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Stem cells derived from the human brain and grown as neurospheres (HuCNS-SC) have been shown to be effective in treating central neurodegenerative conditions in a variety of animal models. Human safety data in neurodegenerative disorders are currently being accrued. In the present study, we explored the efficacy of HuCNS-SC in a rodent model of retinal degeneration, the Royal College of Surgeons (RCS) rat, and extended our previous cell transplantation studies to include an in-depth examination of donor cell behavior and phenotype post-transplantation. As a first step, we have shown that HuCNS-SC protect host photoreceptors and preserve visual function after transplantation into the subretinal space of postnatal day 21 RCS rats. Moreover, cone photoreceptor density remained relatively constant over several months, consistent with the sustained visual acuity and luminance sensitivity functional outcomes. The novel findings of this study include the characterization and quantification of donor cell radial migration from the injection site and within the subretinal space as well as the demonstration that donor cells maintain an immature phenotype throughout the 7 months of the experiment and undergo very limited proliferation with no evidence of uncontrolled growth or tumor-like formation. Given the efficacy findings and lack of adverse events in the RCS rat in combination with the results from ongoing clinical investigations, HuCNS-SC appear to be a well-suited candidate for cell therapy in retinal degenerative conditions.

Purpose Retinal degenerative diseases (RDDs) affect millions of people and are the leading cause of vision loss. Although treatment options for RDDs are limited, stem and progenitor cell–based therapies have great potential to halt or slow the progression of vision loss. Our previous studies have shown that a single subretinal injection of human forebrain derived neural progenitor cells (hNPCs) into the Royal College of Surgeons (RCS) retinal degenerate rat offers long-term preservation of photoreceptors and visual function. Furthermore, neural progenitor cells are currently in clinical trials for treating age-related macular degeneration; however, the molecular mechanisms of stem cell–based therapies are largely unknown. This is the first study to analyze gene expression changes in the retina of RCS rats following subretinal injection of hNPCs using high-throughput sequencing. Methods RNA-seq data of retinas from RCS rats injected with hNPCs (RCShNPCs) were compared to sham surgery in RCS (RCSsham) and wild-type Long Evans (LEsham) rats. Differential gene expression patterns were determined with in silico analysis and confirmed with qRT-PCR. Function, biologic, cellular component, and pathway analyses were performed on differentially expressed genes and investigated with immunofluorescent staining experiments. Results Analysis of the gene expression data sets identified 1,215 genes that were differentially expressed between RCSsham and LEsham samples. Additionally, 283 genes were differentially expressed between the RCShNPCs and RCSsham samples. Comparison of these two gene sets identified 68 genes with inverse expression (termed rescue genes), including Pdc, Rp1, and Cdc42ep5. Functional, biologic, and cellular component analyses indicate that the immune response is enhanced in RCSsham. Pathway analysis of the differential expression gene sets identified three affected pathways in RCShNPCs, which all play roles in phagocytosis signaling. Immunofluorescent staining detected the increased presence of macrophages and microglia in RCSsham retinas, which decreased in RCShNPCs retinas similar to the patterns detected in LEsham. Conclusions The results from this study provide evidence of the gene expression changes that occur following treatment with hNPCs in the degenerating retina. This information can be used in future studies to potentially enhance or predict responses to hNPC and other stem cell therapies for retinal degenerative diseases.

SUMMARYTwo therapeutic paths have been proposed to treat inherited retinal dystrophy using clustered regularly interspaced short palindromic repeats (CRISPR). One strategy is to genetically correct patient cells ex vivo for autologous transplant, whereas the second is to modify cells in vivo by delivering CRISPR effectors to the retina. The feasibility of both editing strategies has been demonstrated within three years of CRISPR’s adaptation to mammalian systems. However, the functional integration of transplanted cells into host retinae has been a long-standing challenge that currently represents the 2025 moonshot of the National Eye Institute’s Audacious Goals Initiative. The clinical translatability of each path is discussed with regard to current investigations and whether cell replacement can be circumvented by in vivo editing.

We have examined how transplantation of an RPE cell line to the subretinal space of RCS rats affects the distribution of synaptic connectivity markers in the outer plexiform layer of the retina. Using markers of pre- and post-synaptic profiles (bassoon and synaptophysin as presynaptic markers and mGluR6 for postsynaptic profiles) we found that the normal orderly patterns seen between photoreceptors and rod and ON-cone bipolar cells were severely disrupted in dystrophic rats. In areas in which injected cells preserved photoreceptors, more normally appearing pairing of pre- and post-synaptic markers was seen for both rods and cones. The degree of normality correlated with the amount of photoreceptor rescue. The secondary changes that are normally seen in bipolar and horizontal cells were prevented by the photoreceptor preservation. ERG recordings in the animals subsequently studied morphologically showed that both a- and b-waves could be rescued by grafting, albeit with lower amplitudes than normal. Together these anatomical and physiological studies indicate that besides the integrity of outer nuclear layer cells and phototransduction processes, relay circuitry through the outer retina was rescued by cell grafts. This work was supported by NIH (EY14038), Wynn Foundation, Lincy Foundation and FFB. Dr. Pinilla and Dr. Cuenca were supported by grants from the Spanish Government (FIS BA03/0016, PI042399 and BFU2006-00957/BFI), ONCE and FUNDALUCE. Dr. Lund is a recipient of a Research to Prevent Blindness Senior Scientific Investigator Award.

