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Distinct cortical and sub-cortical neurogenic domains for GABAergic interneuron precursor transcription factors NKX2.1, OLIG2 and COUP-TFII in early fetal human telencephalon
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The extent of similarities and differences between cortical GABAergic interneuron generation in rodent and primate telencephalon remains contentious. We examined expression of three interneuron precursor transcription factors, alongside other markers, using immunohistochemistry on 8–12 post-conceptional weeks (PCW) human telencephalon sections. NKX2.1, OLIG2, and COUP-TFII expression occupied distinct (although overlapping) neurogenic domains which extended into the cortex and revealed three CGE compartments: lateral, medial, and ventral. NKX2.1 expression was very largely confined to the MGE, medial CGE, and ventral septum confirming that, at this developmental stage, interneuron generation from NKX2.1+ precursors closely resembles the process observed in rodents. OLIG2 immunoreactivity was observed in GABAergic cells of the proliferative zones of the MGE and septum, but not necessarily co-expressed with NKX2.1, and OLIG2 expression was also extensively seen in the LGE, CGE, and cortex. At 8 PCW, OLIG2+ cells were only present in the medial and anterior cortical wall suggesting a migratory pathway for interneuron precursors via the septum into the medial cortex. By 12 PCW, OLIG2+ cells were present throughout the cortex and many were actively dividing but without co-expressing cortical progenitor markers. Dividing COUP-TFII+ progenitor cells were localized to ventral CGE as previously described but were also numerous in adjacent ventral cortex; in both the cases, COUP-TFII was co-expressed with PAX6 in proliferative zones and TBR1 or calretinin in post-mitotic cortical neurons. Thus COUP-TFII+ progenitors gave rise to pyramidal cells, but also interneurons which not only migrated posteriorly into the cortex from ventral CGE but also anteriorly via the LGE.
KeywordsGanglionic eminences Inhibitory interneurons Neurodevelopment Neuronal fate specification Pallium Subpallium
Chicken ovalbumin upstream promotor-transcription factor 2
Distal-less homeobox 2
NK2 homeobox 1
Oligodendrocyte lineage transcription factor 2
Paired box 6
- TBR1 and TBR2
T-box brain 1 and 2
Caudal ganglionic eminence
Lateral ganglionic eminence
Medial ganglionic eminence
Humans have considerably expanded cognitive abilities compared to all other species which may be dependent on the evolution of a greater interconnectedness of a larger number of functional modules (DeFelipe 2011; Buckner and Krienen 2013). This not only depends on the physical presence of neurons, axon pathways, and synapses, but also on synchronicity of neural activity between cortical areas binding together outputs of all neurons within a spatially distributed functional network (Singer and Gray 1995; Fries 2009). The synchronicity essential to higher order processing is dependent on the activity of gamma-aminobutyric acidergic (GABAergic) interneurons (Whittington et al. 2011; Buzsaki and Wang 2012), and we might predict a more sophisticated functional repertoire for interneurons in higher species (Ballesteros-Yáñez et al. 2005; Molnár et al. 2008; DeFelipe 2011; Povysheva et al. 2013; Clowry 2015).
Is this expanded repertoire of functional types matched by an evolution of their developmental origins? It is well established in rodents that GABAergic interneurons are born almost entirely outside the neocortex in the ganglionic eminences and associated structures (such as the preoptic area) from which they migrate tangentially into the cortex (De Carlos et al. 1996; Parnavelas 2000; Marín and Rubenstein 2001; Welagen and Anderson 2011). The ganglionic eminences are divided into three main neurogenic domains: the lateral, medial, and caudal ganglionic eminences (LGE, MGE, and CGE, respectively). The LGE is the origin of the striatal projection neurons and a small population of olfactory bulb interneurons (Waclaw et al. 2009). The MGE and the CGE are the major sites of cortical interneurogenesis (Xu et al. 2004; Butt et al. 2005).
Recent studies support the idea that generation of interneurons in the ventral telencephalon may be more complicated in primates, which have evolved a large and complex outer subventricular zone in the ganglionic eminences (Hansen et al. 2013). In addition, proportionally, more interneurons appear to be produced in the CGE, the majority of which populate the superficial layers of the cortex (Hansen et al. 2013; Ma et al. 2013). Whether or not the cortical proliferative zones are a source of interneurogenesis, to what extent and significance, is a contentious issue (Molnár and Butt 2013; Clowry 2015). Some researchers have proposed that primates generate interneurons in the proliferative zones of the cortex (Letinic et al. 2002; Petanjek et al. 2009; Zecevic et al. 2011; Radonjic et al. 2014a; Al-Jaberi et al. 2015) as well as in the ganglionic eminences. Other groups have convincingly argued that interneuronogenesis is essentially the same in primates as in rodent models (Hansen et al. 2013; Ma et al. 2013; Arshad et al. 2016). As there is growing evidence that conditions, such as autism, schizophrenia, and congenital epilepsy, may have developmental origins in the failure of interneuron production and migration (De Felipe 1999; Lewis et al. 2005; Uhlhaas and Singer 2010; Marín 2012), it is important that we understand fully the similarities and differences between human development and that in our animal models.
Therefore, we have carried out a detailed study of expression of three transcription factors expressed by interneuron progenitors, NKX2.1, OLIG2, and COUP-TFII. We looked between the ages of 8–12 post-conceptional weeks (PCW) which have been a relatively neglected period of development in the previous studies of interneurogenesis. NKX2.1 is considered the key regulator of MGE-derived GABAergic interneuron specification (Sussel et al. 1999; Xu et al. 2004; Butt et al. 2008; Du et al. 2008) and the only transcription factor that distinguishes the MGE from other subcortical domains, including in the human embryo at 7 PCW (Pauly et al. 2014). In mice, following the early loss of Nkx2.1 function, the MGE acquires an LGE-like molecular specification (Sussel et al. 1999), whereas the late conditional loss of function switches the MGE to CGE in character (Butt et al. 2008). In rodents, the MGE is the major source of cortical GABAergic interneurons and Nkx2.1 expression in this region is required for the specification of somatostatin and parvalbumin expressing interneurons from MGE progenitors (Xu et al. 2004; Butt et al. 2008; Du et al. 2008).
In the rodent, Olig2 expressing progenitors in the MGE give rise to GABAergic interneurons at an earlier stage of development and oligodendrocytes at later stages (Miyoshi et al. 2007). In the human, OLIG2 has been detected principally in the proliferative zones of the ganglionic eminences between 5–15 PCW, prior to significant expression of markers for oligodendrocyte precursors, with a spread into the cortex by 20 gestational weeks, along with co-expression of OLIG2 with markers for immature neurons, neurogenic radial glia, and intermediate progenitor cells (Jakovceski and Zecevic 2005; Jackocevski et al. 2009).
COUP-TFII, in rodents, is preferentially expressed in the CGE as well as in interneurons migrating into the cortex (Kanatani et al. 2008; Lodato et al. 2011). CGE-derived interneurons migrate caudally to the most posterior part of the telencephalon (Yozu et al. 2005; Faux et al. 2012), and COUP-TFII is essential to establish this caudal migratory stream (Kanatani et al. 2008). Reinchisi et al. (2012) have provided some evidence that COUP-TFII may play a similar role in human forebrain development. However, the precise roles of COUP-TFs in specifying the CGE-derived interneurons are still unclear.
Expression of the transcription factor PAX6 was also investigated alongside the three GABAergic markers. PAX6 is considered a marker for dorsal telencephalic radial glia giving rise to glutamatergic neurons in rodents (Hevner et al. 2006), and in human, PAX6 expression delineates the cortical ventricular and subventricular proliferative zones (Bayatti et al. 2008a). However, in humans, it is also known to be expressed in a gradient across the proliferative layers of the LGE revealing its boundary with the MGE (Pauly et al. 2014; Harkin et al. 2016).
The present study aimed to map and quantify the expression of the three interneuron progenitor markers in the human telencephalon at an important stage of development prior to the arrival of thalamic innervation to delineate the extent of cortical interneurogenesis. This aim was achieved, demonstrating distinct neurogenic domains for all three including expression in the developing cortex. In addition, careful observation of these expression patterns revealed a complex organization for the CGE and provided evidence for anterior and medial migration pathways for interneuron precursors into the cortex from the ganglionic eminences in addition to the more generally recognised lateral and posterior pathways.
Methods and materials
Human tissue
Human fetal tissue from terminated pregnancies was obtained from the joint MRC/Wellcome Trust-funded Human Developmental Biology Resource (HDBR, http://www.hdbr.org; Gerrelli et al. 2015). All tissues were collected with appropriate maternal consent and approval from the Newcastle and North Tyneside NHS Health Authority Joint Ethics Committee. Fetal samples ranging in age from 8 to 12 PCW were used. Ages were estimated from the measurements of foot and heel to knee length compared with the fetal staging chart as described by Hern (1984). Brains were isolated and fixed for at least 24 h at 4 °C in 4% paraformaldehyde dissolved in 0.1 M phosphate-buffered saline (PBS) (PFA; Sigma Aldrich). Once fixed, whole or half brains (divided sagittally) were dehydrated in a series of graded ethanols before embedding in paraffin. Eight brain samples were cut at 8 μm section thickness in three different planes; horizontally, sagittally, and coronally, mounted on slides and used for haematoxylin and eosin staining (H&E) and immunostaining.
Immunoperoxidase histochemistry
Primary antibodies used in this study
Primary antibody
Mouse monoclonal
Dako, Ely, UK
Rabbit polyclonal
Abcam, Cambridge, UK
Rabbit polyclonal
Rabbit polyclonal
Cambridge Bioscience, Cambridge, UK
Mouse monoclonal
Mouse monoclonal
R&D Systems, Abingdon, UK
Rabbit polyclonal
Merck Millipore, Watford, UK
Mouse monoclonal
Swant, Marly, Switzerland
Rabbit polyclonal
Merck Millipore
Immunofluorescence (double and triple labelling)
We used a novel immunofluorescent staining method, Tyramide Signal Amplification (TSA), that permits sequential double and triple staining using antibodies from the same species without cross-reactions (Goto et al. 2015; Harkin et al. 2016). Sections were treated as described above until the secondary antibody stage, then they were incubated with HRP-conjugated secondary antibody for 30 min [ImmPRESS™ HRP IgG (Peroxidase) Polymer Detection Kit, Vector Labs], washed twice for 5 min in TBS, and incubated in dark for 10 min with fluorescein tyramide diluted at 1/500 in 1× Amplification buffer (Tyramide Signal Amplification (TSA™) fluorescein plus system reagent, Perkin Elmer, Buckingham, UK). Tyramide reacts with HRP to leave fluorescent tags covalently bound to the section.
Prior to starting the second round of staining, sections were first washed in TBS and boiled in 10 mM citrate buffer to remove all antibodies and unbound fluorescein from the first round. Sections were then incubated in 10% normal serum before incubating with the second primary antibody for 2 h at room temperature. Following washing, sections were again incubated with ready to use HRP-conjugated secondary antibody and then incubated with CY3 tyramide for 10 min [Tyramide Signal Amplification (TSA™) CY3 plus system reagent, Perkin Elmer]. The same steps were repeated for the third round of staining (if triple labelling was needed) using CY5 Tyramide (Tyramide Signal Amplification (TSA™) CY5 plus system reagent, Perkin Elmer). Sections were washed before applying 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI; Thermo Fisher Scientific, Cramlington, UK) and mounted using Vectashield Hardset Mounting Medium (Vector Labs).
All immunoperoxidase staining figures presented in this study were captured using a Leica slide scanner and Zeiss Axioplan 2 microscope. The double immunofluorescent figures were obtained with a Zeiss Axioimager Z2 apotome and Triple Immunofluorescent images were obtained with a Nikon A1R confocal microscope. Processing of images, which included only adjustment of brightness and sharpness, was achieved using the Adobe Photoshop CS6 software.
Cell counts in proliferative zones of 12 PCW fetus
Volume (mm3)
Density (cells/mm3 × 103)
Number (×106)
Density (cells/mm3 × 103)
Number (×106)
Density (cells/mm3 × 103)
Number (×106)
Examination of our immunoperoxidase labelled sections for various markers at low magnification revealed details of the characteristics of the CGE and septum in human not fully reported on before in detail. Therefore, we have begun the results section by describing these regions, before moving on to describe the level of expression of each GABAergic interneuron precursor transcription factor in different parts of the telencephalon, aided by a more detailed knowledge of CGE and septal sub-compartments.
The position and subdivisions of the caudal ganglionic eminence (CGE)
The position of the CGE can be determined with respect to other subcortical landmarks in H&E stained sections (Suppl. Figure 1). For example, in the horizontal plane, at the level of the internal capsule, the MGE and LGE appeared as prominent bulges into the lateral ventricles, and in a rostral position relative to the internal capsule. The CGE can be seen as the part of the GE positioned caudally to the internal capsule immediately adjacent to the ventral/temporal cortex (Suppl. Figure 1a). In sagittal sections, the most dorsal part of the CGE appeared as well-defined protrusion into the lateral ventricle, close to the hippocampus (Suppl. Figure 1b). The central part lies next to the narrow ventral extension of the lateral ventricles (Suppl. Figure 1c). In a coronal plane at the level of the rostral half of thalamus, parts of MGE and LGE can be seen dorsal to the internal capsule (Suppl. Figure 1d and e) and only the most ventral part of the CGE was observed ventral to the internal capsule and close to the ventral/temporal cortex (Suppl. Figure 1e). At the level of the caudal half of thalamus and caudal to the internal capsule, the CGE was present but not the MGE and LGE (Suppl. Figure 1f).
Interestingly, these two domains could not be distinguished in the most ventral part of CGE, which was located immediately adjacent to the ventral/temporal cortex (Figs. 1e, f, 2a″, b″). Thus, we propose that there is a third compartment to the CGE in human, "ventral CGE" (vCGE), which was characterized by strong immunoreactivity for PAX6, but not for NKX2.1. Despite the high PAX6 expression in the vCGE, there was still a distinct boundary between it and the adjacent cortex, characterized by a thicker cortical VZ compared with more condensed PAX6+ cells in the SVZ of the vCGE (Fig. 2a″, b″). As the CGE is recognised as the birth place of calretinin (CalR) expressing interneurons in rodents (Nery et al. 2002; Butt et al. 2005), we studied the expression of CalR in the three defined compartments of the CGE. CalR was preferentially expressed in cells of the VZ and SVZ of the lCGE and vCGE. Only scattered cells were observed in mCGE. CalR immunostaining also revealed a distinct boundary between the vCGE and the ventral cortex. In vCGE, CalR was expressed in the VZ and SVZ, but in the ventral cortex, expression of CalR was mainly confined to the SVZ with only scattered CalR+ cells in the VZ (Fig. 2c, c′, c″).
Subdivisions of the septum
Similar to the ganglionic eminences, the septum is a subcortical structure that exhibited complementary expression of PAX6 and NKX2.1. The most ventral part of septum could be defined as MGE-like septum characterized by strong immunoreactivity for NKX2.1 but not PAX6 expression. More dorsally, we found LGE-like septum, which was characterized by moderate expression of PAX6 but not NKX2.1. The most dorsal part of septum had a cortical rather than sub-cortical identity, manifested by higher PAX6 expression in the VZ and SVZ and expression of TBR1 by post-mitotic cells in the SVZ, IZ, and cortical plate (Fig. 1e–h; Suppl. Figure 2).
Expression of NKX2.1 in human fetal telencephalon 8–12 PCW
However, at 12 PCW, we found scattered NKX2.1+ cells in the cortical VZ and SVZ sometimes far removed from the ganglionic eminences and septum (Fig. 3b), but no NKX2.1 positive (NKX2.1+) cells were observed to co-express KI67 (not shown) a marker for active cell division (Scholzen and Gerdes 2000). We next quantified the average density of NKX2.1+ in the proliferative zones of the MGE, septum, LGE, vCGE, and the cortex of a 12PCW brain cut in the coronal plane (Fig. 3c; Table 2), and estimated that 93% of NKX2.1 cells in proliferative layers were found in the MGE and ventral septum, 4.6% in the LGE and vCGE, and only 2.4% in the cortex.
Expression of OLIG2 in human fetal ventral telencephalon 8–12 PCW
