBs for the four workhorse models of the modern trade literature in computable general equilibrium models (CGEs). CGE models feature intermediate linkages and thus allow us to study global value chains (GVCs). We show that the Ethier-Krugman monopolistic competition model, the Melitz firm heterogeneity model and the Eaton and Kortum model can be defined as an Armington model with generalized marginal costs, generalized trade costs and a demand externality. As already known in the literature in both the Ethier-Krugman model and the Melitz model generalized marginal costs are a function of the amount of factor input bundles. In the Melitz model generalized marginal costs are also a function of the price of the factor input bundles. Lower factor prices raise the number of firms that can enter the market profitably (extensive margin), reducing generalized marginal costs of a representative firm. For the same reason the Melitz model features a demand externality: in a larger market more firms can enter. We implement the different models in a CGE setting with multiple sectors, intermediate linkages, non-homothetic preferences and detailed data on trade costs. We find the largest welfare effects from trade cost reductions in the Melitz model. We also employ the Melitz model to mimic changes in Non tariff Barriers (NTBs) with a fixed cost-character by analysing the effect of changes in fixed trade costs. While we work here with a model calibrated to the GTAP database, the methods developed can also be applied to CGE models based on the WIOD database.

Input Aggregation in Models of Data Envelopment Analysis: A Statistical Test with an Application to Indian Manufacturing

A problem frequently encountered in Data Envelopment Analysis (DEA) is that the total number of inputs and outputs included tend to be too many relative to the sample size. One way to counter this problem is to combine several inputs (or outputs) into (meaningful) aggregate variables reducing thereby the dimension of the input (or output) vector. A direct effect of input aggregation is to reduce the number of constraints. This, in its turn, alters the optimal value of the objective function. In this paper, we show how a statistical test proposed by Banker (1993) may be applied to test the validity of a specific way of aggregating several inputs. An empirical application using data from Indian manufacturing for the year 2002-03 is included as an example of the proposed test.

The Devil’s Calculus: Mathematical Models of Civil War

In spite of the movement to turn political science into a real science, various mathematical methods that are now the staples of physics, biology, and even economics are thoroughly uncommon in political science, especially the study of civil war. This study seeks to apply such methods - specifically, ordinary differential equations (ODEs) - to model civil war based on what one might dub the capabilities school of thought, which roughly states that civil wars end only when one side’s ability to make war falls far enough to make peace truly attractive. I construct several different ODE-based models and then test them all to see which best predicts the instantaneous capabilities of both sides of the Sri Lankan civil war in the period from 1990 to 1994 given parameters and initial conditions. The model that the tests declare most accurate gives very accurate predictions of state military capabilities and reasonable short term predictions of cumulative deaths. Analysis of the model reveals the scale of the importance of rebel finances to the sustainability of insurgency, most notably that the number of troops required to put down the Tamil Tigers is reduced by nearly a full order of magnitude when Tiger foreign funding is stopped. The study thus demonstrates that accurate foresight may come of relatively simple dynamical models, and implies the great potential of advanced and currently unconventional non-statistical mathematical methods in political science.

Age models of sediment cores from the Southern Ocean

Recent geochemical models invoke ocean alkalinity changes, particularly in the surface Southern Ocean, to explain glacial age pCO2 reduction. In such models, alkalinity increases in glacial periods are driven by reductions in North Atlantic Deep Water (NADW) supply, which lead to increases in deep-water nutrients and dissolution of carbonate sediments, and to increased alkalinity of Circumpolar Deep Water upwelling in the surface Southern Ocean. We use cores from the Southeast Indian Ridge and from the deep Cape Basin in the South Atlantic to show that carbonate dissolution was enhanced during glacial stages in areas now bathed by Circumpolar Deep Water. This suggests that deep Southern Ocean carbonate ion concentrations were lower in glacial stages than in interglacials, rather than higher as suggested by the polar alkalinity model [Broecker and Peng, 1989, doi:10.1029/GB001i001p00015]. Our observations show that changes in Southern Ocean CaCO3 preservation are coherent with changes in the relative flux of NADW, suggesting that Southern Ocean carbonate chemistry is closely linked to changes in deepwater circulation. The pattern of enhanced dissolution in glacials is consistent with a reduction in the supply of nutrient-depleted water (NADW) to the Southern Ocean and with an increase of nutrients in deep water masses. Carbonate mass accumulation rates on the Southeast Indian Ridge (3200-3800 m), and in relatively shallow cores (<3000 m) from the Kerguelen Plateau and the South Pacific were significantly reduced during glacial stages, by about 50%. The reduced carbonate mass accumulation rates and enhanced dissolution during glacials may be partly due to decreases in CaCO3:Corg flux ratios, acting as another mechanism which would raise the alkalinity of Southern Ocean surface waters. The polar alkalinity model assumes that the ratio of organic carbon to carbonate production on surface alkalinity is constant. Even if overall productivity in the Southern Ocean were held constant, a decrease in the CaCO3:Corg ratio would result in increased alkalinity and reduced pCO2 in Southern Ocean surface waters during glacials. This ecologically driven surface alkalinity change may enhance deepwater-mediated changes in alkalinity, and amplify rapid changes in pCO2.

