CITED2-Mediated Mechanotransduction and its use for Chondroprotection

Novel prevention and therapeutic treatment for cartilage degradation is urgently called for, as cartilage degradation is a hallmark for arthritic diseases including osteoarthritis (OA) and rheumatoid arthritis (RA), and there is a high incidence of arthritis-related disability and high medical costs. While both underuse (e.g. physically inactive lifestyle) and overuse (e.g. high impact or intense repetitive joint use as seen in certain sports) are risk factors for cartilage degradation, recent studies highlight that dynamic moderate loading is associated with reduced incidence of developing OA. Exercise is prescribed in most cases at moderate levels for both OA and RA patients, and accumulating studies demonstrate appropriate exercise maintains cartilage homeostasis and may exert a role in chondroprotection, but the mechanisms underlying how mechanical signals are translated into chondroprotective actions are largely unknown. Identifying the molecules that mediate mechanotransduction and its mechano-responsive nature will not only provide a biomechanical basis for developing more effective mechanical loading-based exercises for chondroprotection, but also can provide novel targets or molecular switches to develop chemical-based modalities for disease treatment. The overall objectives of this dissertation were to determine the mechanical response of transcriptional regulator CBP/p300 Interacting Transactivator with ED-rich Tail 2 (CITED2) to various mechanical loading regimes, elucidating CITED2-mediated chondroprotective pathways, and determining the potential of CITED2 as a target for the prevention and treatment of cartilage degradation in arthritis. The global hypothesis was that CITED2 mediates a mechanical pathway of chondroprotection, CITED2 is required for cartilage integrity, and restoration or increasing levels of CITED2 exerts efficacy in the prevention and treatment of cartilage degradation. This hypothesis was tested with four specific aims: 1) To determine the gene expression response of CITED2 to various mechanical loading regimes, and the role of CITED2 in mediating mechanical regulation of matrix metalloproteinases (MMPs), 2) To determine the CITED2-mediated loading-induced pathway and test whether it is required for loading-induced downregulation of MMPs, 3) To determine whether deficiency of CITED2 is a causal factor for cartilage degradation in arthritic diseases such as OA, and 4) Test the concept of CITED2 as a target for chondroprotection. The key findings of this dissertation include: 1) CITED2 expression is induced by moderate dynamic loading in chondrocytes in an intensity- and duration-dependent manner, and the upregulation of CITED2 is sustained for at least 12 hours after loading. The induction of CITED2 is required for the downregulation of MMPs (i.e. MMP-2, -3, and -13), 2) Dynamic moderate loading induces CITED2 by activating p38δ, which in turn triggers Sp1 and HIF-1α to transactivate CITED2. CITED2 competes with MMP transactivator Ets-1 for binding to limiting amounts of co-factor p300, resulting in repression of MMP expression. 3) Deficiency of CITED2 is associated with cartilage degradation in human OA and disease progression of post-traumatic OA in mice subject to destabilization of the medial meniscus (DMM). Experimental knockdown of CITED2 caused cartilage degradation and deletion of CITED2 in adult cartilage not only resulted in an early OA phenotype, but also accelerated the disease progression of cartilage degradation in DMM mice, revealing a chondroprotective role of CITED2, which is required for cartilage integrity maintenance. 4) Restoring levels of CITED2, via gene transfer or small molecule epigallocatechin gallate (EGCG), exerts efficacy in slowing cartilage degradation in RA and OA mouse models. Together, these studies provide feasibility for developing CITED2-activation-based therapies for the prevention and treatment of cartilage degradation

Identifying Capacity for Local Community Participation in Wildlife Management Planning Case 1: White-tailed Deer Issues at Fire Island National Seashore

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Deer, People, and Parks: Perspectives of Residents in Communities Near Valley Forge National Historical Park

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IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA.