Since OLIG2 was highly expressed in the NKX2.1-expressing neurogenic domain (MGE and ventral septum), we examined the cellular co-localization of these two markers in the MGE at 8 and 12 PCW. Interestingly, we found three population of cells, NKX2.1-/OLIG2+ , NKX2.1+/OLIG2−, and NKX2.1+/OLIG2+ (Fig. 5a). To confirm that OLIG2+ cells at this stage of human forebrain development (8–12 PCW) were GABAergic interneuron precursors, we performed OLIG2 and GAD65/67 double labelling, and found most of OLIG2+ cells expressed GAD65/67 (Fig. 5b, c). Furthermore, a proportion of cells in the MGE were triple labelled with OLIG2, NK2.1, and GAD65/67 (Fig. 5d–g). However, although both OLIG2 and CalR were expressed in lCGE and mCGE, no double labelling for these two markers was detected (Suppl. Figure 3S).
Expression of OLIG2 in human fetal dorsal telencephalon 8–12 PCW
At 12 PCW, a proportion of OLIG2+ cells in the cortex were also found to co-express KI67 (Fig. 6b). However, OLIG2+ cells were not double-labelled with either PAX6 or TBR2 (Fig. 6c, d), showing that OLIG2 is not expressed by typical cortical radial glial progenitors or intermediate progenitors (Bayatti et al. 2008a; Lui et al. 2011). OLIG2+ cells populated the whole cortex and were mainly seen in the SVZ and IZ; nevertheless, scattered positive cells were sometimes observed in the VZ and the cortical plate (CP; Fig. 6e–i). We quantified the average density of OLIG2+ cells in the proliferative zones of the four different cortical regions. A higher density was found in the medial cortex with a decreasing gradient to the latero-ventral regions (Fig. 6k). Overall, OLIG2 expression was far less confined to the MGE than NKX2.1, with approximately 38% of OLIG2+ cells in proliferative layers found in the MGE and ventral septum, 50% in the LGE and vCGE, and 12% in the cortex (Fig. 6j; Table 2).
Expression of COUP-TFII in the ventral telencephalon 8–12 PCW
Expression of COUP-TFII in the dorsal telencephalon 8–12 PCW
We found a distinct distribution of COUP-TFII+ cells between the anterior and posterior cortex at 8 PCW. In the anterior cortex, COUPT-FII protein was localized to all layers. Although most of COUP-TFII+ cells were located in the SVZ and IZ, a considerable number of cells were also observed in the VZ and CP (Fig. 7c, e). A different distribution of COUP-TFII+ cells was observed in the posterior cortex, where cells were restricted to what appeared to be two migratory streams; a major one in the SVZ, and a less defined one in the nascent pre-subplate at the border between the IZ and the CP (Fig. 7c, d). No COUP-TFII positive cells were found in the VZ (Suppl. Figure 5d).
All these findings suggest that the neurogenic domain for COUPT-FII precursors in the vCGE extends into the cortical wall of the ventral cortex, but not dorsal cortex, and includes radial glial progenitor cells that generate glutamatergic neurons. We quantified the average density of COUP-TFII+ cells in the proliferative zones across the cortex (Fig. 9a–f) and found a decreasing gradient of density from higher gradient in the ventral cortex to a lower gradient more dorsally. In a recent study, Reinchisi et al. (2012) reported that COUP-TFII+ cells are more abundant in the temporal/caudal cortex of human fetal brain, which was attributed to a caudal migratory stream from the CGE. However, our results suggest, in humans, the presence of an additional anterior migratory stream, and provide evidence that the neurogenic domain of COUP-TFII expressing progenitor cells is not confined to the CGE, but extends to the ventral cortex, including the frontal lobe (Fig. 9g). In addition, we found most COUP-TFII+ cells in the ventral cortex to be double-labelled with CalR. However, a proportion of COUP-TFII+ cells in all other regions of the cortex were also shown to be a subpopulation of CalR expressing cells (Suppl. Figure 5c–e).
We have described the expression patterns of three transcription factors important to the generation of cortical interneurons in the early fetal human telencephalon and demonstrated that they occupy distinct (although overlapping) neurogenic domains which can extend into the cortex. NKX2.1 was very largely confined to the MGE, mCGE, and ventral septum, and at this stage of development, these observations support the previous studies suggesting that interneuron generation from NKX2.1 positive cells may be identical in nature with the process occurring in rodents (Hansen et al. 2013; Ma et al. 2013; Arshad et al. 2016). OLIG2 was expressed by cells in the proliferative zones of the MGE, mCGE, and septum, co-expressed with GAD65/67, but not necessarily co-expressed with NKX2.1, and was also extensively expressed in the LGE, lCGE, and in dividing cells in the cortex; observations previously unreported at this key stage of development. Within the ganglionic eminences, dividing COUP-TFII precursors were localized to the vCGE as previously described (Hansen et al. 2013) but were also numerous in adjacent regions of ventral cortex. From careful examination of multiple expression patterns, we have been able to more accurately compartmentalise the CGE than has previously been attempted, and describe additional ventral to dorsal migratory streams for interneuron precursors not previously reported in rodents, as will be discussed in more detail below. Further evidence for interneuron generation in the human dorsal telencephalon has been presented.
Anatomical and molecular subdivisions of the CGE
In rodents, the CGE has been identified as a source of specific GABAergic interneuronal subtypes different from those generated from the MGE (Miyoshi et al. 2010; Rudy et al. 2011). Some researchers have concluded that the CGE comprises caudal extensions of LGE and MGE, respectively, by virtue of its gene expression patterns (Corbin et al. 2003; Flames et al. 2007). However, as additional transcription factors, such as COUP-TFI and COUP-TFII, are enriched in CGE, it is possible that the CGE has evolved as a distinct neurogenic domain separate from the MGE and LGE (Kanatani et al. 2008). This study has revealed that in the developing human brain, the lateral and medial portions of the CGE share the expression patterns of PAX6, OLIG2, and NKX2.1 of the LGE and MGE, respectively. However, in addition to these lateral and medial portions of the CGE, the extension of the CGE along the lateral ventricle into the greatly enlarged temporal lobe has produced a third compartment distinguishable by its characteristic co-localisation of intense COUP-TFII and PAX6 expression in the proliferative layers. Dividing COUP-TFII+ cells were confirmed as being confined to this ventral region of the CGE (Hansen et al., 2013). In addition, unlike the dorsally located lateral and medial portions, almost no NKX2.1+ cells were found in the vCGE. These findings suggest that the anatomical and molecular boundaries of the CGE should be defined carefully and separately, with the dorsal region formed from caudal extensions of the LGE and MGE, albeit with a higher density of post-mitotic COUP-TFII and CalR positive cells, and the ventral region having its own molecular signature including COUP-TFII positive progenitor cells.
Are anterior and medial migratory streams prominent in the human telencephalon?
Quantitative PCR, microarray, in situ hybridisation, and immunohistochemical studies between 8–12 PCW have previously identified an anterior-to-posterior gradient of expression of multiple genes identified with GABAergic interneurons and GABAergic neurotransmission, including transcription factors characteristic of interneuron precursors, isoforms of GAD, GABA receptor sub-units, and calcium-binding proteins (Bayatti et al. 2008a; Ip et al. 2010; Al-Jaberi et al. 2015) seemingly at odds with the accepted lateral (MGE derived) and posterior (CGE derived) pathways of migration for interneuron precursors from ventral to dorsal telencephalon (Wonders and Anderson 2006). This led to speculation that the anterior cortex in particular may be a novel site for generation of interneurons in the primate telencephalon, perhaps, to populate the enlarged prefrontal lobes of the primate brain (Al-Jaberi et al. 2015; Clowry 2015). This study offers up the alternative explanation that migrating interneurons may more rapidly invade the anterior than the posterior cortex, even from apparently caudal structures, such as the vCGE. We saw evidence of a rostral migratory stream of COUP-TFII and CalR expressing cells from the vCGE, where COUPTFII expressing progenitors exclusively underwent division, to the anterior cortex via the lCGE, LGE, and ventral pallium (Fig. 9). Such cells were more numerous in the anterior than posterior cortex, as previously described for CalR+ neurons (Bayatti et al. 2008a). Examination of our 3D reconstructions of the 12 PCW fetal brain confirmed that this path length is similar or even shorter than that from the vCGE to the dorso-posterior cortex via the temporal lobe (Fig. 9g). Although rostral migratory streams from the LGE to olfactory bulbs are well described in mammals (Corbin et al. 2001; Waclaw et al. 2009), a rostral migratory stream from the GE to the rostral pallium has only been reported in shark (Quintana-Urzainqui et al. 2015) and so may be overlooked or missing in rodent models.
In addition, we have observed increased expression of OLIG2 in the anterior compared to posterior cortex in agreement with the previous studies (Ip et al. 2010; Al-Jaberi et al. 2015) particularly at 8 PCW where there was also a distinct medial to lateral gradient of OLIG2 expression. In this case, the migratory stream appeared to derive from progenitor cells in the MGE and sub-cortical septum, and enter the cortex via the medial wall. This is in direct contradiction to what has been reported in rodents where interneurons populating medial wall-derived structures, such as the hippocampus, are described as deriving from the MGE and CGE via lateral migration (Pleasure et al. 2000; Wonders and Anderson 2006; Morozov et al. 2009; Faux et al. 2012). In our preparations, we found evidence that OLIG2+ and NKX2.1+ progenitors reside in the septum and OLIG2+ cells, at least, migrate medially to the cortex. Again, this is in disagreement with findings in rodents, where septum derived cells were reported not to enter the cortex at all (Rubin et al. 2010). Thus, we propose that the human or primate brain possesses an additional medial migratory pathway for GABAergic interneurons populating frontal and medial areas of the cerebral cortex. The much larger human cortex may require additional migratory pathways compared to smaller mammalian brains. However, it is worth noting that a medial migratory pathway for Nkx2.1 positive precursors from the MGE to the medial pallium has recently been reported in the shark (Quintana-Urzainqui et al. 2015); therefore, such a pathway cannot be proposed as evolutionarily novel to the human brain. Instead, we might speculate that this is missing or relatively small and overlooked in rodent compared to other vertebrate species.
Potential dorsal telencephalic origin of GABAergic interneurons
Based on studies carried out principally around mid-gestation, Radonjić et al. (2014a) proposed that three mechanisms exist for the production of cortical interneurons in primates: generation in the ventral telencephalon followed by migration to the cortex, precursors arriving in the cortex from the ventral telencephalon, and undergoing further division intra-cortically, and cortically derived progenitors giving rise to interneurons. The last two proposals are controversial, being firmly rejected by recent influential and persuasive studies (Hansen et al. 2013; Ma et al. 2013; Arshad et al. 2016). However, our present study found clear evidence for the second mechanism. OLIG2+ precursors appeared to follow migratory paths into the cortex; however, OLIG2+ cells were also shown to be undergoing proliferation and these OLIG2+ cells did not co-express any markers of cortically derived progenitors, such as PAX6 or TBR2 (although such double-labelling has been reported at later stages of human development; Jakovceski and Zecevic 2005). This firmly suggests that OLIG2 is not immediately downregulated in cells entering the cortex from subcortical structures, unlike NKX2.1, and that these cells may retain the ability to divide within the cortex, preferentially within anterior and medial locations, where the highest density of such cells was found. However, there also remains the possibility that OLIG2+/TBR2- intermediate progenitor cells are generated by cortical radial glial progenitor cells which go on to produce GABAergic interneurons.
It is also clear that in the more ventral areas of the anterior and temporal cortex, there is high expression of COUP-TFII expressing progenitor cells and post-mitotic neurons. These progenitor cells co-express either PAX6 or TBR2 and post-mitotic cells co-expressing TBR1 and COUPTFII were also observed, which demonstrates that in the cortex, dividing COUP-TFII+ progenitors give rise to glutamatergic neurons. Although there are also COUP-TFII+/CalR+ presumptive interneurons present, it is impossible to judge whether these have migrated in from the adjacent CGE, or been generated intra-cortically. However, a neuronal progenitor marker GSX2, expressed upstream of COUP-TFII, which localises to the LGE and CGE in rodent (Hsieh-Li et al. 1995; Wang et al. 2013), has been found to be expressed in cells undergoing division in the VZ/SVZ of the human fetal cortex (Radonjić et al. 2014b) making intra-cortical generation a possibility.
Whether or not proliferative NKX2.1+ progenitor cells are present in the cortex is contentious. Our observation at 12 PCW of NKX2.1+ cells throughout the latero-medial extent of the cortical wall, making up about 2.4% of all NKX2.1+ cells in the proliferative zones of the telencephalon at this time, is in conflict with Hansen et al. (2013) who reported nearly no NKX2.1+ cells in the cortex and only close to LGE/lateral cortex border. However, our findings are in partial agreement with Radonjić et al. (2014a) who found NKX2.1+ cells in the cortical wall of human and macaque monkey fetal forebrains (at later stages of development, 15–22 PCW for human) undergoing active division, as did Arshad et al. (2016) in human between 16–28 PCW although in very small numbers. As no NKX2.1+ cells were seen in the cortex at 8PCW in agreement with the previous studies (Hansen et al. 2013; Pauly et al. 2014), we propose that with age, the incidence of NKX2.1+ cells in the cortex gradually increases, along with the capacity to undergo proliferation. Whether these cells are generated in the cortex or have migrated there from the ventral telencephalon without downregulating NKX2.1 remains a question for further investigation.
OLIG2 and COUP-TFII as regulators of cortical arealisation
The division of the cerebral cortex into functional areas (the cortical map) differs little between individuals in any given species (Rakic et al. 2009). The previous work on rodent development has identified certain transcription factors (e.g., PAX6, SP8, EMX2, and COUP-TFI) expressed in gradients across the neocortex that appear to control regional expression of cell adhesion molecules and organization of area specific thalamocortical afferent projections (López-Bendito and Molnár 2003; O'Leary et al. 2007; Rakic et al. 2009). There may be common mechanisms between species, as the developing human neocortex displays counter-gradients of PAX6 and EMX2 at the early stages of cortical development (Bayatti et al. 2008b). However, the human cerebral cortex is composed of different and more complex local area identities and so might be specified by a wider range of transcription factor gradients; for instance, an anterior-to-posterior gradient of CTIP2 expression has been observed in human early fetal cortex (Ip et al. 2011). In this study, we observed a prominent anterior-to-posterior gradient of OLIG2 expression, and a ventral-to-dorsal gradient of COUP-TFII expression. In both the cases, the transcription factors are also expressed at moderate levels in the cortical plate as well as the proliferative zones, suggesting that areal specification mechanisms in cells extend into the post-mitotic period. The extent to which these gradients interact with interneuron precursors is not known, but we might speculate that OLIG2 or COUP-TFII controls expression of cell adhesion molecules locally that attract migrating cells expressing the same transcription factors, setting up the migratory pathways into the cortex for interneurons arriving medially via the septum (OLIG2+) or laterally via ventral anterior or temporal cortex (COUP- TFII+).
Evidence continues to accumulate that cortical GABAergic interneuron production in primates differs in certain details from what has been learnt from our rodent models. A higher proportion of interneurons arise from the CGE in primates and we provide a description of the compartmentalisation of the CGE. This study presents further evidence that interneuron precursor cells may undergo division in the cortex, although it remains to be proven whether they are originally generated in the dorsal telencephalon. Finally, whereas in rodents, interneuron precursors are believed to enter the cortex from the ganglionic eminences exclusively via lateral and posterior routes, in human, we provide evidence of pathways via the anterior and medial cortex.
The human embryonic and fetal material was provided by the jointly funded Human Developmental Biology Resource (http://www.hdbr.org) MRC/Wellcome Trust grant# 099175/Z/12/Z). Ayman Alzu'bi is in receipt of a studentship from Yarmouk University, Jordan. We are grateful to Dr Peter Thelwall for capturing the MRI scans and Xin Xu for her help with slide scanning.
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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.


