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Review Article | Open Access
YongPing Li, XiaoChun Wei, JingMing Zhou, Lei Wei, "The Age-Related Changes in Cartilage and Osteoarthritis", BioMed Research International, vol. 2013, Article ID 916530, 12 pages, 2013. https://doi.org/10.1155/2013/916530
The Age-Related Changes in Cartilage and Osteoarthritis
Osteoarthritis (OA) is closely associated with aging, but its underlying mechanism is unclear. Recent publications were reviewed to elucidate the connection between aging and OA. With increasing OA incidence, more senior people are facing heavy financial and social burdens. Age-related OA pathogenesis is not well understood. Recently, it has been realized that age-related changes in other tissues besides articular cartilage may also contribute to OA development. Many factors including senescence-related secretory phenotypes, chondrocytes’ low reactivity to growth factors, mitochondrial dysfunction and oxidative stress, and abnormal accumulation of advanced glycation end products (AGEs) may all play key roles in the pathogenesis of age-related OA. Lately, epigenetic regulation of gene expression was recognized for its impact on age-related OA pathogenesis. Up to now, few studies have been reported about the role of miRNA and long-noncoding RNA (lncRNA) in age-related OA. Research focusing on this area may provide valuable insights into OA pathogenesis. OA-induced financial and social burdens have become an increasingly severe threat to older population. Age-related changes in noncartilage tissue should be incorporated in the understanding of OA development. Growing attention on oxidative stress and epigenetics will provide more important clues for the better understanding of the age-related OA.
Half of the world’s population, aged 65 and older, suffers from OA . Many studies showed that increased age is the most prominent risk factor for the initiation and progression of primary OA in typically affected joints including interphalangeal, hips, knees, and intervertebral. The rare cases of OA diagnosed in young individuals, under the age of 25–30 years old, are mostly due to mutations in matrix genes that cause significant structural abnormalities and/or joint deformities [2–4].
To this day, the mechanism of OA has not been fully clarified. Current hypotheses include the classic “wear and tear” theory [2, 4], senescence-related secretory phenotype , chondrocytes’ low reactivity to growth factors , mitochondrial dysfunction and oxidative stress , and abnormal accumulation of advanced glycation end products (AGEs) . The cumulative effect of mechanical load over the years may cause “wear and tear” clinically and cartilage breakdown pathologically . Hence, OA is regarded as a naturally occurring irreversible phenomenon, rather than a specific, potentially treatable disease. However, OA is not inevitable for all senior adults (age 60+). It has become increasingly clear that OA is not a purely mechanical problem . Age-related changes in cartilage extracellular matrix proteins such as collagen or proteoglycans can induce nonenzymatic collagen cross-linking and shorten aggrecan molecules . Excessive collagen cross-linking affects the biomechanical properties of cartilage, causes increased stiffness, and makes cartilage more brittle  and susceptible to fatigue failure . Shortening and degradation of aggrecan leads to significant loss of sugar side chains and water-binding ability . In addition, increased levels of AGEs are associated with a decline in anabolic activity . These findings suggest that age-related changes in matrix may play a role in the development of OA.
Lately, it has been gradually realized that age-related changes occurring in tissues besides articular cartilage may contribute to the development of OA . Because articular cartilage lacks nerve supply, knee pain could be attributed to OA-related changes of the joint tissues, such as the synovium, bone (including osteophytes), joint capsule, ligaments, and menisci . These tissues could play important roles in the early stages of OA . Thus, OA is considered a “whole joint disease” . Although it raises the complexity of OA, this concept improved our understanding of the disease as well as indicated potential new treatment strategies .
This review focuses on recent studies that shed light on the connection between aging changes in cells and tissues and the propensity for OA occurrence in older adults.
OA is the most common joint disorder in the world and one of the most common sources of pain and disability in the elderly [15, 16]. The incidence of OA is predicted to increase as the senior population grows, placing a significant financial burden on healthcare providers and governments . OA affects at least 27 million Americans and is the leading cause of disability in the United States . Compared to only 7.6% of those 18–44 years of age and 29.8% of those 45–64 years of age, 50% of individuals older than 65 years are diagnosed with this disease . OA affects one in six adults, and by 2030 it is estimated that 20% of people in Europe and the United States will suffer from OA . The senior population is growing rapidly in many Asian countries . It is estimated that the 65+ population in Asia will more than double in the next two decades, increasing from 6.8% in 2008 to 16.2% in 2040. In most of the developed world demographic change is a gradual progress following the steady socioeconomic growth over several decades. In contrast, this change is compressed into 2-3 decades in many Asian countries. For example, during the period between 2008 and 2040, it is estimated that the 65+ population will increase by 316% in Singapore, 274% in India, 269% in Malaysia, 261% in Bangladesh, and 256% in the Philippines. In 2008, Japan had the world’s oldest population (people 65+ represented 21.6% of whole population), and both China and India were ranked top two for the size of 65+ population (106 and 60 million, resp.) . The high prevalence and heavy impact on working capacity make OA a major social issue . Therefore, healthcare and socioeconomics need to put a high priority to the prevention and treatment of OA .
OA in humans usually becomes symptomatic after age 50, which is also when the radiographic changes of OA become more common . Although radiographic signs of OA such as osteophytes and joint space narrowing do not always correlate well with symptoms, epidemiologic studies of large cohorts commonly depend on radiographs to define OA . Goekoop et al. examined a cohort of 90-year olds living in the city of Leiden in Netherlands and found that only 16% of people in that age were free of radiographic OA .
In the Johnson Country OA cohort , the prevalence of radiographic knee OA rose from 26.2% in the 55–64 age group to nearly 50% in the 75+ age group, and the prevalence of symptomatic knee OA likewise increased from 16.3% to 32.8% between these age groups. Symptomatic hip OA in this cohort was reported as 5.9% in the 45–54 age group compared with 17% in the 75+ age group. In the Johnston County OA Project, African American men had a higher prevalence of radiographic hip OA than Caucasian men (32.2% versus 23.8%), whereas no difference was found between African American and Caucasian women (40.3% versus 39.4%) . Individual radiographic features in hip and knee were also noted to differ between two ethnic groups [24, 25]. In the Beijing OA Study, hand and hip OA were less prevalent among Chinese than Caucasians (age-standardized prevalence 44.5%–47% versus 75.2%–85% and 0.8% versus 3.8–4.5%, resp.), but knee OA was more prevalent among Chinese women than Caucasian women (46.6% versus 34.8%) [16, 18, 26].
The heritability of OA is estimated to be 40% to 65% and is higher for hand and hip OA than for knee OA [27–29]. So far, 3 loci have been associated to OA at genome-wide significant levels [30–32], that is, GDF5, which encodes the growth differentiation factor 5 (a bone morphogenetic protein expressed in skeletal and articular structures), chromosome 7q22, and MCF2L (MCF.2 cell line derived transforming sequence-like). Pain severity in OA may also have genetic contributions. A functional polymorphism (Val158Met) in the COMT gene, which was previously correlated with pain sensitivity in other clinical conditions, was associated with hip OA-related pain in a cohort study . TRPV1 and the PACE4 gene Pcsk6 were associated with pain in knee OA in two separate meta-analyses [34, 35].
3. Chondrocyte Changes
The primary function of chondrocytes is to maintain cartilage homeostasis, in part through the production of extracellular matrix components. With age, chondrocytes exhibit features similar to senescent phenotypes, including telomere shortening and increased senescence-associated β-galactosidase activity [5, 36]. These age-related changes impair the ability of chondrocytes to maintain the surrounding extracellular matrix. Accordingly, in aged chondrocytes, synthetic activity is decreased and proteoglycans are smaller and more irregular [37, 38].
A reduction in the number of chondrocytes was observed in normal articular cartilage during aging, comparing with a greater loss of chondrocytes in OA cartilage, but the extent of cell death is debatable [39–41]. A study showed 30% drop in cell density in human hip joint cartilage between the ages of 30 and 70 . However, a study on human knees found less than 5% cell loss during aging . Loss of the chondrocytes can be attributed to increased chondrocyte death and/or apoptosis. Although many studies reported apoptotic chondrocytes in OA cartilage , few have examined apoptosis in cartilage with normal aging, except for one study on rat cartilage . There is evidence showing  that HMGB2, a high-mobility group box (HMGB) protein that may be important for chondrocyte survival, regulates gene transcription through chromatin organization. HMGB2 is mainly expressed in chondrocytes in the superficial zone of articular cartilage, and HMGB2 levels drop during aging . Moreover, the decline in HMGB2 levels was associated with increased chondrocyte death, and HMGB2-deleted mice developed premature OA . Levels of reactive oxygen species (ROS) are increased in cartilage during aging, and chondrocytes from older adults are more susceptible to ROS-mediated cell death .