Interferon-induced proteins with tetratricopeptide repeats (IFITs) are highly expressed during the cell-intrinsic immune response to viral infection. IFIT1 inhibits translation by binding directly to the 5' end of foreign RNAs, particularly those with non-self cap structures, precluding the recruitment of the cap-binding eukaryotic translation initiation factor 4F and ribosome recruitment. The presence of IFIT1 imposes a requirement on viruses that replicate in the cytoplasm to maintain mechanisms to avoid its restrictive effects. Interaction of different IFIT family members is well described, but little is known of the molecular basis of IFIT association or its impact on function. Here, we reconstituted different complexes of IFIT1, IFIT2 and IFIT3 in vitro, which enabled us to reveal critical aspects of IFIT complex assembly. IFIT1 and IFIT3 interact via a YxxxL motif present in the C-terminus of each protein. IFIT2 and IFIT3 homodimers dissociate to form a more stable heterodimer that also associates with IFIT1. We show for the first time that IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to a cap0 Zika virus reporter mRNA and enhances IFIT1 translation inhibition. This work reveals molecular aspects of IFIT interaction and provides an important missing link between IFIT assembly and function.This work was supported by a joint Royal Society/Wellcome Trust Sir Henry Dale Fellowship (202471/Z/16/Z) and a Royal Society Research Grant (RG140708) to TRS. HVM is supported by a University of Cambridge, Department of Pathology PhD studentship. XYL is supported by a King’s Scholarship from the Malaysian government. TJS is supported by a Wellcome Trust PhD studentship (105389/Z/14/Z). RCF and DSM are supported by CAPES Computational Biology (23038.010048/2013-27). DSM is also supported by the Academy of Medical Sciences/UK (NAF004/1005). SCG is a Sir Henry Dale Fellow (098406/Z/12/Z) co-funded by the Wellcome Trust and Royal Society

Public Perceptions of Wildlife-Associated Disease: Risk Communication Matters

Wildlife professionals working at the interface where conflicts arise between people and wild animals have an exceptional responsibility in the long-term interest of sustaining society’s support for wildlife and its conservation by resolving human–wildlife conflicts so that people continue to view wildlife as a valued resource. The challenge of understanding and responding to people’s concerns about wildlife is particularly acute in situations involving wildlife-associated disease and may be addressed through One Health communication. Two important questions arise in this work: (1) how will people react to the message that human health and wildlife health are linked?; and (2) will wildlife-associated disease foster negative attitudes about wildlife as reservoirs, vectors, or carriers of disease harmful to humans? The answers to these questions will depend in part on whether wildlife professionals successfully manage wildlife disease and communicate the associated risks in a way that promotes societal advocacy for healthy wildlife rather than calls for eliminating wildlife because they are viewed as disease-carrying pests. This work requires great care in both formal and informal communication. We focus on risk perception, and we briefly discuss guidance available for risk communication, including formation of key messages and the importance of word choices. We conclude that the risk perception and communication research available is helpful but inadequate, and that thoughtful practice with respect to message and word choice is needed

Millimetre observations of a sample of high-redshift obscured quasars

We present observations at 1.2 mm with MAMBO-II of a sample of z>~2 radio-intermediate obscured quasars, as well as CO observations of two sources with the Plateau de Bure Interferometer. Five out of 21 sources (24%) are detected at a significance of >=3sigma. Stacking all sources leads to a statistical detection of = 0.96+-0.11 mJy and stacking only the non-detections also yields a statistical detection, with = 0.51+-0.13 mJy. This corresponds to a typical far-infrared luminosity L_FIR~4x10^12 Lsol. If the far-infrared luminosity is powered entirely by star-formation, and not by AGN-heated dust, then the characteristic inferred star-formation rate is ~700 Msol yr-1. This far-infrared luminosity implies a dust mass of M_dust~3x10^8 Msol. We estimate that such large dust masses on kpc scales can plausibly cause the obscuration of the quasars. We present dust SEDs for our sample and derive a mean SED for our sample. This mean SED is not well fitted by clumpy torus models, unless additional extinction and far-infrared re-emission due to cool dust are included. There is a hint that the host galaxies of obscured quasars must have higher far-infrared luminosities and cool-dust masses and are therefore often found at an earlier evolutionary phase than those of unobscured quasars. For one source at z=2.767, we detect the CO(3-2) transition, with S_CO Delta nu=630+-50 mJy km s-1, corresponding to L_CO(3-2)= 3.2x10^7 Lsol, or L'_CO(3-2)=2.4x10^10 K km s-1 pc2. For another source at z=4.17, the lack of detection of the CO(4-3) line yields a limit of L'_CO(4-3)<1x10^10 K km s-1 pc2. Molecular gas masses, gas depletion timescales and gas-to-dust ratios are estimated (Abridged).Comment: Accepted by ApJ, 25 pages, 11 figures, 4 table