text:
Chew. Volume 11, issue 52-55, The last suppers.
Record details
- ISBN: 9781632159717 (electronic bk.)
- ISBN: 1632159716 (electronic bk.)
- Physical Description: 1 online resource
- Publisher: [United States] : Image Comics : 2016.
Content descriptions
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|Summary, etc.:
| Tony Chu is close to finding answers about the bird flu that killed millions. The only thing standing in his way is Mason Savoy, fellow cibopath, ex-mentor, and unrepentant murderer! Presenting the second-to-last storyline of the New York Times Bestselling, Harvey and multiple Eisner Award-winner series about cops, crooks, cooks, cannibals, and clairvoyants. Includes crossover CHEW/REVIVAL!
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subset: commoncrawl


text:
Note: This event is not sponsored by The Planetary Society. The Society has no control over, or responsibility for, the content or operation of events sponsored by other organizations. All inquires should be directed to Hira Nadeem.
McMaster Space Initiative Science Cafe
September 23, 2016, 5:15pm EDT
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Become a member of The Planetary Society and together we will create the future of space exploration.
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text:
26th annual SOMERSET ELEMENTARY Back-to-School Classic 8K and 2K
Somerset Elementary School ?
Sun 10/20/2013
1 mile, 5 mile, 8K
4000 Participants
• Montgomery County's finest community race. • More than 1,000 participants and spectators. • Scenic, USATF-certified course on gently rolling hills in Somerset, Chevy Chase, and Friendship Heights. • Locally-designed T-shirt. • Post-race brunch • Awards and Great Prizes: Great prizes for the top 3 male and female overall finishers in the 8K • Age group awards for the top 3 male and female finishers in the 8K for these age groups: 15 & under, 16-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70 & over • Proceeds help Somerset Elementary School provide scholarships for its after-school programs, build its library collections and classroom resources, and offer a rich cultural arts program. On behalf of the students, thanks for your support! • Fun Run for Children! The Fun Run for young athletes 11 & under will take place at Somerset Elementary School following the 2K race. The Fun Run is free to all young athletes, but T-shirts must be ordered separately • Classic T-Shirt: Locally-designed T-shirts to all entrants in the 8K and 2K. • Non-runners and fun runners can order T-shirts by selecting "T-shirt & Brunch Only" • On-line registration closes on Thursday, October 17, at 11:59 PM
- Address:5811 Warwick Place
Chevy Chase, MD 20815