The synthetic activity of chondrocytes is regulated by anabolic growth factors . During aging, chondrocytes exhibit reduced responsiveness to growth factors, such as insulin-like growth factor-1 (IGF-1) [6, 48, 49], osteogenic protein-1 (OP-1) or bone morphogenic protein-7 , and transforming growth factor-β (TGF-β) [51, 52]. For example, TGF-β stimulates proteoglycan synthesis in young animals, but this ability is impaired in old mice [51, 53]. It is hypothesized that age-related alterations in the TGF-β signaling pathway trigger chondrocytes to leave their normally quiescent state into an autolytic phenotype, leading to degradation of cartilage extracellular matrix . Reduced anabolic response to IGF-I was also noted in chondrocytes isolated from OA cartilage [48, 55]. These findings suggest that age-related decline in anabolic activity could tip the balance towards increased catabolism and play a key role in increasing cartilage susceptibility to OA.
Age-related changes inside chondrocytes including cellular senescence and reduced responsiveness to growth factors and extracellular factors affecting chondrocyte aging such as AGE accumulation and oxidative stress may work together to disrupt cartilage homeostasis. These changes will make the cartilage matrix more vulnerable to damage and lead to the onset of OA. The onset of OA is characterized by increased cell proliferation, which leads to formation of chondrocyte clusters and increased synthesis of irregular matrix components such as collagens and proteoglycans [56–58]. With OA progression, excessive catabolic activity causes imbalance of cartilage homeostasis and cartilage matrix breakdown. These catabolic events are largely mediated by proinflammatory cytokines and mediators, for example, matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) . Notably, many characteristics of an aged chondrocyte parallel changes observed in early OA, which might explain why age is highly correlated to OA .
AGEs are produced through a nonenzymatic reaction between reducing sugars and free amino groups of proteins, lipids, or nucleic acids . Excessive levels of AGEs in the body are pathogenic, resulting in elevated oxidative stress and inflammation . In chondrocytes, AGEs can increase the production of inflammatory cytokine tumor necrosis factor-α (TNF-α), inflammatory mediators prostaglandin E2, and nitric oxide. It can also suppress the production of type II collagen and stimulate the expression of degradative enzyme MMPs and ADAMTS [8, 63, 64]. AGEs accumulation also has adverse effects on the cartilage extracellular matrix. AGEs increase collagen cross-linking, which enhances tissue stiffness, making cartilage more brittle and susceptible to mechanical failure [10, 11, 65]. Although not reported in chondrocytes, AGEs also induce ROS generation in murine hepatic stellate cells and bone marrow mesenchymal stem cells [66, 67].
ROS play important roles in many physiological processes and can potentially cause oxidative damages to proteins, lipids, and DNA . Human articular chondrocytes actively produce ROS, and increased levels of ROS were observed in articular cartilage of old rats compared to young rats [69–72]. Furthermore, cartilage of old rats exhibited a significant drop in antioxidant catalase activity . This redox imbalance may be caused by an age-related decline in the activity and number of mitochondria, which play critical roles in protecting cells from ROS damage . The consequence of increased oxidative stress is DNA damage and telomere shortening, leading to reduced matrix production, chondrocyte senescence, and apoptosis [73–75]. Increased ROS also upregulate proinflammatory cytokines and MMPs, factors that mediate cartilage degradation .
Mitochondria is a major source of ROS in the cell, and mitochondrial dysfunction is thought to play a key role in age-related diseases including OA. Evidence has been shown that mitochondrial DNA damage in OA is promoted by inflammatory cytokines such as IL-1β and TNF-α and contributes to chondrocyte death . Mechanical injury to cartilage, such as articular cartilage crushing, shearing force injury, would result in elevated ROS generation in mitochondria and promotes chondrocyte death . Subchondral bone softening, which occurs during age-related osteoporosis , is predicted to alter the biomechanics of the tibiofemoral joint by increasing the maximum tensile strains in cartilage and the magnitudes of joint contact pressure . In addition, due to the aged less activity, the declined quadriceps strength may be another factor responsible for altered joint loading patterns as a consequence of joint laxity . Nonphysiological load or less mechanical load exerted on chondrocytes would induce catabolic signaling and cartilage tissue breakdown .
ROS could play a key role in age-related chondrocyte changes in several signaling pathways . Excessive levels of ROS were found to inhibit activation of the IRS-1-PI-3 kinase-Akt signaling pathway, which normally promotes matrix synthesis  (Figure 1). Meanwhile, ROS activates the ERK MAP kinase which suppresses the expression of chondrocyte aggrecan, type II collagen, and Sox-9  (Figure 1). Sustained activation of ERK can induce cell senescence. A study  using rat chondrosarcoma cells demonstrated that sustained ERK activation mediated by FGFR3 promoted the expression of the senescent phenotype markers. Extracellular ROS could also contribute to inhibition of the Akt pathway through oxidized low-density lipoprotein (LDL). The binding of oxidized LDL to cell surface receptor LOX-1 was found to induce chondrocyte senescence, possibly by inhibiting Akt phosphorylation upon IGF-1 stimulation  (Figure 1). Oxidative stress induced by oxidized LDL is also associated to promotion of hypertrophic chondrocyte phenotype in OA cartilage .
A study  on the expression of the superoxide dismutase (SOD) family of antioxidants demonstrated decreased expression of all three SOD isoforms (copper/zinc (Cu/Zn)-SOD, manganese (Mn)-SOD, and extracellular (EC)-SOD), at the transcriptional level. Decreased expression of mitochondrial SOD (SOD2) was associated with increased methylation inSOD2 promoter region suggesting that epigenetic regulation may be involved in inhibition of the expression of this antioxidant gene . A more recent study reported that people in Spain with mitochondrial DNA haplotype J, which is associated with a lower risk of OA, have lower serum levels of MMP-13 when compared to those with haplotype H, who have higher serum levels of MMP-3 . It is possible that the different haplotypes are characterized by different ROS generation and perhaps different amount of mitochondrial DNA damage, although this is not fully established. Interestingly, a study examining a murine model of premature aging that exhibits increased nuclear DNA damage due to deficiency of a repair enzyme found a significant increase in age-related bone loss but not in cartilage damage .
4. The Changes in Cartilage Matrix
Age-related changes not only occur in chondrocytes but also in cartilage matrix, thereby contributing to OA development. MRI studies showed that knee cartilage thins during aging, particularly on the femoral side of the joint  and in patellae , suggesting a gradual loss of cartilage matrix with age. This could be due to loss of chondrocytes and reduced growth factor activity, but also to something as simple as reduced water content. Type II collagen, the most abundant matrix protein in cartilage, has a half-life over 100 years . Excessive collagen cross-linking increases stiffness and brittleness , thereby increasing susceptibility to fatigue failure . Increased levels of AGEs in cartilage are correlated with declined anabolic activity . Being the second most abundant cartilage matrix protein, aggrecan is a large “aggregating” proteoglycan consisting of a core protein and numerous highly sulfated glycosaminoglycan chains that are covalently attached . Because of the hydrophilic nature of aggrecan’s negatively charged sulfates, articular cartilage has about 70–80% water content and is very resilient. Age-related changes in size, structure, and sulfation of aggrecan [12, 37, 91, 92] affect cartilage resiliency and hydration . When aggrecan is degraded, a fragment containing the binding region for hyaluronic acid is left behind and appears to accumulate in cartilage with age due to a low turnover rate with an estimated aggrecan half-life of 25 years in cartilage .
The balance of anabolism to catabolism is regulated by the fine-tuning of the specific genes in certain signaling pathways. Studies using transgenic and knockout mice continue to provide information on specific genes that may play a role in OA progress . FGFR3 knockout mice  were found to develop more severe OA with age than FGFR1 knockout mice . Together, these results suggest an anabolic/joint protective function of FRGFR3 and a catabolic/joint destructive function for FGFR1.
Transforming growth factor-β (TGF-β) is secreted in an inactive form and requires activation before binding to its receptor . Activated TGF-β binds to the TGF-β type II receptor and forms a complex that recruits the TGF-β type I receptor, ALK5. However, TGF-β is also able to signal via the alternative TGF-β type I receptor ALK1 in chondrocytes  (Figure 2). In endothelial cells as well as chondrocytes, activation of ALK5 is followed by Smad2 or Smad3 phosphorylation, while ALK1 activation results in phosphorylation of Smad1, Smad5, or Smad8 [54, 99–101] (Figure 2). The activated Smads form a complex with the co-Smad Smad4 and translocate to the nucleus to modify gene expression. Interestingly, signaling via either ALK5 or ALK1 can turn the response of cells to TGF-β stimulation in opposite directions [54, 102] (Figure 2). For example, in endothelial cells ALK5 inhibits migration, whereas ALK1 stimulates migration and proliferation . The Smad pathway appears to be the most important for TGF-β signaling but is not the only option. Mitogen-activated protein kinase, Rho-like GTPase, and phosphatidylinositol-3-kinase pathways are involved in TGF-β signaling . Activation of TGF-β activated kinase 1 (TAK1) happens independently of ALK5 kinase activity and induces P38 and JNK signaling . Studies on activin receptor-like kinases (ALKs) activated by TGF-β showed that ALK5 activation is proanabolic, and ALK1 activation is procatabolic  (Figure 2). During aging and in OA, the ratio of ALK1 to ALK5 is increased to promote OA development, and the ratio of FGFR1 to FGFR3 may change in a similar way .
In our previous study, we demonstrated the loss of TGF-β type I receptor ALK5 and phosphorylation of Smad2/3 in murine articular cartilage during aging , but the expression of total Smad2 was not altered by TGF-β. Moreover, in two experimental models of OA—the DMM (meniscus destabilization) model and the STR/ORT mice (spontaneous OA model)—development of the disease was correlated with decreased ALK5 expression. Expression of the alternative TGF-β receptor ALK1 did not decrease to a similar extent as ALK5 . STR/ORT mice develop OA starting at the medial tibia from an age of 2 to 3 months. The ALK1/ALK5 ratio was 5 on the medial tibia at the age of 3 months and was 18 in 1-year-old animals. The lateral tibia showed increased ratio from 1 to 5 over the same period of time. Clearly increased ALK1/ALK5 ratios in chondrocytes are associated with aging and OA development .
