text:
To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:358
Relationship: 358
The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form "upstream KE leads to downstream KE". More help
Synaptogenesis, Decreased leads to Neuronal network function, Decreased
Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Synaptogenesis, Decreased
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Neuronal network function, Decreased
Key Event Relationship Overview
The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help
AOPs Referencing Relationship
This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
Adjacency
Quantitative Understanding
Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities adjacent Low Agnes Aggy (send email) Open for citation & comment TFHA/WNT Endorsed
Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment adjacent Low Low Arthur Author (send email) Open for citation & comment TFHA/WNT Endorsed
Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Scientific Term
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI
Caenorhabditis elegans Caenorhabditis elegans Moderate NCBI
Drosophila melanogaster Drosophila melanogaster Moderate NCBI
Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Mixed High
Life Stage Applicability
Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
During brain development High
Key Event Relationship Description
Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren't inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help
The ability of a neuron to communicate is based on neural network formation that relies on functional synapse establishment (Colón-Ramos, 2009). The main roles of synapses are the regulation of intercellular communication in the nervous system, and the information flow within neural networks. The connectivity and functionality of neural networks depends on where and when synapses are formed. Therefore, the decreased synapse formation during the process of synaptogenesis is critical and leads to decrease of neural network formation and function in the adult brain.
Synaptic transmission and plasticity require the integrity of the anatomical substrate. The connectivity of axons emanating from one set of cells to post-synaptic side of synapse on the dendrites of the receiving cells must be intact for effective communication between neurons. Changes in the placement of cells within the network due to delays in neuronal migration, the absence of a full formation of dendritic arbors and spine upon which synaptic contacts are made, and the lagging of transmission of electrical impulses due to insufficient myelination will individually and cumulatively impair synaptic function. Since synaptogenesis follows the early neurodevelopmental processes such as neuronal and glial cells proliferation, migration, alterations in dendritic arborisation etc., therefore, it encompasses, possible changes in these early stages of brain development that could also be triggered under hypothyroidism, leading to defective synaptogenesis and resulting in abnormal function of neuronal network function. These anatomical alterations are responsible for many structural anomalies reported in various regions of the brain following severe developmental hypothyroidism. Although the primary evidence of synaptic transmission impairments in hypothyroid models have come from studying the hippocampus, it is assumed that the role thyroid hormones play in these processes is likely similar across different brain regions. Altered hippocampal structure induced by decreased TH levels impacts neurogenesis in the developing hippocampus or cortex, contributing to deficits in synaptic function.
Evidence Supporting this KER
Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
The weight of evidence supporting the relationship between decreased synaptogenesis induced by TH insufficiency and altered neuronal network and synaptic function is moderate. Functional change as exemplified by alterations in synaptic transmission may be more easily detected than structural abnormalities. The exact alignment between the neuroanatomical effects (such as decreased synaptogenesis and alteration of GABAergic interneurons) that have been associated with developmental hypothyroidism (e.g., elicited by exposing rat dams to TPO inhibitors) and the neurophysiological impairments has not been entirely elucidated.
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme's activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information). More help
Neuronal network formation and function are established via the process of synaptogenesis. The developmental period of synaptogenesis is critical for the formation of the basic circuitry of the nervous system, although neurons are able to form new synapses throughout life (Rodier, 1995). The brain electrical activity dependence on synapse formation is critical for proper neuronal communication.
Alterations in synaptic connectivity lead to refinement of neuronal networks during development (Cline and Haas, 2008). Indeed, knockdown of PSD-95 arrests the functional and morphological development of glutamatergic synapses (Ehrlich et al., 2007).
The biological plausibility of the known effects of TH insufficiency on brain structure having an impact on synaptic function and plasticity in brain is strong. Reductions in myelination of axons, cell number, dendritic arborization, and synaptogenesis have been described in models of severe hormone deprivation, as comprehensively summarized by Thompson and Potter, 2000. Because synaptic transmission relies on the integrity of synaptic contacts and the electrical and chemical transmission between pre- and post-synaptic neurons, it is well accepted that interference with process of synapse formation (morphological unit of neuronal network) will very much impact the neural network function.
In this section authors are encouraged to cite specific evidence that supports the idea that a change in the upstream KE (KEupstream) will lead to, or is associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. Given the likelihood that new empirical support will be developed over time, particularly as various AOPs are tested and applied, it is most practical to provide empirical support in the form of bulleted lists or tables that include a short description of the nature of the empirical support along with the corresponding reference(s).In particular, it is useful to cite evidence showing that stressors that perturb KEupstream also perturb KEdownstream. Because this section of the KER description cites evidence from specific studies, it is also helpful to provide as much detail about the toxicological and biological context in which the measurements were made, as is feasible, including the stressor(s) tested, the effective doses at each KE, etc. While the KER itself is not intended to be stressor-specific, those details can aid the overall assessment of the individual AOPs that include that KER. These details also help inform the question of consistency of supporting data, consistency across different biological contexts for which the KER is relevant, and the applicability domain of the KER. However, authors are cautioned that this evidence should focus on data that only relate KEupstream to KEdownstream, and should avoid reference to other KEs, KERs and AOPs as much as possible in order to maintain modularity of the KER. Please see pages 40-41 of the User Handbook for more information. More help
Most of the information on developmental hypothyroidism and altered synaptic function has been derived from studies of the hippocampus. It is presumed that structural changes of synaptic connectivity at certain level may lead to functional deficits in synaptic transmission and plasticity impairments (Vara et al., 2002, Sui and Gilbert, 2003, Gilbert, 2004, Dong et al., 2005, Sui et al., 2005), but the precise structural aberration is not known. Within the hippocampus, area CA1 has been investigated primarily with in vitro techniques, using slices of hippocampus from animals exposed to TPO inhibitors (MMI or PTU) and measuring synaptic function across CA1-pyramidal cell synapses (Vara et al., 2002, Sui and Gilbert, 2003, Gilbert, 2004, Taylor et al., 2008). Pyramidal neurons of hypothyroid animals have fewer synapses and an impoverished dendritic arbor (Rami et al., 1986a, Madeira et al., 1992), with reductions ranging between 14.2 and 22.5% as observed in 30 and 180-day-old hypothyroid rats (as described by Madeira et al., 1992).
The other major region in hippocampus investigated in hypothyroid models is the perforant path-dentate gyrus synapse (Gilbert, 2011). Granule cells are the principal cell type of the dentate gyrus region of the hippocampal formation and receive input from cortical neurons in the entorhinal cortex. TPO inhibitors like PTU and MMI decrease the volume of the granule cell layer, the density of cells within the layer, and estimates of total granule cell number (Madeira et al., 1991). Migration of granule cells from the proliferative zone to the granule cell layer is retarded by thyroid deficiency as is dendritic arborization and synaptogenesis assessed by immunohistochemistry for the synaptic protein, synaptophysin (Rami et al., 1986b, Rami and Rabie, 1990, Dong et al., 2005). Impairments in synaptic function from both rodent and human studies are summarized below.
Excitatory and inhibitory synaptic transmission is reduced in CA region of hippocampus in animals with TH insufficiencies in early life (Vara et al., 2002, Sui and Gilbert, 2003, Gilbert, 2004, Dong et al., 2005, Sui et al., 2005). Similarly, excitatory and inhibitory synaptic transmission is reduced in the CA1 and dentate gyrus regions of the hippocampus (Gilbert and Paczkowski, 2003, Gilbert and Sui, 2006, Gilbert, 2011, Gilbert et al., 2013) under decreased TH levels. Parvalbumin (PV) is a calcium binding protein expressed exclusively in GABA inhibitory neurons of the hippocampus. Impairments in inhibitory synaptic transmission are associated with reductions in the number of PV+ cells (Gilbert et al., 2007).
- Vara et al., 2002 This study assessed effects of TH on short-term synaptic plasticity (associated with short-term memory) in control vs hypothyroid rats. Specifically, dams were treated with 0.02% methylmercaptoimidazole (MMI, TPO inhibitor) continually from GD9. A group of pups were also treated with T3 (i.p. daily injections of T3 (20 μg /100 g body weight)) starting 72 h before killing. Data showed that hypothyroid rats presented increase in the Ca(2+)-dependent neurotransmitter release, indicative of altered neuronal network function (i.e., decreased paired-pulse facilitation), and these alterations were reverted by T3 administration. These synaptic changes were determined by an increase of synapsin I and synaptotagmin I levels in the hypothyroid rats, suggesting that TH modulate neurotransmitter release. These results are in contrast with those of Di Liegro et al. (1995), who showed that in primary cultures T3 induces the expression of synapsin I. This difference could be the result of the multiple differences between the two models: different brain regions (hippocampus vs. cortex), the age of the neurons (neonatal vs. embryonic), the preparations (slice vs. culture).
- Sui and Gilbert, 2003 Here developing rats were exposed in utero and postnatally to 0, 3, or 10 ppm propylthiouracil (PTU, TPO inhibitor), administered in the drinking water of dams from GD6 until PND30. Excitatory postsynaptic potentials and population spikes (indicative of neuronal network function) were recorded in area CA1 of hippocampal slices from offspring between PND21 and PND30. PTU caused at PND30 a decrease of maternal total T4 (43.9% with 3-ppm, and 65.0% with 10-ppm) compared to controls, with no change in total T3. Maternal TSH was increased above control levels in a dose-dependent manner. In pups, total T4 was depressed (by 75%) in both treated groups relative to the controls pups, and total T3 was depressed (35.8% in the 3-ppm group and 66.5% in the 10-ppm group) relative to the controls. TH insufficiency was dose-dependently associated with a reduction of paired-pulse facilitation and long-term potentiation of the excitatory postsynaptic potential and elimination of paired-pulse depression of the population spike. Excitatory synaptic transmission was increased by developmental exposure to PTU. This suggests that TH insufficiency compromises synaptic communication in area CA1 of developing rat hippocampus (involved in learning and memory).
