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Neuronal plasticity is essential to enable rehabilitation when the brain suffers from injury, such as following a stroke. One of the most established models to study cortical plasticity is ocular dominance (OD) plasticity in the primary visual cortex (V1) of the mammalian brain induced by monocular deprivation (MD). We have previously shown that OD-plasticity in adult mouse V1 is absent after a photothrombotic (PT) stroke lesion in the adjacent primary somatosensory cortex (S1). Exposing lesioned mice to conditions which reduce the inhibitory tone in V1, such as raising animals in an enriched environment or short-term dark exposure, preserved OD-plasticity after an S1-lesion. Here we tested whether modification of excitatory circuits can also be beneficial for preserving V1-plasticity after stroke. Mice lacking postsynaptic density protein-95 (PSD-95), a signaling scaffold present at mature excitatory synapses, have lifelong juvenile-like OD-plasticity caused by an increased number of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) -silent synapses in V1 but unaltered inhibitory tone. In fact, using intrinsic signal optical imaging, we show here that OD-plasticity was preserved in V1 of adult PSD-95 KO mice after an S1-lesion but not in PSD-95 wildtype (WT)-mice. In addition, experience-enabled enhancement of the optomotor reflex of the open eye after MD was compromised in both lesioned PSD-95 KO and PSD-95 WT mice. Basic V1-activation and retinotopic map quality were, however, not different between lesioned PSD-95 KO mice and their WT littermates. The preserved OD-plasticity in the PSD-95 KO mice indicates that V1-plasticity after a distant stroke can be promoted by either changes in excitatory circuitry or by lowering the inhibitory tone in V1 as previously shown. Furthermore, the present data indicate that an increased number of AMPA-silent synapses preserves OD-plasticity not only in the healthy brain, but also in another experimental paradigm of cortical plasticity, namely the long-range influence on V1-plasticity after an S1-lesion.
Citation: Greifzu F, Parthier D, Goetze B, Schlüter OM, Löwel S (2016) Ocular Dominance Plasticity after Stroke Was Preserved in PSD-95 Knockout Mice. PLoS ONE 11(3): e0149771. https://doi.org/10.1371/journal.pone.0149771
Editor: Anna Dunaevsky, University of Nebraska Medical Center, UNITED STATES
Received: December 17, 2015; Accepted: January 25, 2016; Published: March 1, 2016
Copyright: © 2016 Greifzu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: This work was supported by the Federal Ministry of Education and Research, Germany, grant numbers 01GQ0921 (FG) and 01GQ0810 (SL, BG) and by grants of the Deutsche Forschungsgemeinschaft through the Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing" to SL (Project B5) and OMS (Project B3). The authors acknowledge support by the Open Access Publication Funds of the Göttingen University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
If the brain is injured, for example due to a stroke lesion, neuronal plasticity is crucial for recovery and to promote rehabilitation. The primary visual cortex (V1) is a widely used model region for studying experience-dependent plasticity in the mammalian brain [1, 2]. Neurons in the binocular zone of rodent V1 respond to stimulation of both eyes but are dominated by the contralateral eye [3, 4]. This ocular dominance (OD) can be modified in an experience-dependent manner by depriving one eye of pattern vision for several days (known as monocular deprivation or MD), as originally observed by Wiesel and Hubel more than 50 years ago in cat V1 [5]. In a previous study, we observed that a small photothrombotic (PT) stroke lesion in S1, directly adjacent to V1, or even in M2, nearly 4 mm anterior to the anterior border of V1, abolished OD-plasticity in V1 and impaired experience-enabled improvements of the optomotor reflex of the open eye after MD in adult mice [6, 7].
While OD-plasticity in standard cage raised rodents is limited by age [1, 2], several interventions have been recently published to promote plasticity in V1 of adult rodents [8]. These plasticity promoting interventions include housing animals in an enriched environment [9–11], short-term dark exposure [12–14], running [15], running and visual stimulation [16], strong visual stimulation [17], and previous MD [18]. Most of these interventions likely function via reducing intracortical inhibition. Correspondingly, reducing cortical inhibition pharmacologically in adult rats also promoted OD-plasticity [19].
Notably, enriched environment or short-term dark exposure have previously been shown to also preserve OD-plasticity in V1 after an S1-lesion [9, 12]. Whether changes in excitatory circuitry may also be beneficial for preserving V1-plasticity after a stroke in S1 was—however—not yet tested.
Mice lacking the postsynaptic signaling scaffold PSD-95 have recently been shown to display a lifelong and juvenile-like OD-plasticity, caused by an increased number of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) -silent synapses, but unaltered inhibitory tone in V1 [20]. These new data clearly indicated that inhibitory circuits may play a permissive role for cortical plasticity while silent synapse maturation is critical and rather instructive: the sensitive phase for OD-plasticity did not close in the absence of PSD-95, even if the inhibitory tone matured normally, and OD-plasticity was also restored if PSD-95 was knocked-down in the adult visual cortex [20]. The essential role of silent synapses for OD-plasticity caused a paradigm shift in the way we think about critical period closure in the adult brain. It is therefore important to test whether other experimental paradigms of cortical plasticity such as the long-range influence on OD-plasticity in V1 by a distant lesion share similar mechanisms or are distinct.
We therefore tested whether knockout (KO) mice for PSD-95 display a preserved OD-plasticity in V1 after a small lesion in S1, adjacent to V1. To this end, we induced a photothrombotic stroke lesion in S1, about 1 mm anterior to the anterior border of V1 and visualized OD-plasticity using in vivo optical imaging of intrinsic signals. Additionally, we measured both the spatial frequency and contrast thresholds of the optomotor reflex of the open eye after MD by optomotry. In fact, OD-plasticity after an S1-lesion was preserved in adult PSD-95 KO mice but not in PSD-95 WT mice. In addition, experience-enabled changes of the optomotor reflex were compromised in both S1-lesioned PSD-95 KO and PSD-95 WT mice after MD.
Material and Methods
Animal treatment
Adult female and male PSD-95 KO and WT mice were used [20, 21]. 2–5 mice were housed together in standard cages (32 × 16 × 14 cm) with a 12-h light/dark cycle, food and water available ad libitum. The indicated age is the age at the optical imaging experiment.
Ethics statement: All experimental procedures were performed according to the German Law on the Protection of Animals and permitted by the local government: Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit and approved by the Tierschutz Kommission des Landes Niedersachsen § 15 TSG (Permission no 33.9-42502-04-10/0326 and 33.9-42502-04-14/1516).
Monocular deprivation (MD)
The right eye was deprived for 7 days according to published protocols [6, 22, 23]. Briefly, mice were anesthetized with 2% isoflurane in 1:1 O2:N2O. Lid margins were trimmed and an antibiotic gel (gentamicin gel) was applied. The eye was closed with two mattress sutures. Animals were checked daily to make sure that the eyes remained closed.
Spatial frequency and contrast sensitivity threshold of the optomotor reflex
Both the spatial frequency and the contrast threshold of the optomotor reflex of all mice was measured daily using the virtual-reality optomotor system developed by Prusky et al. [24]. Briefly, freely moving animals were exposed to moving sine wave gratings of various spatial frequencies and contrasts and reflexively track the gratings by head movements as long as they can see the gratings. Spatial frequency at full contrast and contrast at six different spatial frequencies [0.031, 0.064, 0.092, 0.103, 0.192, 0.272cycles/degree (c/d)] were varied by the experimenter until the threshold of tracking was determined. Contrast sensitivity thresholds of the optomotor reflex measured in percent were converted into Michelson contrasts. All animals were first tested in the optomotor setup and then their visual cortical activity was analyzed by optical imaging of intrinsic signals.
Optical imaging of intrinsic signals and visual stimuli
Following the behavioral tests, mouse visual cortical responses were recorded and analyzed as described previously [6].
Briefly, mice were box-anesthetized with 2% halothane in a mixture of O2:N2O (1:1) and received an injection of atropine (Franz Köhler, 0.3 mg/mouse, subcutaneously), dexamethasone (Ratiopharm, 0.2 mg/mouse, subcutaneously), and chlorprothixene (Sigma, 0.2 mg/mouse, intramuscularly). After placing the animals in a stereotaxic frame, inhalation anesthesia was maintained with 0.6% to 0.8% halothane in a mixture of O2:N2O (1:1). The animals' body temperature was maintained at 37°C and heart rate was monitored throughout the experiment.
Data acquisition and visual stimulation.
Mouse visual cortical responses were recorded through the skull using the imaging method developed by Kalatsky and Stryker [25] and optimized for the assessment of OD-plasticity by Cang et al. [23]. In this method, a temporally periodic stimulus is continuously presented to the animal and the cortical response at the stimulus frequency is extracted by Fourier analysis. Optical images of intrinsic cortical signals were obtained using a CCD camera (Dalsa 1M30) controlled by custom software. The surface vascular pattern and intrinsic signal images were visualized with illumination wavelengths set by a green (550±10 nm) or red (610±10 nm) interference filter, respectively. After acquisition of a surface image, the camera was focused 600 μm below the cortical surface. An additional red filter was interposed between the brain and the CCD camera. Frames were acquired at a rate of 30 Hz temporally binned to 7.5 Hz and stored as 512 x 512 pixel images after spatial binning of the camera image. Drifting horizontal bars (2° wide) were presented to the animal at a distance of 25 cm on a high refresh-rate monitor (Hitachi ACCUVUE, HM-4921-D, 21"), positioned 25 cm from the eyes. The distance between two bars was 80° and they were presented at a temporal frequency of 0.125 Hz. The visual stimulus was restricted to the binocular visual field of the left V1 (−5° to +15° azimuth) and animals were stimulated through either the left or the right eye in alternation to assess the OD of the left hemisphere. For visualizing elevation and azimuth maps for map quality calculation, we used full-field stimuli extending 78° horizontally and 59° vertically and contralateral eye stimulation.
Data analysis.
Visual cortical maps were calculated from the acquired frames by Fourier analysis to extract the signal at the stimulation frequency using custom software [25]. The amplitude component represents the intensity of neuronal activation (expressed as fractional change in reflectance ×10−4) and was used to calculate OD. At least three maps per animal were averaged to compute the OD-index (ODI) as (C—I)/(C + I), with C and I representing the response magnitudes of each pixel to visual stimulation of the contralateral (C) and ipsilateral (I) eye. The ODI ranged from −1 to +1, with negative values representing ipsilateral and positive values representing contralateral dominance. ODI-data of sham-treated and PT-lesioned (S1) C57Bl6/J (WT) mice are from Greifzu et al. [6], but newly analyzed as described above ("average map analysis").
The quality of the retinotopic maps was assessed by the calculation described by Cang et al. [26] on contralateral eye full field maps. For each of the pixels in the retinotopic map, the difference between its visual field position and the mean position of its surrounding 24 pixels was calculated. For maps of high quality, the position differences are quite small because of smooth progression. The standard deviation of the position difference was then used as an index of the quality of retinotopic maps with a small standard deviation, which corresponds to low map scatter, indicating high map quality and high values, corresponding to high map scatter, indicating low map quality.
Induction of photothrombosis
A photothrombotic lesion was induced in the left S1 adjacent to V1 by using the Rose Bengal technique introduced by Watson et al. [27], as described previously [6]. Mice were initially anesthetized with 2% isoflurane, and anesthesia was maintained with 1% isoflurane in 1:1 O2:N2O. The animals were placed in a stereotaxic frame and body temperature was maintained at 37°C. The skin above the skull was incised and an optic fiber bundle (aperture: 1.0 mm) mounted on a cold light source (Schott KL 1500) was positioned 2 mm lateral to the midline and 1 mm posterior to the bregma. Next, 100 μl Rose Bengal (Aldrich; 10 mg/ml in 0.9% NaCl) was injected intravenously. After 5 minutes, the illumination period of 15 minutes was started. The skin was sutured and the animals recovered in their cage.
Perfusion and tissue processing
After optical imaging, all mice were perfused transcardially with 1% heparin in 0.9% NaCl for 2 minutes followed by 4% paraformaldehyde (PFA, pH 7.4) for 3 minutes. The brain was removed and postfixed in 4% PFA (pH 7.4) for one day and then transferred to cryoprotectant solution (10% sucrose, 20% glycerol). The brains were frozen in methylbutane and stored at -80°C. Coronal brain sections were cut on a sledge microtome at 40 μm.
Lesion analysis
To determine size and location of the cortical PT-lesions, coronal brain sections were Nissl-stained and every third section was analyzed under the microscope (Axioskop, Carl Zeiss). Quantitative parameters were measured using AxioVision (40 22.214.171.124.).
Location and size of the cortical lesion in the primary somatosensory cortex (S1)
The PT-lesions were always located in the left S1 (Fig 1). The lesion in PSD-95 WT/KO mice was on average 0.8±0.1/1.0±0.2 mm in medio-lateral and 0.7±0.1/1.0±0.2 mm in anterior-posterior direction, and extended vertically until layers 5/6. The lesion center was situated 0.8±0.1/1.1±0.1 mm anterior to the anterior border of V1, 2.2±0.2/2.3±0.1 mm lateral to the midline, and 1.4±0.2/1.1±0.2 mm posterior to the bregma. The lesion extent and location were not different between PSD-95 WT and PSD-95 KO mice (P>0.05). Moreover, the lesion values of the KO mice were not different from the previously published values in WT mice [6] which showed diminished plasticity (P>0.05 for all measured parameters).
(A) Top view of a representative mouse brain illustrating the lesion location in S1, on average 1 mm anterior to the anterior border of the primary visual cortex (V1, blue dashed line). (B) Nissl-stained frontal section through the lesion (same animal as in A). (C) Higher magnification composite image of the superficial vascular pattern of the brain and the superimposed optically recorded retinotopic map of the binocular part of V1 of a PSD-95 KO mouse in which the PT-lesion (L) was very close to V1; nevertheless, OD-plasticity was present in this animal (average ODI = 0.00). Scale bar all, 1 mm.
In adult PSD-95 KO mice, ocular dominance plasticity in V1 was preserved after a stroke lesion in S1
In S1-lesioned PSD-95 WT mice, OD-plasticity in V1 was absent, as previously described for WT mice [6]. After 7 days of MD, activity maps in the binocular zone of V1 were still dominated by the previously deprived, contralateral eye (Fig 2A): activity patches induced by visual stimulation of the contralateral eye were always darker than those after ipsilateral eye stimulation, the average ODI was positive, and warm colors prevailed in the 2‐dimensional OD-maps (Fig 2A). In contrast, PSD-95 KO mice with a PT-lesion in S1 showed an almost equal V1-activation after right and left eye stimulation in the binocular zone after MD, indicating preserved OD-plasticity: the activity spot induced by stimulation of the open (ipsilateral) eye was as dark as the spot induced by stimulation of the deprived (contralateral) eye, colder colors appeared in the OD‐map and the ODI‐histogram was shifted to the left (Fig 2B).
Optically recorded activity maps of the contralateral (contra) and ipsilateral (ipsi) eye in the binocular region of mouse primary visual cortex (V1) in PT-lesioned PSD-95 WT (A) and PSD-95 KO mice (B) after monocular deprivation (MD), and their quantification (C, D). Open and closed eyes indicated by a white or black circle. (A, B) Grayscale coded response magnitude maps of the contra- and ipsilateral eye (including average V1-activation of the illustrated example) and the histogram of OD-scores including the average OD-index (top row), color-coded polar maps of retinotopy and 2-dimensional OD-maps after MD (lower row) are illustrated. (A) In PSD-95 WT littermates, activity patches evoked by stimulation of the contralateral eye were darker than those of the ipsilateral eye, the average ODI was positive, and warm colors prevailed in the OD-maps, indicating contralateral dominance. In contrast, in PSD-95 KO mice, the contra- and ipsilateral eye activated V1 about equally strong, colder colors appeared in the OD-map, and the histogram of OD-scores shifted to the left (B). Scale bar: 1 mm. (C) Optically imaged OD-indices in PT-lesioned PSD-95 WT and PSD-95 KO mice (light red and red triangles). For comparison, ODIs of control (sham-treated) and PT-lesioned Bl6/J mice are illustrated (white and grey squares). Symbols represent ODI values of individuals, means are marked by horizontal lines. (D) V1-activation elicited by stimulation of the contralateral (C) or ipsilateral (I) eye in PSD-95 WT and PSD-95 KO mice after PT and MD. Note that V1-activtation after stimulation of the contra- and ipsilateral eye was not different in PSD-95 KO mice, indicating preserved juvenile-like OD-plasticity in V1 despite the S1-lesion.
