References Arendt T Synaptic degeneration in Alzheimers disease. Acta Neuropathol. Eur J Physiol. Journal of Neural Transmission. Bulletin of Clinical Psychopharmacology. Ann NY Acad Sci. Neurobiol Aging. Eds: Cuello AC. Curr Alzheimer Res. Neurobiology of Aging. Biochemical and Biophysical Research Communications. Arch Neurol. A challenging hypothesis. J Neural Transm. Isik AT Late onset Alzheimers disease in older people. Clinical Interventions in Aging. Adv Stud Pharm. Biochimica Biophysica Acta. N Engl J Med. Neurol Res. Molecular Neurodegeneration. Microvasculature changes and cerebral amyloid angiopathy in Alzheimers disease and their potential impact on therapy.
Wolfe MS The gamma-secretase complex: Membrane-embedded proteolytic ensemble. Biochimica et Biophysica Acta, Part 2. The expression of APP has also been shown to increase in swollen axons and neuronal perikarya after neuronal injury, including ischemia Stephenson et al. As the pathological findings in dementia pugilistica mimic those in AD Roberts et al.
In this study, 1. In addition, we investigated the function of APP by assessing water maze and morphological changes following direct infusion of the anti-APP antibody into the damaged brain region following TBI. Materials and methods 2. The scalp was incised on the midline and the skull was exposed.
Brain injury above the dura mater was then induced with a pneumatic control injury device Itoh et al. Control rats were subjected to a sham operation, but no cortical penetration injury was inflicted. The contralateral hemisphere was not used as a control, since that area may have been affected by the impact. Rats were placed in a heated cage to maintain their body temperature at 37C during the recovery from anesthesia. The cannula was secured with dental cement.
For the control of the Morris water maze experiments, ten animals with no operation sham operation group, no injury were also collected. In sham operation group, a micro-osmotic pump was implanted subcutaneously in the neck without infusion cannula. Moreover, sham operation group was used only the behavioural experiments. As probe and the extent of APP antibody infusion test, although data not shown in this study, we investigated that the extent of APP antibody diffusion with Evans blue using the osmotic pump and confirmed Evans blue extended whole brain from center of infusion area.
A constant asymmetrical array of lamps and pictures served as cues for spatial orientation. A circular dark gray platform 15cm wide submerged 1cm below the water surface served as a platform. The platform was placed in the center of one of the quadrants, i. The experiments were monitored using a digital TV system connected to a computer Elvander et al. Training took place between a. Each daily training session consisted of four trials with a s cutoff time, followed by 30s rest on the platform. The brains were then removed and stored in PFA for three days, before the maximum size of the lesion was sliced into serial coronal sections 50m thick using a microslicer Dousaka EM, Kyoto, Japan.
Labeling was visualized using DAB. Sections were treated with Proteinase K for 10min. Following extensive washing, the sections were further incubated with a polyclonal rhodamine-conjugated anti-rabbit IgG antibody dilution; DAKO for 80 min at room temperature. Following extensive washing, the sections were further incubated with a polyclonal fluorescein isothiocyanate FITC -conjugated anti-mouse IgG antibody dilution; DAKO for 80 min at room temperature. Subsequently, the sections were observed by fluorescence microscopy Nikon E; Nikon, Tokyo, Japan.
Five rats were used for each time point. Briefly, total RNA was isolated from an area of the cerebral cortex without the corpus callosum and hippocampus with a diameter of 2 mm from the center of the lesion using RNA-Bee Tel-Test Inc. RT was performed at 42C for 25 min, followed by heat inactivation at 99C for 5 min. The final step was extended to 5 min at 72C.
After separation by electrophoresis in 1. Bio Max 1D TM1. After treatment of the homogenates with ultrasonic waves at 4C for s and centrifugation at 20, g for 30 min at 4C, the resulting supernatants were collected. ELISAs were performed as previously described. The plates were then washed three times with PBS containing 0. Aliquots l of the diluted samples were incubated in the wells at 4C overnight.
After washing, l of a mouse monoclonal anti-APP antibody dilution in PBS-B; Chemicon was added to each well and incubated for 2 h at room temperature. The detection limit of the assay for APP was 0. The measurements were made in duplicate. Anteroposterior sections were stained with hematoxylin and eosin HE. The area of the damaged region in each image was traced and measured by computer, and the average area of the damaged region calculated over the forty serial sections.
Results 3. NF Fig. At 7 days after cortical traumatic injury, MAPpositive nerve cell cytoplasm Fig. At 7 days after traumatic injury, a few CD11b-positive cells Fig. At 1 day after injury, damaged dystrophic and swollen neurites A, green in the cortex were APP-positive B, red. The merged image C of panels A and B reveals colocalization of these proteins yellow.
The merged image F of panels D and E reveals colocalization of these proteins yellow. The merged image C of panels A and B does not show any colocalization. The merged image F of panels D and E does not show any colocalization. However, there were no APP- immunopositive cells and fivers in the sham-operated cerebral cortex Fig.
There were no such changes in the sham group Fig. Immunostaining for APP around the damaged cerebral cortex after traumatic brain injury. At 1 day after injury, there are many APP-positive damaged dystrophic and swollen neurites A. Graph showing the numbers of APP-immunopositive neurites D and cells E around the damaged cerebral cortex after traumatic rat brain injury. The results are shown as the mean SD. One peak of elevation was determined between 1 day and 30 days after injury. One peak of elevation was determined between 1 day and 90 days after injury Fig.
The sham operation group had no injury. The effects of treatment group on arrival time to platform are shown. PBS group vs.
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The size of the damaged brain region at seven days after TBI. Anti-APP antibody group vs. PBS group. In the anti-APP antibody group there were only a few TUNEL-positive cells which possessed a small cytoplasm, such as glial cells, or a large cytoplasm, such as neural cells Fig. Discussion The hypothesis that head trauma is a risk factor associated with subsequent development of Alzheimer disease is based on the neuropathology of dementia Roberts ; Roberts et al. Some reports have shown that the expression of APP is enhanced by various forms of brain injury, including traumatic Otsuka et al. Further, the overexpression of APP suggests the possibility of an Alzheimer disease-like pathology after traumatic brain injury Rumble et al.
Previously, the appearance of APP in the brain during pathological events was usually attributed to its synthesis by neurons, macrophages, microglia or astrocytes Otsuka et al. Furthermore, we showed that the expression of APP in neurons and neurites was significantly increased in the cerebral cortex after traumatic brain injury. It has been pointed out that increased APP immunoreactivity occurrs in damaged axons due to disturbance of fast anterograde axonal transport Koo et al. These results suggested that APP synthesis was increased from the early phase after brain injury and it lasted for a long period during the experiment.
Furthermore, expression of APP was increased in neurons after ischemia and axonal injury Stephenson et al. TBI occurs as the result of a direct mechanical insult to the brain, and induces degeneration and death in the central nervous system CNS Chirumamilla et al. Following the initial mechanical insult, secondary pathways are activated that contribute to the ischemic damage induced by circulatory disturbance, blood-brain barrier disruption and excitotoxic damage Kawamata et al.
The expression of APP has also been shown to increase in swollen axons and neuronal perikarya after neuronal injuries, including ischemia Stephenson et al. Taken together, these results suggest that APP leaks out from damaged and necrotic axons and neuronal cytoplasm after TBI. Previously, the appearance of APP in the brain during pathological events was usually attributed to its synthesis by neurons, macrophages, microglia, or astrocytes Otsuka et al.
Sun et al. In the present study, a continuous infusion of the anti-APP antibody infusion inhibited neural and glial apoptotic cell death at three days after TBI.
