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  • Longitudinal behavioral, cross-sectional transcriptional and histopathological characterization of a knock-in mouse model of Huntington's disease with 140 CAG repeats. 21192926

    The discovery of the gene mutation responsible for Huntington's disease (HD), huntingtin, in 1993 allowed for a better understanding of the pathology of and enabled the development of animal models. HD is caused by the expansion of a polyglutamine repeat region in the N-terminal of the huntingtin protein. Here we examine the behavioral, transcriptional, histopathological and anatomical characteristics of a knock-in HD mouse model with a 140 polyglutamine expansion in the huntingtin protein. This CAG 140 model contains a portion of the human exon 1 with 140 CAG repeats knocked into the mouse huntingtin gene. We have longitudinally examined the rearing behavior, accelerating rotarod, constant speed rotarod and gait for age-matched heterozygote, homozygote and non-transgenic mice and have found a significant difference in the afflicted mice. However, while there were significant differences between the non-transgenic and the knock-in mice, these behaviors were not progressive. As in HD, we show that the CAG 140 mice also have a significant decrease in striatally enriched mRNA transcripts. In addition, striatal neuronal intranuclear inclusion density increases with age. Lastly these CAG 140 mice show slight cortical thinning compared to non-transgenic mice, similarly to the cortical thinning recently reported in HD.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1. 21307196

    Herpes simplex virus (HSV) infection is a classic example of latent viral infection in humans and experimental animal models. The HSV-1 latency-associated transcript (LAT) plays a major role in the HSV-1 latency reactivation cycle and thus in recurrent disease. Whether the presence of LAT leads to generation of dysfunctional T cell responses in the trigeminal ganglia (TG) of latently infected mice is not known. To address this issue, we used LAT-positive [LAT(+)] and LAT-deficient [LAT(-)] viruses to evaluate the effect of LAT on CD8 T cell exhaustion in TG of latently infected mice. The amount of latency as determined by quantitative reverse transcription-PCR (qRT-PCR) of viral DNA in total TG extracts was 3-fold higher with LAT(+) than with LAT(-) virus. LAT expression and increased latency correlated with increased mRNA levels of CD8, PD-1, and Tim-3. PD-1 is both a marker for exhaustion and a primary factor leading to exhaustion, and Tim-3 can also contribute to exhaustion. These results suggested that LAT(+) TG contain both more CD8(+) T cells and more CD8(+) T cells expressing the exhaustion markers PD-1 and Tim-3. This was confirmed by flow cytometry analyses of expression of CD3/CD8/PD-1/Tim-3, HSV-1, CD8(+) T cell pentamer (specific for a peptide derived from residues 498 to 505 of glycoprotein B [gB(498-505)]), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α). The functional significance of PD-1 and its ligands in HSV-1 latency was demonstrated by the significantly reduced amount of HSV-1 latency in PD-1- and PD-L1-deficient mice. Together, these results may suggest that both PD-1 and Tim-3 are mediators of CD8(+) T cell exhaustion and latency in HSV-1 infection.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • In vitro osteogenic differentiation is affected in Wiedemann-Rautenstrauch-Syndrome (WRS). 16097434

    BACKGROUND: Wiedemann-Rautenstrauch (neonatal progeroid) syndrome (WRS) is a rare autosomal recessive condition, with the characteristic appearance of premature aging already present at birth and other typical features (hypotrichosis, macrocephaly, mental retardation, aged face, generalized lipoatrophy, abnormal tooth status, osteopenia and other skeletal abnormalities). To date, there are no data about the differentiation capacity of WRS progenitor cells available in the literature. PATIENTS AND METHODS: To elucidate the osteoblastic and chondroblastic regeneration potential in WRS, a progenitor cell culture system was used. Bone marrow-derived stem cells of a 16-year-old WRS patient were cultivated and stimulated by dexamethasone, ascorbic acid and beta-glycerolphosphate (DAG) over 21 days. Immunocytochemical stainings of CD34, CD45, CD105, osteocalcin, osteopontin and collagen II served for a quantitative evaluation of the differentiated cells. The results were compared to bone marrow-derived stem cells of a healthy female volunteer donor. RESULTS: It was shown, for the first time, that WRS cells showed a highly significant lower in vitro response to osteoblastic differentiation stimulus. Furthermore, significantly fewer chondrocytes and hematopoietic cells were induced in WRS progenitors compared to the control group. CONCLUSION: Our data suggest a lack of cellular differentiation capacity in WRS patients, which may be responsible for the clinical appearance and symptoms of this rare disorder.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB1870
    Nombre del producto:
    Anti-Osteopontin Antibody

  • NP03, a novel low-dose lithium formulation, is neuroprotective in the YAC128 mouse model of Huntington disease. 22796360