5. Chondrocyte Senescence
Chondrocytes are very unique cells that easily develop into age-related changes with aging. The chondrocytes present in the articular cartilage of an 80-year old are likely to be the very same cells as those present in a 25-year old. There is little to no cell division or cell death in normal adult articular chondrocytes , and there seems to be no ready supply of progenitor cells to replace dead chondrocytes if cell death does occur. The articular chondrocytes which underwent more cell divisions exhibit telomere shortening . Aging itself is not associated with chondrocyte proliferation, but rather with loss of normal mitogenic response of isolated chondrocytes to growth factor stimulation .
There are two types of senescence: intrinsic and extrinsic. The classic replicative senescence or “intrinsic senescence” is attributed to shortened telomeres accompanied by telomere dysfunction . Evidence of telomere shortening in chondrocytes from older adults has been reported . However, the senescence in articular cartilage seems more relevant to the “extrinsic senescence” or stress-induced senescence, which occurs in response to telomere-damaging stimuli, including oxidative damage, activated oncogenes, and inflammation [113, 115] and is a much more likely mechanism for senescence in cartilage .
Accumulation of cells exhibiting the senescent secretory phenotype contributes to tissue aging [115, 117]. This phenotype is characterized by increased production of cytokines including IL-6 and IL-1, matrix metalloproteinases, and growth factors such as EGF with some features in common with the OA chondrocyte phenotype. Studies have shown increased expression of MMP-3 and MMP-13 in aged cartilage [118, 119] as well as age-related accumulation of collagen neoepitopes representing denatured or cleaved collagen [120, 121]. It was shown that increased MMPs mediate cartilage matrix damage during aging, and collagenases and cathepsin K were also implicated in this process recently .
Other mediators of cellular senescence include TRF (telomeric repeat binding factor), XRCC5 (X-ray repair complementing defective repair in Chinese hamster cells 5), and SIRT1 (sirtuin 1). TRF1 and TRF2 are telomeric proteins that function to form and maintain telomere structure [123, 124]. XRCC5 is involved in repairing DNA double-strand breaks . SIRT1 is a negative regulator of p53 and prevents growth arrest, senescence, and apoptosis . Oxidative stress in human chondrocytes induces senescence and accelerates telomere shortening . After acute oxidative insult, TRF1, TRF2, XRCC5, and SIRT1 are upregulated in the early passages of human chondrocytes but induced to a less extent in late passages of chondrocytes . This finding suggests that TRF proteins, XRCC5, and SIRT1 help young chondrocytes to cope with oxidative stress by preventing DNA damage accumulation and telomere shortening. Consistently, aged chondrocytes with lower induction levels of these regulatory proteins have a reduced tolerance to oxidative challenge, and accumulation of DNA damage may trigger chondrocyte senescence. Membrane protein caveolin-1 is also involved in senescence. Expression of caveolin proteins is increased in tissues of old rats , and overexpression of caveolin-1 leads to a senescent phenotype, likely through the p53/p21 pathway . In addition, angiogenic growth factor (AGF) treatment in human chondrocytes downregulated interleukin-1β- (IL-1β-) induced caveolin-1 expression and prevented chondrocyte replicative lifespan shortening. Inhibition of p42/p44 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) abolished the effect of AGF on caveolin-1, suggesting that the AGF-mediated inhibition of IL-1β-induced chondrocyte aging is regulated, at least in part, by p42/44 MAPK and PI3K .
The Wnt family of secreted glycosylated proteins are linked to the development of a number of age-related pathologies such as osteoarthritis. Manipulation of Wnt signaling has the potential to impact both cellular survival and longevity; however, aberrant Wnt signaling can promote cell senescence . Disruption of Wnt signaling has also been associated with altered joint formation, chondrogenesis, and OA [131–133]. Wnt signaling occurs through canonical (β-catenin dependent) and noncanonical (β-catenin independent) pathways. In canonical Wnt signaling, Wnt binding to Frizzled receptors and LRP5/6 coreceptors leads to stabilization of β-catenin via inhibition of GSK-3β mediated ubiquitination and degradation (Figure 3). β-catenin can then translocate to the nucleus and bind to TCF/LEF-1 transcription factors (Figure 3). OA-like changes occur in mice following both under- and overactivation of the Wnt pathway  (Figure 3). Canonical Wnt signaling has been reported to both inhibit and promote early chondrogenesis and to promote hypertrophy and chondrocyte dedifferentiation  (Figure 3). In contrast, the noncanonical pathway, through Wnt5a and Wnt5b, can promote chondrogenesis and inhibit hypertrophy . This suggests that fine regulation of the Wnt pathway is essential for proper cartilage development and homeostasis. Recently, activation of the Wnt pathway was shown to inhibit IL-1-mediated MMP-13 expression in human chondrocytes. This was TCF/LEF independent and mediated through a direct interaction between NF-κB and β-catenin, suggesting a potential protective function of Wnt in aging and OA . Interestingly, HMGB2 and Wnt activity colocalize in the superficial zone of articular cartilage . Age-related loss of HMGB2 and OA could also be associated with loss of Wnt activity in the superficial zone of articular cartilage, although Wnt activity is enhanced in other zones within articular cartilage, along with osteophytes and subchondral bone . Understanding the impact and mechanisms underlying the imbalance of Wnt activity across the joint will provide insights into aging and OA-related cartilage degradation.
There is a growing interest in the role epigenetics play in age-related conditions including OA. Epigenetic regulation of gene expression includes DNA methylation, histone acetylation and methylation, and micro-RNA (miRNA). Sirtuins are a family of NADt-dependent deacetylases that are linked to aging and more recently shown to be involved in OA through the regulation of cellular energy and metabolism . The sirtuin SirT1 promotes chondrocyte survival and matrix gene expression. TNF-α cleaves and inactivates SirT1 and thereby contributes to reduced matrix gene expression . Mice heterozygous for SirT1 (+/−) with significantly decreased SirT1 expression developed premature OA-like changes at 9 months of age, which may be due to increased chondrocyte apoptosis .
Recent evidence  showed that a site within the promoter region of MMP-13 was demethylated in OA chondrocytes. It not only can make the cAMP response element bind to the promoter region but also can upregulate MMP-13 expression. Histone methylation is implicated in the age-dependent expression of the nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) that promotes cartilage homeostasis . In one study , miR-199a-3p and miR-193b were upregulated with age, whereas miR-320c was downregulated. These two upregulated miRNAs were found to reduce collagen and aggrecan expression in vitro, suggesting that they are antianabolic and may be involved in the age-related decrease in matrix gene expression. The development of postgenomics enabled the extensive and intensive study of the role of long noncoding RNA (lncRNA) in gene regulation . So far, few studies on microRNA and lncRNA have been reported in the field of age-related OA . A growing interest in this field of research may provide valuable clues to elucidate the pathogenesis of age-related OA.
OA-induced financial and social burdens have become more and more severe with aging of the population. Age-related changes in cartilage have been identified as critical factors in OA development. However, the underlying molecular mechanisms are not completely clarified yet, even though some theories have been proposed. Critical factors and signaling pathways that may play important roles in age-related changes of OA cartilage need to be further investigated. In addition, the importance of lncRNA in gene regulation is now better understood, and the potential role of lncRNAs as biological markers in diagnosis and prognosis of clinical diseases has also been considered. Studies focusing on these topics will provide more important clues for better understanding of the age-related OA.
The study was supported by Grant R01AR059142 from NIH/NIAMS and P20RR024484 from NIH/NCRR, NSFC 81071495, 81171676, and 81201435 SXNSF 2011011042. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. The authors gratefully acknowledge Ericka M. Bueno, Ph.D., for help with the paper preparation and editorial services.
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- O. Gabay, H. Oppenheimer, H. Meir, K. Zaal, C. Sanchez, and M. Dvir-Ginzberg, “Increased apoptotic chondrocytes in articular cartilage from adult heterozygous SirT1 mice,” Annals of the Rheumatic Diseases, vol. 71, no. 4, pp. 613–616, 2012.
- C. Bui, M. J. Barter, J. L. Scott et al., “cAMP response element-binding (CREB) recruitment following a specific CpG demethylation leads to the elevated expression of the matrix metalloproteinase 13 in human articular chondrocytes and osteoarthritis,” The FASEB Journal, vol. 26, no. 7, pp. 3000–3011, 2012.
- M. Rodova, Q. Lu, Y. Li et al., “Nfat1 regulates adult articular chondrocyte function through its age-dependent expression mediated by epigenetic histone methylation,” Journal of Bone and Mineral Research, vol. 26, no. 8, pp. 1974–1986, 2011.
- E. Steck, S. Boeuf, J. Gabler et al., “Regulation of H19 and its encoded microRNA-675 in osteoarthritis and under anabolic and catabolic in vitro conditions,” Journal of Molecular Medicine, vol. 90, no. 10, pp. 1185–1195, 2012.
- T. Ukai, M. Sato, H. Akutsu, A. Umezawa, and J. Mochida, “MicroRNA-199a-3p, microRNA-193b, and microRNA-320c are correlated to aging and regulate human cartilage metabolism,” Journal of Orthopaedic Research, vol. 30, no. 12, pp. 1915–1922, 2012.
Copyright © 2013 YongPing Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