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Volleyball Canada will pay thousands of dollars for the flights of beach volleyball players to Europe, rather than see the players' chances of qualifying for the London Olympic Games vanish under a mass of bureaucratic red tape.
"If it's an issue for them, we'll buy their air tickets for the tournaments (in Prague, Moscow and Rome)," said Ed Drakich, Volleyball Canada's high performance director for beach volleyball. "We don't want players to miss out on the Olympics because they didn't have a ticket to the qualifying events. We'll make sure the athletes get their flights. ... The bottom line is, we're alive and can get to the Games."
Carding money from Sport Canada's Athlete Assistance Plan – which had been tentatively approved for 20 players – has been held back for six months by a Volleyball Canada appeal concerning a player who had been cut from the men's team.
With the Olympic clock counting down, some of Canada's top beach volleyball players complained they had hit the limit of their personal credit cards and couldn't afford plane tickets to the crucial Europe tournaments in which they could win a spot on the Olympic court.
The chances of the Toronto twosome of Heather Bansley and Liz Maloney and the men's team of Martin Reader of Comox, B.C., and Josh Binstock of Toronto – potential Olympians – were affected by the lack of funds.
"The carding [money]is on hold because of the appeal process," said Drakich, adding that the appeal process has dragged in an unusually long time. "It's extremely unusual that it [the appeal]takes so long but the stars lined up that way. We'd like to resolve the process."
Seven-year veteran Rich VanHuizen is making an appeal after not being picked for the national squad this year.
"It is the responsibility of Volleyball Canada to determine the eligibility of their athletes for carding and to provide this information to Sport Canada," explained Len Westerberg, Sport Canada media relations adviser.
"The appeal process that is under way is internal to Volleyball Canada, and Sport Canada is unable to complete the carding process until Volleyball Canada completes its appeal process."
"The carding money they're not receiving is money they need. In the last couple of days, the decision was made. On a need basis, we'll make sure we have the flights," Drakich said.
The women, ranked 19th in the world, can qualify directly for the London Olympics by improving their ranking to top-16. Bansley and Maloney recently have had seventh- and ninth-place finishes in world tournaments.
They've used their dwindling dollars sparingly – Bansley is tapped out and Maloney is working on a line of credit. They got a coach to the Shanghai tour stop by using up points on a customer loyalty card, Bansley said.
"People might think of it as a 'fringe' sport, but we do it because we have a passion for it and passion for the lifestyle," says Mark Heese, an Olympic bronze medalist and 10-time national champion. He is in Toronto with volleyball gear sponsor Overkill for the world tour (at Ricoh Centre May 18-20) and the national volleyball championship.
The game is bigger than when he won his Olympic bronze with John Childs in 1996. Now 42, and a firth place Olympic finisher at Sydney and Athens, he played until his mid-30s on a teacher's salary. It's tough to do now, he said.
With the growth of the sport has come expensive responsibilities.
"We have a lot more facilities and coaching and a national training centre," he said. Athletes are expected to pay their way to most professional events. "If they want to go, it's up to them," he said. "The appetite from sponsors is not there yet."
Bansley and Maloney have Grand Slam events remaining in Moscow (June 6 to 12) and Rome (June 12 to 17) The men have three Olympic qualifying events left – the Prague Open, May 22 to 27; plus the Moscow and Rome tournaments. The men, ranked 29th in the world tour, are likely to seek a different route to the 24-team Olympic field from the women. They can advance as a regional (NORCECA) representative. They need to win the Continental Cup in Mazatlan, Mexico in late June. Reader won last year's Continental Cup with a different partner.
"For both the men and the women, an Olympic spot is a real possibility," Reader said in an interview.
In a throwback to days of underfunded amateur sport Jane Roos, founder of the independent athlete fund raising body Canadian Athletes Now, started an emergency appeal for $60,000 – by Wednesday afternoon the fund received almost $20,000.
"It's tough when you see the top teams in the world show up with three or four support staff. Ninety per cent of the time, we go without a coach or physiotherapist or a psychologist," Bansley said.
"Volleyball Canada will be paying for our travel to the Continental Cup, World Cup [if we come second or third at the Continental cup] Austrian Grand Slam [preparation tournament]and the Olympic Games," Reader said in a message. However "we must still compete in the final three tournaments of our qualification period on our own dime."
Reader said he and Binstock financed their Olympic dream themselves this season and previously fundraised $20,000 – half of which was a donation from Magna International CEO Don Walker – "but we have emptied that pot. We were proactive in our fundraising efforts as we anticipated these financial stresses but we were only able to do so much by ourselves."
Roos said in her appeal that London is "a dream that has been a journey for more than eight years for most of these athletes."
Roos said donations for the beach volleyball teams can be made at here or on the organization's main site.Report Typo/Error
Follow us on Twitter: @Globe_Sports


