Dioxin Toxicity In Vivo Results from an Increase in the Dioxin-Independent Transcriptional Activity of the Aryl Hydrocarbon Receptor

The Aryl hydrocarbon receptor (Ahr) is the nuclear receptor mediating the toxicity of dioxins -widespread and persistent pollutants whose toxic effects include tumor promotion, teratogenesis, wasting syndrome and chloracne. Elimination of Ahr in mice eliminates dioxin toxicity but also produces adverse effects, some seemingly unrelated to dioxin. Thus the relationship between the toxic and dioxin-independent functions of Ahr is not clear, which hampers understanding and treatment of dioxin toxicity. Here we develop a Drosophila model to show that dioxin actually increases the in vivo dioxin-independent activity of Ahr. This hyperactivation resembles the effects caused by an increase in the amount of its dimerisation partner Ahr nuclear translocator (Arnt) and entails an increased transcriptional potency of Ahr, in addition to the previously described effect on nuclear translocation. Thus the two apparently different functions of Ahr, dioxin-mediated and dioxin-independent, are in fact two different levels (hyperactivated and basal, respectively) of a single function

Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas

Familial Non-Medullary Thyroid Carcinoma (fNMTC) represents 3–7% of all thyroid tumours and is associated with some of the highest familial risks among all cancers, with an inheritance pattern compatible with an autosomal dominant model with reduced penetrance. We previously mapped a predisposing locus, TCO (Thyroid tumour with Cell Oxyphilia) on chromosome 19p13.2, for a particular form of thyroid tumour characterised by cells with an abnormal proliferation of mitochondria (oxyphilic or oncocytic cells). In the present work, we report the systematic screening of 14 candidate genes mapping to the region of linkage in affected TCO members, that led us to identify two novel variants respectively in exon 9 and exon 13 of TIMM44, a mitochondrial inner membrane translocase for the import in the mitochondria of nuclear-encoded proteins. These variants were co-segregating with the TCO phenotype, were not present in a large group of controls and were predicted to negatively affect the protein (exon 9 change) or the transcript (exon 13 change). Functional analysis was performed in vitro for both changes and although no dramatic loss of function effects were identified for the mutant alleles, subtler effects might still be present that could alter Timm44 function and thus promote oncocytic tumour development. Thus we suggest that TIMM44 should be considered for further studies in independent samples of affected individuals with TCO

Effect of Anti-Infective Mechanical Therapy on Clinical Parameters and Cytokine Levels in Human Peri-Implant Diseases

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Background: The objectives of this study were to clinically and immunologically assess the effects of mechanical anti-infective therapies for mucositis and peri-implantitis and to compare the levels of cytokines in untreated and treated peri-implant diseased sites to healthy ones. Methods: Titanium dental implants were assigned to one of the following groups: healthy (n = 10) = control; mucositis (n = 10) = mechanical debridement using abrasive sodium carbonate air-powder and resin curets; and peri-implantitis (n = 20) = open surgical debridement using abrasive sodium carbonate air-powder and resin curets. Visible plaque accumulation, marginal bleeding, bleeding on probing, suppuration, and probing depth were assessed at baseline for all groups and at 3 months after therapies for diseased groups. At these times, the total amounts of interleukin (IL)-4, -10, and -12, tumor necrosis factor-alpha (TNF-alpha), receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoprotegerin (OPG) in the peri-implant crevicular fluid (PICF) were measured by enzyme-linked immunosorbent assay. Results: At 3 months, the anti-infective treatments resulted in a significant improvement in all clinical parameters for mucositis and peri-implantitis (P0.05). Conclusion: The proposed anti-infective therapies may locally modulate the levels of TNF-a and the OPG/RANKL ratio and improve clinical parameters around peri-implant tissues. J Periodontol 2009; 80:234-243.802234243Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [05/02561-3, 06/04604-4

Differential cytokine expressions affect the severity of peri-implant disease

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Objective: This study assessed gene expression by quantitative polymerase chain reaction of inflammatory-[interleukin (IL)-12, tumor necrosis factor-alpha (TNF-alpha), IL-4, and IL-10] and osteoclastogenesis-related factors [receptor activator of NF-kappa B ligand (RANKL) and osteoprotegerin (OPG)] in sites exhibiting different severities of peri-implant disease. Material and methods: Peri-implant soft tissue biopsies (n=48) were harvested from healthy implant (HI), mucositis (MC), initial peri-implantitis (IP) and severe peri-implantitis (SP) sites. Results: IL-12 and TNF-alpha mRNA levels were higher in SP, followed by IP and MC (P < 0.05). IL-4 was higher in HI, followed by MC, SP and IP (P < 0.05). IL-10 was the lowest in HI, while no differences were detected among the diseased groups (P=0.05). OPG mRNA levels were higher in HI, followed by IP, SP and MC, whereas RANKL was increased as the peri-implantitis severity increased (P < 0.05). The highest OPG/RANKL ratio was observed in HI and the lowest in SP (P < 0.01). Conclusion: These findings suggest that expressions of inflammatory- and osteoclastogenesis-related factors may play an important role in the onset and severity of the peri-implant diseases.205514520Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [05/02561-3, 06/04604-4]CNPq [471282/2007-3, 303980/2007-9

Dendritic overgrowth and elevated ERK signaling during neonatal development in a mouse model of autism

Autism spectrum disorder (hereafter referred to as "ASD") is a heterogeneous neurodevelopmental condition characterized by impaired social communication and interactions, and restricted, repetitive activities or interests. Alterations in network connectivity and memory function are frequently observed in autism patients, often involving the hippocampus. However, specific changes during early brain development leading to disrupted functioning remain largely unclear. Here, we investigated the development of dendritic arbor of hippocampal CA1 pyramidal neurons in the BTBR T+tf/J (BTBR) mouse model of autism. BTBR mice display the defining behavioural features of autism, and also exhibit impaired learning and memory. We found that compared to control C57BL/6J (B6) animals, the lengths of both apical and basal dendrites were significantly greater in neonatal BTBR animals. Further, basal dendrites in the BTBR mice had higher branching complexity. In contrast, cross-sectional area of the soma was unchanged. In addition, we observed a similar density of CA1 pyramidal neurons and thickness of the neuronal layer between the two strains. Thus, there was a specific, compartmentalized overgrowth of dendrites during early development in the BTBR animals. Biochemical analysis further showed that the extracellular signal-regulated kinases (ERK) pathway was up-regulated in the hippocampus of neonatal BTBR animals. Since dendritic structure is critical for information integration and relay, our data suggest that altered development of dendrites could potentially contribute to impaired hippocampal function and behavior observed in the BTBR model, and that this might be related to increased activation of the ERK pathway

Age-dependent Relationship Between Socio-adaptability and Motor Coordination in High Functioning Children with Autism Spectrum Disorder

International audienc

Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes

Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium transforms into a hyperplastic invasive tissue that causes destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype in RA and have an important role in these pathological processes. In&nbsp;addition to producing the extracellular matrix and joint lubricants, FLS in RA produce pathogenic mediators such as cytokines and proteases that contribute to disease pathogenesis and perpetuation. The development of multi-omics integrative analyses have enabled new ways to dissect the mechanisms that imprint FLS, have helped to identify potential FLS subsets with distinct functions and have identified differences in FLS phenotypes between joints in individual patients. This Review provides an overview of advances in understanding of FLS biology and highlights omics approaches and studies that hold promise for identifying future therapeutic targets