- Gilbert, 2004 Here developing rats were transiently exposed to PTU (0 or 15 ppm), through the drinking water of pregnant dams beginning on GD18 until PND21. This regimen markedly reduced circulating levels of TH in pups (T3: ∼50% lower than control at PND21; T4: T4 ∼40% below control levels). Analysis of field potentials in area CA1 of hippocampal slices derived from adult male offspring exposed to PTU showed a reduction of somatic population spike amplitudes, with no differences in excitatory postsynaptic potentials (EPSP). Short-term plasticity of the EPSP (as indexed by paired pulse facilitation) was markedly decreased by PTU exposure. These data confirm associations between decrease of synaptic function in the hippocampus and decrease of neuronal network function as a consequence of TH insufficiency.
- Dong et al., 2005 Through gestation and lactation, iodine-deficient or hypothyroid dam rats were administered with either iodine-deficient diet or MMI (TPO inhibitor) added to drinking water. Exposure was terminated on PND30. Both treated groups showed lower concentrations of serum FT3 (~60% decrease on PND30) and FT4 (~80% decrease on PND30), smaller population spike amplitude (~50% decrease) and field-excitatory postsynaptic potential (f-EPSP, 50-60% decrease) slope induced by high-frequency stimulation (HFS). Also, TH insufficiency decreased the levels of c-fos (by ~60% at PND30 in MMI group) and c-jun proteins (by ~20% at PND30 in MMI group) in the hippocampus. C-fos and c-jun expression is regulated by synaptic activity, both play an important role in the neuroplastic mechanisms (synaptogenesis) critical to memory consolidation, and play an essential role in neuronal differentiation (Herdegen et al., 1997).
KEs proceeding the AO (learning and memory deficits), such as "Decreased synaptogenesis" (KEup) and "Decreased Neural Network Function" (KEdown) are also common to the AOP 13, entitled "Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities" (https://aopwiki.org/aops/13). In this AOP 13, data on lead (Pb) exposure as reference chemical are reported. While these studies do not refer to TH disruption, they provide empirical support for the same KER (Decreased synaptogenesis leads to decreased neuronal network function in developing brain) described in the present AOP.
- Otto and Reiter, 1984: At low Pb2+ levels (less than 30 µg/dl), slow surface-positive cortical potentials have been observed in children under five years old, which may reflect axodendritic inhibitory processes, whilst negative slow potentials are observed in children over five years. This is due to the fact that during maturation of the cortex, the locus of inhibitory activity shifts deeper to axosomatic connections. However, age-related polarity reversal has been observed in children with higher Pb2+ levels.
- Kumar and Desiraju, 1992: In experiments carried out in Wistar rats that have been fed with lead acetate (400 µg/g body weight/day) from PND 2 until PND 60, EEG findings show statistically significant reduction in the delta, theta, alpha and beta band of EEG spectral power in motor cortex and hippocampus with the exception of the delta and beta bands power of motor cortex in wakeful state.
- McCarren and Eccles, 1983: Male Sprague-Dawley rats have been exposed to Pb2+ from parturition to weaning though their dams' milk (dams received drinking water containing 1.0, 2.5, or 5.0 mg/ml lead acetate). Starting from 15 weeks of age, the characteristics of the electrically elicited hippocampal after discharge (AD) and its alteration by phenytoin (PHT) showed significant increase in primary AD duration only in the animals exposed to the higher dose of Pb2+, whereas all groups responded to PHT with increases in primary AD duration.
The exact mechanism by which a change in cell number, reduced dendritric arborization and synaptogenesis may lead to decreased neuronal network function has not been fully elucidated. Dose-dependent reductions in synaptic function in hippocampus have been demonstrated in models of moderate degrees of TH reduction, but studies of the anatomical integrity of the specific cell populations examined electrophysiologically have largely been evaluated in models of severe hypothyroidism and often in brain regions distinct from the hippocampus.
Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don't need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook). More help
Quantitative Understanding of the Linkage
The quantitative understanding section of the KER description is intended to capture information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. Empirical support addresses whether data between the two KEs are consistent with the patterns that are expected if the upstream event is causing the downstream event to occur, while the quantitative understanding section helps to define the precision with which the state of the downstream KE can be predicted from knowledge of the state of the upstream KE. These quantitative relationships may be defined in terms of correlations, response-response relationships, dose-dependent transitions or points of departure (i.e., a threshold of change in KEupstream needed to elicit a change in KEdownstream), etc. They may take the form of simple mathematical equations or sophisticated biologically-based computational models that consider other modulating factors such as compensatory responses, or interactions with other biological or environmental variables. Regardless of form, the idea is to briefly describe what is known regarding the quantitative relationship between the KEs and cite appropriate literature that defines those relationships and/or provides support for them.Data that confer quantitative understanding of a KER are not necessarily mutually exclusive from those addressing other weight of evidence considerations. In that respect, the quantitative understanding section of the KER description is not intended to be redundant with the other WoE sections. Rather, it is intended to aid application of the AOP by allowing a reader to rapidly identify the relationships that would support a quantitative prediction of the probability or magnitude of change in KEdownstream based on a known state of KEupstream. For transparency, the toxicological and biological context in which the quantitative relationships were defined should be indicated within the description. However, the ultimate goal is to identify quantitative relationships that generalize across the entire applicability domain of the two KEs being linked via the KER. More help
There are no data on the quantitative linkages between altered (hippocampal or cortical) synaptogenesis and impaired neuronal network function. Developmental window of exposure and duration of exposure can modulate response-response relationships.
Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture. More help
Time-scale
This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook). More help
As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help
The main proof of evidence comes from in vivo studies in rodents. However, Colón-Ramos (2009) has recently reviewed the early developmental events that take place during the process of synaptogenesis in invertebrates, pointing out the importance of this process in neural network formation and function. The experimental findings reviewed in this paper derive from knowledge acquired in the field of neuroscience using C. elegans and Drosophila; at the same time, emerging findings derived from vertebrates are also discussed (Colón-Ramos, 2009).
List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help
Cline H, Haas K. (2008). The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: A review of the synaptotrophic hypothesis. J Physiol 586: 1509-1517.
Colón-Ramos DA. (2009). Synapse formation in developing neural circuits. Curr Top Dev Biol. 87: 53-79.
Di Liegro I, Savettieri G, Coppolino M, Scaturro M, Monte M, Nastasi T, Salemi G, Castiglia D, Cesterlli A (1995). Expression of synapsin I gene in primary cultures of differentiating rat cortical neurons. Neurochem. Res., 20, pp. 239–243
Dong J, Yin H, Liu W, Wang P, Jiang Y, Chen J. (2005). Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus. Neurotoxicology 26:417-426.
Ehrlich I, Klein M, Rumpel S, Malinow R. (2007). PSD-95 is required for activity-driven synapse stabilization. Proc Natl Acad Sci U S A. 104: 4176-4181.
Gilbert ME. (2004). Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism. Brain Res Dev Brain Res 148:11-18.
Gilbert ME. (2011). Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci 124:432-445.
Gilbert ME, Hedge JM, Valentin-Blasini L, Blount BC, Kannan K, Tietge J, Zoeller RT, Crofton KM, Jarrett JM, Fisher JW. (2013). An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Toxicol Sci 132:177-195.
Gilbert ME, Paczkowski C. (2003). Propylthiouracil (PTU)-induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus. Brain Res Dev Brain Res 145:19-29.
Gilbert ME, Sanchez-Huerta K, Wood C. (2016). Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.
Gilbert ME, Sui L. (2006). Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10-22.
Gilbert ME, Sui L, Walker MJ, Anderson W, Thomas S, Smoller SN, Schon JP, Phani S, Goodman JH. (2007). Thyroid hormone insufficiency during brain development reduces parvalbumin immunoreactivity and inhibitory function in the hippocampus. Endocrinology 148:92-102.
Herdegen T, Skene P, Bahr M (1997). The c-Jun transcription factor-bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci, 20, pp. 227–231
Kumar MV, Desiraju T. (1992). EEG spectral power reduction and learning disability in rats exposed to lead through postnatal developing age. Indian J Physiol Pharmacol. 36: 15-20.
Madeira MD, Cadete-Leite A, Andrade JP, Paula-Barbosa MM. (1991). Effects of hypothyroidism upon the granular layer of the dentate gyrus in male and female adult rats: a morphometric study. J Comp Neurol 314:171-186.
Madeira MD, Sousa N, Lima-Andrade MT, Calheiros F, Cadete-Leite A, Paula-Barbosa MM. (1992). Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. J Comp Neurol 322:501-518.
McCarren M, Eccles CU. (1983). Neonatal lead exposure in rats: II. Effects on the hippocampal afterdischarge. Neurobehav Toxicol Teratol. 5: 533-540.
Otto D, Reiter L. (1984). Developmental changes in slow cortical potentials of young children with elevated body lead burden. Neurophysiological considerations. Ann N Y Acad Sci. 425: 377-383.
Rami A, Patel AJ, Rabie A. (1986a). Thyroid hormone and development of the rat hippocampus: morphological alterations in granule and pyramidal cells. Neuroscience 19:1217-1226.
Rami A, Rabie A, Patel AJ. (1986b). Thyroid hormone and development of the rat hippocampus: cell acquisition in the dentate gyrus. Neuroscience 19:1207-1216.
Rami A, Rabie A. (1990). Delayed synaptogenesis in the dentate gyrus of the thyroid-deficient developing rat. Dev Neurosci 12:398-405.
Rodier PM. (1995). Developing brain as a target of toxicity. Environ. Health Perspect. 103: 73-76.
Sui L, Anderson WL, Gilbert ME. (2005). Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency. Toxicol Sci 85:647-656.
Sui L, Gilbert ME. (2003). Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus. Endocrinology 144:4195-4203.
Taylor MA, Swant J, Wagner JJ, Fisher JW, Ferguson DC. (2008). Lower thyroid compensatory reserve of rat pups after maternal hypothyroidism: correlation of thyroid, hepatic, and cerebrocortical biomarkers with hippocampal neurophysiology. Endocrinology 149:3521-3530.
Thompson CC, Potter GB. (2000). Thyroid hormone action in neural development. Cereb Cortex. Oct;10(10):939-45.
Vara H, Martinez B, Santos A, Colino A. (2002). Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus. Neuroscience 110:19-28.
KE Relationship Title
KE Relationship Overview