Embryonic stem cells promise to provide a well-characterized and reproducible source of replacement tissue for human clinical studies. An early potential application of this technology is the use of retinal pigment epithelium (RPE) for the treatment of retinal degenerative diseases such as macular degeneration. Here we show the reproducible generation of RPE (67 passageable cultures established from 18 different hES cell lines); batches of RPE derived from NIH-approved hES cells (H9) were tested and shown capable of extensive photoreceptor rescue in an animal model of retinal disease, the Royal College of Surgeons (RCS) rat, in which photoreceptor loss is caused by a defect in the adjacent retinal pigment epithelium. Improvement in visual performance was 100% over untreated controls (spatial acuity was approximately 70% that of normal nondystrophic rats) without evidence of untoward pathology. The use of somatic cell nuclear transfer (SCNT) and/or the creation of banks of reduced complexity human leucocyte antigen (HLA) hES-RPE lines could minimize or eliminate the need for immunosuppressive drugs and/or immunomodulatory protocols.

The behavior and conditions of liquid-liquid extraction-separation of Fe(III) by ammonium thiocyanate-H 2 O-n-propyl alcohol system in the presence of NaCl were studied, and the possible reactive mechanism of extraction ofFe(III) was deduced. The study showed that, in the presence of a given amount of NaCl, phases were separated thoroughly between n-propyl alcohol and water. In the process of phase separation, the complex [Fe(SCN) n ] ( 3 - n ) formed by NH 4 SCN and Fe(III) was quantitatively extracted into the n-propyl alcohol phase. The extracted Fe(III) exists in the n-propyl alcohol phase mainly as the forms of Fe(SCN) 2 + and Fe(SCN) 3 . Also, the relationship between extraction yield of Fe(III) and the amount of NH 4 SCN agreed well with the quadratic equation E = 0.54 + 58.14x - 8.39x 2 (E and x represent the recovery rate of Fe(III) and the volume (mL) of 0.1 M NH 4 SCN respectively). The quadratic R-Square is 0.9990. With this method, Fe(III) can be completely separated from Co(II), Ni(II), Mn(II), Al(III), Bi(III) and Cd(II) at pH 1.0∼2.0. The present method was applied in determining Fe(III) in samples with satisfactory results such as relative standard deviation from 2.06% to 2.89% and recovery rate in the range of 98.4∼101.4%.

Neurons in the central nervous system often show a transient up-regulation of expression of the immediate early gene c-fos when presented with precise novel stimuli. In normal rats, neurons in most subcortical visual centers show low levels of fos-like immunoreactivity (FLI) expression, but there is a substantial and transient increase in FLI expression if the animal is exposed to a flashing light. This is especially evident in the superior colliculus (SC). We have examined here FLI expression in the subcortical visual centers of the Royal College of Surgeons rat, focusing specifically on the SC. In this animal, as a result of a genetic defect, there is early loss of rod photoreceptors over the first few months of life, along with slower disappearance of cones. Although light stimulation showed that FLI expression was very similar to that seen in normal rats, the basal levels of FLI expression under dark-maintained conditions were much higher than normal, even exceeding the levels seen after visual stimulation. In the SC, the elevation of FLI expression was already evident by 6 weeks of age and reached a plateau by 17 weeks. Other subcortical visual centers also showed elevated basal levels of FLI expression, although in general the increases were less dramatic than the increase in the SC. The elevated FLI expression in dark-maintained condition seen in the SC was abolished by contralateral optic nerve section. It was also severely diminished by subretinal cell transplantation at 3 weeks of age with the objective of limiting photoreceptor loss over part of the retina. These results suggest that the elevated basal FLI expression is a retina-driven event. Although it correlates with the loss of rod photoreceptors, it is unlikely to reflect reduced photoreceptor drive but rather some form of bursting activity generated in the inner retina, as a result of circuit reorganization or receptor up-regulation. J. Comp. Neurol. 472:100–112, 2004. © 2004 Wiley-Liss, Inc.

Pluripotent stem cell-derived retinal pigment epithelial (RPE) cells are currently being tested for cell replacement in late-stage age-related macular degeneration (AMD). However, preserving vision at early-stages may also be possible. Here, we demonstrate that transplantation of neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iNPCs) limits disease progression in the Royal College of Surgeons rat, a preclinical model of AMD. Grafted-iNPCs survived, remained undifferentiated, and distributed extensively in a laminar fashion in the subretinal space. Retinal pathology resulting from the accumulation of undigested photoreceptor outer segments (POS) was significantly reduced in iNPC-injected rats compared with controls. Phagosomes within grafted-iNPCs contained POS, suggesting that iNPCs had compensated for defective POS phagocytosis by host-RPE. The iNPC-treated eyes contained six to eight rows of photoreceptor nuclei that spanned up to 5 mm in length in transverse retinal sections, compared with only one row of photoreceptors in controls. iNPC treatment fully preserved visual acuity measured by optokinetic response. Electrophysiological recordings revealed that retina with the best iNPC-protected areas were 140-fold more sensitive to light stimulation than equivalent areas of contralateral eyes. The results described here support the therapeutic utility of iNPCs as autologous grafts for early-stage of AMD. Stem Cells 2015;33:2537–2549

PURPOSE Stem and progenitor cell transplantation provides a promising clinical application for treating degenerative retinal diseases, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Our previous studies have shown that a single subretinal injection of human cortical-derived neural progenitor cells (hNPCctx) into cyclosporine-treated Royal College of Surgeons (RCS) rats preserved both photoreceptors and visual function. However, it is still unknown whether nonautologous progenitor cell readministration for sustained vision is efficacious and safe in terms of the initial graft initiating an immune response to a subsequent graft. METHODS A cell suspension containing 3×104 hNPCctx into one eye of cyclosporine-treated RCS rats at postnatal day 21 (P21), followed by a second transplantation at P95 into the previously untreated fellow eye. RESULTS hNPCctx delayed photoreceptor degeneration and preserved visual function, as measured by electroretinography (ERG), optokinetic response (OKR), and luminance threshold recordings (LTRs). Visual function and photoreceptors of the initially treated eye were still preserved 6 weeks after hNPCctx were injected into the second eye. Antibodies against T-cell markers showed that CD3, CD4, and CD8 T cells were not detected at P90 and P140 in most cases. No detectable level of anti-nestin antibody was found in serum by enzyme-linked immunosorbent assay (ELISA). CONCLUSIONS This xenograft study with cyclosporine-treated animals demonstrates that readministration of hNPCctx into the fellow eye did not induce anti-graft immune responses or lower therapeutic efficacy of hNPCctx in preserving vision. Thus, readministration of progenitor cells to sustain long-term efficacy may be an option for long-term therapies of retinal degeneration. TRANSLATIONAL RELEVANCE Redosing neural progenitors do not affect the efficacy of the initial grafts in protecting vision or induce unwanted immune responses.

