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[en] Alzheimer's disease (AD) is the most prevalent neurological condition affecting industrialized nations and will rapidly become a healthcare crisis as the population ages. Currently, the post-mortem histological observation of amyloid plaques and neurofibrillary tangles is the only definitive diagnosis available for AD. A pre-mortem biological or physiological marker specific for AD used in conjunction with current neurological and memory testing could add a great deal of confidence to the diagnosis of AD and potentially allow therapeutic intervention much earlier in the disease process. Our group has developed MRI techniques to detect individual amyloid plaques in AD transgenic mouse brain in vivo. We are also developing contrast-enhancing agents to increase the specificity of detection of amyloid plaques. Such in vivo imaging of amyloid plaques will also allow the evaluation of anti-amyloid therapies being developed by the pharmaceutical industry in pre-clinical trials of AD transgenic mice. This short review briefly discusses our progress in these areas. (orig.)
[en] 6-[18F]Fluoro-3,4-dihydroxy-L-phenylalanine (6-[18F]F-L-DOPA) is increasingly used for PET imaging of neuroendocrine tumours. In this study, we investigated the use of 6-[18F]F-L-DOPA to detect and to monitor the progression of medullary thyroid carcinoma (MTC) in a genetically engineered mouse model of multiple endocrine neoplasia type 2A (MEN2A). Dynamic [18F]FDG and 6-[18F]F-L-DOPA small animal PET scans were acquired during 60 or 90 min in 8- to 20-month-old MEN2A transgenic mice. The kinetics of 6-[18F]F-L-DOPA, standardized uptake values (SUV) at 60 min and tumour volumes were recorded. The detection of MTCs using PET was confirmed by autopsy and histological analysis. 6-[18F]F-L-DOPA performs better than [18F]FDG for MTC detection in this transgenic mouse model. Uptake kinetics of 6-[18F]F-L-DOPA in MTCs are very different between mice but, in all cases, high contrast could be observed. Furthermore, 6-[18F]F-L-DOPA can detect tumours with sizes (1.8 mm3) that are near the resolution limit of PET, whereas they were undetectable by autopsy at the macroscopic level. 6-[18F]F-L-DOPA PET imaging can monitor the progression of MTCs in a genetically engineered mouse model. (orig.)
[en] Highlights: • Intestinal barrier and NLRC3 expression are impaired in diabetic mice. • NLRC3 ameliorates tight junctions in colonic epithelial cell. • NLRC3 up-regulates ZO-1 and occludin expression via TRAF6 pathway. • Butyrate improves NLRC3 expression by activating GPR43. • Butyrate ameliorates the intestinal epithelial tight junctions in db/db mice. Intestinal barrier dysfunctions are related to dysbacteriosis and chronic gut inflammation in type 2 diabetes. Although there is emerging evidence that the chronic gut inflammatory response is stimulated by nucleotide-binding oligomerization domain-like receptors (NLRs), the relationship and precise mechanism between NLRC3 and the colonic epithelial barrier remains largely elusive.
[en] Highlights: • miR-3065-5p is significantly up-regulated during odontoblastic differentiation. • miR-3065-5p directly targets Bmpr2 and indirectly targets Adamts2. • Bmpr2 exerts different roles in the different stages of odontoblastic differentiation. Illumination of the molecular mechanisms regulating odontoblastic differentiation of dental papilla cells is of great significance for proper dentinogenesis and dental pulp regeneration. In this study, we discovered that microRNA (miR)-3065-5p is up-regulated during odontoblastic differentiation. Overexpression of miR-3065-5p promoted odontoblastic differentiation in vitro. Dual luciferase report assay verified that miR-3065-5p could bind to the 3′UTR of bone morphogenetic protein receptor type II (BMPR2), which dramatically increased in the beginning of odontoblastic differentiation but decreased in the terminal differentiation stage. Inhibition of Bmpr2 in the early stage retarded odontoblastic differentiation while knockdown of Bmpr2 in the terminal stage enhanced odontoblastic differentiation, resembling the effect of miR-3065-5p. Taken together, our present study suggests that miR-3065-5p positively regulates odontoblastic differentiation by directly binding to Bmpr2 in the terminal differentiation stage.
[en] Highlights: • Unknown patterning mechanisms subdivide early trophoblast into two regions. • These are extraembryonic ectoderm (ExE) and ectoplacental cone (EPC). • Identifying ExE-EPC border/distinguishing entire ExE from EPC not addressed before. • These are prerequisites to grasping trophoblast patterning and were addressed here. • We identified ExE-EPC border and discovered unique features of entire ExE and EPC. The early stages of mouse placentogenesis (placenta formation) involve poorly understood patterning events within polar trophectoderm-derived trophoblast, the progenitor of all placental trophoblast cell types. By early postimplantation [embryonic day 5.5 (E5.5)], this patterning causes early trophoblast to become subdivided into extraembryonic ectoderm (ExE) and ectoplacental cone (EPC). A prerequisite to understanding this patterning requires knowing the location of ExE-EPC border and being able to distinguish the entire ExE from EPC at E5.5/E6.5, a time when the proamnioitic cavity within ExE is not fully established. However, these issues are unknown, as they have not been directly addressed. Here, we directly addressed these using trophoblast explant culture to functionally test for the location of ExE-EPC border, combined with phenotypic characterization of trophoblast proximal and distal to it. We show for the first time that the proximal-distal level of ExE-EPC border within E5.5/E6.5 trophoblast coincides with where Reichert's membrane (outermost basement membrane of conceptus) inserts into early trophoblast and with the proximal limit of extraembryonic visceral endoderm (primitive endoderm derivative covering part of early trophoblast). Based on these novel findings, we discovered that (a) the entire E5.5/E6.5 ExE can be distinguished from EPC because it is epithelial and specifically expresses Erf and Claudin4 and (b) at E5.5/E6.5, the entire EPC differs from ExE in that it is not epithelial and specifically expresses Snail. This work is expected to contribute to understanding the cellular and molecular basis of early trophoblast patterning during placentogenesis.
