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Published 26.08.2014 | Author : admin | Category : What Do Guys Really Want In A Woman

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA. Present address: Research Institute of Molecular Pathology IMP, Vienna Biocenter VBC, Vienna, Austria. HISTORY & BACKGROUNDInitial CMC GuidanceThe BOLD ALLIGATOR Series got its genesis from the Commandant of the Marine Corps (CMC)and the Chief of Naval Operations (CNO) initial guidance dating back to 2008. Initial CNO GuidanceThe CNO followed suit with guidance in 2009 that, “Our operations and procurement plans address the capabilities of both our Navy and Marine Corps. Flexibility & Utility of Amphibious ForcesHistory has shown that the capabilities that allow the amphibious force to conduct a forced entry landing against an opposing military force are the same capabilities that make it the force of choice for crisis response and building coalition partnerships. Seapower plays a key role in preserving the American way of life by maintaining safe, global commerce operations across the seas. Focal epilepsy is commonly pharmacoresistant, and resective surgery is often contraindicated by proximity to eloquent cortex.
Two distinct control groups per condition were tested: rats injected with an AAV5-CamKII?-ArchT-GFP virus, and rats which were not injected with a virus (but otherwise underwent the same surgery and implantations as the other groups). Epilepsy affects up to 1% of the population1 and is resistant to drug therapy in at least 20% of cases2. We first examined seizures acutely evoked by chemoconvulsant injection into layer 5 of the motor cortex 17–52 days after hM4Di AAV injection. We asked whether off-target effects of CNO independent of hM4Di could account for its anti-seizure effect. Finally, we asked if chemical–genetic inhibition of focal seizure activity would result in a significant reduction of behavioural seizures. Chemical–genetic silencing of focal neocortical epilepsyhM4Di activation with CNO is thus effective in two chemoconvulsant models.
Quantification of CEl c-Fos expression in mice intraperitoneal injected with anorexigenic drugs (a), 24 h fasted with or without 3 hr re-feeding (b), or orally infused with water, quinine or sucrose solution (c). Expression of c-Fos (antibody staining) and PKC-δ (indicated by Cre-dependent virus expression of fluorescent proteins) after injecting CCK, LiCl or LPS. Mice in a lickometer with two bottles (a): one contains water and the other contains quinine solution (see concentrations in (b)). The level of freezing (a) and automatically scored motion index (b) are not significantly affected by light activation. The global system of connected economies depends on the freedom of movement across the maritime domain, as it is the principal means for the transit of 90% of the world’s commerce by weight and volume.
A1: Exercise Bold Alligator 2014 is a live, virtual, and constructive (LVC) scenario-driven coalition exercise designed to improve Naval and amphibious core competency. For panels (a) and (c) data from both groups were pooled, while in panels (b) and (d) data from all rats and groups are shown individually. 3c, see Methods) between vehicle and CNO trials in hM4Di-transfected (a, n=7) and untransfected (b, n=6) rats. The resulting fEPSP, evoked every 30?s, was recorded further medial in CA1 with an extracellular electrode. Epilepsy can be focal (arising from a specific brain area) or generalized (arising from both hemispheres). At the same time we implanted both a Teflon cannula guide above the injection site to allow administration of chemoconvulsants and a subcutaneous transmitter (Open Source Instruments Inc.) with the active lead overlying M1 for wireless electroencephalography (EEG) recording.
In CNO trials, both electrographic and motor convulsions were substantially reduced (n=6 rats). We therefore assessed electrographic markers of epilepsy during a 3.5-h window starting with the first of two intraperitoneal injections of either CNO or vehicle, with the second injection at 2?h.
Bitter preference was defined by the number of licks of quinine solution divided by the total number of licks on both bottles.
The expression of Tac2 or CRF was identified by tdTomato expression after crossing the mice with Ai14 Cre-reporter mice.
Navy ships underpin expeditionary operations, thus our procurement resources are intertwined. Marine Corps Forces Command (MARFORCOM) have agreed to conduct an exercise each year, alternating between synthetic and live in order to concentrate on the more complex issues, refresh the practical and mechanical aspects of planning & conducting amphibious operations as well as refine what we learn and develop from these invaluable experiences. With such a global interconnection of economies, shocks to the system caused by region-al conflicts, terrorist attacks, natural disasters, and war all have potential global impact. Improving Navy-Marine Corps amphibious core competencies along with coalition, North Atlantic Treaty Organization (NATO), Allied and partner nations is a necessary investment in the current and future readiness of our forces. Bold Alligator 2011, the first iteration, focused on conducting non-combatant evacuation operations (NEO) simultaneously with other amphibious operations as needed to meet regional combatant commander requirements in a realistic synthetic training environment. Amphibious forces provide the flexible forward presence that will continue to be needed in the complex world environment where 70 percent of the world’s population lives in the littoral regions.