domain: medical


text:
Easy And HEALTHY Zucchini Crust Pizza Recipe. This Is The BEST Way To Bake Your Own Pizza Without The Guilt! It's Full Of Healthy Carbs, No Gluten. Hopefully it tastes better than the cauliflower pizza crust!
15 Serious Salads to Start Your New Year’s Resolutions Right via Brit + Co. I always make the same resolutions: Eat more, drink more, have more fun. But these salads look good, especially this Sriracha Lime Chicken Chopped Salad.
Low Carb Lemon Cheesecake Bars - 3 oz package sugar-free lemon gelatin mix 2 tbsp lemon juice 8 oz packages low-fat cream cheese 1 cup boiling water Stir the boiling water into the box of jello, mixing for about 2 minute. Add the cream cheese and lemon

domain: food


text:
Volkert, a professional services firm with locations in nearly two dozen states, has opened an office in Springfield at 2925 Meadowbrook Rd. as of June 1.
“We do work across central Illinois with Ameren, Prairie Power, IDOT and regulatory agencies here in Springfield,” explained Meghan Oh, an environmental project manager who is based out of the Springfield office along with three other full-time staff and several part-time employees. “It’s a very centralized location, so it’s advantageous for us to be here.”
Volkert’s other office in Illinois is located in Collinsville, with more than 100 employees. Nationwide, the company focuses predominantly on transportation, except for the two Illinois offices, which are piloting an energy initiative.
“One of our main services is commercial real estate for public and private clients,” said Oh, noting that the company will work with land owners on easements, appraisals and relocations on behalf of both public and private clients. At the beginning of the year, Volkert also added new services for environmental surveys, studies and permitting.
“We’re hoping to provide a multi-disciplinary opportunity to clients,” said Oh. “We can be a one-stop shop and offer multiple services at one location.”
Leave A Comment

domain: news


text:
Sound off for April 13, 2014
The Fairfield-Suisun school board heard the results of a survey of residents about a possible parcel tax for schools.
Here are some comments from our website on an article before the meeting:
- Wake up people, zero percent should be supporting a parcel tax. Expenses need to be gotten under control, just like our own have to be . . . Aren’t we all taxed enough? . . . Do not give these vultures one more cent.
- I’m happy to support the parcel tax and increased accountability so our students remain well-prepared for the jittery and inconsistent economic future ahead. We need to invest in education.
- There is little question the district can more money to good use. State funding formulas notoriously underfund large suburban districts like FSUSD.
- I voted for Measure C some years back, thinking the money would be spent on better classrooms and buildings. I am still angry it was spent for the new district office and its furniture. Never again will I vote for school taxes. I really feel the voters were tricked on that one!