[en] Highlights: • Mouse-adapted MERS-CoV can elicit severe respiratory disease at doses ranging 103–105 PFU. • Novel mutations in MERS-CoV may be associated with severe respiratory disease. • The extent of MERS-CoV adaptation determines the minimal effective dose to elicit respiratory disease. We recently established a mouse model (288–330+/+) that developed acute respiratory disease resembling human pathology following infection with a high dose (5 × 106 PFU) of mouse-adapted MERS-CoV (icMERSma1). Although this high dose conferred fatal respiratory disease in mice, achieving similar pathology at lower viral doses may more closely reflect naturally acquired infections. Through continued adaptive evolution of icMERSma1 we generated a novel mouse-adapted MERS-CoV (maM35c4) capable of achieving severe respiratory disease at doses between 103 and 105 PFU. Novel mutations were identified in the maM35c4 genome that may be responsible for eliciting etiologies of acute respiratory distress syndrome at 10–1000 fold lower viral doses. Importantly, comparative genetics of the two mouse-adapted MERS strains allowed us to identify specific mutations that remained fixed through an additional 20 cycles of adaptive evolution. Our data indicate that the extent of MERS-CoV adaptation determines the minimal infectious dose required to achieve severe respiratory disease.
[en] This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of authors. The Journal received an expression of concern from a reader, which noted that: “The problem is that there is no IL-26 gene in the mouse. They claim they bought the KO mouse and the mouse IL-26 protein but given that there is no mouse IL-26 gene, a purchase is not possible and in fact no such reagents are available. Furthermore they do reference and anti-IL-26 antibody but the spec sheet clearly states that it is only reactive with the human protein…., the Enzo Life Sciences online catalog does not have a listing for recombinant IL-26 of any kind.” The authors apologize for their mistakes and have asked to retract the article.
[en] In continuation of our earlier study on the involvement of Heat Shock Protein (HSP) 25 and HSP70 in the induction of adaptive response, we have now examined the involvement of these proteins in the induction of the adaptive response, using an animal model system. C57BL6 mice were irradiated with 5 cGy of gamma radiation 3 times for a week (total of 15cGy) and a high challenge dose (6Gy) was given on the day following the last low dose irradiation. Survival rate of the low dose pre-irradiated mice was increased to 30%. Moreover, high dose-mediated induction of apoptosis was also reduced by low dose pre-irradiation. To elucidate any link existing between HSP and induction of the adaptive response, Reverse Transcriptase (RT)-Polymerase Chain Reaction (PCR) analysis was performed using splenocytes. High dose radiation up-regulated the expression of HSP25 and especially HSP70; while expression of other HSPs such as HSC70, HSP90, and a?-crystalline did not change. When splenocytes from HSP70 transgenic mice were pre-irradiated with a low dose of radiation, a reduction in cell death by high dose radiation was observed. These results, suggest that HSP70 is a key molecule in the induction of adaptive response
[en] The present study aimed to investigate the influence of the host retinal microenvironment on cell migration and differentiation using Neuro2a (N2a) cells transduced with green fluorescent protein. N2a cells were transplanted into the vitreous cavities of developing mouse eyes (C57BL/6) on postnatal days 1, 5, and 10 (P1, 5, and 10). To analyze the effects of the host microenvironment on neural differentiation of N2a cells in vitro, cells were treated with a conditioned medium (CM) collected from retinal cells cultured at each developmental stage. We observed that numerous cells transplanted into P5 mice eyes migrated into all layers of the host retina, and the presence of processes indicated morphological differentiation. Some transplanted N2a cells expressed several neural markers. However, cells transplanted into the P1 and 10 mice eyes only proliferated within the vitreous cavity. Neurite length increased in N2a cells treated with CM collected from the cultured retinal cells from P5 and 10 mice, while western blotting revealed that the levels of proteins related to neural differentiation were not significantly altered in N2a cells treated with CM. We show that the migration and differentiation capacities of transplanted cells were differentially influenced by the microenvironment of the retinal postnatal ontogeny
[en] Highlights: • Ddedifferentiated liposarcoma (DDLPS) is recalcitrant and has the lowest survival rate. • Determine the efficacy of rMETase combined with palbociclib (PAL) against a DOX-resistant DDLPS in a PDOX mouse model. • The combination of PAL and rMETase significantly regressed tumor volume. • The combination of rMETase and PAL could be developed clinically. Liposarcoma is the most common type of soft tissue sarcoma. Among the subtypes of liposarcoma, dedifferentiated liposarcoma (DDLPS) is recalcitrant and has the lowest survival rate. The aim of the present study is to determine the efficacy of metabolic targeting with recombinant methioninase (rMETase) combined with palbociclib (PAL) against a doxorubicin (DOX)-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model. A resected tumor from a patient with recurrent high-grade DDLPS in the right retroperitoneum was grown orthotopically in the right retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, DOX; G3, PAL; G4, recombinant methioninase (rMETase); G5, PAL combined with rMETase. Tumor length and width were measured both pre- and post-treatment. On day 14 after initiation, all treatments significantly inhibited tumor growth compared to the untreated control except DOX. PAL combined with rMETase was significantly more effective than both DOX, rMETase alone, and PAL alone. Combining PAL and rMETase significantly regressed tumor volume on day 14 after initiation of treatment and was the only treatment to do so. The relative body weight on day 14 compared with day 0 did not significantly differ between each treatment group. The results of the present study indicate the powerful combination of rMETase and PAL should be tested clinically against DDLPS in the near future.