Quantitative analyses of V1-activation revealed that the average ODI of the PSD-95 KO mice was 0.02±0.02 (n = 10, PD93-149), and thus significantly lower than the 0.26±0.05 of the PSD-95 WT mice (n = 5, p = 0.006, t-test; PD78-108; Fig 2C). Although the PT-lesion was very close to V1 in one of the PSD-95 KO mice (Fig 1C), this animal still showed OD-plasticity (ODI = 0.00). In fact, ODI values of PSD-95 KO mice after stroke and MD were in the range of nonlesioned sham-treated (control) WT mice (ODI = 0.06±0.02, n = 9, p = 0.279); compare control+MD with KO PT+MD in Fig 2C) and significantly lower than in nonlesioned sham-treated WT mice without MD (control, ODI = 0.28±0.03, n = 7; p = 0.00002). ODI values of PSD-95 WT mice after stroke and MD stayed as high as in C57Bl6/J WT mice with stroke (C57Bl6/J WT with PT: 0.21±0.01, n = 13; with PT+MD: 0.20±0.02, n = 10; p = 0.425; 0.348).
Analyzing V1-activation induced by left and right eye stimulation separately (Fig 2D) after PT and MD showed that in PSD-95 WT mice, V1-activation after stimulation of the contralateral (right) eye (1.80±0.18) was significantly higher than after ipsilateral (left) eye stimulation (1.05±0.08, n = 5; p = 0.013, t-test). In contrast, in PSD-95 KO mice, V1-activation was the same after contralateral (0.98±0.15) and ipsilateral eye stimulation (0.98±0.16, n = 10; p = 0.906, t-test). Furthermore, the lower V1-activation after deprived eye stimulation indicate that the OD-shift in the PSD-95 KO mice was mediated by a reduction in deprived eye responses in V1 (p = 0.026, t-test), a hallmark of juvenile OD-plasticity.
Note that some of the KO mice with persistent OD-plasticity after stroke were already over 110 days old (n = 8) and therefore already beyond the sensitive period for OD-plasticity in standard cage raised WT mice [28]. Furthermore, there was no correlation of the ODI and the age of the animals (Pearson-correlation -0.080, p = 0.826).
In summary, unlike PSD-95 WT mice, PSD-95 KO mice maintained a juvenile-like OD-plasticity in V1 despite a photothrombotic stroke lesion in S1 and an already advanced age.
Retinotopic maps and V1-activation were not different in WT and PSD-95 KO mice after stroke
To analyze baseline V1-activation in the PSD-95 WT (n = 5) and KO mice (n = 6) after the S1-lesion, we used full-field horizontal and vertical moving stimuli and recorded retinotopic and activity maps in V1 after contralateral eye stimulation.
For both genotypes, elevation (stimulation with horizontal bars) and azimuth (vertical bars) maps were neither significantly different in signal strength nor in retinotopic map quality. V1-activation of the elevation maps was 2.8±0.3 for WT mice and 1.9±0.4 for KO mice (p = 0.099, t-test). Likewise, V1-responses after azimuth stimulation were also similar (WT/KO: 1.9±0.2/1.9±0.5; p = 0.949, t-test). The quality of the retinotopic maps was also similar: mean map scatter of the elevation maps was 4.9±2.0 for WT mice and 10.9±4.1 for KO mice (p = 0.229, t-test); map scatter for azimuth maps was 16.3±3.1/15.9±3.6 for WT/KO (p = 0.934, t-test).
The S1-lesion compromised the experience-enabled enhancement of the optomotor reflex of the open eye in both WT and PSD-95 KO mice
Spatial vision of all mice was measured during the 7 days of MD (before the optical imaging experiment) using the virtual‐reality optomotor setup [24]. The highest spatial frequency that elicited an optomotor reflex in the animals before MD and PT was 0.38±0.001 cyc/deg for PSD-95 WT (n = 9, PD 78–149; Fig 3B) and 0.38±0.003 cyc/deg for PSD-95 KO mice (n = 14, PD 93–152; Fig 3A), and thus not different between the genotypes (t-test, p = 0.228). In contrast to nonlesioned mice, daily testing of the PT-lesioned animals after MD did not result in an increase in the measured values: the spatial frequency threshold of the optomotor reflex of the open eye was 0.38±0.001 cyc/deg for WT (p = 0.149) and 0.39±0.003 cyc/deg for KO mice (p = 9.989) after 7 days of MD. A similar absence of the experience-enabled enhancement of the optomotor reflex after MD was previously reported for S1-lesioned WT mice [6]. Finally, values were similar in both PSD-95 WT and PSD-95 KO mice after 7 days of PT and MD (p = 0.402, t-test). PSD-95 KO mice without a lesion showed a significant increase of the optomotor reflex by 22% from 0.36±0.01 cyc/deg before MD to 0.44±0.01 cyc/deg after MD (n = 8, PD 70–296; p<0.001, t-test; Fig 3A).
In contrast, enhancements of spatial vision were present in nonlesioned PSD-95 WT and PSD-95 KO mice. (A, B) Spatial frequency threshold of the optomotor response of the open eye in cycles per degree (cyc/deg) plotted against days after MD. After 7 days of MD, nonlesioned PSD-95 KO mice (A) as well as sham-treated control mice (B; data from Greifzu et al., 2011) showed a significant increase in the spatial frequency threshold of the optomotor reflex of the open eye. This experience-enabled increase was abolished by a PT in S1 (A, B). (C-F) Contrast sensitivity thresholds of the optomotor reflex of the open eye at 6 different spatial frequencies before (day 0) and 7 days after MD. For both nonlesioned PSD-95 KO (C) and PSD-95 WT mice (D), there was an increase in contrast sensitivity after 7 days of MD. After PT, this experience-enabled increase was absent in both groups (E, F).
Baseline (before MD and PT) contrast sensitivity values of the optomotor reflex were also not different between PSD-95 WT and PSD-95 KO mice (values at 0.031cyc/deg: WT/KO: 4±0.1 (corresponds to 26% contrast)/4±0.01 (26%), 0.064cyc/deg: 14±0.2 (7%)/14±0.2 (7%), 0.092cyc/deg: 14±0.2 (7%)/14±0.2 (7%), 0.103cyc/deg: 13±0.2 (8%)/13±0.3 (8%); 0.192cyc/deg: 8±0.5 (12%)/8±0.4 (12%), 0.272cyc/deg: 4±0.2 (25%)/5±0.03 (22%); n = 9/14; p>0.05 for every spatial frequency, t-test). Like the spatial frequency threshold, contrast sensitivity thresholds of the open eye did neither increase in PT-lesioned PSD-95 WT (Fig 3F) nor in PSD-95 KO mice (Fig 3E) during MD (p>0.05 for both groups and every spatial frequency, t-test). Hence, contrast sensitivity thresholds of the optomotor reflex of the open eye after 7 days of MD and PT were not different between WT and KO mice (values at 0.031cyc/deg: WT/KO: 4±0.1 (corresponds to 26% contrast)/4±0.01 (27%), 0.064cyc/deg: 14±0.3 (7%)/15±0.4 (7%), 0.092cyc/deg: 14±0.2 (7%)/15±0.4 (7%), 0.103cyc/deg: 13±0.2 (8%)/14±0.4 (7%), 0.192cyc/deg: 9±0.5 (12%)/9±0.5 (12%), 0.272cyc/deg: 4±0.1 (25%)/4±0.03 (22%); n = 9/14; p>0.05 for every spatial frequency, t-test). Notably, nonlesioned PSD-95 KO (Fig 3C) as well as PSD-95 WT (Fig 3D) displayed a significant increase of contrast sensitivity after MD at all measured frequencies (contrast sensitivity before/after MD; for KO (n = 4): 0.031cyc/deg: 3±0.05 (corresponds to 29% contrast)/4±0.1 (23%), 0.064cyc/deg: 12±0.8 (8%)/19±0.7 (5%), 0.092cyc/deg: 11±0.9 (9%)/17±0.7 (6%), 0.103cyc/deg: 10±0.7 (10%)/16±0.7 (6%), 0.192cyc/deg: 6±0.4 (16%)/9±0.3 (11%), 0.272cyc/deg: 3±0.1 (30%)/4±0.1 (23%); for WT (n = 8): 0.031cyc/deg: 4±0.1 (27%)/5±0.05 (22%), 0.064cyc/deg: 15±0.4 (7%)/22±0.3 (5%), 0.092cyc/deg: 14±0.4 (7%)/19±0.4 (5%), 0.103cyc/deg: 13±0.4 (8%)/18±0.4 (8%), 0.192cyc/deg: 7±0.2 (14%)/10±0.5 (10%), 0.272cyc/deg: 4±0.04 (27%)/5±0.1 (22%); at least p<0.01 for every spatial frequency, t-test).
Thus, in contrast to the preserved OD-plasticity in V1, experience-enabled enhancements of the optomotor reflex of the open eye after MD were compromised in both the S1-lesioned PSD-95 KO and PSD-95 WT mice, as previously also reported for S1-lesioned WT (Bl6/J) mice [6].
Our results demonstrate that OD-plasticity in V1 after a cortical stroke lesion in the adjacent S1-area is preserved in PSD-95 KO mice but not in PSD-95 WT mice. In contrast, the experience-enabled enhancement of the optomotor reflex of the open eye after MD was compromised in both PSD-95 KO and PSD-95 WT mice.
We have previously shown that OD-plasticity in V1 of standard cage raised adult mice does not only depend on modality-specific and local nerve cell networks [1, 2], but is also influenced by long-range interactions even from distant brain regions: a small PT-lesion in both S1 or M2 abolished OD-plasticity in V1, indicating that activity changes in the major thalamocortical afferents to V1 are not sufficient to induce OD-shifts in V1 after MD [6, 7]. Notably, two different nonpharmacological interventions that were shown to reduce intracortical inhibition in V1 of adult rodents, namely raising animals in an enriched environment [9] or exposing adult rodents to complete darkness for two weeks [12] did not only restore OD-plasticity in (nonlesioned) old mice but additionally preserved OD-plasticity in V1 even after a small PT-lesion in S1 [9, 12]. In addition, young standard cage raised mice that genuinely display lower intracortical inhibition in V1 compared to older SC-raised animals were also protected against stroke-induced impairments of OD-plasticity [9]. Whether changes in excitatory circuitry may also be beneficial for preserving V1-plasticity after a stroke in S1 was not yet tested.
Since we recently observed that KO mice for the postsynaptic signaling scaffold PSD-95 preserve a high number of AMPA-silent synapses in V1 into adulthood which cause lifelong juvenile-like OD-plasticity despite a normal maturation of the inhibitory tone [20], we wondered whether OD-plasticity in adult PSD-95 KO mice would also persist after a PT-lesion in S1. This was indeed the case. In the PSD-95 KO mice, but not in the PSD-95 WT mice, strong OD-shifts were induced after MD, even in PSD-95 KO mice already beyond PD 110, an age at which OD-shifts in SC-raised WT mice are no longer present [1, 2, 28].
What could be the mechanism underlying the preserved OD-plasticity after stroke in the PSD-95 KO mice? The current literature points towards a protective role of loss-of-PSD-95 function by decoupling excitotoxic signaling. PSD-95 is enriched at the postsynaptic density of glutamatergic synapses and binds e.g. N-Methyl-D-aspartate receptors (NMDAR), other ion channels, and adhesion molecules [29]. PSD-95 links the NMDAR subunit GluN2B to the death-signaling protein neuronal nitric oxide synthase (nNOS) [30]. nNOS catalyzes the production of nitric oxid (NO), a highly neurotoxic signaling molecule. Following an ischemic insult, PSD-95 binds nNOS to GluN2B, thus positioning nNOS in a way that it is more effectively activated by Ca2+ influx through the NMDAR ultimately producing NO and enhancing neurotoxicity [31, 32]. Following these insights, in vivo studies proved that pharmacological or viral interruption of the GluN2B-PSD-95-nNOS interactions reduces ischemic brain damage and improves neurological scores in both rodents [33–35] and macaques [36, 37]. Moreover, a phase 2 clinical trial was able to demonstrate neuroprotective effects of the drug NA-1 (Tat-NR2B9c), which also disrupts the binding of nNOS to NMDAR by PSD-95 [38]. Thus, disrupting the connection between PSD-95 and excitotoxic signaling can reduce ischemic brain damage and improve neurological scores in rodents as well as in nonhuman primates (reviews [39–41]).
In our lesion model, however, we did not find direct evidence for reduced brain damage. PT-lesions in PSD-95 KO mice were not smaller compared to PSD-95 WT mice. Thus, in contrast to studies addressing the GluN2B-PSD-95-nNOS pathway [33–35, 37], we did not obtain evidence for a reduction in lesion size in PSD-95 KO compared to PSD-95 WT mice. This is most likely due to different lesion models. While we used a small photothrombotically induced lesion in S1, the other studies applied a middle cerebral artery occlusion (MCAO) which typically results in a pronounced penumbra region, which potentially is salvageable if an appropriate treatment is given [42]. Such a penumbra is—however—typically absent after a PT-stroke lesion. Taken together, the increased OD-plasticity that we have observed in V1 of PSD-95 KO mice is most likely not mediated by a reduced lesion size in the PSD-95 KO mice compared to the PSD-95 WT mice.
We rather propose that the increased number of AMPA-silent synapses persisting into adulthood in PSD-95 KO mice represent the substrate which promotes V1-plasticity in both the healthy brain [20] and even after a lesion in S1. Silent synapses in the hippocampus have previously been described as substrates for activity-dependent strengthening of synaptic transmission at excitatory synapses [43, 44]. Therefore, they are most likely beneficial for refinement and reorganization of the cortical network after injury. We recently showed that OD-plasticity was preserved lifelong in V1 of PSD-95 KO mice indicating that high numbers of AMPA-silent synapses prevent the closing of the critical period for juvenile OD-plasticity by preserving a juvenile synaptic state into adulthood [20]. Whether other experimental paradigms of cortical plasticity, such as the long-range influence on OD-plasticity by a distant brain lesion, share similar mechanisms or are distinct had not yet been tested. In fact, our new data unambiguously demonstrate that PSD-95 KO mice showed increased plasticity also in this paradigm: after an S1-lesion, there was preserved OD-plasticity in V1 of the PSD-95 KOs, even when the mice were already at an advanced age, but not in the PSD-95 WT. While this result is phenomenologically similar to our previous observation of preserved OD-plasticity in both young standard-cage raised mice or adult enriched mice after an S1-stroke, the underlying mechanism is clearly different: on the one hand, reduced intracortical inhibition and no changes in AMPA/NMDA excitatory postsynaptic currents (EPSCs) in young or enriched mice [9], and on the other, more silent synapses but normal inhibitory tone in the PSD-95 KO mice [20]. Thus, the same systems level readout can be achieved by clearly differing molecular mechanisms. Since PSD-95 was essential for closing the critical period for juvenile OD-plasticity and knock-down of PSD-95 in the visual cortex of adult WT mice could even restore juvenile-like OD-plasticity, silent synapses are instrumental for network refinement with inhibition having a permissive function [20]. Importantly, the new data show that absence of PSD-95 promotes plasticity also in another experimental paradigm of cortical plasticity.
While PSD-95 KO mice showed preserved OD-plasticity in V1 after the S1-lesion, experience-enabled improvements of both the spatial frequency and the contrast sensitivity threshold of the optomotor reflex of the open eye after MD were—however—not observed. Such a dissociation between OD-plasticity in V1 and experience-dependent changes of the optomotor reflex after MD has already been reported after ibuprofen treatment in stroke-lesioned standard-cage raised mice [6], after enriched environment housing and a stroke lesion in S1 [9], and after a distant PT-lesion in M2 [7]. The diverging effects of the PT-lesion on OD-plasticity vs. experience-enabled enhancement of the optomotor reflex [45] in the PSD-95 KO mice (preserved vs. abolished) adds to the evidence that distinct neuronal subsystems underlie these two forms of visual plasticity as suggested before [6, 46]. The experience-enabled enhancements of the optomotor reflex of the open eye after MD are restricted to the monocular visual field, despite the dependence of the plasticity on binocular interactions [45]. In contrast, OD-shifts occur in the binocular region of V1 [22, 23, 47]. Moreover, OD-plasticity beyond the critical period mainly takes place in superficial cortical layers [48–50], while the enhancement of the optomotor response involves the cortical control of the accessory optic system triggering the reflex, presumably from deep-layer efferents [45]. Furthermore, there is accumulating evidence that stroke-induced inflammatory processes contribute to the impaired experience-enabled reflex enhancements, but not to OD-plasticity. While anti-inflammatory treatment with ibuprofen rescued the visual enhancements after PT to control levels, it had no beneficial effect on OD-plasticity [6]. Supporting this idea, EE-housing reduced the increased inflammation level after stroke in rats [51] and the enhancement of the optomotor reflex after MD in stroke lesioned mice was at least partially preserved in EE-raised mice [9]. Since optomotor enhancements were not present in PSD-95 KO mice, the plasticity promoting effect of PSD-95 is likely not caused via reducing intracortical inflammation.
In conclusion, knocking-out PSD-95 has a plasticity promoting effect on V1-plasticity after a stroke in S1, but does not rescue experience-enabled improvements of spatial vision of the open eye after MD. Our present findings are very important in showing that plasticity promoting effects in V1 after a stroke in S1 can not only be induced by lowering intracortical inhibition [9, 12] but also by modifying excitatory circuitry. In particular, a lower AMPA-NMDA EPSC ratio and an increased number of AMPA silent synapses—as present during the critical period for juvenile OD-plasticity in V1 of WT mice or lifelong in V1 of PSD-95 KO mice [20]–can not only enable a lifelong and juvenile-like OD-plasticity in nonlesioned animals but also protect against impairments of V1-plasticity induced by a distant stroke lesion.
We thank K.-F. Schmidt for help with some of the experiments and M. Schink for excellent animal care.
Author Contributions
Conceived and designed the experiments: FG OMS SL. Performed the experiments: FG DP. Analyzed the data: FG DP BG. Wrote the paper: FG OMS SL.
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Wolf Parade / Frog Eyes Fillmore 2006 F800 SIGNED
Original AUTOGRAPHED concert poster for Wolf Parade and Frog Eyes at The Fillmore in San Francisco. Art by Thomas Scott. 13x19 inches on card stock. Hand-Signed by Spencer Krug,
Dan Boeckner, Arlen Thompson, Dante DeCaro, and Hadji Bakara of Wolf Parade. Light handling marks and corner bend.
Wolf Parade / Frog Eyes /
Designer: Thomas Scott
Dimensions: 13x19 inches
Edition: AUTOGRAPHED
Condition: VF+
Date: 2006
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Press Release
CENRO RM Rescues Philippine Serpent Eagle at Mahayag, ZDSWednesday, Jul 22, 2020
Mahayag, Zamboanga del Sur. . . . Personnel from the Department of Environment and Natural Resources (DENR) in Region IX through its Community Environment and Natural Resources Office (CENRO) of Ramon Magsaysay in said province rescues and retrieves on July 9 a Philippine Serpent Eagle (Spilornis holospilus) locally known as Banog at Barangay Kaangayan, Mahayag. Based on the investigation made by the DENR team, a certain Mr. John Magbanua caught the said bird in their rice field near their...