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Stormzy and Gerry Cinnamon to kick off TRNSMT festival
Stormzy will headline at Scotland's biggest music festival as it gets under way on Friday.
Around 50,000 music fans are expected to attend each day at the TRNSMT festival which takes place on Glasgow Green from July 12-14.
Catfish And The Bottlemen and George Ezra headline on Saturday and Sunday respectively while other bands appearing over the weekend include Bastille, The Kooks, Sigrid and Richard Ashcroft.
Snow Patrol and Jess Glynne were in the original line-up but were replaced by Scottish artists Lewis Capaldi and Emeli Sande after pulling out in the weeks before the festival.
George Ezra will headline on Sunday (Aaron Chown/PA)
Festival director Geoff Ellis told the PA news agency: "Stormzy had a great Glastonbury and he only wanted to do two festivals this year.
"When we got the call – pretty much a year ago – saying he wants to do Glastonbury and TRNSMT, that's really cool to get.
"He played the first year here and had a fantastic gig, went on about 4pm and had a full crowd watching him and that was great. I certainly won't be missing him."
Other acts on the line-up for Friday include Gerry Cinnamon, Years & Years and Example.
However Mr Ellis said the festival is about more than just the music.
He said: "Being at something like TRNSMT isn't just about the bands on stage, it's about the overall atmosphere and being with 50,000 people who are kinda like-minded.
"We've got some great food, different bars all over the site so hopefully you won't have to queue long to get a drink, you can come and chill out and enjoy yourself.
"It's a loud, busy oasis in the city centre of Glasgow."
We're almost ready for you  There's limited tickets available for Friday and Saturday, come join us! BUY NOW ~ https://t.co/P6LlXfxSOP pic.twitter.com/YytMvuFjfL
— TRNSMT Festival (@TRNSMTfest) July 11, 2019
The weather is expected to be generally fine over the weekend with a few showery spells possible on Friday and Saturday and a bright sunny day on Sunday.
Festival-goers would be wise to take sun-cream as temperatures could reach 22C on Friday, 21C on Saturday and 23C on Sunday, forecasters said.
Alex Burkill, a forecaster at the Met Office, said: "There is lots of warm humid weather to come with just a few showers on Friday and Saturday but otherwise dry and bright throughout the whole thing."