domain: sociology


text:
Man, free stuff has just been oozing out left and right these days. Here's the latest contest from my fabulous friend, Rachel Weingarten, who is an all-around culture guru and who has been quoted just about everywhere, including CNN and a gazillion other places. Her latest book, Career and Corporate Cool, is a must-have handbook for navigating even the stickiest of work situations.
Here's the lowdown on the book:
Imagine if life came with a handbook to help get you through just about every potentially awkward, stressful, or over-the-top situation, with humor, grace, and dignity intact. Life doesn't come with a handbook—but now business does. In Career and Corporate Cool™, style and marketing maven Rachel Weingarten defines and details the elements necessary to succeed and stand out in the modern work environment. It's filled with witty and user-friendly advice on building your personal brand equity in the business world while staying true to yourself. Part business memoir, part hybrid of business and style, Career and Corporate Cool™ is a cheat sheet for your professional life, with fun and helpful anecdotes from people who've been there.
And here are the details of the contest:
For those of you who have been waiting to get your hot little hands on a copy of my new book Career and Corporate Cool- now's your chance! To celebrate the first week of autumn on 9/25 from 9 to 5, we'll be having an all (work) day long promotional event that will include hourly giveaways including an icy cool diamond pendant, gift certificates to iTunes, Sephora, FabulousStationery.com, Barnes and Noble, autographed copies of my book, magazine subscriptions and more.
The rules are fairly simple: Purchase a copy of CAREER AND CORPORATE COOL™ from any online retailer on 9/25/07 between the hours of 9:00 a.m. to 5:00 p.m. (EST) and e-mail your receipt to email@example.com for a link with access to exclusive hourly updated content not included in the book. Once purchase is verified, you will be entered to win the cool prize for that hour, with one grand prize winner announced at the end of the workday.
Visit www.CareerandCorporateCool.com for more information and complete contest rules.