Royal College of Surgeons rats are genetically predisposed to undergo significant visual loss caused by a primary dysfunction of retinal pigment epithelial (RPE) cells. By using this model, we have examined the efficacy of subretinal transplantation of two independent human RPE cell lines each exhibiting genetic modifications that confer long-term stability in vitro . The two cell lines, a spontaneously derived cell line (ARPE19) and an extensively characterized genetically engineered human RPE cell line (h1RPE7), which expresses SV40 large T (tumor) antigen, were evaluated separately. Both lines result in a significant preservation of visual function as assessed by either behavioral or physiological techniques. This attenuation of visual loss correlates with photoreceptor survival and the presence of donor cells in the areas of rescued photoreceptors at 5 months postgrafting (6 months of age). These results demonstrate the potential of genetically modified human RPE cells for ultimate application in therapeutic transplantation strategies for retinal degenerative diseases caused by RPE dysfunction.

Multiple sensory inputs to the superior colliculus (SC) play an important role in guiding head and eye movements toward or away from biologically significant stimuli. Much is now known about the visual, auditory, and somatosensory response properties of SC neurones that mediate these behavioural reactions. Rather less is known about the responses of SC neurones to noxious stimuli, and thus far, most of this information has been obtained in anaesthetised animals. Therefore, the purpose of the present study was to use the c-fos immunohistochemical technique and standard extracellular electrophysiology as parallel measures of nociceptive activity in the SC under different conditions of anaesthesia. In unanaesthetised animals, experimental and control treatments induced a qualitatively similar pattern of Fos-like immunoreactivity (FLI) in the SC, which was quantitatively related to the severity or biologic salience of the treatment; thus, baseline control < control injections of saline < a nonpainful stressor (immobilisation) < noxious injections of formalin. Compared with baseline levels, urethane and avertin anaesthesia induced FLI expression in the SC intermediate layers, although the FLI response to both noxious stimulation and control conditions was differentially suppressed in different layers of the SC by anaesthesia. Parallel electrophysiologic recordings found that anaesthesia was associated with high levels of spontaneous activity in the SC intermediate layers, often in neurones which were also nociceptive. High rates of background spike activity were also induced in the SC intermediate layers by noxious stimulation in chronically recorded awake animals. Although these results point to some differences between the nociceptive responses of SC neurones in anaesthetised and unanaesthetised animals, both data sets support the view that there are different populations of nociceptive neurones in the rodent SC that may be related to different adaptive functions of pain. J. Comp. Neurol. 425:599–615, 2000. © 2000 Wiley-Liss, Inc.

Traumatic optical neuropathy (TON) results from trauma to optic nerve by head and eye injuries to both military and civilian population such as accidents, and blast related combat trauma. TON leads to irreversible blindness and represent a major public health burden with both economical and social impacts. Unfortunately, treatment is still rather limited. A large body of evidence indicates that TON affects optic nerve and its target neurons in the central nervous system, which provide vital retrograde trophic support to optic nerve. We hypothesize that systemic administration of bone marrow derived mesenchymal stem cells (MSC) to treat traumatic optic neuropathy (TON) will preserve/repair optic nerve, stabilize the unstable environment due to trauma and promote RGC regeneration and outgrowth by promoting the release of paracrine and autocrine mediators; induced Schwann cells from MSC (M-Sch) will repair the damaged RGC by remyelinating and providing multiple trophic factors. Previous studies have shown that activation in retinoic acid (RA) signalling triggers neurite outgrowth in adult mice. Here we found that intravitreal injection of retinoid X receptor agonist SR11237 not only preserved RGCs, and promoted RGC axon outgrowth at both 8 days and 14 days after TON. We have used Long Evan (LE) rats as a model for TON, MSC were isolated from LE rats, M-Sch were induced from MSC. Our main findings: (a) Using our modified forceps, a reliable and reproducible TON model was created. (b) Rat MSC and M-Sch were reliable produced for experiments. (c) Systemic administration of MSCs significantly preserved retinal ganglion cell survival after TON. (d) Systemic administration of MSCs also promote limited RGC axons regeneration. (e) Intravitreal injection of retinoid X receptor agonist SR11237 also protect RGC survival after TON and promote RGC regeneration. (f) Systemic administration of MSCs induced up expression of trophic factors in the retina (CNTF, BDN

Ultrathin cobalt phosphate (CoHPO4 · 3H2O) nanosheets are successfully synthesized by a one pot hydrothermal method. Novel CoHPO4 · 3H2O ultrathin nanosheets are assembled for constructing the electrodes of supercapacitors. Benefiting from the nanostructures, the as-prepared electrode shows a specific capacitance of 413 F g(-1), and no obvious decay even after 3000 charge-discharge cycles. Such a quasi-two-dimensional material is a new kind of supercapacitor electrode material with high performance.