Additionally, choline acetyltransferase ChAT activity was decreased in the frontal cortex and hippocampus of APP transgenic mice, an Alzheimer model overexpressing APP, and increased the number of apoptotic neurons Feng et al. These APP transgenic mice exhibit increased learning and memory impairment Feng et al. In the present study, in the anti-APP antibody group there was an increase in the number of MAPpositive cells and a reduction in the arrival time to platform versus the PBS group. These data suggested that the anti-APP antibody increased ChAT activity and inhibited neural degeneration induced by overproduced APP in the frontal cortex and hippocampus after TBI, while cerebral function may be improved.
Recent evidence suggests that APP, a ubiquitously expressed, highly conserved integral membrane glycoprotein, is not only a sensitive marker of axonal injury Gentleman et al. Although the mechanisms leading to cell death are unknown, as the precursor to the neurotoxic A protein, the conversion of APP to A may have detrimental effects including an increased risk for development of Alzheimers disease Chen et al.
Indeed, there are numerous clinical studies demonstrating substantial A deposition and the formation of amyloid plaques Smith et al. In contrast to the potential deleterious effects of APP, an early acute rise in APP during the reparative phase of injury has resulted in the hypothesis that APP may actually serve a neuroprotective function Van Den Heuvel et al. APP has been shown to be both beneficial and detrimental depending on its method of posttranslational processing within cells.
The -secretase pathway is a non-amyloidogenic pathway in which the majority of APP is normally processed Suh and Checler , while after brain injury the - and -secretase pathways are activated and are responsible for producing the toxic sAPP Matrone et al. Reiner ; Stone et al. For instance, sAPP was shown to induce apoptotic cell death in PC 12 cells and neuronal degeneration in rat hippocampal neurons Matrone et al. Nakagawa et al. In the present study, anti-APP antibody treatment resulted in a reduction of neuronal and glial apoptotic cell death and recovery of memory and learning function to sham operation group levels, after TBI.
Additionally, overproduction of sAPP after brain injury may facilitate A production and deposition. In the adult CNS, TBI results in a rapid response from resident astrocytes, a process often referred to as reactive astrocytosis or glial scarring Davies et al. Glial scars have been reported to inhibit neurite elongation of damaged neurons and axonal regeneration, and thus prevent functional recovery Davies et al. Furthermore, neurite outgrowth of cultured rat hippocampal neurons was found to be inhibited by glial scars in vitro Rudge and Silver However, gliosis and glial scars protect against secondary insults that contribute to the ischemic damage induced by circulatory disturbance, blood-brain barrier disruption, excitotoxic damage, and free radicals Pekny and Nilsson Moreover, reactive astrocytes secrete neurotrophic factor NTF , nerve growth factor NGF , and extracellular matrix which induce axonal outgrowth and regeneration of the neural network Bechmann and Nitsch ; Deller et al.
In addition, the formation of glial scars prevents leakage of secreted factors, and separates non- damaged areas from damaged areas, thereby maintaining normal CNS homeostasis Silver et al. Therefore, although the role of gliosis and glial scars in neuronal regeneration after brain injury remains controversial, the results from the present study suggest that gliosis and glial scars after TBI might be beneficial.
The results from the present study also demonstrated that infusion of the anti-APP antibody into the damaged region following TBI inhibited degeneration of neuronal and glial cells induced by overproduced APP after brain injury, with a significant reduction in injury size. Conclusion In conclusion, the results of the present study have demonstrated that TBI induces long- term increases in APP overexpression in the neuronal perikarya and neurites. In addition, endogenous overproduced APP after TBI inhibited astrocyte activity around the damaged brain region and induced neural cell degeneration.
On the basis of these findings, we speculate that overexpression of APP after TBI is related to Alzheimer type dementia, and is an important risk factor for this disease. References Azbill, R. Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury. Brain Res, Vol. Bechmann, I. Involvement of non-neuronal cells in entorhinal- hippocampal reorganization following lesions.
Blasko, I. Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer's disease beta- secretase BACE J Neural Transm, Vol. Blumbergs, P. Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury.
J Neurotrauma, Vol. Bouron, A. Eur J Neurosci, Vol. Chen, X. Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol, Vol. Chirumamilla, S. Traumatic brain injury induced cell proliferation in the adult mammalian central nervous system. Ciallella, J. Changes in expression of amyloid precursor protein and interleukin-1beta after experimental traumatic brain injury in rats. Davies, S. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord.
J Neurosci, Vol. DeKosky, S. Association of increased cortical soluble abeta42 levels with diffuse plaques after severe brain injury in humans. Arch Neurol, Vol. Deller, T. Reorganization of the rat fascia dentata after a unilateral entorhinal cortex lesion. Role of the extracellular matrix. Elvander, E. Intraseptal muscarinic ligands and galanin: influence on hippocampal acetylcholine and cognition. Neuroscience, Vol. Feng, Z. Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP transgenic mouse model of Alzheimer's disease.
J Pineal Res, Vol. Gallo, V. Unwrapping glial cells from the synapse: what lies inside? Science, Vol. Gentleman, S. Beta-amyloid precursor protein beta APP as a marker for axonal injury after head injury. Neurosci Lett, Vol. Golde, T. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Goldgaber, D. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Green-Sadan, T. Transplantation of glial cell line- derived neurotrophic factor-expressing cells into the striatum and nucleus accumbens attenuates acquisition of cocaine self-administration in rats.
Hardy, J. Amyloid, the presenilins and Alzheimer's disease.
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- The Indian Vegan Kitchen: More Than 150 Quick and Healthy Homestyle Recipes.
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Trends Neurosci, Vol. Ikonomovic, M. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol, Vol. Itoh, T. Isolation of neural stem cells from damaged rat cerebral cortex after TBI. Neuroreport, Vol. Immature and mature neurons coexist among glial scars after rat traumatic brain injury. Neurol Res, Vol. Expression of amyloid precursor protein after rat traumatic brain injury. Jurynec, M. TIGR is upregulated in the chronic glial scar in response to central nervous system injury and inhibits neurite outgrowth.
Mol Cell Neurosci, Vol. Kawamata, T. Lactate accumulation following concussive brain injury: the role of ionic fluxes induced by excitatory amino acids. Koo, E. Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Lewen, A. Changes in microtubule-associated protein 2 and amyloid precursor protein immunoreactivity following traumatic brain injury in rat: influence of MK treatment. Masters, C.
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Embo J, Vol. Matrone, C. J Alzheimers Dis, Vol. Mattson, M. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron, Vol. Mills, J. Regulation of amyloid precursor protein cleavage. J Neurochem, Vol. Murakami, N. Experimental brain injury induces expression of amyloid precursor protein, which may be related to neuronal loss in the hippocampus.
Nakagawa, K. Sialylation enhances the secretion of neurotoxic amyloid-beta peptides. Nakamura, Y. Amyloid beta-protein precursor deposition in rat hippocampus lesioned by ibotenic acid injection. Nicoll, J. Apolipoprotein E epsilon 4 allele is associated with deposition of amyloid beta-protein following head injury.
Nat Med, Vol. Otsuka, N. Rapid appearance of beta-amyloid precursor protein immunoreactivity in damaged axons and reactive glial cells in rat brain following needle stab injury. Pekny, M. Astrocyte activation and reactive gliosis. Glia, Vol. Pierce, J. Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat. Posmantur, R. Neurofilament 68 and neurofilament protein levels decrease after traumatic brain injury. Rice, A. Proliferation and neuronal differentiation of mitotically active cells following traumatic brain injury.
Robakis, N. Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Roberts, G. Immunocytochemistry of neurofibrillary tangles in dementia pugilistica and Alzheimer's disease: evidence for common genesis. Lancet, Vol. The occult aftermath of boxing. J Neurol Neurosurg Psychiatry, Vol. Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease.