text:
Community Base Project – Community Activities Promote Healthy Lifestyles
Presentation: Project Title & Idea: Community Activities Promote Healthy Lifestyles Driving Question: Students evaluate the relationship between land use, community needs, resources, and a healthy lifestyle. Subjects: ELA, Math, Geography, History, PE, Science Driving Question: What individual and/or collective choices and habits will promote a sustained healthy lifestyle? Entry Event: Video clip or skit related …View full post
Aug 23
(No title)
Jul 25
Community Base Project – Community Activities Promote Healthy Lifestyles
Project Title & Idea:
Community Activities Promote Healthy Lifestyles
Driving Question:
Students evaluate the relationship between land use, community needs, resources, and a healthy lifestyle.
ELA, Math, Geography, History, PE, Science
Driving Question:
What individual and/or collective choices and habits will promote a sustained healthy lifestyle?
Entry Event:
Video clip or skit related to a community event that highlights a healthy lifestyle
Product: Map, Advertisement, Log/Evaluation Graph
Presentation to Audience in Convention Setting with Focus Group
"I like….":
"I wonder…."
"I have…"
Jan 18
Sep 18
Key Ideas that Foster Parent Engagement with Families
Key ideas that foster parent engagement with families
Key ideas that connect with families
Respect – Build Relationships | Respeto – Creando Relaciones
Listening – Active ear | Escuchar – Teniendo una oreja activa
Engage Parents by treating them to have a voice in education and training | Enseñe a los padres a tener una voz en la educacion y entrenamiento
Empowering parents to be facilitators using talents and expertise | Autorizar a los padres a ser facilitadores usando sus talentos y experiencia
Presentations same for all stakeholders only differentiated | Las presentaciones son iguales para todos los grupos representados en la escula solo que diferenciado
Creating trust through following through on what adults say they will do | Creado confianza por medio de cumplimientos de lo que adultos dicen que ellos van ha hacer
Make them part of the solution | Hacerlos parte de la solución
Develop transparency | Desarrollar transparencia
Validating their experiences | Lavidando sus eperiencias
Active Involvement | Participación activa
Acknowledge / Sensitive to parents | Reconocer /Ser sensitivos con los padres
Parent mentoring – i.e. teach parent workshops for parents before parent night, prepping them to ask questions during the teacher/parent meeting.
Tutoría para los padres – por ejemplo – enseñar talleres para padres antes de la Noche de Padres, preparandolos a formular preguntas durante la conferencia de padres y maetro(a).
Feb 19
CST Grade Four Response to Literature Writing Task
X Marks the Spot
by Julian Fleisher
Chapter 1: A Drive to the Mountains
The road twisted and turned, getting higher and higher. Jamal stared straight ahead, frowning. His mom was driving the car and was humming happily to herself.
"Are we there yet?" Jamal asked, crossing his arms across his chest.
"Almost, honey," his mom replied. "Look out the window. Isn't it beautiful?"
Jamal didn't answer, but he did look. Out his mom's window, all he could see was a rising, rocky cliff. Out his own window, the cliff dropped down. Jamal could see the road winding below them. Below that were green fields. A few houses and farms were scattered about. The city was a long way away. It felt like they had been driving forever.
They were driving up into the mountains to spend a week at a ranch. His mom had lived at this ranch when she was a little girl. "Some vacation," Jamal thought to himself.
All of Jamal's friends were doing cool things this summer. Joey was going to an amusement park. Ernesto was spending a whole month with his family at the beach. Vickie had just gotten five new computer games. She was going to spend the entire summer racking up high scores. Jamal and his mother were going to spend a crummy week in the crummy mountains.
"Isn't this exciting?" Jamal's mom asked. "I love the mountains."
"What's so exciting about a bunch of old rocks?" Jamal said.
"Oh, don't worry," his mom said, patting his arm. "There'll be lots of things to do."
"Name one," said Jamal.
"You'll see," his mom replied. "It's very different from the city. Where we live is cluttered with all those buildings. There are cars and trucks and people wherever you look. It's not like that here in the mountains where you can breathe and think and just relax."
Jamal didn't want to relax. He just wanted to sit on the stoop with his friends. In fact, he wished he were sitting anywhere except a car on the way to the boring mountains.
"Hey, look at that," Jamal's mom said. She pointed out her window. The cliffs had leveled off. Below them was a green field. A group of horses was in the field. Jamal had never seen horses before. They were amazing. They were powerful and muscular. And they were bigger than he had expected.
"That's one thing we'll do," his mom said. "We'll ride horses this week."
Jamal didn't say anything. He didn't know if he liked the idea of riding a horse. What if he fell off? What if the horse bit him with those big teeth? Or kicked him with its horseshoe? Just what exactly had his mom gotten them into?
Chapter 2: A Map to Surprises
When they finally arrived at the ranch, Jamal's mom parked the car beside a big wooden building. In front of the building was a yard surrounded by smaller buildings.
"That big building is the barn," his mom said. "We'll be staying in one of the guest cabins. We'll have it all to ourselves."
They got out of the car and crossed the yard. Three men in overalls passed by. They were carrying tools and looked dirty.
"Hello, Olivia," one of the men called out.
"Hey, Livy," said another of the men. "It's been a long time."
"It sure has," Olivia called back. "This is my boy, Jamal. We'll see you all for dinner!"
"Sure thing," the third man said. "Pleased to meet you, son!"
"Why did he call you 'Livy'?" Jamal asked when the men were out of sight.
"I knew them when I was a little girl," Olivia said. "They work on the land. It looks like they're getting ready to fix the barn. I remember doing it myself when I was a girl." "You fixed a barn?" Jamal asked. His mouth was wide open.
"Oh, sure," Olivia said, laughing. "I helped to build that barn."
"No way!" said Jamal.
"Way," said his mom, playfully. "I used to help out with all sorts of things."
Jamal knew that his mom grew up on a ranch. But he couldn't believe she knew how to build a barn. But then he thought about how strong her hands were.
"This is ours," his mom said as they reached one of the cabins. "And now, I have a surprise for you."
Olivia handed Jamal a piece of paper. On it were pictures of houses, trees, and water. There were Xs beside some of the pictures, connected by a dotted line.
"I drew this from memory," said Olivia. It's like a treasure map. If we follow the dotted line, we'll have a lot of fun. And there's a surprise at the end."
Chapter 3: Old Goober
"Let's go!" cried Jamal.
"Hold on a second," his mom said. She began filling Jamal's backpack with stuff from home. "Why don't you go put your bathing suit on?"
Jamal raced into the bathroom. He put his bathing suit on under his shorts. When he returned, his mom was ready to go.
"Okay," she said as they walked outside. "Look at the map. Where do we go first?"
Jamal took out the map. At first he didn't know what to make of it.
"I get it," he said. "We're at the first X. The dotted line goes between our cabin and the one beside us. Then it goes toward this circle thing."
Holding the map out in front of him, Jamal began to walk. He imagined the dotted lines on the ground in front of him. Ahead, he could see a round, fenced-in area. Inside the fence were horses.
"This looks like the second X," he said.
"That's right," his mom replied. She made a clucking noise with her tongue. A brown-and-white horse came trotting over.
"This is Old Goober," Olivia said. She fished a carrot out of the backpack. "He's going to be your horse for the week. Why don't you try feeding him?" Jamal took the carrot. His hand was shaking. Old Goober gently took the carrot from Jamal's hand. His teeth and tongue were huge. "There's no way I'm riding that horse," thought Jamal. Old Goober stuck his head through the fence. Jamal felt the horse nuzzle his arm and he jumped back.
His mom laughed. "Come on. Let's find the next X."
"It looks like the dotted line follows some kind of road," Jamal said as he pointed to a dirt trail that led away from the horses. "Is it this path?"
"Let's find out," his mom replied. They started down the path. Ahead of them, Jamal could see a forest. He could see on the map that his mom had drawn a group of trees. The third X was on the other side of the trees.
"It's this way!" Jamal shouted. "Come on!" He ran into the forest.
Olivia walked through the trees. She felt their leaves and needles. "These ones with needles are called evergreens. There are also maple and oak and ash trees. You can tell them apart by looking at their leaves."
Jamal marveled that his mom knew so many things. Who'd have thought she knew the names of trees?
Jamal and his mom followed the trail out of the forest. They started walking up a steep hill. "It's hard to breathe up here," Jamal said. He was panting a little.
"That's the mountain air," his mom explained. "The higher we go, the thinner the air gets."
They finally reached a pile of big rocks. Farther below them, at the bottom of a cliff wall, was a river. Jamal looked at the map.
"This must be the third X," he said. "But the next X looks like it's down where that river is. How do we get to it? It must be about 20 feet down."
"Well, I guess we'll just have to climb!" Olivia said. Jamal's mouth dropped open. Then he watched his mom fearlessly start to climb down the cliff wall.
Chapter 4: Supermom
"Okay, it's your turn!" Jamal's mom called up when she reached the bottom.
"I can't do it!" Jamal called back.
"Sure you can," his mom shouted up to him. "Just lean into the wall. Feel with your feet for rocks to stand on. There are lots of holds for your fingers, too, but you should let your legs do most of the work."
Jamal followed his mom's directions. He found that if he leaned forward and moved slowly there was no danger of falling. When he reached the bottom his mom scooped him up into her arms.
"That was great!" she exclaimed. "You're a very good climber."
Jamal just shrugged, but inside he felt wonderful. "So this river is the next X?"
"That's right," his mom confirmed.
They checked the map and followed the river downstream. After a while, the river opened up into a small lake. In the middle of the lake was a wooden raft. Jamal looked at the map.
"The next X is in the center of the lake," he said. "Is it that raft?"
"It sure is. Race you there and back!" his mom shouted. She and Jamal took off their outer clothes. They rushed into the water wearing their bathing suits.
Olivia swam powerfully out to the raft. Jamal followed. He touched the raft and started back to shore. He was panting for breath when he reached the edge of the lake.
"You won," Jamal said. "You're a fast swimmer."
"I'm also a lot bigger than you," his mom said. "But you'll be beating me soon enough!"
They dried off with towels Olivia had brought in the backpack. Then they looked at the map again.
"The final X," Jamal said. "It looks like it's back at the barn."
"That's where we'll have our surprise," his mom said. "And we're just in time! It's beginning to get dark."
They hurried along the path marked by the dotted line. When they reached the barn, Jamal peeked inside. The barn was cluttered with bales of hay, tools, two trucks, and a lawn mower. A bunch of wooden planks were piled on top of each other.
"What's the surprise?" Jamal asked.
His mom pulled a little bag of dry dog food out of the backpack. She tossed a handful of nuggets up into the air.
"What are you doing?" Jamal asked his mom.
"You'll see," Olivia said. She threw another handful up toward the sky. Suddenly, something swooped through air.
"What was that?" yelped Jamal.
His mother tossed more dog food in the air. More little creatures swooped over their heads. Then again. More food. More swooping! Finally, Jamal could see what the creatures were.
"Bats!" Jamal screamed. For a moment, he was disgusted. What if they bit him and sucked his blood? But then he looked at his mom. She was laughing and spinning around as she fed the bats. He knew he had nothing to be afraid of.
"This was my favorite thing to do when I was little," his mom said. "For some reason, they love dog food. They spot it with their sonar and they grab it right out of the air. Here, take some and try."
For a long while, Jamal and his mom stood in the twilight and fed the bats. Jamal thought that this was just about the most fun he had ever had.
"Well, we better get in to dinner and then hit the sack," Olivia said. "We have a big day of horseback riding tomorrow."
"Will you show me how?" Jamal asked.
"Of course," his mom replied. She put her arm around him.
"Mom?" he said, looking into her face. "I think you're pretty cool. For a mom."
They headed back arm in arm to their little cabin. Jamal was a little bit tired. But he was not in the least bit bored.
Writing the Essay
What is the lesson the author wants you to learn from this story? Use details from the story to support your answer.
■ to show your understanding of the story
■ to give examples from the story
■ to use correct grammar, spelling, punctuation, and capitalization