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Let $G$ be a finite group, $H \leq G$ such that $[G : H]$ is the least prime which divides $|G|$. Show that $H$ is normal in $G$.
Can someone explain what information we get from knowing that $[G : H]$ is the least prime which divides $|G|$? By Lagrange, $|H| = \frac{|G|}{[G : H]}$. Since $[G : H]$ prime, then $|G|$ should be a power of that prime. By Sylow theorem $1$, then there is a Sylow $p$-group (where $p$ is the prime) with order $p^n$. I don't know if this is the correct path and I also don't know why we care about the least prime.
If someone can explain the solution for this exercise, I would be grateful. I've been banging my head on this for forever.


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For those that love to incorporate holistic wellness, mindfulness and/or gratitude into their spa or clinic practices, we have some exciting news – a new skin mindfulness diary has just launched, created by clean makeup artist and natural skincare advocate Georgina Alexandra.
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Totopara Tea Garden (D) is a village located in Dhupguri Block of Jalpaiguri district in West Bengal. Placed in rural area of Jalpaiguri district of West Bengal, it is one among the 102 villages of Dhupguri Block of Jalpaiguri district. According to the government register, the village number of Totopara Tea Garden (D) is 307425. The village has 700 houses.
According to Census 2011, Totopara Tea Garden (D)'s population is 3208. Out of this, 1572 are males whereas the females count 1636 here. This village has 379 children in the age group of 0-6 years. Among them 212 are boys and 167 are girls.
Literacy rate in Totopara Tea Garden (D) village is 54%. 1735 out of total 3208 population is literate here. In males the literacy rate is 61% as 960 males out of total 1572 are literate however female literacy rate is 47% as 775 out of total 1636 females are educated in this Village.
The Negative part is that illiteracy rate of Totopara Tea Garden (D) village is 45%. Here 1473 out of total 3208 individuals are illiterate. Male illiteracy rate here is 38% as 612 males out of total 1572 are uneducated. In females the illiteracy rate is 52% and 861 out of total 1636 females are illiterate in this village.
The count of occupied person of Totopara Tea Garden (D) village is 1548 whereas 1660 are non-working. And out of 1548 working person 1 peoples are completely reliant on farming.