Rudge, J. Inhibition of neurite outgrowth on astroglial scars in vitro. Rumble, B. Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. N Engl J Med, Vol. Schofield, P. Alzheimer's disease after remote head injury: an incidence study. Selkoe, D. Isolation of low-molecular-weight proteins from amyloid plaque fibers in Alzheimer's disease. Silver, I. Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells.
Smith, D. Protein accumulation in traumatic brain injury. Neuromolecular Med, Vol. Sola Vigo, F. Amyloid-beta precursor protein mediates neuronal toxicity of amyloid beta through Go protein activation. Neurobiol Aging, Vol. Stephenson, D. Amyloid precursor protein accumulates in regions of neurodegeneration following focal cerebral ischemia in the rat. Stone, J. Caspasemediated cleavage of amyloid precursor protein and formation of amyloid Beta peptide in traumatic axonal injury. Suh, Y. Amyloid precursor protein, presenilins, and alpha- synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease.
Pharmacol Rev, Vol. Sun, K. Acidic-rich region of amyloid precursor protein induces glial cell apoptosis. Apoptosis, Vol. Taft, W. Microtubule-associated protein 2 levels decrease in hippocampus following traumatic brain injury. Thornton, E. Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats. Van den Heuvel, C. Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: an ovine head impact model.
Van Den Heuvel, C. Downregulation of amyloid precursor protein APP expression following post-traumatic cyclosporin-A administration. Xie, Y. Potential roles of Alzheimer precursor protein A4 and beta-amyloid in survival and function of aged spinal motor neurons after axonal injury. J Neurosci Res, Vol. Xiong, Y. Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. Introduction Last century, in , Alois Alzheimer first described the disease that now bears his name, relating a year-old female case with presenile dementia. Alzheimers disease AD , an irreversible progressive neurodegenerative disorder, is actually the most common form of dementia.
AD affects more than 24 million people all over the world, and is predicted to double every 20 years, becoming one of the medical burdens of our days. The small number of early onset AD cases, is related to hereditary monogenic defects, and has provided important clues for understanding the AD pathology Bertram, et al. Although the available drugs are able to delay the symptoms and progression of the disease and to positively influence the quality of life of the patients, at present there is still no cure for AD. AD is characterized clinically by progressive decline in cognitive function and neuropatologically by the presence of neuropil threads and neuron loss, in addition to the molecular hallmarks of neurofibrillar tangles and neuritic or senile plaques in the brain.
Neuritic plaques are extracellular amyloid deposits found abundantly in the hippocampus, in the neocortex and in the amygdala of AD brains. These pathological brain changes may occur 20 to 30 years prior to the onset of the clinical symptoms and the symptomatic phase of AD can last from 5 to 12 years DeKosky and Marek The extracellular neuritic plaque deposits of amyloid were first investigated by Glenner and Wong , when they purified microvascular amyloid deposits from AD brains, and provided a partial sequence of a 4kDa subunit protein, that they named amyloid-beta A peptide.
Around the same time, the hyperphosphorylated tau p-tau , a microtubule assembly protein, was identified as the main constituent of the neurofibrillar tangles NFTs that accumulate inside many neurons in AD brains Grundke-Iqbal, et al. Amyloid deposition and neurofibrillar tangles, occur with some frequency in brains of young adults with Down's syndrome Schochet, et al.
Korenberg, et al. Either PS1 or PS2 can be the catalytic subunit of -secretase, which is the final endoprotease in the pathways that generate the A peptide see section 2. All these findings led to the amyloid cascade hypothesis, articulated by John Hardy and others Hardy and Higgins , in which the accumulation of A peptide, generated from the proteolytic cleavage of APP in the brain, could trigger a complex downstream cascade that results in the symptoms of AD. This hypothesis states that gradual accumulation and aggregation of the hydrophobic A peptide initiates a cascade that leads to synaptic alterations, astrocytic and microglial activation, the modification of the soluble tau protein into insoluble paired helical filaments, and progressive neuronal loss associated with multiple neurotransmitter deficiencies and cognitive failure Hardy and Selkoe The cascade hypothesis suggests that stopping or slowing formation of the A plaques would delay the onset of the disease symptoms.
A is found in the extracellular fluids of the brain, including cerebrospinal fluid CSF , and in the interstitial fluid surrounding neurons and glial cells in brain lobes Seubert, et al. Over the last years, several key proteins have been described as being implicated in A production and clearance, but further elucidation of the mechanisms involved in the process will be important for identifying new potential therapies to reduce A accumulation and combat AD. This book chapter reviews the production of A from APP and the proteins involved in its degradation and clearance.
Generation of amyloid beta peptides The amyloid precursor protein, APP, takes a central position in AD pathogenesis, as it is processed by the sequential action of - and -secretase, generating the A peptide, which is deposited as amyloid plaques in brains of AD individuals. APP is an integral membrane protein, with a large N-terminal extracellular domain and a short C-terminal cytoplasmatic domain, which is expressed ubiquitously in neuronal and non-neuronal cells.
The human APP gene is located on chromosome 21 Korenberg et al. APP is hydrolyzed into different fragments Figure 1 during its intracellular trafficking, and these metabolites mediate various functions Haass ; Haass and Selkoe APP is first cleaved by either - or -secretase at the - or -sites, respectively, which lie in the extracellular domain of the APP.
Subsequently, in the lipid bilayer, -secretase acts in the C-terminal end, C83 or C The alternative pathway of APP processing by - secretase followed by -secretase, in which no A is formed, is termed nonamyloidogenic pathway. Schematic diagram of APP processing not drawn in scale. A peptide is normally produced by cells and under physiological conditions there are two major species: A40 and A The minor species produced, A42, is more prone to aggregation due to two additional hydrophobic amino acids, and therefore it is the predominant species accumulated in AD brain plaques. APP is synthesized in the endoplasmic reticulum ER and is transported through the Golgi apparatus to the TGN, where the highest concentration is found in steady state neurons Greenfield, et al.
Available evidence suggests that co-residence of APP and - secretase in the endosomal compartments promotes amyloidogenesis. The double-stranded lipid-modified RNA of the invention has high ability to be delivered intracellularly, even when used alone. Therefore, the double-stranded lipid-modified RNA can be introduced into cells without using any known gene transfection reagents used for introducing siRNA into cells, or by using a known gene transfection reagent in a reduced amount.
The double-stranded lipid-modified RNA of the invention can suppress or inhibit the expression of a target gene, when it is introduced into a cell. Therefore, the double-stranded lipid-modified RNA can be used, for example, in the medicinal field to prevent, ameliorate, or treat a disease caused by the expression of the target gene.
When the double-stranded lipid-modified RNA of the invention is used in the medicinal field, the double-stranded lipid-modified RNA is provided as a pharmaceutical composition produced by using the RNA and a pharmacologically acceptable carrier. The pharmaceutically acceptable carrier to be used in the pharmaceutical composition is not particularly limited, and can be suitably selected according to the dosage form of the pharmaceutical composition.
Examples of such carriers include aqueous carriers such as purified water, aqueous sugar solutions, buffers, physiological saline, aqueous polymer solutions and RNase-free water, excipients, etc. The proportion of the double-stranded lipid-modified RNA in the pharmaceutical composition can be suitably selected from a range that allows the double-stranded lipid-modified RNA to be used in the above-mentioned amount. The proportion of the double-stranded lipid-modified RNA is, for example, 0. The dosage form of the pharmaceutical composition is not particularly limited, insofar as the double-stranded lipid-modified RNA can be introduced into cells.
Examples of the dosage form include liquids such as syrups , drops, injections, and like liquid formulations; lyophilized formulations, dry syrups, tablets, pills, powders, granules, capsules such as soft capsules , and like solid formulations; etc. When the pharmaceutical composition of the invention is a solid preparation, the composition may be used in the form of a solution by adding distilled water for injection, sterile water, or the like, when used.