redpajama_set_name: RedPajamaCommonCrawl


The resources below have been picked specifically for you, we've looked at all the top educational publishers and what teachers are using in classrooms across the UK to make sure we can deliver your complete Subject Solution.
Ensure all pupils make progress relative to their starting points with quick and early intervention at any point in KS3 or GCSE maths. Step 1 write-in workbook roughly equates to the previous national curriculum level 3.
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Edexcel GCSE Maths, Higher Homework Book has been created by experts to help deliver exam success in Edexcel's new Maths GCSE. Written for Higher tier students, the homework book supports the corresponding student book, and provides students with a wealth of fluency practice.
Provide structured support and extra practice with a wealth of problem-solving and exam-style questions, in this fully updated edition written by an author team experienced in teaching and examining.
Our Revision Workbooks help students develop vital skills throughout their course in preparation for the exam.
Focused on the new assessment objectives, GCSE Maths Practice Book: Use and Apply Standard Techniques is full of expertly written practice questions to help students become confident and fluent in maths.
This textbook + e-book can be used alongside the Year 1 book to cover all the content needed for the Edexcel A level Statistics and Mechanics exam.
This textbook + e-book can be used alongside the Year 1 book to cover all the content needed for the Edexcel A level Pure Mathematics exams.
This book covers all the content needed for the compulsory Edexcel AS level Further Core Pure Mathematics exam. It can also be used alongside Book 2 to cover all the content needed for the compulsory Edexcel A level Further Core Pure Mathematics exams.
This book covers all the content needed for the optional Edexcel AS and A level Further Mechanics 1 exams.
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Help students to develop their knowledge and apply their reasoning to mathematical problems with textbooks that draw on the well-known MEI (Mathematics in Education and Industry) series, updated and tailored to the 2017 OCR (MEI) specification and developed by subject experts and MEI.
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This book covers all the content needed for the optional Edexcel AS and A level Further Mechanics 2 exams.
With over 1.3 million copies sold of the previous edition, Pearson's textbooks are the market-leading and trusted resources for AS and A level Mathematics.
This book can be used alongside Book 1 to cover all the content needed for the compulsory Edexcel A level Further Core Pure Mathematics exams.
This Student Book provides full support for year two of an Edexcel A Level course. Written by a well recognised author team of experienced teachers, this book supports the major changes in assessment style. Using clear and concise explanations, and abundant worked examples, it covers all the pure, mechanics and statistics content needed.
This Student Book provides full support for Edexcel's new linear AS Level and A Level specifications. Written by an author team of experienced teachers, this book supports the major changes in assessment style. Using clear and concise explanations, and abundant worked examples, it covers all the pure, mechanics and statistics content needed.
This Student Book has been endorsed for Edexcel and provides full support for their new linear AS Level and for Year 1 of the full A Level. Written by a team of experienced teachers, it supports the major changes in assessment style. Using clear explanations and worked examples, it covers all the pure, mechanics and statistics content needed.
This book covers all the content needed for the optional Edexcel AS and A level Further Pure Mathematics 2 exams.
In full colour and written specifically for the AQA Level 3 Certificate in Mathematical Studies, this book provides plenty of worked examples, practice questions and practice exam papers. Set in engaging contexts relevant to a wide range of other post-16 subjects, AQA Mathematical Studies is also supported by online teacher notes.
New 2017 Cambridge A Level Maths and Further Maths resources help students with learning and revision.
This Revision Guide is suitable for both classroom and independent study, and is the smart choice for those revising for A Level Mathematics 2017.
This book provides six mock papers for the new 2017 Edexcel AS Level (first exams in 2018). With rubric at the front, and space to write answers directly onto the page, this book provides realistic practice of the actual exam. The full mark scheme is available on this website.
This Student Workbook provides supplementary support and practice for the statistics topics in Edexcel's new linear specification. The Workbook provides focussed revision sections, extensive exam practice and guidance on Edexcel's 'Large dataset' (a new exam requirement from 2018). Full step-by-step solutions are provided online.
This book provides six mock papers for the new 2017 Edexcel A Level (first exams in 2019). With rubric at the front, and space to write answers directly onto the page, this book provides realistic practice of the actual exam. The full mark scheme is available on this website.
With our TECbook editions of your textbooks already proving to be classroom favourites we're always looking out for other digital resources to help you get the best out of your students.
Check out the latest additions to TECvideo, over 30 video tutorials covering GCSE Maths topics, and more to come!
In this introduction video we cover off the three types of number bases. Denary, Binary and Hexadecimal. This will start as a basis for our computing series.
In this video we begin our first exploration of exponential graphs. How are they different from previous graphs we've covered. In this video we introduce the basic concepts of exponential graphs and go through a graph with basic points. This video contains no extra activities.
This video will introduce how to simplify algebraic fractions. This is a tricky topic so we will cover lots of different types of examples. There are clear steps to go through each time, this will build confidence when faced with any exam questions. There are no extra activities with this video.
This video is the first covering expanding algebraic brackets. To start simple the video covers single brackets. This video will lay the foundation for understanding further videos on expanding brackets. There are no extra activities with this video.
Classroom support from both Hodder Education's Dynamic Learning and Oxford's Kerboodle.
Small institution (<900 pupils) and big institution (>901 pupils) variants are available for this product. All priced subscriptions end 31/08/2019.
The Online Testbank provides assessment for all phases and abilities at KS3, including written tests, auto-marked onscreen tests with meaningful feedback, and formative and summative assessment.