domain: literature


A L F A N E W S
Alfas new version of the Sportwagon is named Crosswagon and
was presented at the March 2004 Geneva Motor Show. It will have new bumpers and side skirts, and be 60 mm
higher than the original Sportwagon. Four wheel drive and the
1.9 M-Jet diesel engine will be only engine option with more
alternatives to follow. Crosswagon will go on sale in Italy in
October 04. [Crosswagon
147 2004 facelift
Alfa has given the 147 a mid-life facelift including a newly
designed grille and front and rear bumpers. 4-wheel drive
will be available. The car will be presented at the 2005
Paris Motor Show and go on sale early 2005.
The next generation 156 will be launched at the March 2005 Geneva
Motor Show as Alfa Romeo 158, –
probably skipping the 7 to get in sync with the
upcoming 148. It will be build on the Premium platform
developed together with GM and SAAB, and come in both 2 and 4 wheel
– FWD: 1.8 JTS 150bhp, 1.9 JTD 140bhp, 1.9 JTD 160bhp, 2.0 JTS
170bhp, 2.2 JTS 190bhp, 2.4 JTD 200bhp
– 4WD: 2.0 JTS 170bhp, 2.2 JTS 190bhp , 2.8 V6 JTS 230bhp, 3.2
V6 JTS 260bhp, Quadrifoglio 2.2 JTS Uniair 310bhp, GTA (Europe &
Japan) 3.2 V6 JTS bi-turbo 300bhp, GTA (USA) 4.2 V8 JTS Uniair 430bhp,
1.9 JTD 140bhp, 2.4 JTD 200bhp, 3.2 V6 JTD 250bhp.
156 GTA 3.7 V6
London-based Alfa Romeo tuners Autodelta has now also upgraded
the standard 156 GTA. The Autodelta GTA is
powered by a bored-out version of the existing 3.2 V6 unit,
engine capacity now up to 3750cc, delivering 328bhp at
7300rpm and capable of reaching 175mph! Autodelta’s own
styling and manufacturing dept. Creativestudio, has given both
the 156 and
147 a new, distinctive and even sportier look. It will be strictly customer built
and each one will have its own plaque carrying the serial
number. More on
156 GTA] [Autodelta
147 GTA 1]
147 GTA 2]
Italdesign will present their new Alfa Visconti concept at the
Geneva Motor Show March 2004. If everything goes as planned
for Giugiaro and Italdesign, the Visconti will be Alfa’s new
flagship car with it’s 3.2 litre 400bhp V6 twin turbo
engine. According to Italdesign, the concept is practically
ready for production and has been designed for all wheel drive
No return to the U.S. for Alfa
Alfa Romeo has shelved the plan to drive its sleek sportscars
back into the U.S. market in 2007. Head of the brand
Daniele Bandiera said they will rather focus on growing in
Europe and Asia.
GTV and Spider based on Brera concept
Alfa has decided that the Giugiaro/Italdesign concept Brera, which
was presented at the Geneva Motor Show 2002, will form the basis for
the upcoming 2005 Alfa GTV. The original Brera is a classic 2+2 seat
configuration with the bodywork entirely made of carbon fiber
composite and an all-new Alfa 4litre V8 engine with at least 400 hp.
The GTV will probably be somewhat modified and it will first appear at
the Geneva Motor Show in March 2005 and go on sale towards the
end of that year. Rumors has it that a Spider version will be
presented in Geneva 2006.
Italdesign has had a love affair with Alfa Romeo since it was
established and their recent creation was the spectacular Alfa Romeo Scighera
8C Competizione available
8C Competizione is designed and developed by Alfa Design Centre, and
was presented at the Frankfurt Auto Show 2003. Certain modifications –
especially the front – will be made, but the car will go on sale late
2004. A limited run of 1000 will be build at around € 100.000,-
each. The engine will probably be a modified version of the 400hp Maserati 4.2 litre, now with 480bhp! According to Alfa it will be
capable of 0-100 in 4.5 sec and pass the 300 km/h mark. The name is
classic Alfa going back to the pre-war 8 cylinder (8C) models, and Competizione comes from the
1950-model 6C 2500 Competizione Sports Coupé. [8C
Competizione 4] [8C
The GT Coupe was designed by the Bertone Style Centre and represents a
brand new concept of sportiness that blends comfort and elegance the
Italian way. With a length of 4.48 m, width of 1.76 m and a
height of 1.39 m, the GT is aggressive and compact. The car owes its performance to a mechanical
layout that has borrowed the very best features from the 156,
including three power units, the 140 bhp 1.8 T.Spark, the 165
bhp 2.0 JTS and the 150 bhp 1.9 JTD MultiJet 16V. Those who want the
very best in terms of performance and sportiness can choose the GTA
version equipped with a powerful 240 bhp 3.2 V6 24 valve engine and
equipped with 6 airbags, Bose Hi-Fi with CD/MP3-player, cruise contol,
xenon lights nav system, 17" wheels etc. It will go on sale late
A 166 facelift was first shown at the 2003 Frankfurt Show in
September. Four engine alternatives will be available;
150bhp 2.0 TS, 188bhp 2.5 V6 24v, 220bhp 3.0 V6 and 240hk 3.2 V6 24v
plus 2 diesel options – 150bhp 2.4 JTD 10v and 175bhp 2.4 Multijet 20v.
The 166 will come with three styling options: Impression,
Progression or Distinctive, – plus a lowered TI version with 18"
wheels and black leather with an embroidered red TI logo.
& Sportwagon 2003 facelift
Both the 156 and the Sportwagon has
got an elegant update signed Italdesign and Giorgetto Giugiaro
himself. Italdesign was also responsible for the Brera concept, now
going into production as TZ3.
Alfa 156 made it’s debut in 1997 and Walter deSilvas excellent
design is still a knock out. The 2003 Italdesign facelift is therefore
pretty discrete. The front has got a larger grille, a narrower bumper
and changed headlights. More Alfa if you like. Inside, the dash is
slightly modified – with a leather-trimmed facia for some models, and
a new video/nav-display.
New color options and a microfiber cloth – Alfatex – for parts of
the interior has been developed and patented by Alfa. Several new
engines are offered and Selespeed will be available on even more
models. The sporty TI – Turismo Internazionale – is also offered.
& Spider 2003 facelift
The current, long serving GTV and Spider final facelift
was presented at the Geneva Motor Show in March 2003. Now with a much larger and more aggressive grille together
with a deeper front spoiler. They both come with newly designed 16" light alloy
wheels and three body shade options: Brunello Red, Racing Green and
Cobalt Blue. The dashboard has been reworked, while a new centre
console which houses the optional sat-nav system as well as radio and
ASR controls. New seating
trims are available, to seats that have been lowered as Alfa seek to
improve the model’s centre of gravity. Two new engines are offered.
The 240bhp 24V 3.2-litre V6 with a 255km/h top speed, and the 165bhp
2.0-litre JTS unit. Also a reworked 150bhp 2.0-litre TwinSpark is
SUV concept revealed at Geneva
The Kamal concept presented at the Geneva International
Motor Show 2003 is a little shorter that the 156 Sportwagon, but high
enough (1620mm) to be clearly a SUV in its concept. The vehicle is
designed by the Arese Style Centre and was shown as an exterior-only
model. The rugged yet voluptuous design shows a likely future
direction for Alfa Romeo and would be a logical addition to their
current range, and could share parts with the 147 and 156. Kamal is
powered by 3.2 litre V6 with 250bhp driving all four wheels. [Kamal1]
comeback for the TI
The TI – Turismo Internazionale – is back. The letters used to be assigned to
Alfa’s best-equipped cars. Standard production models which underwent
both styling and mechanical changes to create thoroughbred sports car
for the ordinary road. They now designate a sporty kit that will be
available for the whole Alfa range. The code stands for quality and a guarantee
that changes such as wider tyres, alloy
wheels and sideskirts have been made in the factory. The TI interior
will be identified by
sporty configuration seats, leather-trimmed steering wheel and
gear knob, an aluminum sill plate and
black facia and ceiling. [147 TI]
to be given the green light?
The "m" version of the 156 GTA displayed at the Bologna Motor Show
in December 2002, will probably be given the green light for a 500
unit run. Built by N-Technology – Fiat’s competition department – the 156 GTAm
transfers racing technology from the 2002 156 GTA SuperTouring race
cars (which swept all before them in the European Touring Car
Championship) into a car designed for the road with an
increased version of the 147/156 GTA 3.2-litre V6 engine. The cylinder
displacement has been increased to 3548cc and power is
raised from 250 to 300 hp. The body wings and bonnet have
also been changed to composites for less weight. The light alloy
wheels are 8 x 19" fitted with 235/35ZR19 tyres. The sports ride
set-up is also new with height-adjustable shock absorbers by Bilstein
with Eibach springs, and the front brakes come with bigger Brembo
calipers and 330 mm discs. [GTAm1]
166 GTA with 300 hp
Alfa will launch a GTA version of the 166 at the end of 2003.
The car will get a mild facelift, 4×4 and an upgraded version of the
current 3.2 liter GTA engine, now with 3.5 liter and 300 hp. Along
with the GTA, other options will be a 2.0 JTS w/165 hp,
a 2.5 V6 w/192 hp, a 3.2 V6 w/225 hp. Two
diesel alternatives; 150 hp 2.4 JTD and 180 hp 20V 2.4 JTD.
and Spider back to the drawing board
Next generation GTV and Spider have been sent back to the drawing
board. The Alfa management including boss Daniele Bandiera and Fiat CEO Giancarlo Boschetti
haven’t so far been happy with the results presented. If this means
that Pininfarina is out of the picture, I don’t know. The GTV was
expected in the fall 2004 and the Spider sometime spring 2005, but due
to the redesigning, the release plan most likely has to be pushed
back. Rumors still has it that the new models will be "significantly"
different visually, breaking with the pattern of the current model’s
almost identical looks. Sketches: [Spider1]
Alfa design studies
The Master’s Transportation Design students at Pauda Design College
have been working on a project assigned by Alfa’s design dept. Centro Style.
Among the many suggestions, the Alfa "Corsa" and "Eva"
was chosen. The Corsa concept is back wheel drive 2+2 coupe – quite
Ferrari 360 Modena from behind – while "Eva" is an extreme 2-seater
with design details from the 50’s Formula 1 Alfas.
US re-launch delayed
Fiat are to delay the US re-launch of their Alfa Romeo brand again,
now aiming to introduce it to American customers in 2007, two years
later than originally planned. It is believed that factoring stringent
US safety and emission regulations into new models has caused problems
and delays, particularly with the new Spider which was expected to
lead the re-launch. Initially Alfa Romeo were planning to re-launch
the new Spider and GTV in 2005, these being joined by the 156 and 166
replacements as they came on stream. However with Fiat’s enormous
debts, funding an expensive US-wide advertising and promotional
campaign for one model and subsidizing the new dealer network until a
full range becomes available is not viable. With the 156 replacement
due in 2004, the 166 in 2005, the 147 in 2006, and a SUV [Sports Utility Vehicle] in the pipeline, a
2007 re-launch will give Alfa Romeo the opportunity to introduce a
full range of models.
wins the 2002
ETCC [European Touring Car Championship]
For more than 30 years the GTA logo has been used to identify Alfas
prepared for racing. Nordauto’s close link with Alfa has resulted in the
Nordauto GTA Racing Team competing with the new 156 GTA in the European
Touring Car Championship (ETCC). After a superb performance in 2001 – (1st
and 2nd place in the Drivers Championship, and
1st in the Team Championship), Alfa Nordauto have done it again! First
place for both driver and team in ETCC 2002. The Alfa team did great
all through the 2002 season with 13 wins out of 18! The domination was
in fact so strong that FIA midway in the season decided to
make new rules to "optimise the equality
of performances between the cars". Front-wheel drive cars (Alfa Romeo)
was loaded by 15 kg ballast and rear-wheel drive cars had the weight reduced by 15 kg. Alfa Rules! [www.teamnordauto.com]
The 147 GTA made its public debut at the 75th Paris Motor
Show in September. The 147 GTA is fitted with the 3.2-litre 24v V6
engine from the 156 GTA. Along with this powerplant it has a revised
suspension set-up, upgraded braking and improved safety systems, GPS
navigation and 17" alloy wheels with 225/45 tyres.
Special Editions 2002
2 different versions of the Spider has been introduced. The
Edizione Sportiva and
Edizione Elegante. They both have newly designed
leather seats and 17" rims [with 225×45 tyres], and white
side blinkers. The Sportiva also has air vents situated behind the
front wheels. [Read
Center College of Design showes Alfa design
Art Center College of Design recently hosted its Spring 2002 Graduation
Senior Show, featuring work from ten graduating students in the
Bachelor of Science – Transportation Design program. Among the designs
presented was the Alfa Romeo GT Sedan "Elessa" by Tom Matsumoto and
the Alfa Romeo GT "Xapher" by Jae Shin. Shin felt that Alfa needed a
front engined, rear wheel drive, two seater. His goal was to make a
one of a kind car, – just like the Viper and the TT. The "Xaphers"
front design is very aggressive and the overall design is very
romantic which hints at the flavor of Italy. Tom Matsumoto proposed
the "Elessa", – a GT sedan, which would have a strong impact as well
as make profitable sales. The "Elessa" is beautifully proportioned,
with a fluid and sculptural form. A triangular grill, character line
on the body side and a thin long tail lamp signal that this is
unmistakenably Alfa Romeo.
[Art Center College of Design]
156 and Sportwagon facelift
The 2002 upgrade for 156 and Sportwagon has been released in Italy. A new
JTS [Jet Thrust Stoichiometric] engine is replacing the old Twin Spark. The 2.0 liter now comes
with 165 hp. Other new details are Xenon lights, Bose sound system and
a completely new facia [with
the optional infotelematic tool "Connect"].
The Transportation Design students
at the Art Center College of Design in
Pasadena presented their works recently.
Among the concepts was sketches of what could be the next generation
Alfa Romeo GTV. The drawing is
by student Taehoon Kim, and is
Art Center College of Design is one of the
world’s leading in Transportation Design.
Probably more than half the world’s cars
are designed by former students.
The introduction of
the GTA version [like the BMW M versions] in each model range has started
147 GTA, 156 GTA and the Sportwagon GTA. The GTA will include lowered suspension, newly
designed 17 inch wheels with 225/45 tires, enlarged brakes,
Xenon lights, head airbags, better quality dashboard
with GPS navigation and telematic system. The classic
Alfa V6 now has 3.2 liters displacement, and 24 valves, and
the output is 250 bhp. The interior will have a general mild
upgrade and feature sports seats and steering wheel.
The 166 GTA is expected late 2003 and GTV/Spider GTA will be developed for the next
generation, and are scheduled for a 2004/5 release.
recently did a review of the Sportwagon GTA and says:
«Quite simply, it’s possibly the sports car bargain of the decade – and an
estate to boot» Not bad 🙂
For those of you understanding Norwegian, both the magazines
and Drive have taken the 156 GTA for a spin, and give top ratings!
3. generation Sportwagon
The Transportation Design students the the Italian L‘Instituto d’Arte
Applicata e Design di Torino showed their work in July 2001.
The project was based on Alfa sportconcept and the planning of the
3. generation Sportwagon with backwheel drive. See the works by
Fabio Miniati, and
Michele di Lillo.
147 with extra muscle
UK company Autodelta have launched 2 turbo-versions of the Alfa
147 called "J12" and "
J12 Evo" – in
the same series as the J10 Spider/GTV and
J11 156. Autodelta has modified Alfa’s EOBD version III T-Spark
engine (1.6 and 2.0 liter), which has been used by Alfa since the end of 2000. "J12 Evo" –
the 2.0 liter – will manage 0-100 km/h at 5.7 sec. and 240+ km/h. Also read more
about the Alfa 147
Fiat and GM joint venture
In March 2001, General Motors and Fiat Auto formed a joint venture.
Because of this, the next-generation 156, Sportwagon and Spider will
be based on GM’s Epsilon II platform rather than one of Fiat/Alfa’s
own platforms. Alfa’s re-entering the US market will start with
showing off the Spider at the Detroit Auto Show in January 2005 and
sales will start the same year in dealerships shared with Saab and
Autonis – Germanys first cadesign award
I’ve of course always thought that most Alfas looks great, and now
more than 50.000 readers of the German mag AutoStrassenverkehr
do agree. "Die Schönsten Autos 2001"
was chosen in 12 categories and among 339 different models.
Alfa Romeo won TWO categories: The compact class
– Alfa Romeo 147, and the stationwagon
class – Alfa