The target disease or condition for which the pharmaceutical composition of the invention is used is not particularly limited, insofar as the expression of the target gene is associated with the disease or condition. The relationship between the target gene and disease is known in this technical field. The pharmaceutical composition of the invention can be introduced into human-derived cells to treat humans, or can be used to treat animals other than humans non-human mammals.
The present invention is described in detail with reference to the following Examples; however, the invention is not limited to these Examples. Double-stranded RNAs of and base-long sense strands and and base-long antisense strands were designed so that they had sequences homologous to Renilla luciferase and were capable of suppressing the expression of the Renilla luciferase gene. The double-stranded RNAs formed were as follows: When a base-long antisense strand and sense strand were used, a base-long double-stranded RNA having a two-base dangling end at the 3' end was formed.
When a base-long antisense strand and sense strand were used, a base-long double-stranded RNA in which both ends were blunt-ended was formed. The sequences of the RNAs used are as follows. The double-stranded RNAs were prepared using these sense strands and antisense strands. Each double-stranded RNA was prepared by mixing equimolar amounts of a single-stranded sense strand and antisense strand in a universal buffer Hayashi Kasei Co.
Double-stranded lipid-modified sense strands were synthesized by linking double-stranded lipids to the 5' ends of the sense strands of the double-stranded RNAs capable of suppressing the expression of the luciferase gene. In each of these double-stranded lipid-modified sense strands, a double-stranded lipid was covalently bound via an aminoalkyl group Amino Modifier C6; Glen Research linked to the 5' end of the sense strand.
Each double-stranded lipid-modified sense strand was synthesized by reacting, in a liquid phase, a lipid compound containing an active ester group hereinafter referred to as an "active ester-containing lipid compound" with a sense strand whose 5' end was modified by amination Reaction Scheme 1 below. A specific synthesis process is described below. In order to aminate the 5' end of the RNA, a conventional process the phosphoramidite synthesis process was performed using 5'-Amino-Modifier C6 Glen Research in RNA solid phase synthesis, thereby synthesizing a sense strand modified with an aminoalkyl group at the 5' end.
In the resulting sense strand modified with an aminoalkyl group at the 5' end, - CH 2 6 -NH 2 was linked to the 5' end the phosphate residue of the first nucleotide from the 5' end. The concentration of the resulting single-stranded RNA was determined by measuring the absorbance at nm using a UV spectrometer. After the reaction, the reaction mixture was purified by HPLC in order to remove unwanted reagent in the reaction mixture containing the double-stranded lipid-modified sense strand.
The double-stranded lipid-modified sense strand purified by HPLC was lyophilized and dissolved in purified water, after which the concentration and synthetic yield thereof were determined by UV spectral analysis. The structures and yields of the synthesized double-stranded lipid-modified sense strands are shown below. Each of the synthesized double-stranded lipid-modified sense strands was paired with an antisense strand to produce a double-stranded lipid-modified RNA. After 0 h, 0. The product was then stained with a silver staining kit GE Health Care Bioscience see the product manual for staining conditions , and subjected to gel analysis on a ChemiImager Alpha Innotech Corporation.
Moreover, it was found that the degradative enzyme resistance of the double-stranded lipid-modified RNAs was improved because they were bound to serum proteins. These results led to a new finding that the double-stranded lipid-modified RNAs possessed in vivo stability markedly higher than that of 21siRNA that are generally in wide use. The products were then stained with a silver staining kit GE Health Care Bioscience see the product manual for staining conditions , and subjected to gel analysis on a ChemiImager Alpha Innotech Corporation.
As a control, unmodified 21siRNA was also analyzed by gel electrophoresis. The results are shown in FIG. These results have revealed that base-long RNAs to which lipids are linked are recognized by Dicer, and undergo processing. The expression vector was adjusted to 0. In FIG. Double-stranded RNAs of and base-long sense strands and and base-long antisense strands were designed such that they had sequences homologous to VEGF vascular endothelial growth factor and were capable of suppressing the expression of the VEGF gene.
The following experiments were conducted using these double-stranded RNAs. Note that 21siRNA is a double-stranded RNA having two-base dangling ends at the 3' ends of both of the sense strand and antisense strand; and 27nt dsRNA is a completely double-stranded RNA having no dangling ends single-stranded regions , i. These sense strands and antisense strands were annealed in the same manner as in Example 1 to form double strands, thereby producing double-stranded lipid-unmodified RNAs.
Double-stranded lipid-modified RNAs were synthesized by linking lipids to the 5' ends of the sense strands of the above-mentioned double-stranded RNAs capable of suppressing the expression of the VEGF gene. In each of the double-stranded lipid-modified RNAs, a double-stranded lipid was covalently bound via an aminoalkyl group Amino Modifier C6; Glen-Research linked to the 5' end of the sense strand.
Double-stranded lipid-modified single-stranded RNAs sense strands were synthesized according to the same procedure as in Example 1. The elution times for the double-stranded lipid-modified sense strands targeting the VEGF gene were also substantially the same as in Example 1. The synthesized double-stranded lipid-modified sense strands were paired with antisense strands to produce double-stranded lipid-modified RNAs.
The experiments were conducted according to the same method as in Example 1. These results also revealed that the double-stranded lipid-modified RNAs possessed in vivo stability markedly higher than that of 21siRNA that are generally in wide use. Processing of the synthesized double-stranded lipid-unmodified RNAs and double-stranded lipid-modified RNAs by recombinant Dicer was investigated. The Dicer cleavage experiments were performed according to the same procedure as in Example 1. These results revealed that base-long RNAs to which lipids are linked are recognized by Dicer, and undergo processing.
The experiments were performed according to the following procedures. The error in the levels of expression among the cells was corrected based on the level of gene expression of the control gene GAPDH. These results revealed that the base-long and base-long siRNAs and dsRNAs wherein double-stranded lipids were covalently bound to the 5' ends of the sense strands of the double-stranded RNAs exhibited abilities to suppress gene expression higher than that of each of the unmodified double-stranded RNAs.
The VEGF-targeting double-stranded RNAs used herein were demonstrated to suppress the expression of the target gene in a highly sequence-specific manner. Moreover, the test results suggested that side effects upon the cells were reduced by linking the double-stranded lipids to the double-stranded RNAs. The fluorescently labeled double-stranded lipid-modified RNAs were obtained by using 21nt and 27nt antisense strands labeled with 6-FAM at the 5' ends, and pairing the thus-labeled 21nt and 27nt antisense strands with unmodified 21nt and 27nt sense strands, respectively, and with 21nt and 27nt sense strands modified with double-stranded lipids at the 5' ends, respectively, to form double-strands.
The cellular uptake experiments were performed as follows. The cells were subsequently washed with PBS - or the medium three times, and the cellular uptake of the double-stranded RNAs was evaluated using a confocal fluorescence laser microscope and flow cytometry. A Radiance system Bio Rad was used as a confocal fluorescence laser microscope, and fluorescence was observed using an argon laser. In particular, the observations by confocal fluorescence laser microscopy and flow cytometry showed that the base-long RNAs modified with double-stranded lipids at the 5' ends of the sense strands exhibited very high cellular uptake efficiencies, compared to the unmodified RNAs.
Moreover, the observation by confocal fluorescence laser microscopy indicated that the double-stranded lipid-modified RNAs were actively localized into the cytoplasm. In particular, the base-long RNA to which DMPE was linked as a double-stranded lipid was confirmed to have an excellent cellular uptake efficiency. These results led to a new finding that when a lipid is covalently bound to the 5' end of the sense strand of a double-stranded RNA, the double-stranded RNA can demonstrate dramatically improved cellular uptake efficiency, and can also be localized into the cytoplasm of cells.
