The Essendon Football Club, nicknamed the Bombers, is a professional Australian rules football club that plays in the Australian Football League, the sport's premier competition. Thought to have formed in 1872, the club played its first recorded game on 7 June 1873 against a Carlton Second 20, winning 1 goal to nil; the club played a senior club in the Victorian Football Association in 1878, one year after the VFA formed. It is associated with Essendon, a suburb in the north-west of Melbourne, Victoria. Since 2013, the club has been headquartered at The Hangar, Melbourne Airport, plays its home games at either Docklands Stadium or the Melbourne Cricket Ground. While it stopped playing games at the ground thereafter, Windy Hill remained its training and administration base until the end of 2013. Dyson Heppell is the current team captain. A founding member club of both the Victorian Football Association, in 1877, the Victorian Football League, in 1896, Essendon is one of Australia's best-known football clubs.

Essendon has won 16 VFL/AFL premierships, along with Carlton, is the most of any club in the competition. The club won four consecutive VFA premierships between 1891 and 1894, a feat matched only by Collingwood between 1927 and 1930; the club was founded by members of the Royal Agricultural Society, the Melbourne Hunt Club and the Victorian Woolbrokers. The Essendon Football Club is thought to have formed in 1872 at a meeting it the home of a well-known brewery family, the McCrackens, whose Ascot Vale property hosted a team of local junior players. Robert McCracken, the owner of several city hotels, was the founder and first president of the Essendon Football club and his son, its first secretary. Alex became president of the newly formed VFL. Alex's cousin, Collier McCracken, who had played with Melbourne, was the team's first captain; the club played its first recorded match against the Carlton second twenty on 7 June 1873, with Essendon winning by one goal. Essendon played 13 matches in its first season, losing two.

The club was one of the inaugural junior members of the Victorian Football Association in 1877, began competing as a senior club from the 1878 season. During its early years in the Association, Essendon played its home matches at Flemington Hill, but moved to the East Melbourne Cricket Ground in 1881. In 1878, Essendon played in the first match on what would be considered by modern standards to be a full-sized field at Flemington Hill. In 1879 Essendon played Melbourne in one of the earliest night matches recorded when the ball was painted white. In 1883 the team played four matches in eight days in Adelaide: losing to Norwood, defeating Port Adelaide, a combined South Australian team, South Adelaide. In 1891 Essendon won their first VFA premiership, which they repeated in 1892, 1893 and 1894. One of the club's greatest players, Albert Thurgood played for the club during this period, making his debut in 1892. Essendon was undefeated in the 1893 season. At the end of the 1896 season Essendon along with seven other clubs formed the Victorian Football League.

Essendon's first VFL game was in 1897 was against Geelong at Corio Oval in Geelong. Essendon won its first VFL premiership by winning the 1897 VFL finals series. Essendon again won the premiership in 1901; the club won successive premierships in 1911 and 1912 over Collingwood and South Melbourne respectively. The club is recorded as having played at Glass' Paddock and Flemington Hill, it is that these are three different names for the one ground, given that McCracken's Paddock was a parcel of land that sat within the larger Glass's Paddock which in turn was situated in an area known at the time as Flemington Hill. In 1882 the club moved home games to the East Melbourne Cricket Ground, after an application to play on the Essendon Cricket Ground was voted down by Lord Mayor James Taylor on the basis that City of Essendon the mayor considered the Essendon Cricket Ground "to be suitable only for the gentleman's game of cricket",The club became known by the nickname "the Same Old Essendon", from the title and hook of the principal song performed by a band of supporters which occupied a section of the grandstand at the club's games.

The nickname first appeared in print in the local North Melbourne Advertiser in 1889, ended up gaining wide use as the diminutive "Same Olds". This move away from Essendon, at a time when fans would walk to their local ground, didn't go down too well with many Essendon people, it was known firstly as Essendon Town and, after 1905, as Essendon. After the 1921 season, the East Melbourne Cricket Ground was closed and demolished to expand the Flinders Street Railyard. Having played at the East Melbourne Cricket Ground from 1882 to 1921, having won four VFA premierships and four VFL premierships whilst there, Essendon was looking for a new home, was offered grounds at the current Royal Melbourne Showgrounds, at Victoria Park, at Arden St, North Melbourne, the Essendon Cricket Ground; the Essendon City Council offered the team the Essendon Cricket Ground, announcing th

External fertilization is a mode of reproduction in which a male organism's sperm fertilizes a female organism's egg outside of the female's body. It is contrasted with internal fertilization, in which sperm are introduced via insemination and combine with an egg inside the body of a female organism. External fertilization occurs in water or a moist area to facilitate the movement of sperm to the egg; the release of eggs and sperm into the water is known as spawning. In motile species, spawning females travel to a suitable location to release their eggs. However, sessile species are less able to move to spawning locations and must release gametes locally. Among vertebrates, external fertilization is most common in amphibians and fish. Invertebrates utilizing external fertilization are benthic, sessile, or both, including animals such as coral, sea anemones, tube-dwelling polychaetes. Benthic marine plants use external fertilization to reproduce. Environmental factors and timing are key challenges to the success of external fertilization.

While in the water, the male and female must both release gametes at similar times in order to fertilize the egg. Gametes spawned into the water may be washed away, eaten, or damaged by external factors. Sexual selection may not seem to occur during external fertilization, but there are ways it can; the two types of external fertilizers are nest builders and broadcast spawners. For female nest builders, the main choice is the location of. A female can choose a nest close to the male she wants to fertilize her eggs, but there is no guarantee that the preferred male will fertilize any of the eggs. Broadcast spawners have a weak selection, due to the randomness of releasing gametes. To look into the effect of female choice on external fertilization, an in vitro sperm competition experiment was performed; the results concluded that there was a decreased importance of sperm number, but increased the importance of the sperm velocity, thus changing the outcome of sperm competition. The ovarian fluid increased the paternity for the preferred male because they release fewer and faster sperm.