Gene therapy allows cell-type specific inhibition of neuronal excitability, but on-demand seizure suppression has only been achieved with optogenetics, which requires invasive light delivery. Bottom, expanded sections from times indicated (2-s-duration) showing SS, CS and IF activity.
Animals underwent the same experimental protocol as described above, using local intracortical injection of either pilocarpine (six virus-injected and five uninjected rats; Fig. Rats (n=7) underwent a similar treatment as before, but the virus was left to express for 3 months before the first experiment was conducted to achieve high expression levels. We turned to the tetanus toxin model of chronic epilepsy15, 16, which responds poorly to antiepileptic drugs and resembles human epilepsia partialis continua17.
The assessment was then repeated 24?h later, switching vehicle and CNO, to allow for washout of the agonist, and to control for diurnal variability in seizure frequency (Fig. We must integrate warfighting capabilities with the Marine Corps to meet the objectives of the Maritime Strategy and Naval Operations Concept. Improving Navy-Marine Corps amphibious core competencies and training with our coalition, North Atlantic Treaty Organization (NATO), Allied and partner nations is a necessary investment in the current and future readiness of our forces. Bold Alligator 2012 focused on live training to hone the skills needed to conduct large-scale forcible entry operations in the complex littoral region. Here we test a combined chemical–genetic approach to achieve localized suppression of neuronal excitability in a seizure focus, using viral expression of the modified muscarinic receptor hM4Di.


SS activity was associated with no motor seizures (severity score 0) or twitching of limb, head or body (score 1), while IF was associated with repetitive head or body shaking (score 2) or rearing, retrograde locomotion and generalized convulsions (3). The epileptogenic zone in such cases is frequently restricted to a small region that can often be localized with imaging and electrophysiological techniques4. Spike-wave complexes either had a single negative peak (‘simple’ spike-waves, SS) or featured one or more shoulders (polyspike-waves or ‘complex’ spike-waves, CS; Fig. Seizures of the most severe class (score 3, see above and Methods) were counted by an experimenter who was blind to the identity of the injected compound (vehicle versus CNO, 4?mg?kg?1).
This model is characterized by several EEG features, including increased high-frequency (120–160?Hz) power, increased coastline (cumulative difference between successive points on the EEG) and the occurrence of brief bursts of high-frequency EEG activity that can be detected by an automated event classifier7 (Fig. For (b-d) n = 5 (H2O), 8 (quinine), 6 (sucrose) sections from two injection experiments in each group. Bold Alligator 2013 allowed exercise planners the opportunity to apply lessons learned from previous iterations in a synthetic environment to examine the command and control of large-scale forcible entry operations. Between 1990 and 2010 the Navy-Marine Corps team conducted more than 1,000 amphibious operations. However, surgical removal of the seizure focus can successfully treat only about 5% of pharmacoresistant patients, and is often inappropriate in focal neocortical epilepsy because of proximity to eloquent cortex5, 6.Gene therapy targeted to the epileptogenic zone has been shown to be effective in rodent models of epilepsy including focal neocortical epilepsy7.
The seizure activity was on average larger in the vehicle trial than in the matched CNO trial for each rat and every 10?min interval (Fig.
For (a), n = 6 (saline), 7 (CCK), 7 (LiCl), 8 (LPS) brain sections from 4 animals in each condition. Table showing quantification of the number of GFP labeled neurons in each of these brain regions. The Bold Alligator exercise series demonstrates how amphibious forces are critical to maintaining the maritime flexibility required to preserve vital national interests.
These include Navy-Marine Corps amphibious responses to more than 100 crises and 900 cooperative engagement events in support of national security interests. Systemic administration of CNO suppresses focal seizures evoked by two different chemoconvulsants, pilocarpine and picrotoxin.
However, viral delivery of transgenes that alter excitability permanently may impair essential function of circuits near the seizure focus. 1c), and was confirmed by fluorescence microscopy for all rats sacrificed after 4–20 weeks. They were interspersed with runs of intermediate frequency (IF) discharges (5–12?Hz) lasting 0.2–12?s, which typically had a smaller amplitude (Fig. 2e,f).Chemical–genetic silencing of picrotoxin-induced acute seizuresCNO thus profoundly suppressed pilocarpine-triggered seizures. Second, synaptic transmission from excitatory cortical synapses might be directly inhibited, as has been shown for the native muscarinic receptor M4, which is expressed presynaptically21, 22.
Note that sparse labelling was also observed in several other brain regions (such as contralateral insula) that are not included here.
For (g-i) n = 8 (H2O), 8 (quinine), 5 (sucrose) sections from two injection experiments in each group. Fluorescent nerve terminals in acute amygdala slices derived from ChR2-EYFP neurons in insula or LPB, infected with a non-Cre-dependent AAV.