Using a technique different from that of Examples 1 and 2, a double-stranded lipid-modified sense strand was synthesized by linking a double-stranded lipid to the 5' end of the sense strand of a double-stranded RNA capable of suppressing the expression of the WT1 gene. First, a sense strand and an antisense strand were prepared according to a known method. Subsequently, aminoalkylation of the 5' end of the sense strand was performed according to a conventional process the phosphoramidite synthesis process using 5'-Amino-Modifier C6 Glen Research , thereby synthesizing a sense strand modified with an aminoalkyl group at the 5' end.
In the synthesized sense strand modified with an aminoalkyl group at the 5' end, - CH 2 6 -NH 2 was linked via an oxygen atom to the phosphate residue of the first nucleotide from the 5' end. The synthesized sense strand modified with an aminoalkyl group at the 5' end was paired with an antisense strand to produce a double-stranded RNA hereinafter referred to as the "aminoalkyl-modified double-stranded RNA".
The double-stranded RNA was formed according to the same procedure as described above. After the reaction, the reaction mixture was purified by HPLC to remove unwanted reagent in the reaction mixture containing the double-stranded lipid-modified RNA. The HPLC-purified double-stranded lipid-modified RNA was lyophilized and dissolved in purified water, after which the concentration and synthetic yield thereof were determined by UV spectral analysis.
The structure and yield of the synthesized double-stranded RNA are shown below. The double-stranded lipid-modified RNA according to claim 1, which is blunt-ended on the 5'-end side of the sense strand, and is blunt-ended or has a dangling end on the 3'-end side of the sense strand. The double-stranded lipid-modified RNA according to claim 1, which has dangling ends on both the 5'- and 3'-end sides of the sense strand.
The double-stranded lipid-modified RNA according to any one of claims 1 to 3, wherein the sense strand consists of 21 to 27 nucleotides. The double-stranded lipid-modified RNA according to claim 2, which is blunt-ended on both the 5'- and 3'-end sides of the sense strand, each of the sense and antisense strands consisting of 27 nucleotides. The double-stranded lipid-modified RNA according to claim 2, which is blunt-ended on both the 5'- and 3'-end sides of the sense strand, each of the sense and antisense strands consisting of 23 nucleotides.
The double-stranded lipid-modified RNA according to claim 2, which is blunt-ended on the 5'-end side of the sense strand, the sense strand consisting of 25 nucleotides, and the antisense strand consisting of 23 nucleotides. The double-stranded lipid-modified RNA according to claim 3, wherein each of the sense and antisense strands consists of 21 nucleotides. The double-stranded lipid-modified RNA according to claim 1, wherein two hydrophobic groups of the double-stranded lipid are the same or different, and each is a saturated or unsaturated fatty acid residue having 6 to 50 carbon atoms.
The double-stranded lipid-modified RNA according to claim 1, wherein the double-stranded lipid is glycerophospholipid, glyceroglycolipid, diacylglycerol, or ceramide. The double-stranded lipid-modified RNA according to claim 1, wherein the double-stranded lipid is glycerophospholipid. The double-stranded lipid-modified RNA according to claim 11, wherein the double-stranded lipid is phosphatidylethanolamine. The double-stranded lipid-modified RNA according to claim 12, wherein the double-stranded lipid is at least one member selected from the group consisting of dimyristoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, 1-palmitoyloleyl-phosphatidylethanolamine, and dioleoylphosphatidylethanolamine.
The double-stranded lipid-modified RNA according to claim 1, wherein the lipid is bound to at least one of the first to sixth nucleotides from the 5' end of the sense strand via a linker represented by the formula L [Chem. A pharmaceutical composition comprising the double-stranded lipid-modified RNA of any one of claims 1 to 14, and a pharmaceutically acceptable carrier. Use of the double-stranded lipid-modified RNA of any one of claims 1 to 14 to produce a pharmaceutical composition for suppressing the expression of a target gene.
A method for suppressing the expression of a target gene, comprising a step of introducing the double-stranded lipid-modified RNA of any one of claims 1 to 14 into a cell. USB2 en. EPB1 en. JPB2 en. KRA en. CNB en. BRPIA8 en. CAA1 en. EST3 en. ILD0 en. RUC2 en. WOA1 en. ARA1 en. EPA4 en. Single-stranded nucleic acid molecule for regulating expression of gene having delivering function. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid siNA. Methods and compositions for enhancing delivery of double-stranded rna or a double-stranded hybrid nucleic acid to regulate gene expression in mammalian cells.
WOA2 en. CAC en. EPA3 en. AUB2 en. JPA en. Nuclease resistance and modified duplex rna having excellent rna interference effect. According to , the interval correspond to Upper Imbrian 3. Lower Imbrian - Nectarian 3. According to  the mean age of the whole province is 3. Solar System  Slyuta E. Grumpe 1, C. Berezhnoy 2, V.
The observations are compared with modeling results. This technique extends the thermal equilibrium based approach of  by performing an iterative adjustment of the surface temperature, spectral reflectance and spectral emissivity, and by including a correction for surface roughness similar to . It decreases within the next few lunar hours and reaches its minimum in the early afternoon around Results are shown in Fig. This observation is in contrast to  but in consistence with [12, 5]. The physical processes responsible for the behavior of H and OH on regolith surfaces as well as the relevant physical parameters are discussed in .
The behavior of H was analyzed using Monte Carlo methods in  and based on a continuity equation based treatment in . In this work we provide a comparison between our daytime-dependent OHIBD observations and an extension of the continuity equation based approach suggested in [15, 16] towards the interaction between H and OH . The surface temperature depending on the reflectance spectrum and the illumination conditions was estimated according to . This model results in two coupled ordinary differential equations describing the H and OH column densities .
The boundary condition that the difference between the OH column densities at sunrise and sunset corresponds to the amount of micrometeoroid-delivered OH during the lunar night is imposed, under the presupposition that no evaporation, photolysis or condensation occurs at night. The OH activation energy was set to 0.
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The model was simultaneously fitted to the 18 regions with uniform H activation energy but region-specific offset component. The other physical parameters were chosen as in . The best-fit value of the H activation energy corresponds to 0. Modeling results are shown in comparison with observational data in Fig. We have provided a comparison with the results of a continuity equation based model of the sources and sinks of lunar H and OH. Lunar Symp. Rommel 1, C. Grumpe 1, H. Due to its early formation and large size, the basin has been subject to further impacts, and on the basis of the ejected material conclusions can be drawn about the internal composition of the lunar crust.
They revealing exposed anorthosite rich material inside their crater rims or crests. Elemental abundance maps and petrological maps were constructed by applying the techniques of . In the petrographic maps, the red, green and blue channel corresponds to basalt, Mg-rich rock and ferroan anorthosite, respectively. Hence, our observations indicate anorthositic subsurface deposits also relatively close to the SPA centre, indicating a complex layering of the crust.
This finding is unexpected, given the model of . It exhibits a large ferroan anorthosite patch in its southern part. This structure looks like a large debris flow of about 20 km extent and appears to superpose the inner and outer sides of the crater rim. A possible source of the anorthositic material is an outcrop on top of the crater rim, and there is evidence that material has been excavated from an anorthosite rich layer at great depth in the crust float structure.
The central peak and the eastern part of the crater rim show a high Mg-rich rock content. The crater floor and the surrounding regions mainly show a basaltic signature. It has a flat floor covered by basaltic lava see e. A high Mg-rich rock content is apparent for the central peak and the inner peak ring. In the western part, the rim of Antoniadi intersects the rim of Minnaert and the crater walls on both sides display patches of ferroan anorthosite material, which appears to have slided down the crater wall onto the floor.
