The P-chain: relating sentence production and its disorders to comprehension and acquisition

This article introduces the P-chain, an emerging framework for theory in psycholinguistics that unifies research on comprehension, production and acquisition. The framework proposes that language processing involves incremental prediction, which is carried out by the production system. Prediction necessarily leads to prediction error, which drives learning, including both adaptive adjustment to the mature language processing system as well as language acquisition. To illustrate the P-chain, we review the Dual-path model of sentence production, a connectionist model that explains structural priming in production and a number of facts about language acquisition. The potential of this and related models for explaining acquired and developmental disorders of sentence production is discussed.     

Postprandial chylomicrons: potent vehicles for transporting cholesterol from endogenous LDL+HDL and cell membranes to the liver via LCAT and CETP

We examined whether postprandial (PP) chylomicrons (CMs) can serve as vehicles for transporting cholesterol from endogenous cholesterol-rich lipoprotein (LDL+HDL) fractions and cell membranes to the liver via lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities. During incubation of fresh fasting and PP plasma containing [(3)H]cholesteryl ester (CE)-labeled LDL+HDL, both CMs and VLDL served as acceptors of [(3)H]CE or cholesterol from LDL+HDL. The presence of CMs in PP plasma suppressed the ability of VLDL to accept [(3)H]CE from LDL+HDL. In reconstituted plasma containing an equivalent amount of triglycerides from isolated VLDL or CMs, a CM particle was about 40 times more potent than a VLDL particle in accepting [(3)H]CE or cholesterol from LDL+HDLs. When incubated with red blood cells (RBCs) as a source for cell membrane cholesterol, the cholesterol content of CMs, VLDL, LDL, and HDL in PP plasma increased by 485%, 74%, 13%, and 30%, respectively, via LCAT and CETP activities. The presence of CMs in plasma suppressed the ability of endogenous lipoproteins to accept cholesterol from RBCs. Our data suggest that PP CMs may play an important role in promoting reverse cholesterol transport in vivo by serving as the preferred ultimate vehicle for transporting cholesterol released from cell membranes to the liver via LCAT and CETP.     

Mitochondrial function, zinc, and intermediary metabolism relationships in normal prostate and prostate cancer

Human prostate secretory epithelial cells have the uniquely specialized function of accumulating and secreting extremely high levels of citrate. This is achieved by their ability to accumulate high cellular levels of zinc that inhibit citrate oxidation. This process of net citrate production requires unique metabolic/bioenergetic mitochondrial relationships. In prostate cancer, the malignant cells undergo a metabolic transformation from zinc-accumulating citrate-producing sane cells to citrate-oxidizing malignant cells that lost the ability to accumulate zinc. This review describes the metabolic/bioenergetic, zinc and mitochondrial relationships involved in normal and malignant prostate. Hopefully, this report will generate much needed interest and research in this neglected, but critically important, area of investigation.     

The bioelectric field of the catfish Ictalurus nebulosus.

The variability of the bioelectric field of the electrosensitive catfish, Ictalurus nebulosus, was investigated by recording the potential variation occurring when the fish passed a stationary electrode, and by recording the field of a stationary fish by a 15-electrode array. A good first order approximation of the recorded field of a 20 cm long fish is a dipole dc source with the source and sink about 7 cm apart, carrying a current of about 1 microA in water with a specific resistivity of 3.3 kohm cm. At 5 cm distance from the dipole axis such a source generates an electric potential swing in the order of 50 microV in free space, head negative, tail positive. Superimposed on the basic component are respiration related fluctuations, and fluctuations related to the activity of the alimentary canal, gills, and skin. Novel stimuli, or stressors like investigators approaching the aquarium, evoke sudden increases in field strength. which last about 15 min. Demineralization of the aquarium water causes changes in field strength and reversal of field polarity. The administration of food causes field variations in the vicinity of the anal opening. The bioelectric field shows diurnal fluctuations of 100 microV. The peak is at about 04:00, the dip at 14:00. The fluctuations of the bioelectric field are sufficiently strong and specilic to serve as electrical stimuli to other electrosensitive catfish. It is suggested that the field changes allow a simple form of electrocommunication. i.e. inform conspecifics about some physiological properties of the field source. The cellular mechanisms underlying the fluctuations of the bioelectric field are homeostatic processes mediated by ion pumps and ion channels.     