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The information about Vietnam Embassy in Malaysia and the guidance on how to apply for Vietnam visa from Malaysia for the applicants who are staying or residing here. It also instructs people getting a tourist or business visa to Vietnam within 36 hours or even 2 hours.
Address of Vietnam Embassy in Malaysia
- Address: No.4, Persiaran Stonor 50450, Kualar Lumpur, MALAYSIA
- Phone: +603-2148 4036;
- Fax: (603) 2148 3270
- Email: firstname.lastname@example.com email@example.com
No matter you are Malaysian citizens or foreigner living in Malaysia, you may get a Vietnam visa through the above Vietnam Embassy in Malaysia or apply for a visa on arrival (for air travel only) then get the visa stamped at arrival airports. Vietnam visa on arrival is made available to avoid the long procedures with the local embassy.
The very best things to have with the service are the 100% hassle free procedures at low service fee and the visa will be granted to the applicants without presenting the original passport at the time of making a visa application. The processing time will take a maximum of 48 hours to issue an approval letter or of 2 hours if you are in hurry.
View more:
Vietnam visa requirements for foreigners in Malaysia
Vietnam e-Visa for foreigners in Malaysia
Applying Vietnam visa at Vietnam Embassy in Malaysia
At the embassy, you will have to fill the Visa application form in English. You will also have to mention the place of submission and collection of the Visa as Vietnam. You must ensure that you hold a valid and original passport and also that it has some pages left for stamping. Along with the form, you will have to submit one recent passport sized photograph, one self-addressed envelope and your original passport. Also, you will be required to pay the Visa fees. The fees can be paid in favor of the Embassy of Vietnam through money order or cashier's check.
The embassy will take at least five working days to process your documents. Once the documents are processed, you will be issued a fully stamped Visa. The greatest benefit of applying for Visa through the embassy is that you can get hold of a fully stamped Visa before your departure to Vietnam. However, this procedure is time consuming and complicated.
What is Vietnam visa on arrival or Vietnam e-visa?
Visa on arrival or e-visa is a new visa facilitative measure that allows the local visa agency or trusted partner to print the visa electronically without making a trip to the Vietnam Embassy to collect the visa sticker.
In fact, Malaysian citizens are allowed to enter Vietnam within 30 days without Vietnam visa, so they just need to apply for visa in case they want to stay longer.
This is one of, if not, the quickest, easiest and cheapest way to get your visa for Vietnam. We can confirm that Vietnam visa on arrival is true and works legally under approval of Vietnam Immigration Department (Vietnam government). In order to obtain Vietnam visa on arrival, tourists or investors must contact with visa agency or company in Vietnam to ask for sponsored and arrange approval letter from Vietnam Immigration Department for allowing pick up your visa on arrival at international airports of Vietnam. You just need to fill in Apply Vietnam Visa form, pay the service fee, get your "Visa approval letter" within 2 working days and pick up your visa at your destination airport (Hanoi airport, Danang airport or Ho Chi Minh city airport).
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Required documents to apply VOA for foreigners
- Vietnam visa approval letter
- Passport (6 months validity FROM THE DATE you arrive in Vietnam)
- 2 passport photos of 4×6 cm
- Entry and exit form
- Money to get stamped (in cash)
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text: Pam Monk of Voices for Children, presents a check to Sue Carpenter of Voices. The check is a donation from The New Pretenders Club in Candler Hills. This $500 check will be used to help support the many children the Guardian ad Litem program assists. We thank the club and members for their generosity to these children.


