Working Memory Cells' Behavior May Be Explained by Cross-Regional Networks with Synaptic Facilitation

Neurons in the cortex exhibit a number of patterns that correlate with working memory. Specifically, averaged across trials of working memory tasks, neurons exhibit different firing rate patterns during the delay of those tasks. These patterns include: 1) persistent fixed-frequency elevated rates above baseline, 2) elevated rates that decay throughout the tasks memory period, 3) rates that accelerate throughout the delay, and 4) patterns of inhibited firing (below baseline) analogous to each of the preceding excitatory patterns. Persistent elevated rate patterns are believed to be the neural correlate of working memory retention and preparation for execution of behavioral/motor responses as required in working memory tasks. Models have proposed that such activity corresponds to stable attractors in cortical neural networks with fixed synaptic weights. However, the variability in patterned behavior and the firing statistics of real neurons across the entire range of those behaviors across and within trials of working memory tasks are typical not reproduced. Here we examine the effect of dynamic synapses and network architectures with multiple cortical areas on the states and dynamics of working memory networks. The analysis indicates that the multiple pattern types exhibited by cells in working memory networks are inherent in networks with dynamic synapses, and that the variability and firing statistics in such networks with distributed architectures agree with that observed in the cortex

Comparison of methods for handling missing data on immunohistochemical markers in survival analysis of breast cancer

Background:Tissue micro-arrays (TMAs) are increasingly used to generate data of the molecular phenotype of tumours in clinical epidemiology studies, such as studies of disease prognosis. However, TMA data are particularly prone to missingness. A variety of methods to deal with missing data are available. However, the validity of the various approaches is dependent on the structure of the missing data and there are few empirical studies dealing with missing data from molecular pathology. The purpose of this study was to investigate the results of four commonly used approaches to handling missing data from a large, multi-centre study of the molecular pathological determinants of prognosis in breast cancer.Patients and Methods:We pooled data from over 11 000 cases of invasive breast cancer from five studies that collected information on seven prognostic indicators together with survival time data. We compared the results of a multi-variate Cox regression using four approaches to handling missing data-complete case analysis (CCA), mean substitution (MS) and multiple imputation without inclusion of the outcome (MI) and multiple imputation with inclusion of the outcome (MI). We also performed an analysis in which missing data were simulated under different assumptions and the results of the four methods were compared.Results:Over half the cases had missing data on at least one of the seven variables and 11 percent had missing data on 4 or more. The multi-variate hazard ratio estimates based on multiple imputation models were very similar to those derived after using MS, with similar standard errors. Hazard ratio estimates based on the CCA were only slightly different, but the estimates were less precise as the standard errors were large. However, in data simulated to be missing completely at random (MCAR) or missing at random (MAR), estimates for MI were least biased and most accurate, whereas estimates for CCA were most biased and least accurate.Conclusion:In this study, empirical results from analyses using CCA, MS, MI and MI were similar, although results from CCA were less precise. The results from simulations suggest that in general MI is likely to be the best. Given the ease of implementing MI in standard statistical software, the results of MI and CCA should be compared in any multi-variate analysis where missing data are a problem. © 2011 Cancer Research UK. All rights reserved

D3-instantons, Mock Theta Series and Twistors

The D-instanton corrected hypermultiplet moduli space of type II string theory compactified on a Calabi-Yau threefold is known in the type IIA picture to be determined in terms of the generalized Donaldson-Thomas invariants, through a twistorial construction. At the same time, in the mirror type IIB picture, and in the limit where only D3-D1-D(-1)-instanton corrections are retained, it should carry an isometric action of the S-duality group SL(2,Z). We prove that this is the case in the one-instanton approximation, by constructing a holomorphic action of SL(2,Z) on the linearized twistor space. Using the modular invariance of the D4-D2-D0 black hole partition function, we show that the standard Darboux coordinates in twistor space have modular anomalies controlled by period integrals of a Siegel-Narain theta series, which can be canceled by a contact transformation generated by a holomorphic mock theta series.Comment: 42 pages; discussion of isometries is amended; misprints correcte

Influence of root and leaf traits on the uptake of nutrients in cover crops

Aims: Cover crops play an important role in soil fertility as they can accumulate large amounts of nutrients. This study aimed at understanding the nutrient uptake capacity of a wide range of cover crops and at assessing the relevance of acquisition strategies. Methods: A field experiment was conducted to characterize 20 species in terms of leaf and root traits. Plant traits were related to nutrient concentration and shoot biomass production with a redundancy analysis. Acquisition strategies were identified using a cluster analysis. Results: Root systems varied greatly among cover crop species. Five nutrient acquisition strategies were delineated. Significant amounts of nutrients (about 120 kg ha−1 of nitrogen, 30 kg ha−1 of phosphorus and 190 kg ha−1 of potassium) were accumulated by the species in a short period. Nutrient acquisition strategies related to high accumulations of nutrients consisted in either high shoot biomass and root mass and dense tissues, or high nutrient concentrations and root length densities. Species with high root length densities showed lower C/N ratios. Conclusions: The same amounts of nutrients were accumulated by groups with different acquisition strategies. However, their nutrient concentrations offer different perspectives in terms of nutrient release for the subsequent crop and nutrient cycling improvement