Efficacy of the hydrogeomorphic model (HGM): A case study from western Tennessee

Hydrogeomorphic models (HGM) for wetland classification and functional assessment have been developed for several regions in the United States. However, validation of models is lacking, even though models are already in use and the general idea is that each is a working model, developing over time with new ideas and information. We examined the HGM developed for western Tennessee using novel data collected from six stream systems, two channelized, two channelized and leveed, and two unchannelized. The western Tennessee HGM has the ability to differentiate altered and unaltered rivers based mainly on changes to hydrologic floodplain functions, although functional capacity index values were validated from independent measures. Effects of channelization were confounded in western Tennessee by other disturbances, channel recovery processes, and variability due to levee construction. Levees render the greatest change to floodplains as they disconnect the channel and floodplain system, decreasing water tables and possible exchanges. One of the main factors controlling productivity along channels without levees was sedimentation. We recommend that estimated rates of sedimentation be incorporated into an updated version of the HGM. Variability of human alterations and natural floodplain heterogeneity suggest landscape factors (e.g., beta diversity, degree of ponding) and use of gradient indices may result in greater resolution for determining functional capacity of low gradient, riverine systems.     

Genomic runs of homozygosity record population history and consanguinity

The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (N(e)), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental N(e) (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects.     

Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer

Background

Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease.

Methodology/Principal Findings

We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with ≥10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90α, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES) that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC.

Conclusions/Significance

This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification of classifier performance provides evidence against over-fitting and is encouraging for the next development phase, independent validation. This careful study provides a solid foundation to develop tests sorely needed to identify early stage lung cancer.     

A dual-targeting PDGFRβ/VEGF-A molecule assembled from stable antibody fragments demonstrates anti-angiogenic activity in vitro and in vivo

Targeting angiogenesis is a promising approach to the treatment of solid tumors and age-related macular degeneration (AMD). Inhibition of vascularization has been validated by the successful marketing of monoclonal antibodies (mAbs) that target specific growth factors or their receptors, but there is considerable room for improvement in existing therapies. Combination of mAbs targeting both the VeGF and pDGF pathways has the potential to increase the efficacy of anti-angiogenic therapy without the accompanying toxicities of tyrosine kinase inhibitors and the inability to combine efficiently with traditional chemotherapeutics. However, development costs and regulatory issues have limited the use of combinatorial approaches for the generation of more efficacious treatments.The concept of mediating disease pathology by targeting two antigens with one therapeutic was proposed over two decades ago. While mAbs are particularly suitable candidates for a dual-targeting approach, engineering bispecificity into one molecule can be difficult due to issues with expression and stability, which play a significant role in manufacturability. Here, we address these issues upstream in the process of developing a bispecific antibody (bsAb). Single-chain antibody fragments (scFvs) targeting pDGFRβ and VeGF-A were selected for superior stability. the scFvs were fused to both termini of human Fc to generate a bispecific, tetravalent molecule. resulting molecule displays potent activity, binds both targets simultaneously, and is stable in serum. assembly of a bsAb using stable monomeric units allowed development of an anti-pDGFRB/VeGF-A antibody capable of attenuating angiogenesis through two distinct pathways and represents an efficient method for rapid engineering of dual-targeting molecules.Key words: bispecific, antibody, PDGFRβ, VEGF-A, stability, angiogenesis     

Species traits affect the performance of species distribution models for plants in southern California

Questions: To what extent do plant species traits, including life history, life form, and disturbance response characteristics, affect the degree to which species distributions are determined by physical environmental factors? Is the strength of the relationship between species distribution and environment stronger in some disturbance‐response types than in others? Location: California southwest ecoregion, USA. Methods: We developed species distribution models (SDMs) for 45 plant species using three primary modeling methods (GLMs, GAMs, and Random Forests). Using AUC as a performance measure of prediction accuracy, and measure of the strength of species–environment correlations, we used regression analyses to compare the effects of fire disturbance response type, longevity, dispersal mechanism, range size, cover, species prevalence, and model type. Results: Fire disturbance response type explained more variation in model performance than any other variable, but other species and range characteristics were also significant. Differences in prediction accuracy reflected variation in species life history, disturbance response, and rarity. AUC was significantly higher for longer‐lived species, found at intermediate levels of abundance, and smaller range sizes. Models performed better for shrubs than sub‐shrubs and perennial herbs. The disturbance response type with the highest SDM accuracy was obligate‐seeding shrubs with ballistic dispersal that regenerate via fire‐cued germination from a dormant seed bank. Conclusions: The effect of species characteristics on predictability of species distributions overrides any differences in modeling technique. Prediction accuracy may be related to how a suite of species characteristics co‐varies along environmental gradients. Including disturbance response was important because SDMs predict the realized niche. Classification of plant species into disturbance response types may provide a strong framework for evaluating performance of SDMs.