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We invite you to take a look at some snapshot moments at Monkey Ranch. The events, the land and the folks that make it paradise. We even have a retired volunteer fire truck that's been fun to trot out from time-to-time!


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You are here : Home / Programs And Activities / Break the Silence / Animation Film Toolkits
Over the past decade, Stairway has produced three animation films for the promotion of children's rights and the prevention of child sexual abuse. The 3 films, addressing different aspects of child sexual abuse and exploitation, have earned international acclaim for their unique qualities to communicate an unspeakable issue to a wide audience. They confront incest, pedophilia, sex trafficking of children and children abused in pornography. These 3 films make up the pillar in Stairway's training programs. Used in trainings and capacity-building activities they provide a concrete and realistic picture of a child sexually abuse.
The animations, when distributed or sold to partners, come with their own toolkits so that even those who have not attended Stairway's trainings would know how to discuss and process the films with the children. Included as well is a section on Handling Disclosures, to prepare for the possibility that a child in the audience would find the courage to break her/his silence about the abuse.
The value of the animations in the drive against child sexual abuse has been recognized internationally. Both Daughter and A Good Boy have won international awards. The films have been widely distributed and translated in several languages, including Spanish, French, Khmer, Vietnamese, Thai, Malay Bahasa and Nepalese. They are also available in both Filipino and Cebuano.
The three animations were adapted from short stories found in the collection called Black Angels, Street Children Realities by Monica D. Ray. Used extensively in Stairway's Personal Safety workshops, the films have proven an innovative and invaluable tool for children and young people to open up and to discuss the issue of sexual abuse. As young people watch and listen, discuss and tell their stories, they learn to connect to themselves, to each other, and to the world of ideas, to cultivate the imagination, to heighten social awareness by exploring the conflicts depicted with simplicity and wisdom.
How many times does a child have to tell an adult about being sexually abused before he or she is believed? Daughter is a heartfelt story about a young girl who is left with the responsibility of taking care of her father and her siblings while her mother works overseas. The role becomes distorted when her father starts to have an incestuous relationship with her. She attempts to tell various adults about the abuse, but no one believes her.
"Daughter" is a harsh and, unfortunately, a very authentic story about a 12 year old girl who has been a victim of incest. Upon its release, the film won 2 prestigious awards at the Annecy International Animation Film Festival in France; one for best Educational Film, and another Special Award from UNICEF. This international recognition of not only the film, but also of its justification and relevance, helped propel Stairway's campaign against child sexual abuse into an entirely new gear. Ever since, "Daughter" has proven great qualities as a vehicle for advocacy and breaking the silence around this most delicate and insidious form of child abuse, sealed in layers of taboo in almost any culture.
"Daughter" is used consistently in all Stairway workshops and training sessions on Child Sexual Abuse Prevention, and it continues to receive acclaim and appreciation wherever and whenever it is shown. It encourages disclosures, because it makes any victim of child sexual abuse understand that they do not carry any responsibility for what happened to them.
Written by Monica D. Ray
Directed by Monica D. Ray, Paw Ravn and Oscar Perez
Storyboard by Paw Ravn
Animation by Philippine Animation Studios
Translations: English, Filipino, Cebuano, Spanish, Khmer, Thai, Malay Bahasa, Vietnamese, Nepalese and French. Also available with American and Filipino sign language.
A Good Boy is a powerful depiction of the crime of pedophilia. It is a tale about how a young street kid named Jason is entrapped by Bob, a pedophile. Bob befriends Jason and his family with money and gifts. He gains their trust and invites Jason on a little "business trip" where he abuses him. Out of deep obligation to provide for his family, Jason keeps the abuse a secret until one day, Raffy, a street educator, helps him.
The ending of the original story is quite different from the animated version, which offers resolution and hope. In the original story the boy Jason, who is the victim of Bob (pedophile), did not escape the web of the perpetrator. Instead, he was made to render his services as a sex object for all of Bob's friends, who in return provided financial assistance to Jason's family. While the original ending is still closer to the realities in the Philippines and most other places in the world, the alteration to make a more positive ending of the animated version was a necessary move to offer hope and an opportunity for change and justice for child victims of sexual abuse and exploitation.
While the specific story is about a street child, its portrayal of a pedophile's manipulation, grooming and abuse of a child applies a lot broader than to a street situation. "A Good Boy" has been particularly valuable in helping to create awareness and educate on the fact that not only girls fall prey to sexual offenders. Very far from!
Written and directed by Monica D. Ray
Produced by Stairway Foundation
Animation by Dog n' Bon
Post Production by Wild Fire and Katrina Nyholm
Translations by International School Manila and Euro-Campus
Languages: English, Filipino, Cebuano, Spanish, Khmer, Thai, Malay Bahasa, Vietnamese, Nepalese and French. Also available with American and Filipino sign language
Red Leaves Falling
Red Leaves Falling is Stairway's latest animation film. It is a story of child sex trafficking and online pornography. Under the stress of poverty and a dying child, a mother agrees to send her daughters off to work in the city as house help–but the girls end up as sex slaves in a brothel.
The animation illustrates how the growing use of smart devices makes protection of our children more complicated, and even more urgent to attend to. Every click on a site holding an image of an abused child is a crime, which fuels the demand for recruiting more children into a sick industry of pornography.
As the 2 first animations, "Red Leaves" is full of pictures and metaphors in order to communicate a reality so gruesome and unbelievable that any healthy mind will not be able to conceive of the details of this heinous crime committed against the most vulnerable of children. "Red Leaves" is not intended for children audiences as part of Personal Safety training. This animation is directed towards more mature audiences that are in a position to help create a safe environment for children, so stories like what transpires in "Red Leaves" will no longer stain our idea of humanity.
This animation tells an all too common story. Parents are often unaware that they are 'selling' their children into sex slavery. Sexual abuse and exploitation of children is on the rise. Perpetrators take advantage of sophisticated means of communication and networking, making it more complicated to intervene in their criminal activities.
Red Leaves Falling is intended to help break the silence and to raise public awareness that child sex trafficking and child pornography is a prevalent issue.
Animation by Neko Animation Studio Manila
Post Production by Wild Fire and Hit Productions
Languages: Cebuano, English, Filipino, Khmer, Malay Bahasa, Vietnamese, Nepalese, Thai, Burmese, and Sinhalese. Also available with American and Filipino sign language