The superior colliculus (SC) has an established role in the sensory guidance of motor commands required to orient an animal towards novel stimuli. In addition to the representations of visual, auditory, and somatosensory stimuli, the SC also contains a large population of nociceptive neurones. The purpose of the present investigation was to see if nociceptive neurones in the SC can be characterised with c-fos immunohistochemistry as a prelude to establishing anatomical connectivity with specific target regions in the brainstem. To ensure comparability with previous electrophysiological investigations, the present study was conducted in animals anaesthetised with urethane. A series of independent issue relating to basic aspects of experimental protocol were investigated. The principal findings were: (i) Despite minimising the exposure of animals to extraneous stimuli, basal levels of immunostaining were observed. (ii) Urethane anaesthesia induced an increase in Fos-like immunoreactivity (FLI) over the basal condition. (iii) No additional labelling was induced by non-noxious tactile stimulation of the hindpaw. (iv) Unilateral noxious mechanical stimulation elicited a reliable increase in FLI over all control conditions. (v) This increase in FLI was expressed bilaterally and restricted largely to the intermediate white layer. (vi) The induction of FLI was related to noxious stimulation intensity. (vii) No reliable differences in the spatial topography of FLI expression were observed when unilateral noxious mechanical stimulation was administered to the face or hind foot. (vii) A higher level of urethane anaesthesia had a generally suppressive effect on FLI expression. (ix) There were no differences in the distribution of FLI induced by noxious mechanical or noxious chemical stimulation. (x) The increase in FLI induced by noxious pinch was abolished by a naloxone reversible pre-treatment with morphine. These data confirm that c-fos immunohistochemistry can be used to characterise nociceptive cells in the rat superior colliculus, and generally complement recent electrophysiological data. The identification of nociceptive cells in the stratum album intermediale, the source of collicular input to regions of the contralateral brainstem involved in orienting, suggests the SC may play a significant role in the localisation of pain.

Dedication. Acknowledgements. Foreword Jun Liu Part 1: Writing Systems in Chinese, Japanese, and Korean 1. The Process of Reading in Non-Alphabetic Languages: An Introduction Ken Goodman 2. How a Morphosyllabic Writing System Works in Chinese Yueh-Nu Hung 3. Similarities and Dissimilarities in Reading Chinese and English: Goodman's Reading Model Perspective Yueh-Nu Hung 4. Chinese Writing Reform: A Social-Cultural Perspective Shaomei Wang 5. Ideography and Borrowing in Chinese Ning Yu 6. Chinese Unconventional Characters:Characteristics, Controversial Arguments, and Pedagogical Implications Junlin Pan 7. A Successful Mixture of Alphabetic and Non-Alphabetic Writing: Chinese Characters in Korean Rodney E. Tyson 8. Orthography: Human Creativity and Adaptability Mieko Shimizu Iventosch Part 2: Studies of Reading in Chinese and Japanese 9. Making Sense in Reading Chinese: An Error Detection Study Jingguo Xu 10. Miscues and Eye Movements of Japanese Beginning Readers Daniel Ferguson, Yasuhiko Kato, and Mariko Nagahiro 11. How Readers Process Japanese Orthography with Two Different Texts Koomi Kim 12 . The Taxonomy of Chinese Reading Miscues Shaomei Wang Part 3: Implications and Applications for Instruction 13. Understanding and Facilitating Literacy Development among Chinese Speaking Young Children Lianju Lee 14. Teachers' Reflections on Chinese Miscue Analysis: A Graduate Course in Reading Wen-Yun Lin 15. Experiencing Korean Culture and Language Through Korean Children's Literature Yoo Kyung Sung 16. Teaching Japanese Written Language Mieko Shimizu Iventosch 17. Kamishibai Junko Sakoi. Contributors. Index

Stem cells derived from the human brain and grown as neurospheres (HuCNS-SC) have been shown to be effective in treating central neurodegenerative conditions in a variety of animal models. Human safety data in neurodegenerative disorders are currently being accrued. In the present study, we explored the efficacy of HuCNS-SC in a rodent model of retinal degeneration, the Royal College of Surgeons (RCS) rat, and extended our previous cell transplantation studies to include an in-depth examination of donor cell behavior and phenotype post-transplantation. As a first step, we have shown that HuCNS-SC protect host photoreceptors and preserve visual function after transplantation into the subretinal space of postnatal day 21 RCS rats. Moreover, cone photoreceptor density remained relatively constant over several months, consistent with the sustained visual acuity and luminance sensitivity functional outcomes. The novel findings of this study include the characterization and quantification of donor cell radial migration from the injection site and within the subretinal space as well as the demonstration that donor cells maintain an immature phenotype throughout the 7 months of the experiment and undergo very limited proliferation with no evidence of uncontrolled growth or tumor-like formation. Given the efficacy findings and lack of adverse events in the RCS rat in combination with the results from ongoing clinical investigations, HuCNS-SC appear to be a well-suited candidate for cell therapy in retinal degenerative conditions.

Young grass carp (12-13 g) were kept at five ration levels ranging from starvation to ad libitum feeding at 30-degrees-C. They were fed duckweed. Food consumption, absorption efficiency and growth were determined directly, and metabolism and nitrogenous excretion calculated indirectly from energy and nitrogen budgets, respectively. The relationship between specific growth rate and ration size was linear. Absorption efficiency for energy was not affected by ration size and averaged 50.6 +/- 0.57% (mean +/- s.e.). Depending on ration size, energy lost in excretion accounted for 4.5-5.9% of the food energy, energy channelled to metabolism accounted for 34.4-48.3% of the food energy, and energy retained as growth accounted for 6.7-11.9% of the food energy. Regardless of ration, a constant proportion of food energy (30.7%) was accounted for by feeding metabolism (total metabolism minus fasting metabolism). The energy budget at the maximum ration was: 100 C = 49.1F + 4.5U + 3.6R(fa) + 30.9R(fe) + 11.9G, where C, F, U, R(fa), R(fe) and G represent food consumption, faecal production, excretion, fasting metabolism, feeding metabolism and growth, respectively.