text:
"The Plates Are Not Enough" is an episode of Special Agent Oso.
Oso is trained to slide down a mountain on his snowboard when Paw Pilot calls in a special alert. Three sisters, Isabella, Ali, and Elizabeth, are preparing a big family dinner. Isabella volunteers to set the table. However, Isabella doesn't know how to set a table, so it's up to Oso help her before dinner time.


text:
Hackers and Gabon Burst Dotcom's Bubble, MegaUpload Successor Won't Use Spiffy Domain As Planned
Not to be confused with Gaben, which refers to Valve head Gabe Newell, Gabon is a sovereign state located in Africa which just so happens to control the .ga top-level domain. Because Kim Dotcom is clearly a clever wordsmith, it was announced that the upcoming successor to MegaUpload would be called "Mega" and -- you guessed it -- exist at the Me.ga address. It looks like that's not going to happen, though, as both the Gabon government and an anonymous group of hackers have pulled the plug on Me.ga before the service even had a chance to launch.Read More
MegaUpload Successor May Launch on the Anniversary of Kim Dotcom's Arrest
Despite the best efforts of copyright-holders everywhere, it looks like MegaUpload is poised to make a comeback of sorts. The pirate site's founder Kim Dotcom already announced that he's working on a cloud-based successor to the site. Ever the troll, Dotcom now says that he plans to launch his new streaming site, simply entitled "Mega", exactly one year after a SWAT team arrested him during an assault on his New Zealand estate.Read More


text:
- A match made … well, you decide where! R. Crumb illustrates Charles Bukowski.
- How to survive an online pan: in this case, persuade the author to remove it.
- A history of cricket in literature.
- A new attempt at a Breakfast at Tiffany's musical is headed for Broadway.
- "I've never read anything so badly written that got published." Salman Rushdie on Fifty Shades of Grey.


text: UNE's fight against chronic pain championed in 'Press Herald' editorial February 19, 2015 On February 7, 2015, the Portland Press Herald printed an editorial by Susan Dudley Gold, founder of the Chronic Pain Support Group of Southern Maine, in which she lauded the... Interprofessional Graduate Student Team Awarded Mini-Grant for Research Project February 12, 2015 An interprofessional team of UNE Health Professions graduate students has been awarded a mini-grant from the Center for Excellence in Interprofessional Education (CEIPE) for their research project "Visual Voices: An... UNE launches 2015 CLARION case competition February 05, 2015 The University of New England CLARION committee of the Interprofessional Student Advisory Team (IPSAT) recently held its third annual CLARION case competition kick-off event. Founded by the University of Minnesota,... UNE partnership with Apothecary by Design featured in MaineBiz January 29, 2015 The partnership between UNE's College of Pharmacy and Apothecary by Design was featured in MaineBiz this week for its role in keeping knowledgeable, talented employees in Maine. The article discussed... Westbrook College of Health Professions featured in the Bangor Daily News for partnership with Cumberland County Jail November 24, 2014 UNE's Westbrook College of Health Professions was highlighted in both a video and article on the Bangor Daily News website this week for facilitating a 30-day drug rehabilitation program for... UNE-Cumberland County Jail partnership acknowledged by MPBN November 07, 2014 UNE's Westbrook College of Health Professions (WCHP) appeared in an MPBN news article for its partnership with the Cumberland County Jail (CCJ). The article described the month-long pilot drug treatment... UNE staff present jointly at National AHEC Conference July 18, 2014 Staff from the School of Community and Population Health's Maine Area Health Education Center (AHEC) Network: Karen O'Rourke, M.P.H., director; Maryfrances Smith, B.S., program manager; and Kira Rodriguez, M.H.S., AHEC... Susan St. Pierre and Mindy Golden present on interprofessionalism June 27, 2014 On June 6, 2014, Susan St. Pierre, DO, assistant clinical professor in the College of Osteopathic Medicine, and Mindy Golden, MSN, RN, assistant clinical professor in the Department of Nursing,... UNE IPCP Summit featured on National Center for Interprofessional Practice and Education blog June 18, 2014 The University of New England's 2014 Interprofessional Collaborative Practice (IPCP) Summit, "Developing Interprofessional Collaborative Practice," held on UNE's Biddeford Campus May 28-29, was featured in a column on the National... IPCP speakers (l to r): Stephen Shannon, Frederick Chen, George Thibault and Barbara Brandt UNE Interprofessional Collaborative Practice Summit attracts scores of Maine health care professionals, leaders June 09, 2014 Close to 200 health care leaders and organizations from across the state attended University of New England's 2014 Interprofessional Collaborative Practice (IPCP) Summit, "Developing Interprofessional Collaborative Practice," on UNE's Biddeford... Pages« first ‹ previous … 3 4 5 6 7 8 9 10 11 … next › last »