UPDATE - 8:55 P.M. - 22nd Street and Lorraine Road have been reopened to traffic following a temporary closure due to a crash. Thank you for your patience.
ORIGINAL POST - 6:45 P.M. - The Wheaton Police Department is currently responding to a traffic crash near 22nd Street and Lorraine Road. 22nd Street is currently closed between Lambert and Briarcliffe, and Lorraine is closed between Buena Vista and 22nd Street. Drivers are advised to avoid the area and find an alternate route while officers conduct an investigation.


text:
NEW PHILADELPHIA -- A Perry Township Search and Rescue benefit is set for Sunday, April 12 from 5 to 7 p.m. at the Park Place Teen Center, Tuscora Park, New Philadelphia. The benefit will feature the many voices of Randy Velez.
There will be door prizes, 50/50 raffle and silent auction.
Tickets are $5 for those 18 years and older; 17 and under are free.
To learn more about Velez, visit www.randyvelez.com or facebook.com/velezvocals.


text:
(Last Updated on : 24/02/2014)
Kannada language newspapers are mostly published from several major cities of southern India like Bengaluru
, Manipal, Mangalore
, etc. Some of the Kannada language newspapers concentrate only on providing local news, while many of them provide all types of local, national and international news catering to the need of the readers. Kannada is counted amongst the major Dravidian languages
in southern India and is also considered one of the oldest languages in India. Kannada is the official state language of Karnataka
and is included among the official languages of India. Kannada language newspapers have huge circulation in southern India.
The history of Kannada language newspapers dates back to the early half of the twentieth century, during the freedom movement of India. Like most of the newspapers in other languages, Kannada language newspapers also started their journey as a powerful instrument to fight against the British rule. They propagated and promoted patriotism, truth and nationalist ideals and encouraged the young Indians to try to free India from the rule of the British. Among the oldest Kannada language newspapers, Samyukta Karnataka is considered one of the prominent ones. Mohare Hanamanthraya, a renowned literary person and journalist, started the newspaper in the year 1929 and it was published by the Loka Shikshana Trust.
After India attained independence, Kannada language newspapers started to emphasise on the other important issues regarding the total development of Karnataka as well as of India. They started to cover relevant news items giving importance to the need of rural development, the upliftment of underdeveloped sections of people, the need of increasing literacy rate in the state, etc. The ownership pattern of the Kannada language newspapers also changed with time. Most of the Kannada language newspapers were run by private ownership in their initial period.
There are many Kannada language newspapers that have served the media industry significantly and have also earned significant recognition. Some of the prominent Kannada language newspapers include Hosa digantha, Kannada Prabha, Kranti Kannada Daily, Prajavani, Samyukta Karnataka, Sanjevani, Sanmarga, Udayavani, Usha Kirana, Vartha Bharathi and more. Prajavani is considered as the largest circulated Kannada newspaper in the recent years and it is the sister publication of the Deccan Herald. The Kannada language newspapers are playing an important role in disseminating valuable information about the latest happenings in and around the world.