The seasonal dynamics in the nutrient concentrations, chlorophyll-a amount (Chl-a), total algal volume (CV), Chl-a/CV ratio, seston structure were studied at two sampling stations in a shallow, highly eutrophicated subtropic lake (the Guozheng Hu area of the East Lake) on the plain of the middle basin of the Chang Jiang (the Yangtze River) of China. The lake ecosystem of the Guozheng Hu area is dominated by two planktivorous fishes (silver carp and bighead carp), phytoplankton and zooplankton. Macrophytes are extremely scarce in this area. Concentrations of the total dissolved nitrogen and phosphorus in the Guozheng Hu area in 1990 were very high. Fish yield, of which, more than 90 % was composed of silver carp and bighead carp in the Guozheng Hu area was very high (ca. 1140 kg/ha or 45.6 g/m3 in 1990). Grazing pressure by the fishes on the plankton community is considered to be rather strong. The annual average biomass of zooplankton was ca. 1/3 - 1/2 that of phytoplankton. On the average, dry matter in the living plankton only constituted ca. 3-7 % of the total dry seston, and plankton carbon only constituted ca. 5 - 10 % of the seston carbon. The present results indicate that, in the Guozheng Hu area of the East Lake, of the organic part of the seston, detritus is quantitatively an important constituent, while living plankton is only a very small component.

Feeding intensities (number of bites per minute) were recorded each hour over a 24-h diel cycle for young grass carp fed three diets. The grass carp did not show distinct meals. Grass carp receiving plant diets (duckweed or elodea) fed almost continuously throughout the 24 h, while fish fed the animal diet (tubificids) ceased feeding or had very low feeding intensities for about a quarter of the diel cycle. The average feeding intensity in fish fed duckweed was three times higher than that in fish fed elodea and tubificids. Average dry matter intake per bite was much higher in fish fed the animal diet than in those fed the plant diets. In most individuals, there was no significant difference in feeding intensity between daytime and nighttime.

At container terminals, containers are transported from the marshalling yard to the quay and vice versa by Container Trucks (CTs). This study discusses how to dispatch CTs by utilizing information about pickup and delivery locations and time in future delivery tasks based on dynamic dispatching strategy in which multiple tasks are matched with multiple CTs. In this paper, Multi-agent system (MAS) is used as the basis for an intelligent dispatch system. Relationship between transport tasks and service of CTS has been taken as a contract net using the fuzzy set theory and method. Considering the load of communication and consultation efficiency in system, the bidirectional negotiation mechanism is adopted. The dispatching model based on Contract Network Protocol (CNP) using bidirectional negotiation is provided for assigning optimal delivery tasks to CTs and fuzzy reasoning process of dispatching decisions is suggested. The method has both virtues of precision of static planning and flexibility of CNP and has been confirmed by cases.

Visual impairment associated with photoreceptor degeneration is a largely untreatable condition affecting millions of people worldwide. Cellular therapies offer an attractive alternative for the treatment of retinal degeneration. Human adult bone marrow-derived somatic cells (hABM-SCs) present particular advantages for interventional therapy to the eye because they are non-immunogenic, effective at low dose, maintain a stable phenotype and secrete factors known to promote photoreceptor cell survival. Here we assess the potential of hABM-SCs (developed by Garnet BioTherapeutics) to sustain vision in a rodent model of human retinal disease-the Royal College of Surgeons (RCS) rat. A cell suspension of 5 x 10(4) cells in 2 microl carrying medium was injected into the subretinal space of RCS rats at P21, control animals received medium alone and untreated. Animals were maintained with/without oral cyclosporine A through the experimental period. Visual functions including optokinetic response (OKR) and luminance threshold recording were conducted in both cell-treated and control animals. Histological study was performed afterward to examine donor cell survival and photoreceptor rescue. OKR measured at P60 and P90 in cell-injected groups with/without immunosuppression was significantly better than controls (P

Young grass carp held under laboratory conditions were fed either duckweed or tubificid worms. Food consumption (C), faecal production (F), excretion (U), metabolism (R) and growth (G) were estimated for fish fed both diets. Fish fed tubificid worms had higher growth rates than those fed duckweed, in terms of wet weight, dry matter, protein, lipid and energy. Fish fed duckweed consumed more wet and dry matter than did the fish fed tubificids, but rates of protein and lipid consumption were lower. The energy budget was estimated to be 100C = 9F+ 8U+ 61R+ 22G for fish fed tubificids, and 100C = 35F+ 5U+ 51R+ 9G for fish fed duckweed. Linear relationships existed between specific growth rate in wet weight and rate of food absorption (consumption minus faecal production) in dry matter, protein or energy. Food type did not have a significant effect on these relationships. It was concluded that differences in growth rate between grass carp fed different diets were mainly caused by differences in absorption rate.

BACKGROUND: Retinitis pigmentosa (RP) is characterized by progressive night blindness, visual field loss, altered vascular permeability and loss of central vision. Currently there is no effective treatment available except gene replacement therapy has shown promise in a few patients with specific gene defects. There is an urgent need to develop therapies that offer generic neuro-and vascular-protective effects with non-invasive intervention. Here we explored the potential of systemic administration of pluripotent bone marrow-derived mesenchymal stem cells (MSCs) to rescue vision and associated vascular pathology in the Royal College Surgeons (RCS) rat, a well-established animal model for RP. METHODOLOGY/PRINCIPAL FINDINGS: Animals received syngeneic MSCs (1x10(6) cells) by tail vein at an age before major photoreceptor loss. PRINCIPAL RESULTS: both rod and cone photoreceptors were preserved (5-6 cells thick) at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells) and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs. CONCLUSIONS/SIGNIFICANCE: These results underscore the potential application of MSCs in treating retinal degeneration. The advantages of this non-invasive cell-based therapy are: cells are easily isolated and can be expanded in large quantity for autologous graft; hypoimmunogenic nature as allogeneic donors; less controversial in nature than other stem cells; can be readministered with minor discomfort. Therefore, MSCs may prove to be the ideal cell source for auto-cell therapy for retinal degeneration and other ocular vascular diseases.