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hi INDiA Copyright 2020
Salma Hayek reveals her unpleasant encounter with a monkey
Washington D.C. [USA], Jan 12 (ANI): Salma Hayek recently opened up about a vicious monkey attack she faced back in 2002 while filming for a movie.
As reported by Fox News, the 53-year-old actress told Vogue that she underwent this traumatic experience on the set of her movie 'Frida'.
Later that year, she had to muster the courage to do a photoshoot with the same monkey.
According to Fox News, Hayek told Vogue that, "this monkey, who was named Tyson, actually attacked me during the filming of 'Frida,' and I was really severely injured."
She further added: "But I was brave enough to let him come back and work again in the movie, and then I still did a photoshoot with him for Vogue afterwards."
Hayek has somewhat of a love-hate relationship with monkeys as she was gifted two of them in 2015 by Antonio Banderas, who co-starred alongside her in the movie 'Desperado'.
She revealed her love for her two pet monkeys named Mariachi and Carolina on the Jimmy Kimmel show where she said, "I had fallen in love with these two monkeys that were supposed to be in the movie 'Desperado' and then they got cut out."
"I was spending all my time with them and they were gonna take them away and I was sobbing because they were actually staying with me. I was devastated."
"The next day was my birthday and he [Banderas] gave me this big box and my monkeys came out of it. He gave me the monkeys… They lived for a long time and very happily." (ANI)


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is a registered trademark of CDM Publishing, LLC.
Vaccine development is proceeding at an unprecedented pace, but could still hit snags on the way to approval.
The World Health Organization coordinates efforts to create flu and COVID-19 vaccines and to fight other global health issues.
The NIH-funded network has launched its first clinical trial in response to the new pandemic.
Monday, May 18 is HIV Vaccine Advocacy Day. Support science. Not sound bites.
The trial will enroll healthy volunteers to test the vaccine's safety and ability to trigger an immune response.
An $80,000 grant from The Campbell Foundation will help scientist Natalia Freund continue her HIV vaccine studies.
Intravenous administration allowed the marginally effective BCG vaccination to work better in monkeys.
Sci-B-Vac may offer more protection for older people and those with a weaker immune system.
People who received the vaccine did, however, show stronger immune responses against the virus.
Promising news on the prevention front
The Phase IIb/III HVTN 702 trial will begin enrollment in southern Africa in the fall.
The International AIDS Vaccine Initiative (IAVI) marks 20 years in the search for an end to the epidemic.
The International AIDS Vaccine Initiative (IAVI) is collaborating with NineSigma, one of the world's topmost innovation service providers, to...
Initiatives launched aimed at sparking a resurgence of interest and commitment to finding a safe and effective vaccine for HIV.
Sign-on letter from advocates demands that HIV-positive people not be left out.
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Basic cruise prices cover the cabin and meals, although there are upgraded packages such as the Aurea Experience that includes priority boarding, anytime dining, drinks, access to the private sun deck and thermal suite and cabin perks such as a bathrobe and slippers.For those who want to cruise without piling on the pounds, Splendida recently debuted the new Wellness Package, which includes a personalised fitness programme, daily gym class, and dietary advice.
A 15 per cent bar service charge is automatically added to all purchases.
A 15 per cent service charge is added to all spa and salon services.
That said, Splendida has a really inclusive feel, with a very friendly atmosphere.
Reflecting the typical Mediterranean lifestyle, most young children onboard stay up late and will be out and about with their parents -- attracting none of the stern glares they might get on more traditional ships.
Also, when you're orientating yourself with the ship the penny eventually drops that there is no Deck 17 (this is considered an unlucky number in Italy).
Splendida places an emphasis on being an "eco-ship", with various energy saving, water recycling and waste management systems in place.Notable differences from dedicated English-speaking ships include announcements in multiple languages -- the main five being English, Italian, Spanish, German and French -- and sometimes Russian, Chinese and Japanese, depending on the passenger mix on a particular cruise.All credit to members of the crew in all departments, the majority of whom switch seamlessly from one language to another.MSC also attracts couples, families and groups of friends -- including students on their college holidays -- who are generally younger than cruisers on more traditional ships, which makes for an all-encompassing, and sometimes lively, atmosphere.There are few singles onboard and no special activities for solo travellers.Until the debut of MSC Meraviglia in June 2017, the 3,959-passenger Splendida was one of the biggest in the fleet.