The exercise showcases the advantages of sea-basing and the Navy and Marine Corps' full range of amphibious operations.
These amphibious operations covered the spectrum ranging from peaceful humanitarian assistance to major combat operations. CNO also has a robust anti-seizure effect in a chronic model of focal neocortical epilepsy. An attractive strategy would be to suppress circuit excitability ‘on demand’ upon detection of a seizure. However, the interpretation of this anti-seizure effect is potentially confounded by an overlap of downstream signalling cascades of pilocarpine acting on muscarinic receptors and CNO acting on hM4Di14. While the former hyperpolarizing effect has been repeatedly documented for the modified receptor hM4Di, it is unclear if its potential for synaptic silencing may also contribute to the inhibitory effect we observe. For (b), n = 15 brain sections from 4 animals (24 h fasted) and 17 brain sections from 5 animals (re-fed). Mice received light stimulation (20 min of 473 nm, 5 Hz, 10 ms light pulses) either in chamber A or chamber B (c). After more than a decade of armed conflict, the Navy-Marine Corps team is working hard to revitalize, refine, and strengthen fundamental amphibious competencies and reinforce the Navy and Marine Corps roles as "fighters from the sea”. Chemical–genetic seizure attenuation holds promise as a novel approach to treat intractable focal epilepsy while minimizing disruption of normal circuit function in untransduced brain regions or in the absence of the specific ligand. Recently, progress in optogenetic seizure suppression in rodents has shown that this is, in principle, feasible7, 8, 9. We injected the hM4Di-expressing AAV into the CA3 subfield of the hippocampus in three rats under isoflurane anaesthesia at 4 weeks of age, and prepared acute hippocampal slices 10–11 weeks later.
Percent of time that the mice spent in each chamber on day 1 pre-test (d) or day 4 post-test (e) following training on days 2 and 3 is not affected.
For (l-m) n = 6 (H2O), 5 (quinine), 6 (sucrose) sections from two injection experiments in each group. Food intake during photostimulation of Tac2-Cre mice (d-e) and CRF-Cre mice expressing ChR2 (f-g).
In previous years, Bold Alligator tested the ability of the Navy-Marine Corps and our coalition partners’ team to conduct a full-scale amphibious landing in a medium threat environment. Beirut Multi-National non-combatant evacuation operations (NEO) – In July 2006, Israel assaulted southern Lebanon, forcing thousands of American citizens to flee.
One of the main limitations to clinical translation is the need to deliver light of the appropriate wavelength, intensity and duration to the region of transduced neurons. Motor seizures ranged from brief twitches of the contralateral limb, the head or the body (score 1), repetitive head, limb or body shaking (score 2), to rearing, retrograde locomotion and generalized convulsions lasting several seconds (score 3) (Fig. Picrotoxin injection into the primary motor cortex (10?mM, 100–600?nl) also elicited electrographic and motor seizures. A field excitatory postsynaptic potential (fEPSP) was evoked in stratum radiatum of CA1 by extracellular stimulation. For (c), n = 12 (water), 15 (quinine), 12 (sucrose) sections from 3 animals in each condition.


Bold Alligator 2014 will exercise the ability to conduct crisis response operations in a complex maritime environment. The Iwo Jima Expeditionary Strike Group (ESG) with the embarked 24th Marine Expeditionary Unit (MEU) evacuated more than 15,000 American citizens between July 15 and August 20, 2006.
This necessitates the implantation of optical devices and suffers from the strong attenuation of light in brain tissue.We report an alternative gene therapy approach to achieve targeted and temporally limited suppression of neuronal excitability that relies on systemic delivery of a small molecule inhibitor. These were similar in overall duration, composition of spike-wave and IF complexes, and behavioural correlates (Fig.
Bath perfusion of CNO (10??M) reversibly decreased the initial slope of the fEPSP without affecting the fibre volley, consistent with a decrease in glutamate release (n=9 slices; Fig. The capabilities that allow the amphibious force to conduct forcible entry are the same capabilities that make it the force of choice for crisis response and building partnerships. Specificity is achieved by regional and cell-type specific expression of a designer receptor exclusively activated by a designer drug (DREADD). Monosynaptic rabies-traced (GFP labeled neurons) and c-Fos expressing neurons in LPB (a), BLA (b), and insula (c), in mice intraperitoneal injected with saline, CCK, or LiCl. Neurons transduced with a DREADD are in principle unaffected in the absence of the selective ligand, and only affected when the ligand is present, thereby avoiding permanent alteration of their properties10. Among minor differences, electrographic bursting switched on and off more abruptly and individual polyspike-wave complexes lasted longer (Fig.