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Modern houses are often dismissed as little more than boxes, simple to the point of sacrifice. But as recent back-to-back trips to Chicago and Copenhagen underscored, a lot can be done architecturally with a box. It was purely chance that I ended up visiting Mies van der Rohe's Farnsworth House (1951) a couple of weeks before Hanne Kjærholm gave me a tour of the 1962 home that she designed for herself, her husband Poul, and their children. Aside from a few superficial similarities—the first is situated on the Fox River, the latter on the Oresund; both feature structural innovations and incorporate elements meant for other applications—the two have little in common. Still, I couldn't help but compare them, particularly how they accommodate life within the box.
The truth is that in this house with its four walls of glass I feel like a prowling animal, always on the alert. I am always restless. Even in the evening. I feel like a sentinel on guard day and night. I can rarely stretch out and relax…What else? I don't keep garbage under my sink. Do you know why? Because you can see the whole "kitchen" from the road on the way in here and the can would spoil the appearance of the whole house. So I hide it in the closet further down from the sink. Mies talks about "free space": but his space is very fixed. I can't even put a clothes hanger in my house without considering how it affects everything from outside. Any arrangement of furniture becomes a major problem, because the house is transparent, like an X-ray.
The architect confined the interior functions to a central wall that holds two bathrooms, the kitchen, utilities, and a fireplace. Because he made it of beautiful (and costly) primavera wood, Mies avoided cutting any holes or inserting any hardware into it, hiding schloss hinges behind the doors and positioning electrical outlets in the marble floor. By radically reducing interior walls and all but eliminating the vertical steel structure, Mies produced the perfect platform for experiencing the surrounding landscape. To be fair, Farnsworth knew exactly what she was getting (as a photo of her studying the plans confirms), and the house was strictly designed to be a summer residence, not for full-time occupancy. Even though she had to fight for some essential concessions—for example, a wardrobe for storing personal effects; Mies only wanted to give her a single hanger in the bathroom for her clothes—Farnsworth did keep and use the house until 1972, when a noisy highway was built nearby and she sold it to Lord Peter Palumbo. Impossible in an urban context, the Farnsworth House was an experiment in transparency—and perhaps the greatest artistic achievement in minimalist architecture. Yet as the saying goes: It's a nice place to visit….
While Hanne Kjærholm's intentions for her family home were much less lofty, her design is no less purposeful. One of the first things she said about the house was that we should take photos from down low, as the cozy space (the ceilings can't be more than eight feet high) is meant to be experienced from a seated position. And while the Farnsworth house propels your attention outward, the Kjærholm house wraps itself around you. Here, the wood walls are made of humble, untreated pine—and rather than being left reverently bare, they are hung with personal items throughout. The room that now serves as Kjærholm's office has a collection of global sandals mounted in long rows. The three sides of the house that face land and are surrounded by neighboring structures have relatively modest windows, hung closer to the ground than the ceiling. Only the fourth, water-facing wall is entirely glass. The family had both privacy and an optimal view of the natural surroundings. Though Kjærholm did not design her own door handles as Mies had, she did give them careful consideration, selecting a model intended for ships. Tactile Haitian straw mats (the third set in 24 years) cover the floors. The bedroom was formerly subdivided into a studio by a storage wall of Kjærholm's design; a pale mark is still visible where the sliding wall was once positioned. This compact house allowed for a great deal of flexibility as the family's circumstances changed.
They are two simple rectangles housing wholly dissimilar programs. The first—a spot for a single woman to escape to on weekends to pursue peaceful interests like poetry and music—was more suited to architectural experimentation, while the second had to accommodate the unpredictable, evolving, and very real demands of a family. With such different purposes any comparisons of the Farnsworth and Kjærholm houses is ultimately unfair, other than to conclude that though Modernism has popularly been deemed unlivable there's no reason it has to be.


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Examining the MLB Non-Waiver Trade Deadline
By: Andrew Riley, Ruling Sports Intern (Twitter: @Buriedtalents)
As the MLB non-waiver trade deadline approaches, there has already been a number of major transactions. The trade deadline marks the moment teams decide to either swing for the fences for a championship this year or to sacrifice bunt for a better chance next year. The closer the deadline gets, teams are classified into buyers or sellers based on their current record or the general sense of how possible it is to reach the playoffs. As a seller, a team has likely come to the conclusion that they are missing a too many crucial pieces needed for a championship team. As a result, based on many factors from both a talent and a financial standpoint, the team decides it is willing to field offers for current talent with the hopes of acquiring a useful player down the road. A buyer on the other hand, feels they are close to fielding a championship team and need one more arm or bat to put them over the top to achieve success. A buying team will then be willing to part with a less active but high valued talent, like a prospect, to obtain the final pieces. The significance of the non-waiver trade deadline is that the players involved in trades do not have to be put on waivers before being traded.
After the July 31st trade deadline trades may still occur, however the players must clear waivers first. When a player is waived, every team is afforded the option to pick that player, and his contract, to be a member of that club. Three things can occur if a player is picked up on waivers. The first option is that the waiving team and the receiving team can negotiate a trade for the waived player. The second option is that the waiving team can cancel the waiver and the player remains on the waiving team. Third, the waiving team does nothing, allowing the receiving team to get a free player without having to give up any talent of its own. Due to these limitations the possibility of being able to obtain top players lessens significantly after the non-waiver trade deadline. For this reason, there always seems to be a scramble near the deadline for top players. Which teams are scrambling this year?
The Texas Rangers have persevered through a decimated pitching staff the first half of the season. The Rangers have had ten different pitchers start games this year due to the injuries of Derek Holland, Neftali Feliz, Roy Oswalt,, Alexi Ogando, and now Colby Lewis. Even without the injuries, the Rangers were lacking a true number one starter and there have been reports that they are interested in some pitchers available. The most prominent pitcher available is Zack Greinke. Greinke is arguably one of the top pitchers in the game and would be exactly what the Rangers need. Greinke is the only true number one left after the Phillies extended the contract of Cole Hamels. After Greinke and Hamels, the quality of the pitchers brought up in trade rumors is at least one tier below. Some names include James Shields of the Tampa Rays, and Josh Johnson of the Miami Marlins.
The Pirates quietly let it be known that they plan to make a run this year with the acquisition of Wandy Rodriguez from Houston. Currently they are in position of grabbing one of the Wild Card spots. The success of the Pirates can be narrowed down to the emergence of four players. Andrew McCutcheon is performing like the player that many scouts projected him to become. Despite a low batting average, Pedro Alvarez has hit twenty homeruns and many of them were timely enough to result in walk-off wins. James McDonald has struggled lately but has pitched masterfully during the first half of the season. The resurgence of A.J. Burnett has been a pleasant surprise and has eleven wins to his credit. The Pirates currently sit two games back of the Reds, but like the Rangers they lack a true number one starter. Rodriguez is hardly a number one starter but he is a significant upgrade and could provide the wins they were looking for. The question remains as to whether they will make more trades or they feel they have already filled the gap.
The curious case of the Miami Marlins continues to baffle. The season began with such hope and optimism after the big name, off-season acquisitions of Jose Reyes, Mark Buerle, and Heath Bell. The Marlins currently sit seven games below five hundred and nine games back from one of the Wild Card spots. The initial perception was that they would be a buyer as the deadline approached, especially after the acquisition of Carlos Lee. However, their record has been on a steady decline since then and it appears the Marlins management are tired of the lack of performance, as demonstrated by the Hanley Ramirez trade. Reports have suggested that they will entertain offers from just about anyone with the exception of Emilio Bonifacio. It is unclear what went wrong at this point but it appears the Marlins are looking to regroup and try again next year.
It is unclear whether the Red Sox are truly going to be sellers at this point but it would make sense for them to at least entertain the idea. It is no secret that the Red Sox are in the toughest division in baseball and it is highly unlikely that they will overtake the Yankees to win the division. The possibility to obtain a Wild Card spot seems just as unlikely with the Angels having turned around an abysmal start, the Athletics playing consistent baseball and the Detroit Tigers looking like they are prime for a win streak. This year is as good as any for the Red Sox to reconsider some of the personnel and decide whether they fit in the scheme that Buck Martinez has laid out for the team. The whole first half has been marred with controversy with Martinez being at the center of it all. This year is Martinez' opportunity to make some changes to the roster and get players that are his type of players. Martinez could have input in acquiring players that will buy into his style of managing and who will not have the baggage from teams of the previous years.
The MLB non-waiver trade deadline is both scary and exciting from a fan's standpoint. The fan wants the best for their team but at the same time has developed a loyalty to the players he or she has watched for years. There would likely be an intense emotional reaction from a diehard fan if his or her favorite player were traded away. However, winning is a great cure for such things. In general a fan likely wants to know that their teams front office is trying to make the best possible decisions to win games, whether be immediately or eventually.
Alicia Jessop July 28, 2012
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The Wigby Lab
Stuart Wigby
BBSRC David Phillips Research Fellow
More on Stu
Irem Sepil
BBSRC-funded Postdoctoral Researcher
More on Irem
Eleanor Bath
Junior Research Fellow,
Christ Church College
More on Ellie
Dani Edmunds
BBSRC DTP DPhil Student
More on Dani
Ben Hopkins
Sally Le Page
Ilona Fils
Elizabeth Sandham
Juliano Morimoto
Cedric Tan
Quick bio
BBSRC David Phillips Research Fellow, University of Oxford (2014–present)
Lecturer, St John's College, Oxford (2018-2019)
NERC Research Fellow, University of Oxford (2013–2014)
Lecturer, Wadham College, Oxford (2010–2013)
Research Fellow, University of Oxford (2008–2011)
HFSP Short-Term Research Fellow, Cornell University (2008)
Postdoc, University College London (2005–2008)
PhD, University College London (2001–2005)
BSc Zoology, University of Sheffield (1997–2000)
BBSRC-funded Postdoctoral Researcher, University of Oxford (2014–2019)
Research Associate, University of Oxford (2013)
DPhil, University of Oxford (2008–2012)
Research Assistant, University of California, Los Angeles (2005–2007)
BSc Molecular Biology and Genetics, Bogazici University (2000–2005)
Junior Research Fellow, Christ Church College, University of Oxford (2016-2020)
Lecturer, Keble and St Catherine's Colleges (2019)
DPhil, University of Oxford (2012-2016)
BSc (Advanced)/BA, University of New South Wales (2007-2011)
BA (Biological Sciences), University of Oxford (2013-2016)
Want some great fly-themed merchandise?
Check out Dani's artwork here.