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HONG KONG - Oil prices extended gains Monday as rising US-Iran tensions fuelled supply concerns, while Asian equities also edged up ahead of a crunch meeting between Donald Trump and Xi Jinping this week.
Both main crude contracts are up almost 10 percent since Tehran last week shot down a US "spy drone" for breaching its airspace, ratcheting up fears of a conflict between the old foes.
At the weekend Trump said he would impose fresh sanctions on Iran, following bans of countries buying its oil, while US media reports said Washington secretly launched cyber-attacks against missile control systems and a spy network.
Both sides say they want to avoid war, but tensions have spiralled as a series of incidents, including the drone downing and recent attacks on tankers, raised fears of an unintended slide towards conflict.
The US president said he was ready to reach out to Iran if it renounced nuclear weapons, adding that if leaders did so "I'm going to be their best friend". But Iran continues to insist its atomic programme is for civilian purposes.
Brent rose 0.4 percent Monday and WTI was 0.9 percent higher.
"The geopolitical escalation in the Middle East is unquestionably a bullish short-term signal for oil markets, as even the thought of 20 percent of the world oil supply being affected is enough to trigger significant tremors," said Stephen Innes, managing partner at Vanguard Markets.
"And these tremors are noticeably moving up the Richter scale."
The stand-off, coupled with a weak dollar as the Federal Reserve flags an interest rate cut, has helped push gold prices to six-year highs above $1,400 as dealers look for a safe haven to park their cash.
Bitcoin back in vogue
Still, share markets remain buoyant on hopes Trump and Xi can break an impasse in their trade war when they meet on the sidelines of the G20 summit in Osaka this week.
Global equities have been rallying since Trump hailed positive telephone talks last week and said the two would have a face-to-face in Japan, fuelling hopes of a possible end to their long-running tariffs battle.
"No one thinks the US and China will do a deal in Osaka, but there is some hope that we will have a positive development that marks a shift in the rhetoric and a re-energising of talks following the breakdown in the recent discussions," said Neil Wilson, chief market analyst at Markets.com.
Hong Kong added 0.1 percent, Shanghai ended up 0.2 percent and Tokyo was 0.1 percent higher.
There were also gains in Seoul, Sydney, Wellington, Manila and Bangkok, though Singapore, Taipei, Mumbai and Jakarta were in the red.
In early trade London and Paris each rose 0.1 percent while Frankfurt dipped 0.3 percent.
The dollar continues to face pressure from bets on the Fed lowering borrowing costs as soon as July in a bid to head off the effects of the trade spat and as the US economy shows signs of softening.
The greenback slipped against its major peers and most high-yielding units, with the Australian dollar and South Korean won 0.4 percent higher.
The Turkish lira jumped 0.8 percent after the opposition candidate in Istanbul's controversial mayoral election re-run again beat President Recep Tayyip Erdogan's ruling party.
Bitcoin continued to rise, breaking the $11,000 mark briefly for the first time since March last year, as the cryptocurrency sector gets a huge boost from Facebook's unveiling of its own unit.
The tech titan said it will launch Libra next year, with the backing by a basket of real-world currencies and a consortium of companies including Visa, MasterCard, PayPal and Uber.
"Libra will now have to deal with a ton of regulatory scrutiny, but that won't matter in the bigger picture for crypto traders of other coins," said OANDA senior market analyst Edward Moya.
"Bitcoin volatility is likely to persist, with $12,000 and $15,000 as the next two critical resistance levels."
Bitcoin has risen about 20 percent this month alone but is still well off the record levels near $20,000 seen at the end of 2017.