    Huntington disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene, remains without a treatment to modify the course of the illness. Lithium, a drug widely used for the treatment of bipolar disorder, has been shown to exert neuroprotective effects in a number of models of neurological disease but may have various toxic effects at conventional therapeutic doses. We examined whether NP03, a novel low-dose lithium microemulsion, would improve the disease phenotypes in the YAC128 mouse model of HD. We demonstrate that NP03 improves motor function, ameliorates the neuropathological deficits in striatal volume, neuronal counts, and DARPP-32 expression, and partially rescues testicular atrophy in YAC128 mice. These positive effects were accompanied by improvements in multiple biochemical endpoints associated with the pathogenesis of HD, including normalization of caspase-6 activation and amelioration of deficits in BDNF levels, and with no lithium-related toxicity. Our findings demonstrate that NP03 ameliorates the motor and neuropathological phenotypes in the YAC128 mouse model of HD, and represents a potential therapeutic approach for HD.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB1574
    Nombre del producto:
    Anti-Polyglutamine-Expansion Diseases Marker Antibody, clone 5TF1-1C2

  • Identification of a varicella-zoster virus replication inhibitor that blocks capsid assembly by interacting with the floor domain of the major capsid protein. 22933294

    A novel anti-varicella-zoster virus compound, a derivative of pyrazolo[1,5-c]1,3,5-triazin-4-one (coded as 35B2), was identified from a library of 9,600 random compounds. This compound inhibited both acyclovir (ACV)-resistant and -sensitive strains. In a plaque reduction assay under conditions in which the 50% effective concentration of ACV against the vaccine Oka strain (V-Oka) in human fibroblasts was 4.25 μM, the 50% effective concentration of 35B2 was 0.75 μM. The selective index of the compound was more than 200. Treatment with 35B2 inhibited neither immediate-early gene expression nor viral DNA synthesis. Twenty-four virus clones resistant to 35B2 were isolated, all of which had a mutation(s) in the amino acid sequence of open reading frame 40 (ORF40), which encodes the major capsid protein (MCP). Most of the mutations were located in the regions corresponding to the floor domain of the MCP of herpes simplex virus 1. Treatment with 35B2 changed the localization of MCP in the fibroblasts infected with V-Oka but not in the fibroblasts infected with the resistant clones, although it did not affect steady-state levels of MCP. Overexpression of the scaffold proteins restored the normal MCP localization in the 35B2-treated infected cells. The compound did not inhibit the scaffold protein-mediated translocation of MCP from the cytoplasm to the nucleus. Electron microscopic analysis demonstrated the lack of capsid formation in the 35B2-treated infected cells. These data indicate the feasibility of developing a new class of antivirals that target the herpesvirus MCPs and inhibit normal capsid formation by a mechanism that differs from those of the known protease and encapsidation inhibitors. Further biochemical studies are required to clarify the precise antiviral mechanism.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB8616
    Nombre del producto:
    Anti-Varicella-Zoster Virus Antibody, Immediate Early Gene 62

  • Disruption of dopamine homeostasis underlies selective neurodegeneration mediated by alpha-synuclein. 18005066

    A key challenge in Parkinson's disease research is to understand mechanisms underlying selective degeneration of dopaminergic neurons mediated by genetic factors such as alpha-synuclein (alpha-Syn). The present study examined whether dopamine (DA)-dependent oxidative stress underlies alpha-Syn-mediated neurodegeneration using Drosophila primary neuronal cultures. Green fluorescent protein (GFP) was used to identify live dopaminergic neurons in primary cultures prepared on a marked photoetched coverslip, which allowed us to repeatedly access preidentified dopaminergic neurons at different time points in a non-invasive manner. This live tracking of GFP-marked dopaminergic neurons revealed age-dependent neurodegeneration mediated by a mutant human alpha-Syn (A30P). Degeneration was rescued when alpha-Syn neuronal cultures were incubated with 1 mm glutathione from Day 3 after culturing. Furthermore, depletion of cytoplasmic DA by 100 microm alpha-methyl-p-tyrosine completely rescued the early stage of alpha-Syn-mediated dopaminergic cell loss, demonstrating that DA plays a major role in oxidative stress-dependent neurodegeneration mediated by alpha-Syn. In contrast, overexpression of a Drosophila tyrosine hydroxylase gene (dTH1) alone caused DA neurodegeneration by enhanced DA synthesis in the cytoplasm. Age-dependent dopaminergic cell loss was comparable in alpha-Syn vs dTH1-overexpressed neuronal cultures, indicating that increased DA levels in the cytoplasm is a critical change downstream of mutant alpha-Syn function. Finally, overexpression of a Drosophila vesicular monoamine transporter rescued alpha-Syn-mediated neurodegeneration through enhanced sequestration of cytoplasmic DA into synaptic vesicles, further indicating that a main cause of selective neurodegeneration is alpha-Syn-induced disruption of DA homeostasis. All of these results demonstrate that elevated cytoplasmic DA is a main factor underlying the early stage of alpha-Syn-mediated neurodegeneration.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB5300
    Nombre del producto:
    Anti-Dopamine Antibody, clone K56A

  • Orexins in the midline thalamus are involved in the expression of conditioned place aversion to morphine withdrawal. 20951152