Our investigation suggests that the crater Minnaert may already have lifted up anorthosite-rich to shallow depth below the surface, and the impact of Antoniadi excavated parts of this layer. In the eastern part of Antoniadi, a similar abstact. Both occurrences on the crater rim indicate that consecutive impacts may have lifted up anorthositic material. The crater Dryden 54 km diameter, centred at 33 S, W is located in the eastern part of SPA at about km distance from the basin centre between the Apollo basin rim and peak ring. Its central peak and crater rim show a significant Mg-rich rock content.
The floor is partially covered by basaltic material but still shows a signature of Mg-rich rock. Due to the fact that the crater rim of Dryden intersects the peak-ring structure of the Apollo basin , parts of the northeastern crater wall reveal a deposit with an anorthosite signature, like the surrounding material of the peak ring structure of the Apollo basin. The deposit appears to superpose the inner side of the rim of Dryden onto its floor like a flow, and looks like well-defined continuous Apollo-peak-ring material.
Petrologic mapping of the craters Antoniadi and Alder indicates that even at distances of less than km to the SPA centre anorthositic material can be found. A possible mechanism to explain these occurrences is the uplift by subsequent impacts of anorthositic crustal material previously buried during formation of the the SPA basin. The anorthositic material at the northwestern rim of the crater Dryden is probably due to mass-wasting of material from the western peak ring of the Apollo basin, which contains a significant fraction of anorthosite, into the crater after its formation.
This anorthositic material was presumably excavated from shallow depth due to the proximity of the Apollo basin to the northeastern SPA rim. All in all, our observations indicate a highly complex layering of the crust at the examined crater locations. E  Kim, K. P  Morgan et al. Earth Planet.
Sci V P  Pieters, C. E00H abstract.
Buchenkova 1,2, A. Skalsky 1 A. The paper is aimed to review actual observations and different mechanisms of wave and magnetic disturbances generation in plasma environment around the Moon: in solar wind closely to the Moon, over the magnetic field anomalies at its surface, in the lunar wake and around its boundaries. The generating mechanisms, propagation and other characteristics of waves are presented.
Particular attention is pointed on Electrostatic Solitary Waves ESWs , monochromatic whistlers, large-amplitude monochromatic ULF waves and non-monochromatic whistler waves. Brain, D. Lin, and L.
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Harrison, On the occurrence of magnetic enhancements caused by solar wind interaction with lunar crustal fields, Geophysical research letters,  K. Kojima, H. Matsumoto, and T. Mukai, Characteristics of electrostatic solitary waves in the Earth s foreshock region: Geotail observations, Journal of geophysical research,  X. Deng, R. Tang, H. Matsumoto, J.
Pickett, A. Fazakerley, H. Kojima, W. Baumjohann, A. Coates, R. Nakamura, D. Gurnett, Z. Liu, Observations of electrostatic solitary waves associated with reconnection by Geotail and Cluster, Advances in space research, abstact. Vorburger 1, P. Wurz 1, S. Barabash 2, M. Wieser 2, Y. Bhardwaj 3, M. Dhanya 3, K. With such high ENA fluxes coming from the lunar surface, ENA monitoring offers a powerful method for investigating the solar wind interaction with the lunar surface.
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CENA s field of view consisted of seven angular sectors five of which were purely surface pointing , with surface-projected footprints of approximately km km, depending on the sector number and spacecraft altitude. Panel a shows that there is a substantial flux of reflected, neutralized hydrogen coming from the lunar surface. The plot shows a clear cosine-correlation with solar zenith angle, as is expected for pure geometrical reasons. The ENA reflection ratio is rather featureless over the lunar surface, showing only strong variations at local crustal magnetic fields due to the interaction of the plasma with so-called mini-magnetospheres.
An example of such a mini-magnetosphere ENA image is shown in Panel b : There is a clear void of ENAs coming from the centre of the magnetic anomaly, where the surface is shielded from the impinging solar wind ions, whereas there is an enhanced ring surrounding the void, denoting the region where the ions have been deflected to. CENA measurements were also used to identify a large, positive electric potential associated with the magnetic anomaly. This electric potential was expected based on charge separation in the impinging plasma, where ions can penetrate further into the mini-magnetosphere region than electrons, which are deflected by the magnetic field.
The charge separation produces an outward-facing electric field. Scientific results based on measurements conducted by CENA. Panel a : Reflected neutral hydrogen flux measured during one orbit of Chandrayaan Panel b : Electric potential and reflection ratio imaging of a mini-magnetosphere above a lunar magnetic anomaly. Panel d : Correlation between ENA characteristic energy and solar wind velocity. Panel e : Mass spectra recorded during flight containing neutral hydrogen, oxygen, and helium.
Panel g : Energy spectrum of dayside and nightside ENAs showing the similarity of the two. Panel h : Energy spectrum of ENAs measured in the solar wind and in the terrestrial plasma sheet. Panel i : Scattering function of ENAs measured upstream, in the magnetosheath, and in the terrestrial plasma sheet. An additional mystery is the correlation between the characteristic energy and the solar wind velocity, and not the solar wind energy, a fact hinting at the backscattering processes at the surface being controlled by the momentum of the impinging particle velocity rather than its energy see Panel d.
Whereas all these findings were based on energetic neutral hydrogen measurements, other mass groups were also observable by CENA. In addition, backscattered helium was detected in the CENA data set see Panel e , but due to uncertainties in the instrument s geometric factor, no surface or column densities could be derived.
Energy analysis showed, that whereas the nightside ENAs energy spectrum clearly resembles the dayside backscattered ENAs energy spectrum, their characteristic energy is slightly lower by about 4 ev , hinting at the plasma having been decelerated in the lunar wake see Panel g. CENA measurements in the terrestrial plasma sheet Panel h revealed that the characteristic energy and the backscatter ratio in Earth s plasma sheet is similar to the upstream solar wind case.
In contrast to the upstream observations, though, no ENA void was observed over large and strong magnetized lunar surface regions. Analyses suggest that the magnetic shielding of the lunar surface in the plasma sheet is less effective in the terrestrial plasma abstact. A final analysis included lunar ENAs recorded when the Moon was located inside the terrestrial magnetosheath see Panel i.
Similar to the upstream solar wind case, and contrary to the terrestrial plasma sheet case, clear signatures of plasma shielding by magnetic anomalies were observed. Overall, the scattering process seems unchanged in the Earth s magnetosheath, with the only exception being that in the terrestrial magnetosheath the energy spectrum becomes broader and less peaked, probably due to the increase in plasma temperature. Overall, CENA was exceptionally successful. The instrument not only achieved all its set science goals but also revealed several hitherto unknown and unexpected properties of the solar wind interaction with the lunar surface.
P  Feldman W. P  McComas D. L  Wieser M. Wurz P. P  Kazama Y. P  Bhardwaj A. P  Goswami J. Sanin 1, I. Mitrofanov 1, M. These locations can be considered as possible landing sites for future lunar missions. Here we present three most promising sites and discuss their properties. Pieters 1, A. Basilevsky 2, D. Dhingra 3, J. Head 1 1 Dept. Earth Sciences, Indian Institute of Tech. One of the fewm 3 scenes of data acquired at optimalfull resolution Target  includes the Luna 24 site in Mare Crisium shown in Figure 1.
We have evaluated these high-resolution data in order to identify the principal types of basalt in the region and possible effects of secondary craters from Giordano Bruno. As shown in Figure 2, the properties of these absorptions can be evaluated by estimating and removing a sloped but featureless continuum. Well-developed, weathered soils have weak absorptions and basalts freshly exposed by a crater have strong absorptions as shown in Fig.