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Who better to know the realities behind the country's permanent war economy than a former spear carrier for the empire? Chalmers Johnson, author of the Blowback trilogy and professor emeritus at UC San Diego spells out again what nobody lining their pockets in "defense" wants to hear. A national treasure speaks out on the squandering of the nation's treasure.
Archive for the 'Neocon Decade' Category
Chalmers Johnson: Speaking Freely About US Foreign Policy
Not Crazy Horse 18's Best Work
Friend to RW370 WikiLeaks has released a video of a 2007 murder of two Reuters journalists and ten other civilians in Iraq by an US Army aircrew in an Apache helicopter overhead. The clip is major evidence of a cover-up of what can only be called (toward the end of the encounter) legitimized murder and maiming of civilians including children.
The justification for firing on the targets in this encounter is flimsy/arguable at the beginning (camera equipment carried by the men on the ground is visually mistaken for illegal heavy weapons) and nonexistent at the end (a van arrives to help a wounded victim, only to be blown apart by the enthusiastic gunner while two children sit in the van). The institutional culpability in the massacre is shown twice: first by the audio of the gunner and aircrew asking for and receiving permission to fire, and second by the cover-up in the years following.
WikiLeaks co-founder Julian Assange is interviewed below about the clip and the role of WikiLeaks in the release of the video. In a world that seems willing to do away with journalism – sometimes by 30mm cannon – Assange's stance is especially poignant and heroic.
This Reddit thread contains a thoughtful discussion started and maintained by an active-duty US military officer (by the sound of it) on the specifics. It is impossible to read that thread and not come away with a clearer understanding of where the lines are drawn and were crossed – starting, but not ending with March, 2003.
David Simon Lays It Down
In which the creator of The Wire singlehandedly validates Vice Magazine's existence while expertly demonstrating the nuanced reality of social criticism in the late capitalist period:
It's one thing to recognize capitalism for the powerful economic tool it is and to acknowledge that, for better or for worse, we're stuck with it and, hey, thank God we have it. There's not a lot else that can produce mass wealth with the dexterity that capitalism can. But to mistake it for a social framework is an incredible intellectual corruption and it's one that the West has accepted as a given since 1980—since Reagan. Human beings—in this country in particular—are worth less and less. When capitalism triumphs unequivocally, labor is diminished. It's a zero-sum game. People paid a much higher tax rate when Eisenhower was president, a much higher tax rate for the benefit of society, and all of us had more of a sense that we were included….I guess what I'm saying is that the overall theme was: We've given ourselves over to the Olympian god that is capitalism and now we're reaping the whirlwind. This is the America that unencumbered capitalism has built. It's the America that we deserve because we let it happen. We don't deserve anything better. The Wire was trying to take the scales from people's eyes and say, "This is what you've built. Take a look at it." It's an accurate portrayal of the problems inherent in American cities.
New At HuffPo: Mary Matalin To Abused Women Of The GOP: Quit Your Bitching
Tags: Mary Matalin, Republican
You can't make up this stuff. Mary Matalin, weathered GOP strategist casually lets it slip that life on the Republican national campaign trail is a great place for a gal to get smacked in the mouth – and that's just dandy with her.
Massa: Get Out
What's this on the House floor? Common sense. Comparative numbers. Simple realities. Get out of Afghanistan.
Truth To Power: Daniel Ellsberg Documentary Opens This Week
Tags: Daniel Ellsberg, Pentagon Papers
On October 1, 1969, Dr. Daniel Ellsberg, RAND corporation consultant to Henry Kissinger and Richard Nixon found in his offices 7,000 pages marked Top Secret exposing a vast program of US government lies surrounding the Vietnam war. The report showed that without disclosure, the war had expanded to carpet bombing of Laos and Cambodia, that US combat troops had been sent by Lyndon Johnson independent of any consultation with advisors, that John Kennedy had actively sought to overthrow South Vietnamese President Ngo Dinh Diem.
Ellsberg delivered proof of these and numerous other US foreign policy atrocities to the editorial offices of the New York Times. The Times 1971 publishing of the Pentagon Papers had a decisive effect on the ending of the Vietnam War and forever put to bed the idea that the US foreign policy establishment acts according to the will and with the assent of the people of the United States.
This week, the documentary film "The Most Dangerous Man In America" will hit screens, telling Ellsberg's story. A whistleblower whose speaking truth to power cost him his career and possibly saved as many lives as his earlier work took in enabling the carpet bombing, he is a rare figure deserving of study and support. Particularly now, at a time when the climate for intellectuals who take democracy seriously is so unfavorable. Former RAND consultant and neo-conservative-cum-Wilsonian Francis Fukuyama illustrates that climate best when he frets about the role of the intellectual in the corridors of power. Despite being a chastised former cheerleader for the Iraq war – a war built upon lies endorsed by institutional intellectuals – Fukuyma recently invoked Ellsberg as a negative example. Some people just prefer intellectuals to be handmaidens to the institution:
I myself worked for more than ten years at the RAND Corporation, the original "think tank" satirized in Stanley Kubrick's Dr. Strangelove that did contract research for the U.S. Air Force and Defense Department. Obviously, one cannot be a free thinker in a place like that (Daniel Ellsberg tried to be and he was fired), and that is one of the reasons that I eventually left to go to a university. But overall, I believe that a democracy is better off having intellectuals pay systematic attention to policy issues, even if it is occasionally corrupting. Having to deal not with ideal solutions but with the real world of power and politics is a good discipline for an intellectual. There is a fine line between being realistic and selling one's soul, and in the case of the Iraq war many neoconservatives got so preoccupied with policy advocacy that they blinded themselves to reality. But it's not clear that virtue necessarily lies on the side of intellectuals who think they are simply being honest.
It may not be clear to you, Francis, but it's clear to me, and to millions.
Lifestyles Of The White And Suggestible
Bless you, Max Blumenthal. Order his book Republican Gomorrah: Inside The Movement That Shattered The Party for a clear insight into what exactly has fed, nurtured, and unleashed the stupid. Jaw-dropping previews at this September 4th Democracy Now interview.
EDIT: A brave soul accompanied by a phalanx of Capitol Campus Police counter-demonstrates:
Make Up Your Mind: He Can't Be All Four
Nice work, Adam Sacks / Shepherd Fairey / Mannie Garcia / (in a sense) Fox News.
One For Every Star On The Flag: Fifty Top US War Criminals
As has been demonstrated by recent UC Berkeley protests against the employment of torture legal advocate John Yoo, some of the Neocon Decade's most notorious figures haven't been able to shake their war criminal reputations even after passing from public "service".
This is not especially common. Rewarding failure is indeed a reliable hallmark of institutional power. Usually, the respectable milieu of the academy is a kind of palliative that can let atrocious bygones be bygones. Alternatively, disappearing into the boardrooms of big business has historically done wonders to hide, if not cleanse, bloody hands.
Maybe not this time.
Fifty Top US War Criminals That Need To Be Prosecuted is a high-quality list courtesy of Pubrecord.org of the enablers, co-dependents, toadies, other-way-lookers, war pimps, defense industry shills, and others responsible for the illegal wars of choice, cash and resource grabs and torture.
Confidential to Attorney General Eric Holder: many home and work addresses of persons on this list are included.
Whenever you're ready.
TV Tiff Not Between Equals
After the on-screen rancor between MSNBC's Keith Olbermann and Fox News' Bill O'Reilly escalated to the boardrooms of their respective bosses (GE for Olbermann and News Corp for O'Reilly) the two talking heads have been told from above to cool it.
For reasons I can't fathom, this development has prompted some to suggest that Olbermann and O'Reilly are equivalent figures, indistinguishably corrupted in their content and presentations, each the other's opposite number and both deserving of the same skepticism as sources of information.
Obviously, no major-media figure whose job it is to provide value to mass advertisers should escape skeptical analysis. But there is no equivalence here. None.
I hope I don't have to be a defender of Keith Olbermann to notice that O'Reilly's and Fox News's unique stock in trade is its regular, nearly uninterrupted cover for corporate interests. Fox News has zero equivalence to any other news network that score. This truth is found in the details of the cat-fight: Only because they're Olberman's boss, O'Reilly needles GE about one (ostensibly) legal aspect of its overseas business. Compare that to the dead quiet from Fox and O'Reilly in nine years concerning Haliburton/KBR, Bechtel, L-3, SAIC, CACI, and other overseas profiteers in Iraq. Nor has there been a peep from Fox about GE's four-plus decades of habitual criminal activity as a US defense contractor – between 1990 and 2002, GE settled with the feds for nearly $1 billion in 63 separate cases, more than any US corporation in that time.
But if you're Bill O'Reilly, GE is only worth talking about if they're a TV competitor's boss.


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Ghanaian Rapper, Strongman approaches with this new hip jump music titled 'My Voice', produced by TubhaniMuzik.
From all signs, the rapper has had a decent year in 2020 from Bossu to Pilolo, both singles have topped charts.
To place a few grins on the essences of fans in these difficult times of COVID-19 pandemic, He falls off with My Voice, a tune pressed with his punchlines, extraordinary conveyance, and his typical cleverness.
Known for his extraordinary creativity behind the mic, Strongman has solidified his region in the music business as truly outstanding to ever do it.
Strongman – My Voice [Prod. By TubhaniMuzik] Download
Check out these latest hits…


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Founded in 1994 and headquartered in Quebec City, with international subsidiaries, InnovMetric Software Inc. is the leading global 3D metrology software company.
Experiencing rapid growth, InnovMetric offers excellent career prospects with advantageous terms.
As a member of a team responsible for the connectivity of our PolyWorks® software suite and manufacturing enterprise information systems, such as product lifecycle management (PLM) software, you will be called upon to maintain existing or develop new ones, to diagnose problems raised by customers related to databases, networking, IT security and performance (for example, transfer rates and latency). You will be involved in the search for innovations and the optimization of our customers' business processes.
You will be part of an experienced team, benefit from excellent coaching from your teammates as soon as you arrive, and actively participate in all stages of development, including analysis, technical design, programming, test automation and validation. We offer a three-day user training on PolyWorks|InspectorTM to all new developers. We have been using the Agile method (SCRUM) for over 10 years.
The conditions of employment are very advantageous:
Thank you for your interest in applying. Please note that we will only contact successful shortlisted candidates.
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Thermoplastic Lightweight Construction – Choice for the Future?
Themes: Process-Tech Forum
Partner: VDMA-Arbeitsgemeinschaft Hybride Leichtbau Technologien
New technologies as well as the continuous development of existing products enable the plastics industry to establish innovative processes. The need and the pressure on the industry to offer sustainable for ecological problems are increasing. Thermoplastic lightweight construction plays an important role in the automotive industry and can contribute to CO2 reduction. More and more fiber-reinforced thermoplastic lightweight components are in use, such as door module, front-end or airbag housing.
But their use also involves restrictions. The production of fiber plastic material costs additional energy, the added value of lightweight construction in electric vehicles is critically questioned, and after end of their service life, no proper solution for recycling was found so far. So does thermoplastic lightweight construction lack the right to exist in future and won't be able to solve tomorrow's problems?
The answer will depend very much on the future mobility and the importance of weight reduction. The possibilities for material recycling of such structures have not yet been exhausted and the speed at which the energy transition is achieved also determines the carbon footprint of these products.
A contribution to energy saving is already being made by thermoplastic lightweight construction today. Through functional integration and anisotropic material optimization, material and thus weight can be saved. It is precisely such properties that can provide the necessary added value in the future. The corresponding production facilities are available and are capable of processing short, long or continuous fiber in series.


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OSP Ultimate II. offensive blade
We created the Ultimate II. for those who need 7 ply blade behaviour with high amount of spin as well as speed. We redesigned the layer structure of the predecessor to increase control and the cooperation with the new PVC balls.
The result of redesigning is a brand new dynamic OSP offensive blade for those who are looking for a blade can generate huge spin even if the dwell time is short when you hit the ball fast.
We started to apply a new laminating procedure so with the OSP Ultimate II. you can amaze your opponent how big is the rotation of even a PVC ball with a short stroke. They will hardly recognize the amount of spin. Thanks to the new power core we also dramatically increased the playing area, so you can use it comfortably from further distance than the Ultimate. With the new model you can easily switch between low trajectory, fast, heavy spin strokes and higher arc balls if you need ultimate spin or you want to play in the safety zone.
The Ultimate II. is slightly thicker so you will get a bit more extra stability that with the other developments provide more effective operation with short strokes like serves or short game. This table tennis blade is tuned for wider repertoire of playing strategy and meet the requirements of the new PVC balls and the rubbers made for PVC balls. There is no classical vibration in the Ultimate II. We provide accurate and required feedback that an offensive player need.
Made for PVC ball and rubbers for PVC balls, higher spin, wider playing strategies, easy spin, lower vibration, the ultimate table tennis weapon
Data sheet
- Weight
- 86-93g
- Speed (higher is faster)
- 19
- Control (higher is better)
- 19
- Spin (higher is spinnier)
- 19
- Arc (higher lifts more)
- 17
- Dwell time (higher is longer)
- 19
- Stiffness (higher is stiffer)
- 18
- Surface hardness (higher is harder)
- 14
- Outer ply
- Limba
- Ply nr.
- 7
- Thickness
- 6.20 +/- 0.1mm
- Weight balance
- Center / Head optimized
- Feedback
- Modern