    Previous studies have implicated the bed nucleus of the stria terminalis, central nucleus of the amygdala and the shell of the nucleus accumbens (collectively called the extended amygdala) as playing an important role in mediating the aversive emotion associated with opioid withdrawal. The paraventricular nucleus of the thalamus (PVT) provides a very dense input to the extended amygdala, and the PVT is densely innervated by orexin neurons, which appear to be involved in producing some of the physical and emotional effects associated with morphine withdrawal. In the present study, we confirm that the PVT is densely innervated by orexin fibers, whereas the regions of the extended amygdala associated with the effects of morphine withdrawal are poorly innervated. Microinjections of the orexin-1 receptor (OX1R) antagonist SB334867 or the orexin-2 receptor (OX2R) antagonist TCSOX229 at doses of 5.0 or 15.0 microg into the PVT region did not affect the acquisition of the conditioned place aversion (CPA) nor the physical effects produced by naloxone-precipitated morphine withdrawal. In contrast, microinjections of TCSOX229 (15.0 microg) in the PVT region significantly attenuated the expression of naloxone-induced CPA while microinjections of SB334867 at the same dose had no effect. The results from these experiments indicate a role for OX2R in the PVT on the expression of CPA associated with morphine withdrawal. Orexins may mediate the aversive effects of morphine withdrawal by engaging the extended amygdala indirectly through the action of orexins on the PVT.
    Tipo de documento:
    Referencia
    Referencia del producto:
    AB3704
    Nombre del producto:
    Anti-Orexin-A Antibody

  • Changes in salivary and fecal secretory IgA in infants under different feeding regimens. 19400812

    One of the causes of food allergy in infancy is assumed to be immunological immaturity of the intestinal tract. The purpose of the present study was to examine changes in salivary and fecal secretory IgA (sIgA) levels in infants under different feeding regimens to evaluate the immunological maturity of the intestinal tract.
    Tipo de documento:
    Referencia
    Referencia del producto:
    05-100

  • Indibulin, a novel microtubule inhibitor, discriminates between mature neuronal and nonneuronal tubulin. 19118000

    Microtubule inhibitors interfere with microtubule dynamics, causing cell cycle arrest and apoptosis. These effects are responsible for the chemotherapeutic activities of members of the taxane and Vinca alkaloid families in oncology. Unfortunately, a major side effect of the taxanes and Vinca alkaloids is the development of peripheral neuropathies. Indibulin (N-[pyridin-4-yl]-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid; D-24851; ZIO-301), a novel synthetic small molecule microtubule inhibitor, destabilizes microtubules and has antitumor activity but does not exhibit neurotoxicity in preclinical animal studies. In the present study, it has been found that indibulin is able to discriminate between highly posttranslationally modified tubulin present in mature neuronal microtubules, and less-modified tubulin present in immature neuronal or nonneuronal microtubules. Vincristine and colchicine act on either tubulin equally well. The binding site of indibulin on mature neuronal microtubules seems to be inaccessible due to the posttranslational modifications, a theory that is supported by the observation that indibulin did not disrupt the integrity of highly modified microtubules present in neurites of pheochromocytoma (PC12) cells. The specificity of indibulin for unmodified microtubules seems to be dependent on the pyridyl moiety of indibulin because derivatives that have the pyridyl moiety replaced are not able to discriminate between highly and less-modified tubulins. The observed broad antitumor activity of indibulin and the lack of central and peripheral nervous system toxicity in preclinical studies make it a promising candidate for development as a cancer treatment. Indibulin is currently in phase I clinical trials.
    Tipo de documento:
    Referencia
    Referencia del producto:
    05-100

  • Adenoviral expression of suppressor of cytokine signaling-1 reduces adenovirus vector-induced innate immune responses. 18354218

    Adenovirus (Ad) vectors are among the most commonly used viral vectors in gene therapy clinical trials. However, the application of Ad vectors has been limited to local injection in many cases, because the systemic administration of Ad vectors triggers innate immune responses such as inflammatory cytokine production and tissue damage. To overcome this limitation, it will be necessary to develop safer Ad vectors less likely to induce the innate immune response. In the present study, we demonstrated that a suppressor of cytokine signaling-1 (SOCS1)-expressing Ad vector, Ad-SOCS1, reduces the innate immune response induced by Ad vectors. RAW264.7-SOCS1, a macrophage-like cell line that stably expresses SOCS1, was shown to produce lower levels of inflammatory cytokines after the transduction of Ad vectors. The systemic administration of Ad-SOCS1 into mice elicited the reduced production of inflammatory cytokines, as compared with that elicited by control Ad vectors, i.e., luciferase-expressing Ad vector, Ad-L2. Furthermore, the coadministration of Ad-L2 with Ad-SOCS1 attenuated inflammatory cytokine production and liver toxicity as compared with injection with Ad-L2 alone, and this was achieved without the suppression of luciferase production in various organs. The JAK/STAT pathway was involved in Ad vector-mediated cytokine production, which was impaired by the overexpression of SOCS1. These findings indicate that Ad-SOCS1 could be useful for reducing Ad vector-mediated innate immunity.
    Tipo de documento:
    Referencia
    Referencia del producto:
    05-100