M 3 images of the Mare Crisium region that includes the Luna 24 area arrow. The two large craters near the image top are Picard Y left; 4 km and Fahrenheit right; 6 km. M 3 reflectance spectra for several small areas 3x3 pixel average within craters Picard Y and Fahrenheit, illustrating two different types of basalt a, b exposed by these craters. Shown on the right are the same spectra after continuum removal. Although this basalt type does not dominate at Fahrenheit, outcrops do exist and components might be expected in the Luna 24 core.
However, these craters are often embedded in a diffuse field of relatively bright soils dark blue in Fig. We interpret this to be a small bright and featureless foreign component that contaminates the well-developed local basaltic soil without significantly stirring the regolith. This is similar to Copernicus compositional rays , and likely represents minor fine grained feldspathic debrisfrom Giordano Bruno.
Head, Planet. Zharkova 1,2, N. Kozlova 2, Zh. Rodionova 1, E. Feoktistova 1, V. We used craters profiles to perform the comparative morphometric analysis of the southern subpolar regions. Four profiles were automatically created on the each crater. The length of profiles deliberately exceeded the diameters of craters. The profiles covered external rims; profiles length allowed us to take possible inaccuracies in the determination of craters initial diameter into account, and avoid them Fig. IMG . Also we used various craters catalogs. For Mercury: 1. The vector catalog provided by the Brown University USA , which attributive table contains the coordinates for the central points of each object, diameter, craters area, and the objects names in English.
This catalog contains craters coordinates and diameters, like the previous one; but also, it provides the information about the craters preservation degree covers different features, as terraces, peaks, ridges, fissures, secondary craters chains, and ray systems. Besides, we applied the SAI morphological catalog of the Moon craters to explore their features as well. This catalog provides us with the coordinates which were refined by the modern global mosaics of the Lunar Reconnaissance Orbiter LRO.
The new data including higher resolution images of the celestial bodies allows us to update the morphological catalogs and use the most recent data for further studies. The referred papers [7,8] revealed: the depths of the Mercury s impact craters their diameters are ranging from 1 to km agreed with the depth measures from the previous studies in almost all explored cases. The exception was discovered while measuring the large complex craters depth.
In that particular diameter, they appeared to be shallower than the Mariner 10 data have showed. It s occurred that Mercury has less firstclass craters the newest ones than the Moon: Comparing to 19 percent of such craters that was observed on the Moon, on Mercury surface we discovered as little as 2 percent of their kind Table 1.
Table 1. Remote Sens. Spatial Inf. Analisis of Mercurian craters by means of cartographic methods. Morphological catalogue of the craters of the Moon. Issued by Moscow State University. Geomorphology of impact craters on Mercury. In: Vilas, F. Deutsch 1, James W. Head 1, Gregory A. Earth-based radar images ofmercury first revealed highly reflective materials that are consistent with water ice [1 6]. These radar-bright materials collocate with PSRs derived from images and topography [7 9]. Thermal models derived from topography indicate that PSRsare stable environments for near-surface and sometimes surface water ice on geologic timescales.
Furthermore, enhanced concentrations of hydrogen have been detected inthe north polar region .
On Mercury,most water-ice deposits have anomalously low r s values indicative of an insulating layer beneathwhich ice is buried . Previous detections of surface water ice without an insulating layer werelimited to seven craters . These three permanently shadowed craters host extensive radar-bright deposits indicative of water ice . However, MESSENGER only acquired limited off-nadir observations of these craters due to their proximity to the pole, and they were never identified as hosting water-ice deposits. The greater density of returns observed within the PSRs prompted a reexamination of the calibration to account for a downward bias due to highly oblique geometry .
Utilizing the complete orbital dataset and empirically re-calibrated data, we calculate the mean r s within the craters and outside the craters, and discuss the implications for surface water-ice deposits hosted by permanently shadowed craters close to the north pole of Mercury. Additionally, we investigate the presence of possible micro-cold traps, or smallscale exposures of ice. Following the Earth-based identification of high radar-backscatter deposits in polar craters, the only detections of exposed water ice have been in large, permanently shadowed craters: Prokofiev crater, as well as limited off-nadir MLA measurements of A, C, D2, Kandinsky, i5, and Y craters  For craters that do not have formal IAU names, we adopt informal nomenclature from published maps.
Here we investigate the presence of specific micro-cold traps by searching for clustered MLA-measured r s enhancements at nm wavelength that can be observed at the resolution of MLA footprints. RESULTS: There is a bimodal distribution of surface reflectance on Mercury in which anomalously low-reflectance deposits correlate with lag deposits insulating water ice and anomalously high-reflectance deposits correlate with exposed water ice.
The overall surface reflectance is observed to sharply increase from 8MS3-PG Here we investigated the possibility that micro-cold traps could be resolved at the spatial scale of the MLA footprint by searching for clusters of r s enhancements. MLA-derived surface reflectance, r s, at nm from Micro-cold traps n5, o7, e5, and l7 that are identified as hosting exposed water ice are labeled. Polar stereographic projection. Each crater has high radar cross sections indicative of water-ice deposits , and the derived r s value for each crater exceeds 0. Thus we identify three new large craters on the surface of Mercury that host extensive water-ice deposits exposed at their surfaces.
It is possible that surface and subsurface ice in rough surfaces  may be more accessible than ice in large PSR craters. We suggest that large craters are not the only hosts of substantial water-ice deposits on the surface of Mercury, which is consistent with thermal modeling  and reflectance mapping  results that indicate that micro-cold traps are capable of hosting substantial quantities of water-ice deposits. Here we identify four deposits within MES- abstact. We expect that the BepiColombo Laser Altimeter  will be able to resolve additional high reflectance deposits indicative of surface water ice in mapping the south polar region of Mercury.
Butler, and D.
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Muhleman, and M. Slade, R. Crespo, M. Dryer, and J. Perillat, and M. Slade, and M. Ernst, B. Denevi, J. Harmon, S. Murchie, D. Blewett, S. Solomon, and E. Ernst, J. Murchie, S. Solomon, D. Blewett, and B. Planets, 1 ,  Deutsch, A. Chabot, E. Mazarico, C. Head, G. Neumann, and S. Sun, E. Mazarico, A. Deutsch, J. Head, D. Paige, L. Rubanenko, and H. Mazarico, G. Neumann, and D. Shevchenko 1, E. Feoktistova 2,A. Radar-bright regions were revealed by earth-based radar observations at both poles of Mercury [1, 2]. Further studies have shown the correlation of these features with locations of high-latitude impact craters.
It was suggested that these features are formed by volatiles deposits including water ice and located in permanently shaded areas in host craters. We investigated the possibility existence and stability of volatiles deposits in several craters at South Pole region of Mercury, which contain radar-bright features.
To do this we used data from . We take into account four altitude profiles for each crater, thus the crater was divided into 8 sectors. Because of this we simulated the inner structure of these craters, using the relationship for morphologic characteristics of impact craters from  and crater s images from . Thermal regime of a surface area is determined by solution of the one-dimension heat conductivity equation.
In upper boundary condition the flux of direct solar radiation incident on a given surface element, the fluxes of reflected and infrared radiation from all adjacent illuminated surface elements visible from a given element, and the heat flux from the Mercury s interior were taken into account.
The combined effect of the orbital motion of Mercury around the Sun and its axial rotation is that the duration of a solar day on the planet is equal to three sidereal Mercurial days or two Mercurial years. To investigate the diurnal variation of solar flux and illumination conditions for surface area we have computed the distance from the Sun, Mercury s orbital velocity and part of the solar disk above the horizon for each moment of time. For each elements of surface the position of the Sun has been determined by its coordinates in the horizontal system: zenith distance z and azimuth A.
The time increment has corresponded to the Sun s azimuth displacement by 1. We considered the possibility existence deposits of volatile compounds on the surface and under insulation layer of regolith in host craters. Paige et al. For this reason four models of structure of volatiles deposit were used in our calculations: 1 pure water ice on the surface; 2 pure water ice under the layer of regolith; 3 mixture of water ice and other volatiles compounds on the surface and 4 under the layer of regolith.