domain: library


text:
I watched her hovering near the back door. Snowballs were flying fast and furious and she was clearly torn between staying away, where it was safe, and throwing herself into the fray.
With a final longing look at the warmth and safety of the kitchen she leaned forward and scooped up a handful of snow. She threw it blindly at her little brother and dashed towards the swingset.
“This is home base!” She called as her hand connected with the swing. “You can’t get me here!”
She was now closer to the action, but her declaration had once again set her safely away from the thick of it. The smile pasted on her face as she ran faded and was once again replaced with longing. But this time she didn’t let go of the swing, didn’t put herself in the middle again. She was safe. Alone, isolated, but safe.
I watched her sadly. She so wanted to be in there having fun with everyone throwing snow around, laughing hysterically as it dripped down their backs into their pants. I wanted to go over and encourage her, tell her it would be ok to relinquish control for a moment, to let herself go.
Instead I lifted my camera to my eye and snapped a picture of her sad face.
C came into blurry focus in the viewfinder just as I was about to take another, snow filled mitten raised, aiming directly at me.
“No! Not me! I have the camera!”
Her face fell for a moment, then she shrugged and turned, pelting her uncle in the back.
I smiled and raised the camera to my face again. Snow and laughter whirled around me and I looked longingly at the powder at my feet. Maybe I could find a safe spot to put down the camera and join in the fun… But every surface glistened with wet snow.
Suddenly it occurred to me that I was drawn to my niece’s plight because it was the same as mine. I knew how she felt because it was how I felt – wanting to be in the middle of the fun, not knowing how to bridge the gap between the fringe and the inner circle. Wanting to play, not wanting to get wet and messy.
Snow swirled around my island of safety. With an expensive camera in hand no one would dare pelt me with a snowball. I was not languishing by the house or near the swing set, but I was no less holding back than the child I framed in the shot. Just as the shutter closed she let go of the swing with a shriek and threw herself into the snowball fight with complete abandon. Her giggles filled the yard, joining her cousin and parent’s giggles.
I just took another picture.

domain: artistic


LegaPro announced the name of the Sambenedettese-Reggiana’s referee. He will be Mr. Andrea Giuseppe Zanonato from Vicenza. Zanonato has called Ac Reggiana once during the season: the 0-0 in Lumezzane. Zanonato’s first assistant will be Mr Franco Tribelli from Castelfranco Veneto. The second assistant will be Mr. Nicola Badoer from Castelfranco Veneto.


Nike is teaming up with Womans Sportswwear for a new line of womens sportshoes.
The brand will launch the first womens shoes featuring the new Womanic Swoose.
The new womens footwear will be released in early 2019.
The womens shoe collection is designed to feature an assortment of Nike’s most popular womens style silhouettes.
The new womans footwear collection is the latest installment of Nike Womains original line of women’s shoes.
Womans sportswears are traditionally a limited-edition line that is limited to specific retailers and events.
Nike’s original womens sneaker line has been a hit for Nike over the years.
Nike launched the Womancaster in 2010, which has sold out over the last decade.
The Womacanaster is still available at Nike’s retail stores and online.
The womens brand is also adding a new women’s shoe, the WOMAN CORE.
The Nike WOMANCaster is currently available at the Nike+ online store and Nike+ at the shoe retailer.
The shoe will be available for purchase in June 2019.
The Nike WOOMANS collection includes women’s sports footwear, men’s footwear, and womens apparel.
It also includes womens accessories, including womens socks and womans handbags.WOMANS sportswatches are the first Nike womens collection to feature the WOAMAN COSMO shoe.
The shoes were unveiled at the Women’s Wear Daily 2017 event in New York City.
The WOMANS WOAMPANACE will be Nike’s first womans sport shoe in five years.
The sneakers are available for pre-order now.


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$98 BridgeClimb Ticket
Enjoy some of Sydney’s best views with your $98 BridgeClimb Ticket
The Bridgeclimb Sydney is turning 21.
And to celebrate they are offering some lucky visitors a Bridgeclimb at 1998 prices – which is just $98.00!
Tickets are a available for the day of Bridgeclimb’s birthday, which is Tuesday 1 October 2019.
And to keep the party spirit happening, once at the summit you’ll enjoy a soundtrack of hits from 1998.
So read on to find out how you can get a $98.00 BridgeClimb Ticket.
How do I get a $98 BridgeClimb ticket?
To get your $98.00 tickets you will need to be quick!
Tickets will go on sale at exactly 9.00am on 12 September 2019.
Tickets are limited so you’ll need to get in early.
You will need to book your tickets online.
How else is the Bridgeclimb celebrating?
But the fun doesn’t just stop there.
Can’t afford the Bridgeclimb?
The Pylon Lookout offers pretty amazing views too
Even if you can’t afford the BridgeClimb, one of the best things to do in Sydney is to walk across the Harbour Bridge. This amazing FREE walk takes you across the Harbour Bridge leaving from either Milsons Point or The Rocks.
Or if you want to just head up onto the Bridge for a short walk or a quick squizz at the view, then the lifts at various points around the Bridge make this possible.
For a cheaper alternative to the BridgeClimb (but still pretty awesome) you can head to the Pylon Lookout. Which for $15.00 entry offers amazing views across the harbour, as well as a neat museum which provides great info on the history of the Sydney Harbour Bridge.
Terms and Conditions for $98 BridgeClimb Ticket
For full terms and conditions make sure to check out the BridgeClimb website.
Offer: $98.00 BridgeClimb tickets valid for 1 October 2019
On sale: 9.00am, 12 September 2019
Contact: 1300 90 80 57 or email

domain: travel


There was tension on Thursday night as two legislators clashed on a television show over the recent Apaa land clashes that have claimed lives in Amuru and Adjumani districts.
Hon. Gilbert Olanya (Kilak South County MP) and Hon. Ababiku (Adjumani WMP) nearly removed their gloves as they disagreed on Amuru land question while appearing on “NBS Frontline” programme.
Hon. Ababiku kicked off the discussion by accusing fellow legislators of fuelling land wrangles just after Olanya had accused first deputy Prime Minister, Gen Moses Ali, of being behind the conflicts.
“First of all, I want to say that MPs are the ones instigating the clashes and Gen. Ali didn’t sell any land,” Ababiku stated.
She said Hon. Olanya is the team leader of the people who are instigating these clashes.
“This issue didn’t start yesterday. It was started by political leaders especially Olanya. I have the evidence,” she went on, opening a Parliamentary report.
She said that to say the map of UK is final to confirm boundaries of this country is ‘fake’.
“I believe Olanya mobilized/ferried these people. If you go there after 6 months, you will not find them there.”
This was corroborated by government spokesperson, Ofwono Opondo, who maintained that people were ferried from Pabbo to Apaa to cause clashes.
Hon. Olanya, in defence, said what his colleague was explaining was quite wrong.
Olanya said he wasn’t part of the committee Ababiku was talking about.
In 2005, Gen. Ali gave to an investor because the land was vacant [the Acholi were still in camps], Olanya explained.
The dramatic exchange
Olanya: We want security to be provided and let people cultivate. People are stuck in camps.
Ababiku: We want government to solve this. We are tired. Our people are in camps.
Olanya: But Adjumani is not affected. Which camp?
Ababiku: I have proved that Olanya is a liar. I have showed you the documents. Hon. Olanya is mobilising the event beyond Amuru.
Olanya: It’s unfortunate that my colleague (Ababiku) was coached poorly. We want government to degazette that land and let people live in.
Ababiku: No! No! We don’t want.


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South Korea's tax agency said Wednesday that it has collected some 40 billion won (US$35.8 million) in taxes from nonprofit organizations run by the country's conglomerates over their illegal wealth transfers.
The National Tax Service said they had not reported wealth transfer taxes to related authorities and even their holdings of stocks in affiliates that exceeded a certain level.
Currently, stock holdings are exempted from taxation if the stake in an affiliate does not exceed 5 percent.
Such organizations have been under fire for their roles in helping expand business group owners' control over various companies.
In December last year, the Fair Trade Commission (FTC) started an investigation into such organizations.
According to the FTC, 51 conglomerates subject to a slew of strict regulations had set up 165 foundations with average assets of 123 billion won by the end of 2016.
The corporate watchdog said that group founding family members, heads of affiliated companies and related parties took board seats at 138 foundations.
Sixty-six nonprofit organizations, or 40 percent, hold stocks in 119 companies affiliated with the conglomerates, accounting for 74 percent of stocks held by such organizations as assets.
Meanwhile, the government is moving to revise relevant laws to ban these organizations from wielding voting rights in group affiliates. (Yonhap)

domain: finance