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MUMBAI: Mohsin Khan and Shivangi Joshi, who plays the role of Kartik and Naira Star Plus' show Yeh Rishta Kya Kehlata Hai is one of the popular jodis of the small screen. The duo's pair is doing wonders for the show and fans simply love them to see together.
Well, like their onscreen pairing lights up the small screen, we all know that the couple is also dating in real life. It's been a long time since the duo is together and has given us major relationship goals.
Apart from being a lovey-dovey couple, the duo is also known for their amazing fashion sense. Both Mohsin and Shivangi are spot on when it comes to fashion. No, we are not just saying it but their Instagram accounts are proof.
The couple's Instagram is filled with some of the most beautiful pictures where they are all decked up in traditional attires. We can't get our eyes off this lovely couple. The couple has given us major fashion goals with their choice of outfits and how perfectly they complement each other. Couples can surely take tips from this hot jodi and dress up this festive season.
So here are some of the best pictures of Mohsin-Shivangi. Have a look:
So folks, what do you think about Mohsin and Shivangi's fashion style? Tell us in the comments.


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The alarm goes off
To greet a new day
I turn on the light
To guide my way
Two feet touch the floor
I head through the door
To a working commode, shower and sink
Then to the kitchen for food and drink
Then into my car to embrace the roads
Travel the bridges, tunnels and tolls
Out my window I take in the sights
Hospitals, schools, hotels, planes taking flight
Inside me a new passion arises
As I realize then there is no disguising
The lives we live are greater each day
Because of the contractors who made it that way!
The electrician, the plumber, the carpenter and crew
Without each of them what would we do?
Each talented contractor general or trade
How else would it have been made?
Our houses, our roads, places of work and of play
We could dream and design them day after day
But without the contractor to bring it to life
It stays just a plan with no execution in sight
Craftsman they're called for obvious reasons
Without their talents just imagine our seasons
The beach house, the ski lodge , the place to take view
The race track, the theme park, the resorts all of new
None would be there for us to take pleasure in
Thank you Contractors for sharing your talents within
The world doesn't always view you in love
It's now obvious to me, you're a gift from above!


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Lisa Oates
Marketing Manager
As a former competitive athlete and an ambivert at heart, Lisa loves teams and the camaraderie they offer. She spent her earlier career days in business development analytics before transitioning into sales and advertising, where she began building on her skill set with web design and development, SEO, content creation, social marketing, graphic design and branding. Lisa started her own business to offer these brand-building services to small business owners and "solopreneurs", labeling herself a "big-picture creative with web savvy" who puts a high value and focus on giving clients the best experience possible.
Lisa joined WinShape Teams in 2017 and immediately got to work building strategies, planning for growth, and managing all aspects of marketing for the brand. In her role, she oversees things like communication and brand messaging, collateral, social media content and story development, client relationships, to name a few. She's excited to have a second family in WinShape Teams and introduce the work-as-family concept to clients who envision their teams to be more than just coworkers.
Lisa and her husband have three children – Maddie, Adah, and Keller – plus two dogs: a Blue Heeler mix named Max, and a Lab Retriever named Baker. She loves rich desserts, a good Netflix binge and tearing it up on a nice golf course. She appreciates a good cup of coffee and hopes to tour a coffee farm someday.
"The future belongs to those who believe in the beauty of their dreams."
Recent posts from Lisa Oates
A ready-to-use resource kit with everything included for Team Leaders to walk through a development experience with their team -- no matter how the team is structured or scattered.
see resource
We interviewed Emily Katherine Dalton, WinShape College Program's Assistant Coordinator of Discipleship Intensives about the importance of rest and mindfulness.
see resource
Jalen Matthews, a rising leader at CFA Annapolis, struggled to balance managing operations and managing people. At a Leader Summit, he realized he may be a leader who can get results, but if he's not looking to grow himself it limits his capacity to grow those around him.


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List of Oloyans and their Ruling Houses. As expected, there are many different lists from different sources and ruling houses because of personal interests. The major difference between most of these lists is in terms of succession and the name used for each Oba. The other groups oof lists is in terms ones that intentionally omitted the names of Oloyans that Onile Ruling House produced including Oba Nathaniel Omotosho who reigned for almost fourty (40) years (1958 – 1996AD)
History had it that most Oloyans from Epe to Ige reigned for an average of fourty (40) years each until the turn of Abegunde who reigned for only nine (9) years. Surprisingly, the next three (3) Obas after him also reigned for nine (9) years each. It was then believed that all Oloyans, from then on, were jinxed to reign for only nine (9) years. So, when Oba Oyelere ascended the throne in 1930, he sounded it loud and clear that he would not be a'9- year' Oloyan. He added that being at twin, he would reign for at least 18 years to make up for his twin. He did reign for 18 years. Therefore, in estimating the reigns of each Oloyan, for their reigns and any interregnums, 40 years are assigned to each Oloyan from Epe to Abegunde. This puts the founding of Oyan to between year 1250 and 1300 AD. This falls within the reign of Oba Fagbamila Ajagunla of Ila Orangun whom historians claimed reign for about 130 years before he 'sank' into mother earth.
Accordingly, the best acceptable list with approximate4 dates is as follows:-
1.Epe- Onile 1254-1294 (2) Oyeleye- Onile 1294-1334 (3) Oluwaiye-Onile 1334-1374 (4) Onduloye-Laojo 1374-1414 (5)Akinmoyero-Onile 1414-1454 (6) Olode Okuta- Onile 1454-1494 (7) Olarinoye-Elemo 1494-1534 (8) Suku – Laoja 1534-1574 (9) Asoroko – Laojo 1574-1614 (10) Oyediran- Onie 1614-1654 (11) Okunoye – Olomooba 165-1694 (12) Areoye – Daodu 1694-1734 (13) Akinrinlo – Laojo 1734-1774 (14) ADemola- Laojo 1774-1814 (15) Orisalolu- Daodu 1814-1854 (16) Ige- Elemo 1854-1894 (17) Abegunde –Laojo -1894-1912 (18) Adegbile-Laojo 1903-1912 (19) Akinloye –Olomooba 1912-1921 (20) Onnuola-Elemo 1921-1930 (21) Oyelere- Olomooba 1930-1948 (22) Folayan- Daodu 1949-1957 (23) Omotoso- Onile 1958-1996 (24) Adekeye – Elemo Aresinkeye 1998 to date.
2.List of the incumbent kingmakers in order of Seniority with Title and Compound. (1) Chief Oladimeji Suliaman- Esa, Esa (under dispute with case in court 3 High Court, Osogbo since 2016) (2) Chief Oyesanya Olasunkanmi – Ojomu, Ojomu (3) Chief Yusufu Saberedowo – Osolo, Osolo (4) Vacant ……………. Inurin, Inurin (5) Chief I.F. Omotosho- Arogun, Arogun (6) Chief Olayiwola – Ola
3.List of Council of Chiefs Iware with their Compounds in alphabetical order. As at April 2017, out of 20 members of Ilu 18 seats are vacant for some reasons. Only two chiefs are now serving as members of Ilu Council. They are (1) Chief Zacheus Oluwasegun Adedoyin-Odoka, Lakolu (2) Chief Timothy Adeyemi – Jagun, (Aromoso); while the vacant seats are:- (1) Aade- Aade (2) Alaagba – Alaagba (3) Alawe- Alawe (4) Balogun- Onto (5) Elemona – Elemona (6) Elemoso – Elemoso (7) Ikolaba- Ikolaba (8) Iyalode- Open (9)Iyaloja – Open (10) Majekobaje- Oloba (11) Obafa- Agarawu (12) Odofin – Odofin (13) Olowa- Olowa (14) Olowaeyin- Otupepeye. (15) Oluawo – Oluawo (16) OLuoko- Oluoko/Oloya (17) Sakin-Alaaka (18) Oyesan – Obitikun are vacant.
4.List of Traditional Spiritual Heads in alphabetical order. (1) Alaagba- Head of Masquerades (2) Babamogba- Head of Sango Worshippers (3) Oluawo- Head of Diviners (4) Oluode- Head of Hunters. The title holders are open to many compounds.


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Page 3 - firstgrammar_1
Let's Practice More
expands the story in the previous first page of each
unit. It provides meaningful context and expanded
exercises. These exercises can help students increase
their knowledge and skills and understand how the
target grammar is used.
Remember This introduces several key sentences
from each unit. It is designed to wrap up the unit's
grammar points. Teachers may encourage students to
memorize the sentences in whole.
Grammar Review is provided
after every three units. It is
designed to incorporate the
three target grammar points
that students have learned. It
can assess and evaluate the
students' understanding and