Although the depression was modest, this experiment underestimates the effect of hM4Di activation on individual synapses because not all stimulated axons were supplied by transduced neurons. Navy, Marines, and Coast Guard provide global capabilities supporting national interests and are a natural medium for forging and maintaining international relationships. The 22nd MEU was the first major Marine force to respond, managing the hardest hit area west of Port au Prince. We chose the engineered inhibitory Gi-coupled human muscarinic receptor hM4Di, which has been made sensitive to the orally bioavailable and normally inert metabolite of clozapine, clozapine-N-oxide (CNO)11, 12.
The inhibition of synaptic transmission likely contributes to the overall antiepileptic effect of hM4Di. All mice were then put back into their home cage with access to food for 24 h, and then food was deprived on day 2. Bold Alligator provides a premium venue to improving and under-standing operational proficiencies between U.S. The MEU conducted immediate relief operations by distributing food, water and providing medical care. Importantly, hM4Di is relatively insensitive to acetylcholine, the endogenous agonist of the parent receptor.
When CNO was administered by intraperitoneal injection immediately after focal picrotoxin the electrographic discharges were again attenuated (Fig. Naval amphibious forces, coalition, North Atlantic Treaty Organization (NATO), allied and partner nations’ forces. Units within the MEU consisted of 1,600 Marines with the Combat Logistics Battalion 22, 3rd Battalion 2nd Marines, Marine Heavy Helicopter Squadron 461 and MEU Command Element while the ARG consisted of USS Bataan, USS Carter Hall and USS Fort McHenry. Improving Navy-Marine Corps amphibious core competencies alongside coalition, NATO, allied and partner nations is a necessary investment in the current and future readiness of our forces.Given the realities of the 21st century security environment, coalition participation is incorporated to provide additional resources and capabilities. 150 Marines aboard the USS Gunston Hall joined the MEU along with the 24th MEU on the USS Nassau, USS Mesa Verde and USS Ashland. Within the context of the 21st century maritime environment, Bold Alligator scenarios are realistic and relevant to current operations.
From February to March, the MEU transitioned to sustained relief operations and focused on turning over responsibilities to the Government of Haiti and major relief organizations ashore before departing at the end of March. Crisis response operations like Tomadachi in Japan and Unified Response in Haiti illustrate the need for rapid, reliable and ready amphibious forces pro-vided by the Navy-Marine Corps team and our coalition partners.Bold Alligator 14 truly is rapid response for today’s crisis.
While supporting relief operations, the Marines and Sailors of the 22nd MEU combined a network of sea-based logistics and land-based support with as many as 1,100 Marines and Sailors ashore to conduct immediate aid efforts. Food intake on day 3 (test) is not decreased in mice expressing hM3Dq (red), indicating that no conditioned taste aversion has occurred. The Marines focused on a 60-kilometer area west of Port-Au-Prince, from Carrefour to Leogane, through Grand Goave to Petit Goave.
Mounting towards a female intruder mouse (red dashed outline) was not obviously affected by photostimulation of the male mice expressing ChR2 (yellow dashed outline). Increased feeding in these mice compared with control mice expressing mCherry (gray) may reflect the slow wash-out kinetics of CNO, resulting in decreased feeding during the 24 h ad libitum feeding recovery period on day 2.
In order to move and distribute supplies in these areas, Marines and Sailors partnered with the United Nations, United States Agency for International Development, non-governmental organizations, and Canadian and Spanish military forces. Right, latency to stop mounting in response to control light (571 nm) or 473 nm light stimulation. Consequently, on the test day (day 3), these mice may be hungrier than mCherry expressing mice, resulting in increased feeding.
Operation Tomadachi – In response to the magnitude-8.9 earthquake and subsequent tsunami that struck Japan March 11, 2011, the President of the United States called for a swift and coordinated response. Box plots (d, e, i) show mean (+), median, quartiles (boxes), and range (whiskers).
The UNSCR authorizes use of force with an explicit commitment to pursue all necessary measures, to include the enforcement of a no-fly zone over Libya.
Naval forces participated in cruise missile strikes as part of Operation Odyssey Dawn designed to set the conditions for a coalition no-fly zone, striking more than 20 integrated air defense systems and other air defense facilities ashore in Libya March 19, 2011.
Amphibious ships supporting the Joint Task Force (JTF) included USS Kearsarge (LHD 3) and USS Ponce (LPD 15).
Marine Corps AV-8B Harriers aboard Kearsarge launched in support of Operation Odyssey Dawn March 20, and conducted strikes against Qadhafi's ground forces and air defenses. March 21, 2011 Marines from 26th MEU along with MV-22 Ospreys and CH-53E Super Stallion helicopters conducted a tactical recovery of aircraft and personnel (TRAP) mission after a U.S. The amphibious ships, added a robust ship-to-shore movement ability to include landing craft, both air-cushioned and utility, for moving large amounts of cargo and equipment ashore, as well as the transport of the 31st MEU which operated heavy equipment for debris removal.



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