Comparing the quality of three models of postabortion care in public hospitals in Mexico City

artículo publicado en la revista Int Fam Plan Perspect. 2003 Sep;29(3):112-20

Age models of ODP sites from the Barents Sea-Svalbard region

Based on a revised chronostratigraphy, and compilation of borehole data from the Barents Sea continental margin, a coherent glaciation model is proposed for the Barents Sea ice sheet over the past 3.5 million years (Ma). Three phases of ice growth are suggested: (1) The initial build-up phase, covering mountainous regions and reaching the coastline/shelf edge in the northern Barents Sea during short-term glacial intensification, is concomitant with the onset of the Northern Hemisphere Glaciation (3.6-2.4 Ma). (2) A transitional growth phase (2.4-1.0 Ma), during which the ice sheet expanded towards the southern Barents Sea and reached the northwestern Kara Sea. This is inferred from step-wise decrease of Siberian river-supplied smectite-rich sediments, likely caused by ice sheet blockade and possibly reduced sea ice formation in the Kara Sea as well as glacigenic wedge growth along the northwestern Barents Sea margin hampering entrainment and transport of sea ice sediments to the Arctic-Atlantic gateway. (3) Finally, large-scale glaciation in the Barents Sea occurred after 1 Ma with repeated advances to the shelf edge. The timing is inferred from ice grounding on the Yermak Plateau at about 0.95 Ma, and higher frequencies of gravity-driven mass movements along the western Barents Sea margin associated with expansive glacial growth.

Age models of five ice cores from the Dronning Maud Land, Antarctica

For the first time, annually resolved accumulation rates have been determined in central Antarctica by means of counting seasonal signals of ammonium, calcium, and sodium. All records, obtained from three intermediate depth ice cores from Dronning Maud Land, East Antarctica, show rather constant accumulation rates throughout the last 9 centuries with mean values of 63, 61, and 44 mm H2O yr**-1 and a typical year-to-year variation of about 30%. For the last few decades, no trend was detected accounting for the high natural variability of all records. A significant weak intersite correlation is apparent only between two cores when the high-frequency part with periods less than 30 years is removed. By analyzing the records in the frequency domain, no persistent periods were found. This suggests that the snow accumulation in this area is mainly influenced by local deposition patterns and may be additionally masked by redistribution of snow due to wind. By comparing accumulation rates over the last 2 millennia a distinct change in the layer thickness in one of the three cores was found, which might be attributed either to an area upstream of the drilling site with lower accumulation rates, or to deposition processes influenced by surface undulations. The missing of a clear correlation between the accumulation rate histories at the three locations is also important for the interpretation of small, short time variations of past precipitation records obtained from deep ice cores.

Age models of ODP Site 184-1143

Here we present an improved astronomical timescale since 5 Ma as recorded in the ODP Site 1143 in the southern South China Sea, using a recently published Asian summer monsoon record (hematite to goethite content ratio, Hm/Gt) and a parallel benthic d18O record. Correlation of the benthic d18O record to the stack of 57 globally distributed benthic d18O records (LR04 stack) and the Hm/Gt curve to the 65°N summer insolation curve is a particularly useful approach to obtain refined timescales. Hence, it constitutes the basis for our effort. Our proposed modifications result in a more accurate and robust chronology than the existing astronomical timescale for the ODP Site 1143. This updated timescale further enables a detailed study of the orbital variability of low-latitude Asian summer monsoon throughout the Plio-Pleistocene. Comparison of the Hm/Gt record with the d18O record from the same core reveals that the oscillations of low-latitude Asian summer monsoon over orbital scales differed considerably from the glacial-interglacial climate cycles. The popular view that summer monsoon intensifies during interglacial stages and weakens during glacial stages appears to be too simplistic for low-latitude Asia. In low-latitude Asia, some strong summer monsoon intervals appear to have also occurred during glacial stages in addition to their increased occurrence during interglacial stages. Vice versa, some notably weak summer monsoon intervals have also occurred during interglacial stages next to their anticipated occurrence during glacial stages. The well-known mid-Pleistocene transition (MPT) is only identified in the benthic d18O record but not in the Hm/Gt record from the same core. This suggests that the MPT may be a feature of high- and middle-latitude climates, possibly determined by high-latitude ice sheet dynamics. For low-latitude monsoonal climate, its orbital-scale variations respond more directly to insolation and are little influenced by high-latitude processes, thus the MPT is likely not recorded. In addition, the Hm/Gt record suggests that low-latitude Asian summer monsoon intensity has a long-term decreasing trend since 2.8 Ma with increased oscillation amplitude. This long-term variability is presumably linked to the Northern Hemisphere glaciation since then.