Assessments of safety and efficacy are crucial before human ESC (hESC) therapies can move into the clinic. Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness. Here we show long-term functional rescue using hESC-derived RPE in both the RCS rat and Elov14 mouse, which are animal models of retinal degeneration and Stargardt, respectively. Good Manufacturing Practice-compliant hESC-RPE survived subretinal transplantation in RCS rats for prolonged periods (>220 days). The cells sustained visual function and photoreceptor integrity in a dose-dependent fashion without teratoma formation or untoward pathological reactions. Near-normal functional measurements were recorded at >60 days survival in RCS rats. To further address safety concerns, a Good Laboratory Practice-compliant study was carried out in the NIH III immune-deficient mouse model. Long-term data (spanning the life of the animals) showed no gross or microscopic evidence of teratoma/tumor formation after subretinal hESC-RPE transplantation. These results suggest that hESCs could serve as a potentially safe and inexhaustible source of RPE for the efficacious treatment of a range of retinal degenerative diseases. Disclosure of potential conflicts of interest is found at the end of this article.

The photoreceptor degeneration seen in age-related macular degeneration (AMD) and retinitis pigmentosa (RP) represents the major cause of blindness in developed countries, for which no cure is available.1–3 Cell-based therapies have been shown effective in rescuing vision in animal models of retinal degeneration.4–9 For donor cells to be suitable in a clinical setting they should be human derived, must be effective in reversing or slowing the degenerative events, must be readily renewable and not senescent, and must be effective over a long period. In a series of studies, we have used the Royal College of Surgeons (RCS) rat to explore the efficacy of cell-based therapies in rescuing vision. In this animal, the retinal pigment epithelial cell (RPE) fails to phagocytose shed outer segment material at a normal rate because of a mutation in the Mertk gene.10 This results in an accumulation of outer segment debris and subsequently leads to photoreceptor cell loss.11,12 Although comparable defects have been seen in a cohort of patients with retinitis pigmentosa,13 the animal does serve to some degree as a model for photoreceptor loss caused by defective or dysfunctional RPE and for retinitis pigmentosa in general. In previous work,14 we showed that human cortical neural progenitor cells (hNPCctx) rescued vision at near normal levels when injected into the subretinal space of the RCS rat. Some-what unexpectedly, they formed an RPE-like layer between photoreceptors and the host RPE layer and migrated to the retina. Given the potential for such cells to provide a therapy for degenerative diseases throughout the central nervous system,15 including the retina, we felt it important to evaluate the long-term effects of grafting. Critical questions that remained centered on the duration of cell survival and vision rescue and on the long-term behavior of and host response to the transplanted cells. To answer these questions, we observed a new group of rats that underwent transplantation at postnatal day (P) 21; functional tests were conducted at approximately P90, P150, and P280. A crucial part of the study was to observe the performance of individual rats at three times. Some rats were observed separately for validation of the previous morphologic results at the earlier times and to provide a context for the later data.

With the regard of trailer scheduling problem, the hybrid flow shop problem with blocking (HFS-B) was introduced to analyze the flow of container with different attributes (import container, export container) in order to describe and optimize trailer scheduling problem. The mathematics model that was described using HFS-B with attribute for trailer scheduling problem was setup. The four section chromosomes based on the coding of job form and machine form were constructed. The weight approach was introduced to solve multi-objective problem of trailer scheduling. At last an instance of trailer dynamic scheduling based on HFS-B with output container attribute was simulated and the outputting data were compared with the data of trailer static scheduling. It showed that the method could effectually solve the trailer scheduling problem.

The first studies showing the potential of retinal cell transplantation to alleviate the progress of blindness in an animal model of retinal disease, the Royal College of Surgeons (RCS) rat, were focused on the fact that in this animal there was a known defect in the retinal pigment epithelium (RPE) that resulted in secondary loss of photoreceptors. It seemed logical to effect cell replacement, by introducing into the subretinal space, normal RPE cells to replace the affected ones. A series of studies showed that the procedure did indeed rescue photoreceptors, presumably by replacing the deficiently functioning cells with ones that function normally. However, RPE cells have many functions, including phagocytosis of outer segments (OS), visual pigment recycling, maintenance of Bruch’s membrane, and transport of materials in and out of the retina (1, 2, 3, 4, 5).. How many of these several roles are replicated by the grafted cells was not explored in the early studies—indeed very little other than photoreceptor rescue per se was ever measured and, in the absence of suitable labels, it was not even clear how long the donor cells actually survived. Because it was thought that in age-related macular degeneration (AMD), dysfunction, or depletion of RPE cells might be a cause of the photoreceptor loss, the successes in the laboratory were quickly applied to patients with advanced AMD. Irrespective of the causes of AMD, one clear role for RPE cell transplantation was after removing choroidal neovascularization (CNV) membranes that invade the space between Bruch’s membrane and the RPE, RPE cells would inevitably be removed too. Repopulation with new cells might correct that deficiency. Results were disappointing: there was suggestion of graft rejection and although little hope of functional improvement might have been expected in the advanced stage patients that formed the subjects of these investigations, attempts to demonstrate visual improvement were equivocal at best.