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I will wake her up if we have a schedule to keep...
My girl has slept from 8:00 to 7:00 for a long time now (I can't remember when it started). Sometimes she'll sleep until 8:00 though, which I kind of like. The problem is we have some regular activities at 10:30 on Tues & Thurs. If she sleeps until 8:00 she always wants to nap at those times and she ends up really grumpy. I'll wake her up at 7:00am on the dot on those days so she'll nap & eat before we have to go. It makes the day more enjoyable!
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I'm the proud mama of my daughter Avery, born on June 6, 2013. I'm 26 years old, I work from home as a graphic designer, I will be testing for my 5th degree black belt in Tae Kwon Do in 2015. My husband, Derek, and I have been happily married for 3 years.


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Restaurant Review: Gwen Is a Hollywood Temple to Curtis Stone's Meaty Ambition
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A new law that went into effect Tuesday did not force the Lawrence Humane Society to kill any of the cats living at its shelter for abandoned, stray and unwanted animals.
Renee Harris, the shelter's manager, said the shelter had 26 cats Tuesday morning, including five kittens living with their mother.
New state regulations that went into effect require cat cages at least 24 inches high. Only 21 of the shelter's 75 cat cages meet the new requirement.
Two weeks ago the shelter at 1805 E. 19th had nearly 40 cats waiting to be adopted. But since then some have been adopted by new owners.
The cat population at the shelter typically declines in winter -- when the dog population peaks -- and picks up again in spring and summer, Harris said.
"We're going to start receiving more animals," Harris said. "We need to get prepared while we're in a lull."
Harris said the shelter needs at least 45 new cat cages that cost about $250 each.
Last year about a third of the 2,400 dogs and 2,500 cats that came into the shelter were put to death because they were either too sick to adopt or because they were not adopted after at least two weeks at the shelter. The rest were either adopted or, if strays, returned to their owners.
Copyright 2017 The Lawrence Journal-World. All rights reserved. This material may not be published, broadcast, rewritten or redistributed. We strive to uphold our values for every story published.


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Worldview Weekend Radio
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Captain Marvel soars with new uniform and strong personality
Captain Marvel, the superheroine formerly known as Ms. Marvel, has the potential to stand alongside Captain America and Spider-Man as one of Marvel Comics' best characters, starting with some good traits.
"She's a gorgeous, toyetic, statuesque, powerful blonde who shares the name of the company. I think she'll do all right," says Kelly Sue DeConnick, the writer of the new Captain Marvel series debuting today online and in comics shops.
The Avenger is getting an extreme makeover in a few different ways, from costume and hairstyle to a new name and rank to a boosting of her personality, in the book illustrated by up-and-coming artist Dexter Soy.
"He has this side-of-a-van, Led Zeppelin style. It's great," DeConnick says of Soy. She points out an image in the second issue in which the heroine is standing next to a plane wearing a t-shirt, jeans and star-spangled belt buckle, with her hip just slightly out. "She looks at once stunningly beautiful and like she could deck a Mack truck."
The book also is a big break for DeConnick, who wrote the Osborn: Evil Incarcerated miniseries and co-wrote two Castle graphic novels with Brian Michael Bendis.
"It feels like leveling up," she says of her first ongoing Marvel title. "Maybe not quite sitting at the big kids' table but inching closer."
Marvel editor Stephen Wacker wanted to fit DeConnick with the right monthly comic, and also has been trying to get a Captain Marvel book going for a couple of years. DeConnick had just the take on the character that he was looking for — fortunately, at a time Marvel had an open slot in its lineup.
Captain Marvel focuses on Carol Danvers as an Air Force pilot and soldier, but also as a superheroine grounded in her values and relationships.
The first six issues are a time-travel arc, DeConnick says, and is "about the shoulders on which she stands — what it means for her to take this new mantle, and the direction we're going with her personality."
When the character was created in the 1970s, DeConnick found her to be iconoclastic, yet in recent years she has fallen into a law-and-order role, which has made it difficult to cheer for her. For example, in Civil War, she was on the side of Iron Man and the Superhero Registration Act, rounding up and arresting her friends.
"It's hard to get in line to be like, 'Woo hoo!' What we're trying to do is nudge her back to her swagger, get her back to her hungry place, and you can't do that like a needle scratch. It's got to be done kind of gently," DeConnick says.
Wacker acknowledges he took a cue from DC Comics' Green Lantern: Rebirth series, which he worked on before leaving for Marvel. He liked how that book played into test pilot Hal Jordan's brashness.
"People that pilot these planes are a different breed of human, and just playing Carol as another insecure character didn't resonate with me. It seemed like so many other characters we had," Wacker says. "She needed to pop and, to me, she is a Captain America."
Captains Marvel and America are seen busting each other's chops in the first issue — they have a bit of a military rivalry with her being Air Force and him being Army. There is also a battle between Captain Marvel and the Avengers vs. the Absorbing Man, but DeConnick focuses on the little personal moments, too.
She makes coffee for a friend of hers — a rare occurrence in superhero comics — and creates a toasty ambience in a scene that originated with Wacker and DeConnick talking about what makes a hero.
"We were looking for ways she could use her powers, both big and small, to help people," DeConnick explains. Her presence naturally warms up the room and "that one really hit home with me, that she might make the choice to be with someone just to be there with them to warm the room to make them more comfortable.
"When she's there and the coffee machine is broke, she's a tinkerer, she's a mechanic, and she can use her finger as a blowtorch. Of course she would fix the coffee machine! Why not?" the writer adds. "It's like when your dad comes to visit — he doesn't know what to do so he starts fixing things around the house. Carol's like that."
While she hasn't always been a big Ms. Marvel fan, DeConnick found a kinship with her in a few ways. Carol Danvers is from a military background, and DeConnick grew up in a military family.
"She's more driven than I am. But she's also a superhero and I'm not. She can blow things up with her hand - I can't do that yet but I'm working on it," DeConnick says.
They're both chasing something though, and Carol — the eldest of three kids who enlisted so she could attend college — desperately wants her father's approval.
"As funny as it may sound, the Marvel Universe is built on daddy issues and Carol's no exception," DeConnick says. "She loved her dad, and now he's gone so she can never get that thing she needs the most. There are seeds for good fiction in that, I think.
"She has a quick temper, she has that something to prove, she's an alcoholic, and there's a kernel of insecurity in there from that daddy thing that she's never going to probably shake. But she's trying so hard to be better."
In the midst of the Captain Marvel drama are aesthetic changes, specifically a refresh of the costume. Created by artist Dave Cockrum in the 1970s, the Ms. Marvel wardrobe until recently included a black swimsuit with a sash, thigh-high boots and long gloves. It's iconic, sexy and distinctive, "but I do think it's of its time," Wacker says. "I couldn't logic why she would wear that outfit."
DeConnick had been pitching a series with that costume in mind, but Wacker told her to think bigger.
Designed by Jamie McKelvie, the new threads keep the sash, but paired with a shorter, stylized hairdo, DeConnick feels like the costume could be the dress uniform for a superhero branch of the military.
"The basic notion was put her in a flight suit," the writer says. "That's what this is about, her as a flier and all of the metaphor that's so rich in that imagery, so let's reflect that on what she's wearing."
The old costume also tended to distract from her power base — DeConnick recalls finding a Tumblr site that collected pictures of Ms. Marvel's posterior in the previous costume.
"You can be sexy without being oversexualized," she says. "She's hot as hell, but I don't think she has to have her butt cheeks hanging out to do that."
Uniform tweaking, a strong personality and a long-overdue name change are just some aspects that could help Captain Marvel soar, according to Wacker.
"It sounds like a main character," he says of the new moniker. "There's no reason Captain Marvel can't be a woman, and I'm not going to rest until this character has a movie."
Posted | Updated