Association between physical activity and reduced mortality in inoperable lung cancer

We examined device-measured physical activity (PA) and sedentary behaviour at the time of diagnosis in people with inoperable lung cancer and investigated their associations with 12-month mortality. The people with inoperable lung cancer wore an accelerometer for seven days prior to the treatment commencement. The analysed PA/sedentary behaviour variables included light-intensity PA, moderate-to-vigorous-intensity PA (MVPA), step count, the total time spent sedentary, and the usual sedentary bout duration. The data on the disease stage, clinical covariates and 12-month mortality were extracted from medical records. Cox regression models were used to estimate the association between the PA measures and 12-month mortality, and the sedentary behaviour measures and 12-month mortality. The models were adjusted for the stage and neutrophil-to-lymphocyte ratio. All the PA and sedentary behaviour variables were dichotomised at their medians for analysis. Eighty-nine participants (70 ± 10 years; 55 [62%] males) contributed valid data. The twelve-month mortality was 30% (n = 27). Compared to the participants who spent ≤ 4.6 min/day in MVPA (n = 45), those who spent \u3e 4.6 min/day (n = 44) had a relative risk of 12-month mortality reduced by 60% (hazard ratio, 0.40; 95% CI, 0.16 to 0.96; 18 versus nine deaths, respectively). The other variables of PA/sedentary behaviour were not associated with 12-month mortality. Higher device-measured MVPA was associated with reduced 12-month mortality in people who were newly diagnosed with inoperable lung cancer

Green tea polyphenol treatment is chondroprotective, anti-inflammatory and palliative in a mouse posttraumatic osteoarthritis model

Introduction Epigallocatechin 3-gallate (EGCG), a polyphenol present in green tea, was shown to exert chondroprotective effects in vitro. In this study, we used a posttraumatic osteoarthritis (OA) mouse model to test whether EGCG could slow the progression of OA and relieve OA-associated pain. Methods C57BL/6 mice were subjected to surgical destabilization of the medial meniscus (DMM) or sham surgery. EGCG (25 mg/kg) or vehicle control was administered daily for 4 or 8 weeks by intraperitoneal injection starting on the day of surgery. OA severity was evaluated using Safranin O staining and Osteoarthritis Research Society International (OARSI) scores, as well as by immunohistochemical analysis to detect cleaved aggrecan and type II collagen and expression of proteolytic enzymes matrix metalloproteinase 13 (MMP-13) and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5). Real-time PCR was performed to characterize the expression of genes critical for articular cartilage homeostasis. During the course of the experiments, tactile sensitivity testing (von Frey test) and open-field assays were used to evaluate pain behaviors associated with OA, and expression of pain expression markers and inflammatory cytokines in the dorsal root ganglion (DRG) was determined by real-time PCR. Results Four and eight weeks after DMM surgery, the cartilage in EGCG-treated mice exhibited less Safranin O loss and cartilage erosion, as well as lower OARSI scores compared to vehicle-treated controls, which was associated with reduced staining for aggrecan and type II collagen cleavage epitopes, and reduced staining for MMP-13 and ADAMTS5 in the articular cartilage. Articular cartilage in the EGCG-treated mice also exhibited reduced levels of Mmp1, Mmp3, Mmp8, Mmp13,Adamts5, interleukin 1 beta (Il1b) and tumor necrosis factor alpha (Tnfa) mRNA and elevated gene expression of the MMP regulator Cbp/p300 interacting transactivator 2 (Cited2). Compared to vehicle controls, mice treated with EGCG exhibited reduced OA-associated pain, as indicated by higher locomotor behavior (that is, distance traveled). Moreover, expression of the chemokine receptor Ccr2 and proinflammatory cytokines Il1b and Tnfa in the DRG were significantly reduced to levels similar to those of sham-operated animals. Conclusions This study provides the first evidence in an OA animal model that EGCG significantly slows OA disease progression and exerts a palliative effect. Electronic supplementary material The online version of this article (doi:10.1186/s13075-014-0508-y) contains supplementary material, which is available to authorized users