PURPOSE. To evaluate the efficacy of immunologically compatible Schwann cells transplanted without immunosuppression in the RCS rat retina to preserve vision. METHODS. Syngeneic (dystrophic RCS) Schwann cells harvested from sciatic nerves were cultured and transplanted into one eye of dystrophic RCS rats at an early stage of retinal degeneration. Allogeneic (Long-Evans) Schwann cells and unoperated eyes served as controls. Vision through transplanted and unoperated eyes was then quantified using two visual behavior tasks, one measuring the spatial frequency and contrast sensitivity thresholds of the optokinetic response (OKR) and the other measuring grating acuity in a perception task. RESULTS. Spatial frequency thresholds measured through syngeneically transplanted eyes maintained near normal spatial frequency sensitivity for approximately 30 weeks, whereas thresholds through control eyes deteriorated to less than 20% of normal over the same period. Contrast sensitivity was preserved through syngeneically transplanted eyes better than through allogeneic and unoperated eyes, at all spatial frequencies. Grating acuity measured through syngeneically transplanted eyes was maintained at approximately 60% of normal, whereas acuity of allogeneically transplanted eyes was significantly lower at approximately 40% of normal. CONCLUSIONS. The ability of immunoprivileged Schwann cell transplants to preserve vision in RCS rats indicates that transplantation of syngeneic Schwann cells holds promise as a preventive treatment for retinal degenerative disease. (Invest Ophthalmol Vis Sci. 2007;48:1906‐1912) DOI:10.1167/ iovs.06-1117

BackgroundA promising clinical application for stem and progenitor cell transplantation is in rescue therapy for degenerative diseases. This strategy seeks to preserve rather than restore host tissue function by taking advantage of unique properties often displayed by these versatile cells. In studies using different neurodegenerative disease models, transplanted human neural progenitor cells (hNPC) protected dying host neurons within both the brain and spinal cord. Based on these reports, we explored the potential of hNPC transplantation to rescue visual function in an animal model of retinal degeneration, the Royal College of Surgeons rat.Methodology/principal findingsAnimals received unilateral subretinal injections of hNPC or medium alone at an age preceding major photoreceptor loss. Principal outcomes were quantified using electroretinography, visual acuity measurements and luminance threshold recordings from the superior colliculus. At 90-100 days postnatal, a time point when untreated rats exhibit little or no retinal or visual function, hNPC-treated eyes retained substantial retinal electrical activity and visual field with near-normal visual acuity. Functional efficacy was further enhanced when hNPC were genetically engineered to secrete glial cell line-derived neurotrophic factor. Histological examination at 150 days postnatal showed hNPC had formed a nearly continuous pigmented layer between the neural retina and retinal pigment epithelium, as well as distributed within the inner retina. A concomitant preservation of host cone photoreceptors was also observed.Conclusions/significanceWild type and genetically modified human neural progenitor cells survive for prolonged periods, migrate extensively, secrete growth factors and rescue visual functions following subretinal transplantation in the Royal College of Surgeons rat. These results underscore the potential therapeutic utility of hNPC in the treatment of retinal degenerative diseases and suggest potential mechanisms underlying their effect in vivo.

In this paper, the theory of wavelet decomposition with its Mallat algorithm is introduced and the method of features extraction based on the wavelet decomposition for the acoustic emission (AE) signals is presented. Additionally, a database of wideband acoustic emission signals is used to examine the method. The characteristics of two typical AE signals sources both crack and lead snap are abstracted. Experimenting by several typical acoustic emission sources signals, we validate its feasibility and validity.

Progressive photoreceptor degeneration resulting from genetic and other factors is a leading and largely untreatable cause of blindness worldwide. The object of this study was to find a cell type that is effective in slowing the progress of such degeneration in an animal model of human retinal disease, is safe, and could be generated in sufficient numbers for clinical application. We have compared efficacy of four human-derived cell types in preserving photoreceptor integrity and visual functions after injection into the subretinal space of the Royal College of Surgeons rat early in the progress of degeneration. Umbilical tissue-derived cells, placenta-derived cells, and mesenchymal stem cells were studied; dermal fibroblasts served as cell controls. At various ages up to 100 days, electroretinogram responses, spatial acuity, and luminance threshold were measured. Both umbilical-derived and mesenchymal cells significantly reduced the degree of functional deterioration in each test. The effect of placental cells was not much better than controls. Umbilical tissue-derived cells gave large areas of photoreceptor rescue; mesenchymal stem cells gave only localized rescue. Fibroblasts gave sham levels of rescue. Donor cells were confined to the subretinal space. There was no evidence of cell differentiation into neurons, of tumor formation or other untoward pathology. Since the umbilical tissue-derived cells demonstrated the best photoreceptor rescue and, unlike mesenchymal stem cells, were capable of sustained population doublings without karyotypic changes, it is proposed that they may provide utility as a cell source for the treatment of retinal degenerative diseases such as retinitis pigmentosa.

Scheduling problem is a kind of well-known combination optimization problem, and many scheduling problems are NP problems. Particle swarm optimization is used to solve the permutation flow shop-scheduling problem. The particle representation based on particle position sequence is presented, which can ensure that the feasible scheduling solutions are made and is applicable to computational model of particle swam optimization. The local search method based on particle position crossing-over is introduced. The computational results prove that hybrid particle swarm optimization can effectively solve the permutation flow shop-scheduling problem, and outperforms genetic algorithm and NEH heuristic method.

From human-computer interaction to human-human interaction and from information sharing to function collaborative are major advances from traditional single-user design to collaborative design. This work presents a road map to achieve this goal with computer-aided tools. The models, methods and techniques in developing collaborative tools for collaborative integrated design environment are discussed in details. The proposed ideas have been implemented in an aware collaborative tool to support transparent CAx/DFx systems.

The key technique of virtual prototyping is real-time a performance simulation for a product, such as virtual assembly simulation and mechanism movement simulation. However, the key to realize this simulation is yet the representation of a product model, and but, the traditional digital model of a product (such as relation model and hierarchical model) doesn't meet the demand. Therefore, this paper provides a scene graph model of a digital product based on DAG. The definition of the scene graph model is given and the features to represent a virtual product with DAG are analyzed o Finally, the principles of dynamically assembling and disassembling product with DAG and its simulating method are explained with an example.

The negotiation of conflict problem in the cooperation design system was studied from the view of solving negotiation problems. A bilateral negotiation algorithm, which was based on genetic algorithm, was presented for the cooperative design system, the realizing project and step of the algorithm was designed. The Pareto solution of the negotiation problem was solved by transferring vector-optimal problems into scalar-optimal problems to support the designer to harmonize the conflict of the design project. The result shows that the method of this paper can get more Pareto solutions, which can provide more selecting chances and selecting space in the cooperative design course.