Dairy consumption and cardiometabolic diseases: systematic review and updated meta-analyses of prospective cohort studies

Purpose of Review Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by reviewing the literature and updating meta-analyses of observational studies. Recent Findings We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with a 3–4% lower risk of diabetes. Yogurt was non-linearly inversely associatedwith diabetes (RR = 0.86, 95%CI: 0.83–0.90 at 80 g/ d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with an 8% lower risk of stroke. Summary The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic diseases

Obesity, antenatal depression, diet and gestational weight gain in a population cohort study

Purpose: The aims of this paper are to examine: (1) the relationship between high pre-pregnancy BMI and antenatal depression; (2) whether BMI and antenatal depression interact to predict diet and gestational weight gain (GWG). Methods: Data came from the Avon Longitudinal Study of Parents and Children (ALSPAC). Underweight women were excluded. Pre-pregnancy BMI was self-reported and antenatal depression was assessed using the Edinburgh Postnatal Depression Scale at 18 and 32 weeks’ gestation to identify persistently elevated depressive symptoms (EPDS>12). Dietary patterns were calculated from food frequency questionnaires at 32 weeks’ gestation. GWG was categorised using the USA Institute of Medicine guidelines. Results: This study included 13,314 pregnant women. Obese women had significantly higher odds of antenatal depression than normal weight controls after adjusting for sociodemographics and health behaviours (aOR 1.39, 95%CI 1.05–1.84). Every unit increase in pre-pregnancy BMI was associated with approximately 3% higher odds of antenatal depression (aOR 1.03, 95%CI 1.01-1.05). Antenatal depression was not meaningfully associated with dietary patterns after adjusting for confounders and was not associated with inadequate or excessive GWG. There was no evidence for an interaction of depression and BMI on either diet or GWG. Conclusions Healthcare professionals should be aware of the dose-response relationship between high pre-pregnancy BMI and antenatal depression

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

RNAi Screening in Drosophila Cells Identifies New Modifiers of Mutant Huntingtin Aggregation

The fruitfly Drosophila melanogaster is well established as a model system in the study of human neurodegenerative diseases. Utilizing RNAi, we have carried out a high-throughput screen for modifiers of aggregate formation in Drosophila larval CNS-derived cells expressing mutant human Huntingtin exon 1 fused to EGFP with an expanded polyglutamine repeat (62Q). 7200 genes, encompassing around 50% of the Drosophila genome, were screened, resulting in the identification of 404 candidates that either suppress or enhance aggregation. These candidates were subjected to secondary screening in normal length (18Q)-expressing cells and pruned to remove dsRNAs with greater than 10 off-target effects (OTEs). De novo RNAi probes were designed and synthesized for the remaining 68 candidates. Following a tertiary round of screening, 21 high confidence candidates were analyzed in vivo for their ability to modify mutant Huntingtin-induced eye degeneration and brain aggregation. We have established useful models for the study of human HD using the fly, and through our RNAi screen, we have identified new modifiers of mutant human Huntingtin aggregation and aggregate formation in the brain. Newly identified modifiers including genes related to nuclear transport, nucleotide processes, and signaling, may be involved in polyglutamine aggregate formation and Huntington disease cascades

Early life factors, childhood cognition and postal questionnaire response rate in middle age: the Aberdeen Children of the 1950s study

BACKGROUND: Little is known about the relationship between early life factors and survey response in epidemiological studies of adults. METHODS: The Children of the 1950s cohort is composed of 12,150 children (boys 51.7%) born in Aberdeen 1950–56 and in primary schools in the city in 1962. Information on birth weight, gestational age, growth, behaviour and socio-economic position at birth and in childhood were obtained from contemporaneous records. Cognitive test scores at ages 7,9 and 11 years were also available from school records. The outcome was response to a postal questionnaire sent (2001–2003) to surviving cohort members in middle age. RESULTS: Of 11,282 potentially mailed subjects, 7,183 (63.7%) returned questionnaires. Response rates were highest among females, and those whose parents were married at birth, were in a non-manual social class at birth or in childhood, had fewer siblings, were taller and heavier in childhood for their age and had lower Rutter B behavioural scores. Childhood cognitive test scores at every age were strongly and positively related to the response rate to a postal questionnaire independently of other early life factors monotonically across the entire range of test scores. Those in the bottom fifth at age 11 had a response rate of 49% while those in the top fifth 75%. CONCLUSION: The strength and consistency of the association of childhood cognition with questionnaire response rate in middle age is surprisingly large. It suggests that childhood cognition across the entire normal range is a powerful influence on the complex set of later behaviours that comprise questionnaire response. The extent of possible response bias in epidemiological studies of the associations between childhood characteristics (particularly those related to cognition) and later health is probably larger than is generally realised, at least in situations where the survey instrument is a postal questionnaire

Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance

In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) α-synuclein (αS) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braak’s and McKeith’s, currently in use for the assessment of αS pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 αS-positive-subjects. These subject were selected from a large autopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection of αS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of αS-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of αS-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread αS pathology (Braak’s PD stages 5–6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer’s disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with αS pathology. However, finding that around half of the subjects with abundant αS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process