For each crater the thickness of a layer of regolith, that necessary to protect the deposits of volatiles from thermal evaporation was calculated. Simulated morphometry of crater hosting the radar-bright feature B4 a and diurnal maximum surface temperatures in this crater b. In the northern part of the crater there is an area that corresponds to radar-bright deposit. The maximum temperatures in this area do not exceed K. A, Rice M. Tucson: Univ. Arizona Press P   Vasavada A. Pugacheva, E.
Feoktistova, V. The photometry method searches out the intensity of reflectivity of planet s surface and provides studying of ground fine texture . Main materials of the research are photographic images of Mercury surface transferred by Messenger interplanetary station during its passing near Mercury.
For Mercury surface relief structure evaluation the images of Mercury Southern hemisphere have been used. Surface of Mercury is the combination of craters, worn-down plains, saw-edged cliffs escarps and ray patterns. The relief of Mercury surface differs with numerous escarps hundreds kilometers long, formation of which is linked with compression processes in crust taken place during cooling of mantle and partial consolidation of planet s core. There are more ray craters on Mercury than on the Moon probably, the impact force here is strengthened by bigger planet s mass and its vicinity to the Sun.
On photographic images of Mercury there are also spots of some dark substance that is much darker than general background, which are probably the traces of meteorite hits. Composition of the dark Fig. The mosaic of craters on the South pole of Mercury. The mosaic includes numerous craters with lava streams and great spaces of even volcanic plains, which by their structure resemble volcanic deposits on the Moon  Fig.
The illumination of surface on the South pole of Mercury. The craters painted dark blue are located in permanent shadow. In such areas there are probably deposits of water ice, presence of which had been predicted by scientists on the assumption of Mercury surface albedo observations performed by means of radio telescope. During the second passing Messenger had monitored changes of Mercurian relief. In history of Mercury and the Moon there was a period when streams of lava exposed to surface. The significant part of plains of Mercury Western hemisphere is covered with lava.
In addition, lava beds occur inside and around huge Caloris basin, as well as at the bottom of other big basins. Probably, the plains of Mercury had been formed by huge flows of molten material expelled to the surface after basin-forming hits. The lava-covered areas look brighter than other ones. Two main types of Mercury surface are: cratered terrain and intercrater plains that had demolished craters with low diameter. At the bottom of big basins, including areas around and inside huge Caloris basin, there are even plains formed by molten materials. The cratered terrain has approximately the same mean albedo the Moon continents have, how- abstact.
This new color-coded photo mosaic of Mercury s south polar region, Severnyiy-polyus Mekuriya1 S, W. This new color-coded photo mosaic of Mercury s south polar region shows these freezer areas as dark blotches. Each image has reference data and a calibration scale for translating the image density into relative brightness values. Photometric processing of space photographs made by Mariner and Messenger space vehicles allowed us to evaluate various type of Mercury surface reflectivity and define its soil structure . In general the surface of Mercury is being more homogeneous and monotonous by its photometric parameters.
Radar researches of circumpolar areas reveal presence of ice in shadow points of craters in polar areas of Mercury. The minimum temperature of surface in polar craters reduces to 90 K, while maximum temperature within Caloris Planitia reaches K. The temperature differentials on the surface of Mercury are related with different intensity of surface s insolation during planet s orbital movement.
The relief of the Southern pole of Mercury is characterized with bigger crater density. On the photographs of surface there are flows of molten material at the bottom of craters and lava streams on their top. We have selected several photographs of Mercury Southern hemisphere made by Messenger. The photographs have been processed by pixel scanning system for definition of surfaces with equal brightness [5, 6].
At the same time, using MultiSpecWin32 system we have defined areas with different reflectivity . Thus, we have evaluated surface roughness and relative number of impact craters on it. As a result, three main morphological units have been obtained: the surface with low reflection coefficient characterized by high roughness and high density of impact craters; the surface of linear form characterized by extra low reflection coefficient; and even surface characterized by less density of craters and median reflectivity, which is typical for relatively recent formations.
Messenger space vehicle is an American automatic interplanetary station designed for research of Mercury. The vehicle had been launched on August 3, with help of carrier booster Delta H Photographic prints transferred to Earth helped to determine that in the past on Mercury quite intense tectonic activity had place. Its traces can be found in the Eastern and Western hemispheres of the planet in the form of large even plains.
Messenger discovered new earlier unknown craters within the area of Mercury South pole. Science V P Shevchenko V. Wordsworth 2, F. Forget 3, and M. Turbet 3 1 Brown Univ. Impacts are knownto have size-dependent effects in terms of ejecta and influence on the atmosphere, ranging from blowing off a significant part of the atmosphere, through global distribution of silicate vapor that results in precipitation of silicate vapor cloud condensate, and significant but short-lived very hot rainfall . Could the global effects form a global stratigraphic marker horizon for the major Noachian basin analogous to the Imbrium basin on the Moon?
A solution to this paradox might be found in the formation of impact basins earlier in the Noachian: In an update  of the global effects of impact basin formation , the immediate aftermath of the vapor cloud condensation is shown to be characterized by the global precipitation of sustained hot rains considerably above K , and lasting for several centuries.
This mechanism Fig. Support for this hypothesis  comes from extensive the association of many of the phyllosilicates with the Noachian basins Hellas, Isidis and Argyre [9,] and other extensive deposits dated to this period . These deposits may provide stratigraphic time- markers for the specific impact basins [6, 15]. This is the post-argyre basin period; impact cratering at the sub-large basin scale continues with declining flux.
This abstact. The Late Noachian dominance of the VN-CBL-OBL geomorphic assemblage is envisioned as representing a climatic optimum , producing warm and wet conditions characterized by sufficient rainfall precipitation to over come infiltration, and cause widespread fluvial and lacustrine activity. Could the formation of the earlier Noachian impact basins have played a role?
Following ,  have proposed that global deluge-scale rainfall phases that immediately follow basin formation could obliterate small craters and cause extensive planation and infilling of pre-existing distal craters. Furthermore,  have shown that smaller basins and large craters may also produce regional erosion and degradation effects. Detailed stratigraphic analyses are required to assess this option further . A second alternative, involving the cold and icy climate scenario ;  explores the effects of a regional ice sheet predicted by this model in masking the sub-ice surface from smaller impacts, and facilitating the observed rim degradation and infilling of Noachian craters.
Key questions are: Nature of ambient climate [10, 18], source of water , volume of water , continuous or discontinuous conditions , intermittency , total duration , and presence of oceans ? Clearly, these two aspects are in- compatible and represent a paradox.
The formation of each basin emplaced a global meters-thick isochronous silicate condensate time marker accompanied by significant associated alteration to phyllosilicates . The Early Noachian ambient background climate was profoundly perturbed by each impact event, with exact recovery pathways and times uncertain . These ideas can be tested with further analyses of the critical stages as described above. Estimates for VN formation duration from . Lisov 1, A. Kozyrev 1, M. Litvak 1, I. Mitrofanov 1, A. Boatwright, J. Surveys of the valley networks have shown that they likely formed through the action of liquid water flowing at the surface .
This cold and dry model maintains a subfreezing, hyperarid environment during the Noachian with a global cryosphere more typical of present-day Mars . Liquid water would have existed on the surface only during transient warming events caused by volcanism  or impact heating . This is seemingly in contradiction to the geologic evidence, which suggests that the Noachian was instead warm and wet, with a robust hydrologic cycle dominated by precipitation and surface runoff .
Recent work on an icy highlands model has attempted to reconcile some of these differences by allowing limited runoff from glaciers while maintaining MAAT below freezing .