Aimed at multi-object group decision problem, this paper advances a negotiation mechanism based on game theory, and presents composing method of negotiation alliance to the negotiation problem. Based on importing Nash balance concept, it verifies the stability of negotiation alliance, it realizes the negotiation mechanism by Java language under the J2EE condition, and expatiates the forming mechanism of negotiation alliance by an example.

Non-repudiation and fairness are two important issues in the implementation of electronic commerce. This paper discusses non-repudiation services and fair non-repudiation protocols. After analyzing two widely used fair non-repudiation protocols the fair non-repudiation protocol and the certified mail protocol, we propose a new fair non-repudiation protocol, which transports less data, has better confidentiality of message and better fairness. We analyze it with accountability framework on its non-repudiation and fairness.

This paper discusses implementing multi-agent systems with component software techniques. Studies on how to implement autonomy, adaptability, interaction, and interoperability of agents and multi-agent systems based on CORBA and COM are carried out and presented respectively. The paper elaborates those main features of agents and multi-agent systems that could be obtained naturally by applying component software techniques. It indicates that a CORBA based or COM based development approach is a practical way to develop large scale and complex multi-agent systems running under distributed heterogeneous environments.

Injections of formalin into the rodent paw elicit a rapid orientation of the head and mouth to the source of discomfort, followed by licking and biting the injected area. Previous work has shown this response is dependent on the integrity of the midbrain superior colliculus. The present experiments were initiated to examine the ontogeny of this oral nocifensive reaction and to determine whether it is correlated with the functional maturation of collicular responses to noxious stimuli (as indicated by c-fos immunohistochemistry). Rat pups at various postnatal ages received formalin injections in either the hindpaw or perioral regions. Behaviour was videotaped, and after 120 min, animals were killed and the brain and spinal cord processed for Fos-like immunoreactivity. Uninjected controls were treated identically. Formalin-induced oral responses following injections into the hindpaw and the expression of Fos in the superior colliculus were virtually absent until 10 days postnatal, despite the presence of Fos-like immunoreactivity in many other structures (e.g. spinal cord, parabrachial area, periaqueductal grey). In contrast, animals from day 1 were able to use limbs to localise the perioral injection site. From day 10 onward, there was a progressive increase in oral nocifensive behaviours and Fos expression in the superior colliculus. Our observations are consistent with the hypothesis that the normal elaboration of pain-induced oral behaviour is initiated only after a functionally active superior colliculus has developed, and support previous observations that link the colliculus particularly with oral nocifensive behaviours.

Cell transplantation is one way of limiting the progress of retinal degeneration in animal models of blinding diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Here we transplanted a human retinal pigment epithelial (RPE) cell line into the subretinal space of one such model, the Royal College of Surgeons (RCS) rat, and showed, using head tracking to moving stripes and pattern discrimination in conjunction with single-unit cortical physiology, that cortically mediated vision can be preserved with this treatment.

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive decline in learning, memory, and executive functions. In addition to cognitive and behavioral deficits, vision disturbances have been reported in early stage of AD, well before the diagnosis is clearly established. To further investigate ocular abnormalities, a novel AD transgenic rat model was analyzed.Transgenic (Tg) rats (TgF344-AD) heterozygous for human mutant APPswe/PS1ΔE9 and age-matched wild type (WT) rats, as well as 20 human postmortem retinal samples from both AD and healthy donors were used. Visual function in the rodent was analyzed using the optokinetic response and luminance threshold recording from the superior colliculus. Immunohistochemistry on retinal and brain sections was used to detect various markers including amyloid-β (Aβ) plaques.As expected, Aβ plaques were detected in the hippocampus, cortex, and retina of Tg rats. Plaque-like structures were also found in two AD human whole-mount retinas. The choroidal thickness was significantly reduced in both Tg rat and in AD human eyes when compared with age-matched controls. Tg rat eyes also showed hypertrophic retinal pigment epithelial cells, inflammatory cells, and upregulation of complement factor C3. Although visual acuity was lower in Tg than in WT rats, there was no significant difference in the retinal ganglion cell number and retinal vasculature.In this study, we observed pathological changes in the choroid and in RPE cells in the TgF344-AD rat model; choroidal thinning was observed further in human AD retina. Along with Ab deposition, the inflammatory response was manifested by microglial recruitment and complement activation. Further studies are needed to elucidate the significance and mechanisms of these pathological changes [corrected].

Publisher Summary This chapter focuses on the role of superior colliculus (SC) in determining the animals' immediate reactions to sudden novel events, including the activation of emotional motor mechanisms. The role of the SC in visual orienting has been widely recognized. More recently, its role in the production of orienting movements to a wide range of innocuous multimodal stimuli has been emphasized. The present results demonstrate that the orientation-approach role of the SC is not limited to innocuous stimuli. Rather, the SC plays a significant role in organizing approach responses to persistent noxious stimuli when immediate withdrawal responses prove to be ineffective in ameliorating discomfort. The neural basis by which the initial withdrawal and escape behaviors, that are appropriate in certain situations, are converted to more adaptive approach and orient behaviors that are required when dealing with a persistent noxious stimulus, as well as how this relates to the circuitry of the SC, remains far from clear.

Copper (Cu) superstructures have been originally synthesized by using natural sapless leaves. A novel hybrid nanoarchitecture, Cu–MnO2 composite, is prepared through facile coating of a thin MnO2 nanofilm onto the highly electronically conductive Cu superstructures. Benefiting from their unique structures, as electrode materials of supercapacitors the composite superstructures have a high specific capacity of 1024 F g−1 at 1.5 A g−1 and good capacity retention of around 96% after 2000 electrochemical cycles.