text:
package org.apache.causeway.extensions.secman.applib.role.dom;

import java.util.Collection;
import java.util.Optional;

import org.apache.causeway.extensions.secman.applib.user.dom.ApplicationUser;

/**
 * @since 2.0 {@index}
 */
public interface ApplicationRoleRepository {

    /**
     *
     * @return detached entity
     */
    ApplicationRole newApplicationRole();

    Collection<ApplicationRole> allRoles();

    ApplicationRole newRole(String name, String description);

    Collection<ApplicationRole> findNameContaining(String search);
    Collection<ApplicationRole> getRoles(ApplicationUser user);

    /**
     * auto-complete support
     * @param search
     */
    Collection<ApplicationRole> findMatching(String search);

    Optional<ApplicationRole> findByName(String roleName);
    Optional<ApplicationRole> findByNameCached(String roleName);

    default ApplicationRole upsert(final String name, final String roleDescription) {
        return findByName(name)
                .orElseGet(() -> newRole(name, roleDescription));
    }

    void addRoleToUser(ApplicationRole role, ApplicationUser user);
    void removeRoleFromUser(ApplicationRole role, ApplicationUser user);

    boolean isAdminRole(ApplicationRole role);

    void deleteRole(ApplicationRole holder);

}

redpajama_set_name: RedPajamaGithub


text:
RCW 28B.15.069
Building fees—Services and activities fees—Other fees.
(1) The building fee for each academic year shall be a percentage of total tuition fees. This percentage shall be calculated by the office of financial management and be based on the actual percentage the building fee is of total tuition for each tuition category in the 1994-95 academic year, rounded up to the nearest half percent. After October 9, 2015, the dollar value of the building fee shall not be reduced below the level in the 2014-15 academic year adjusted for inflation. As used in this subsection, "inflation" has the meaning in RCW 28B.15.066(2).
(2) The governing boards of each institution of higher education shall charge to and collect from each student a services and activities fee. A governing board may increase the existing fee annually, consistent with budgeting procedures set forth in RCW 28B.15.045, by amounts that shall not exceed four percent per year, judged reasonable and necessary by the services and activities fee committee and the governing board. The governing boards of the community and technical colleges may increase the existing student and activities fee annually, consistent with budgeting procedures set forth in RCW 28B.15.045, by a percentage not to exceed the annual percentage increase in student tuition fees for resident undergraduate students: PROVIDED, That such percentage increase shall not apply to that portion of the services and activities fee previously committed to the repayment of bonded debt. These rate adjustments may exceed the fiscal growth factor. The services and activities fee committee provided for in RCW 28B.15.045 may initiate a request to the governing board for a fee increase.
(3) Tuition and services and activities fees consistent with subsection (2) of this section shall be set by the state board for community and technical colleges for community and technical college summer school students unless the college charges fees in accordance with RCW 28B.15.515.
(4) Subject to the limitations of RCW 28B.15.910, each governing board of a community or technical college may charge such fees for ungraded courses, noncredit courses, community services courses, and self-supporting courses as it, in its discretion, may determine, consistent with the rules of the state board for community and technical colleges.
(5) The governing board of a college offering an applied baccalaureate degree program under RCW 28B.50.810 or a bachelor of science degree program described in RCW 28B.50.825 may charge tuition fees for those courses above the associate degree level at rates consistent with rules adopted by the state board for community and technical colleges, not to exceed tuition fee rates at the regional universities.
[ 2018 c 202 § 1. Prior: 2016 sp.s. c 33 § 2; 2016 c 202 § 57; prior: 2015 3rd sp.s. c 36 § 5; 2015 3rd sp.s. c 4 § 945; 2015 c 55 § 212; 2013 2nd sp.s. c 4 § 959; 2012 c 229 § 701; 2005 c 258 § 10; 2003 c 232 § 5; 1997 c 403 § 2; 1995 1st sp.s. c 9 § 5.]
Short title—2015 3rd sp.s. c 36: See note following RCW 28B.15.031.
Effective dates—2015 3rd sp.s. c 4: "This act is necessary for the immediate preservation of the public peace, health, or safety, or support of the state government and its existing public institutions, and takes effect immediately [June 30, 2015], except for section 971 (RCW 77.12.203) of this act, which takes effect July 1, 2015." [ 2015 3rd sp.s. c 4 § 1902.]
Effective dates—2013 2nd sp.s. c 4: See note following RCW 2.68.020.
Effective date—2012 c 229 §§ 101, 117, 401, 402, 501 through 594, 601 through 609, 701 through 708, 801 through 821, 902, and 904: See note following RCW 28B.77.005.
Findings—Intent—2005 c 258: See note following RCW 28B.45.014.
Finding—Intent—2003 c 232: See note following RCW 28B.15.031.
Intent—Purpose—Effective date—1995 1st sp.s. c 9: See notes following RCW 28B.15.031.