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Formation Z
Review by BimmyandJimmy
"Formation azz."
What do the games Gradius, R-type and UN Squadron all have in common? If you've guessed that they are all classic side scrolling shooter games that have appeared on Nintendo consoles, then you are correct. In fact, there are many classic side scrolling shooter games on Nintendo consoles that are either mainstream or have cult followings that will never die. Formation Z, on the other hand, is a game that is unknown for all the right reasons.
It sucks.
To be fair, for a game released in 1984 on the NES, the graphics are impressive. The game has a wide assortment of colors and backgrounds such as gigantic mountain ranges, tall pyramids and buildings which blanket the screen. Hell, the game even has a grassy foreground, and it's animated to make it look like it's being blown around by the wind. However, I'd rather play a game with amazing gameplay instead.
The character sprites are horrible. Everything is too short and monochromatic compare to the gigantic background and it leaves the game feeling empty. What's interesting about the guy you control is that he kind of looks like Jet Jaguar from the movie Godzilla vs. Megalon, which is muddling and awesome at the same time.
The only songs you'll hear in the game are at the title screen and before you enter battle. After that, the game is just dead silence. Occasionally you'll hear a couple of wimpy sound effects to break up the boring monotony, but it's not enough to prevent you from passing out due to the piss poor gameplay.
Well, let's just get this out-of-the-way, there are only two levels in this game, but you've got to have such massive luck in order to beat them because the controls in this game are awful.
For example, Super Mario Bros lets you control the rate of the jump by pressing back or forward on the D-pad. In this game, you can't control this, which forces you to time your jumps exactly to clear enemies, and because the screen is always automatically scrolling to the left, judging the timing on these jumps is a nightmare. Worse, the enemies home in on you constantly, you can only get hit once, and you only get three extra guys before the game is over.
You can also transform into an airplane in Formation Z, but getting that to work is ridiculous; you basically have to mash buttons as far as I know. Also, you use up gas when you're flying, and you're going to need to save every last drop in order to get over huge bodies of water and gaps, so you'll probably be walking on the ground most of the time just to make it over. This is absolutely pathetic because flying is the only fun part about this game.
There's also a total lack of action in this game, but, really, I'm not at all surprised.
Ya right, there is hardly any other reason to play the game after the first time through. Sure, there's a two player mode available, but either than that, there is nothing at all in this game that I would consider entertainment value.
For some strange reason, I use to play this game a lot when I was a kid, mostly because I could never beat it, even though I always wanted to. I've given up now because I've seen the ending on YouTube and it's awful. Just stick with your other 2D shooter games instead, and let this one rot to nothing.
Reviewer's Rating: 1.5 - Bad
Originally Posted: 09/14/12, Updated 03/18/14
Game Release: Formation Z (JP, 04/04/85)
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A peri was a kind of fairy in Persian mythology which started off evil before turning good. Recently regenerated, the temporarily deranged Sixth Doctor took this as sufficient to attempt to kill his companion, also named Peri. (TV: The Twin Dilemma)
Behind the scenes Edit
- Before strangling Peri, the Doctor quotes from the poem "Paradise and the Peri" by Thomas Moore.


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SEBI and RBI have ensured that NRIs are put through many hurdles before they can invest in Indian stocks. A first-person account of the pains
I have lived about half of my life in the United States and the other, in India where I was born. Growing up in a Socialistic country, it was ingrained into me that your education was your passport to a successful future and nothing else mattered. After completing an undergraduate degree, I was drawn towards the share market. These were the '80s where every IPO was oversubscribed (the face value of a stock was always Rs10 or Rs100 or Rs1,000 (rare)). Many years later, I worked for a company incorporated in India and to cash my options, I had to get a PAN (Permanent Account Number) from the Indian Income Tax Office. After several mis-steps, I finally got the card (it felt like an achievement after the application was rejected twice on flimsy grounds) and I started looking at what I could do with my PAN number.
It was August 2013 and I was browsing a newspaper when an article caught my attention. The RBI had just released guidelines for NRIs and other foreign investors to invest in the Indian market. This spurred me to think that it is perhaps time to invest in India's equity markets. I was armed with my PAN card and a million passport size photos and other documentation such as my local address, permanent address, etc. I approached HDFC Bank to open an NRI Demat account. And then the fun began...
The liaison agent's role withdrew into the background. At the same time, the new media got busy with the business at hand - of mind-bending (PR), of influencing policy (policy groups), of influencing decisions (lobbying) and finally, of pre-empting future movements at and before the decision making stage in governance (espionage)
Nifty's bullishness will stall if it closes below 8,760


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Ampeg longtime endorser BILLY SHEEHAN played the London Guitar Show this past weekend at ExCel, Docklands, London. Our intrepid trainspotter/anorak David Phillips caught the gig/clinic and snapped a few shots for us. Billy played both solo and as a duo … more »
Billy Sheehan: Let's All Go Down to London… Guitar ShowJune 16, 2008
We've Released The Hounds on Radiohead…June 12, 2008
Not on the whole band, I guess, but at least on COLIN GREENWOOD, Radiohead's esteemed bass player and a big fan of Ampeg. And actually there's only the one hound, Charlie The Bloodhound, but what a handsome hound he is! … more »
Schoolyard Heroes Zero In On AmpegApril 1, 2008
Seattle's own Schoolyard Heroes have been touring and touring and TOURING supporting their Island/Stolen Transmissions release Abominations for longer than their guitarist's 'fro. On the latest leg of this coast-to-coast journey via van, guitarist Steve Bonnell donned an Ampeg Dan … more »
Araya and Slayer Snag a GrammyFebruary 11, 2008
Bassist Tom Araya's band Slayer was honored with a Grammy in the "Best Metal Performance" category in the pre-telecast ceremony at the 50th annual Grammy Awards, which was held yesterday (Sunday, February 10) at the Staples Center in Los Angeles. … more »
Mars Volta Debuts at #3 with The Bedlam in GoliathFebruary 7, 2008
In its first week on the chart, The Mars Volta's new CD The Bedlam in Goliath debuted at number three in the US. As you probably know, bassist Juan Alderete is an Ampeg player. He's been playing dual SVT rigs … more »
Good Morning… NAMM!January 23, 2008
Your bass-loving pals at Ampeg attended the 2008 NAMM show in Anaheim last week. We brought a bunch of new products which you're already seeing on the website (www.ampeg.com), and we had numerous Ampeg players stop by to sign autographs … more »
Don't Shoot Me, I'm Only The BassistNovember 13, 2007
It's not very often that four of the world's coolest bass players show up in one place, but they did last week in Hollywood. Ampeg spent an entire day in one of the soundstages at SIR (thanks guys!) photographing four … more »
Annie Clements: Ampeg on the Sugarland Express…August 28, 2007
Born and raised in New Orleans, bassist Annie Clements' style encompasses the warmth, soul and groove of her hometown. Add to that a degree in Bass Performance from the Berklee College of Music and it's no wonder she's become a … more »
Waters Explores The Dark Side With AmpegJune 11, 2007
Legendary Pink Floyd bassist Roger Waters has been touring the globe since before Christmas, and lucky concert-goers have been treated to the performance of Dark Side Of The Moon in its entirety. Waters, who not only plays bass but is … more »
Silversun Pickups: Hardest Working Band on the RoadDecember 1, 2006
Bassist Nikki Monninger of Silversun Pickups is pictured above rockin' out at the Capitol Hill Block Party in July 2006, playing through an Ampeg SVT810AV and a SVTCL head. The band recently toured with Australian rockers Wolfmother and will open … more »


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Dear visitor,
you can find thorough information about Estonian music and music life in the various sections of our website. You are also welcome to ask further questions by e-mail or at the phone number +372 6454395. As finding the answer to your question might require delving into EMIC's database or other information sources, we recommend you to make your query at the e-mail address email@example.com.
EMIC's archive of manuscripts, publications and audio recordings is open to music researchers and other interested persons from Tuesday to Friday from 11:00 to 14:00; other times can also be scheduled. All audio recordings and publications are intended for use on the spot only. Please coordinate the time of using the archives and your field of interest with us prior to your visit at the e-mail address email@example.com or the number + 372 6454395.
EMIC is situated in the centre of Tallinn, behind the Viru shopping centre, near the Gonsiori - Tartu maantee junction, address Kivisilla 4-2.
EMIC Music Shop
Kreek's Notebook, for mixed choir and string orchestra
In Paradisum, for mixed choir
Piano Music, for piano
Õhtu ilu (Beauty of the Evening), for mixed choir


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- November 14, 2013
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Dear Ashwani,
I guess you need help of study abroad counselor who can guide you in your process.
In USA, each university is independent and hence admission requirements will vary and also course content, research availability, funding opportunity, cost, etc.
Here is general checklist for you.
1. Fill online application form
2. Pay Application Fee (normally credit card or dollar draft)
3. Fulfill admission requirement like SOP, Letter of Recommendation, Transcript, GRE, TOEFL, and Financial requirements.
4. Application and documents should reach university before DEADLINE.
5. Correspond with university via email regarding admission status. Some of the USA university offers online application tracking system.
6. visa preparation.
Best regards,
Richard Lasrado, Education Abroad Counselling Centre, Mumbai, India
- November 25, 2013
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