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Fauci: Some messages from Trump's COVID-19 task force don't match reports from 'the trenches'
Mon, July 27 by ABC News
Official White House Photo by D. Myles Cullen
HomePoliticsFauci: Some messages from Trump's COVID-19 task force don't match reports from 'the trenches'
By MIKE LEVINE, ABC News
(WASHINGTON) — As the COVID-19 pandemic surges within the United States, the Trump administration's task force leading federal efforts to slow the spread of the virus continues to relay some optimistic messages.
But according to Dr. Anthony Fauci, a key member of the task force as the nation's top infectious disease expert, those claims do not always match the reports he receives from the front lines of the crisis.
During an in-depth interview that will air Tuesday night on ABC News as part of a primetime special, American Catastrophe: How Did We Get Here?, Fauci was pressed to explain why, months after COVID-19 first reached U.S. soil, the U.S. government is still struggling to provide adequate testing for Americans and sufficient personal protective gear for essential workers.
"We keep hearing when we go to these task force meetings that these [issues] are being corrected," Fauci said. "But yet when you go into the trenches, you still hear about that."
Fauci said he does not have a "good answer" and "cannot explain" the discrepancy, especially since those matters are not part of his "day-by-day" responsibilities, but part of the problem stems from the fact that "many of the things that we needed were not produced in the United States."
The U.S. government ended up competing for those materials with other nations stricken by the pandemic, and the White House ultimately had to invoke emergency powers to push U.S. companies to help.
Those challenges were exacerbated by what Fauci admitted were early missteps on testing by the Centers for Disease Control, which developed tests that "didn't work" initially because — it turned out — their results were based on potentially contaminated samples. That forced the federal government to further rely private companies.
Asked about any missteps he may have made himself — including initially telling the public that the average American didn't need to wear a mask — he said such decisions were "based on the information at the moment."
"As a scientist, the thing you must always do is to be humble enough to know that when you get additional information, even information that might conflict what was felt earlier on, you then change your viewpoint and you change your recommendations based on the data," he said. "That's what science is all about. Science is a learning process."
During a White House briefing on Thursday, President Donald Trump declared that the United States has seen "a tremendous increase" in its testing capabilities, conducting more than 51 million tests across the country so far, and insisted that the country is "very strong on supplies."
"Remember I used to say the cupboards were bare?" Trump said. "Well, now the cupboards are the opposite."
Trump also said it's been "a tremendous week" for the United States in the fight against COVID-19, insisting, "We're doing very well all over the country."
In his interview with ABC News, however, Fauci expressed concern over the "explosion" of cases in several southern states, which he said is being fueled by "a surge of community spread," in which people infected with the disease but not showing symptoms are spreading it to others.
It's "a real serious problem," he said. "They need to be concerned because even though they themselves may not get any serious outcome, they are part of the propagation of the pandemic."
The U.S. government, Fauci said, certainly wasn't the only one to make costly mistakes. In his interview with ABC News, Fauci said the Trump administration's response to the growing pandemic was significantly handicapped by the Chinese government's lack of candor during its initial spread throughout the country.
"We were still hearing from the Chinese that it wasn't efficiently spread from human to human," Fauci said. "And then as the weeks went by, it became very clear that that was the case, and that there really would be trouble."
The Chinese government even barred U.S. officials, Fauci said, from visiting the areas most impacted by the deadly virus.
"They were not allowed to go there in real-time and see what was going on," he said, and that "was very disconcerting to us."
It wasn't until January, when the Chinese government finally released the scientific makeup of the virus, that Fauci fully realized the gravity of the situation.
"All right," he recalled thinking at the time. "All hands on deck."
Fauci has been fighting infectious diseases for nearly four decades, but he said COVID-19 has been his "worst nightmare." Infectious diseases that spread easily tend to be "very weak" and rarely lethal, he said, while the diseases that can't spread as widely tend to be the most deadly. But COVID-19 hasn't followed that paradigm.
"You have those two things coming together with what we're dealing with now" — a deadly disease that's "efficiently spread" — creating "the perfect storm," Fauci said. "When those things come together … it really is historic."
He urged Americans across the country — no matter where they are — to follow "some fundamental principles."
"The fundamentals are not rocket science," he said. "It's universal wearing of masks, avoiding crowds, close the bars, [maintain] physical distance [and] personal hygiene, washing your hands. … No doubt you're going to be able to turn these things around with some things as simple as that."
Tune in to ABC on Tuesday at 9 p.m. ET for the 20/20 special report American Catastrophe: How Did We Get Here?
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Sessions' DOJ 'driving force' behind 'zero-tolerance' family separation policy: Watchdog report
POLL: With partial blame for the Capitol attack, majority favors barring Trump from office
Fourth House member tests positive for COVID-19 following siege on Capitol
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Key moments from the House debates on Trump's 2nd impeachment


text:
Canadian Media Producers Association welcomes Heritage Review advisory panel
OTTAWA, June 28, 2016—The Canadian Media Producers Association (CMPA) today issued the following statement on behalf of President and CEO, Reynolds Mastin:
"We welcome today's announcement of an appointed advisory group that will provide ongoing feedback and support for Minister Joly as she moves forward with a comprehensive policy review, aimed at bringing Canada's cultural policies into the digital age.
We are very encouraged by the breadth and depth of experience of the individuals named to the panel, and are particularly pleased to see the inclusion of voices from Canada's independent production sector. There is tremendous value in drawing upon experts who have produced audiovisual content for both traditional and emerging platforms, and have done so while operating within the existing policy and regulatory framework.
As the Minister moves forward with the review, we are hopeful that any future policy toolkit will leverage the creative entrepreneurship and diversity of voices of Canada's indie producers, so they can embrace innovative approaches to develop and deliver world-class content for audiences at home and abroad."


According to local pundits, the world of commercial property is changing in Sofia, and retail business's are now returning to the high street. Away from the retail shopping malls – many of which are in secondary positions – popular names can now be seen once more in pedestrianized Vitosha Street, and its many City centre offshoots. Once regarded as one of the most expensive districts in Sofia, out of town retail has at least helped city centre rental values, to achieve an acceptable level.
In the office sector, since most of the major international commercial players are now present in Sofia, there has been an an oversupply of office space, and renting offices on the outskirts of the city has always been a destination of last resort. Many western property developers have come into the Sofia marketplace, since the changes in 1990, because much of the office space was badly planned, and insufficiently ergonomic.