The success of a male fertilizing an egg relies on the ability of a male's sperm to outcompete other sperm, looking to fertilize the same egg. Sperm chemotaxis is the use of chemical signals to give sperm the ability to navigate an egg and is a huge contributor to reproductive success. Benthic sessile animals that make up the majority of invertebrates using external fertilization rely on ambient water motion to bring the sperm and eggs together. Other invertebrates that externally fertilize are organisms like the sea urchin, are confined to shallow burrows on exposed shores. Turbulent flows in the surf zone create a transport of gametes. Hydrodynamic conditions and gamete properties control the efficiency of fertilization because they influence the rate at which the water mixes; the only dilemma with turbulence is the possibility of dilution of sperm and egg because of over mixing. Rapid mixing can cause a lower probability to fertilize. Sessile adult staged animals produce gametes at the same times known as a synchronized release of gametes, for external fertilization in the water column.

This is helpful because of the lack of mobility these organisms share. They can rely on turbulent mixing and sperm mobility to enhance the chances of fertilization; the presence of food, favorable environmental conditions, the lack of predators are thought of when thinking of survival of the next generation. When the female is producing eggs, they perform predator satiation, when multiple females will release gametes in a mass reproductive event; the Great Barrier Reef is known for having a “mass spawn.” This occurs the week after the full moon in October. This mass reproductive event is given by reef forming corals, which perform a synchronized release of gametes in one evening from dusk to midnight. Up to 130 species release gametes during this time. In some cases, fertilization can take place on a spawning animal's surface and when the animals are in the turbulent wake. Although fertilization is thought of as a short-term process, there is the possibility of gametes being retained on the surface of an animal for an extended period of time.

In order to release an egg or sperm over time, clumps are formed that float in the water column. This allows for a variation in locations and time differences of fertilization taking place by the same invertebrate; the earliest amphibians were all internal fertilizers. It wasn't until 300 million years ago that the Caudata orders had begun. Most anurans now externally fertilize. Anurans are the amphibians lacking a tail such as toads. Anurans are used as a model organism for amphibians, because of the large, easy to manipulate eggs, fast developmental rate, high fecundity rate, no parental involvement, external fertilization. Males will pond and establish calling stations. Females approach the area and listen to all of the different male calls, continue to move towards the mate she chooses; this is the anuran's sexual selection. It has been concluded that females prefer a male with a more attractive call, the larger male. Copulation occurs, they move to a spot near water to release their sperm and eggs.

Other males in the area can release sperm onto the eggs to attempt to fertilize the eggs. If the female does not want to reproduce with the male that jumps onto her back, she will wait until the male leaves or move to a new location. Sperm released into the water must be in close

Receptor activator of nuclear factor κ B known as TRANCE receptor or TNFRSF11A, is a member of the tumor necrosis factor receptor molecular sub-family. RANK is the receptor for RANK-Ligand and part of the RANK/RANKL/OPG signaling pathway that regulates osteoclast differentiation and activation, it is associated with bone remodeling and repair, immune cell function, lymph node development, thermal regulation, mammary gland development. Osteoprotegerin is a decoy receptor for RANK, regulates the stimulation of the RANK signaling pathway by competing for RANKL; the cytoplasmic domain of RANK binds TRAFs 1, 2, 3, 5, 6 which transmit signals to downstream targets such as NF-κB and JNK. RANK is constitutively expressed in skeletal muscle, liver, small intestine, adrenal gland, mammary gland epithelial cells, vascular cell, pancreas. Most activation of NF-κB is mediated by RANKL, but over-expression of RANK alone is sufficient to activate the NF-κB pathway. RANKL is found on the surface of stromal cells, T cells.

RANK is a 616 amino acid type. Its extracellular domain consists of 184 amino acids, its transmembrane domain has 21 amino acids, its cytoplasmic domain consists of 383 amino acids. Like other members of the TNFR family, it has four extracellular cysteine-rich pseudo-repeat domains, it shares 40% amino acid identity with CD40. RANK is encoded on human chromosome 18q22.1. It shows 85% homology between mouse and human homologues. There are two monomers of RANK related by noncrystallographic 2-fold symmetry perpendicular to the long axis of the molecules in the asymmetric unit. RANK contains four CRDs spanning a length of 100 Angstroms which makes it the longest member of the TNFR family to date; the binding of RANKL to RANK activates a signaling pathway. The RANK-RANKL complex forms a heterohexameric complex. Only two of the four RANK CRDs are in direct contact with the RANKL; the majority of the complex’s residues are hydrophilic. Unlike other members of the TNFSF, each surface interaction in RANK-RANKL is continuous.

TRAF6 has been shown to be imperative to the RANK-related osteoclastogenesis pathway. RANKL binds to RANK, which binds to TRAF6. TRAF6 stimulates the activation of the c-jun N-terminal kinase and nuclear factor kappa-b pathways which trigger differentiation and activation of osteoclasts; this system is balanced by the relative expression of OPG to RANKL, which are regulated by many factors including hormones, immune signals, growth factors. An overexpression of RANKL can cause an overproduction and activation of osteoclasts, which break down bone; the balance between RANKL and OPG is a target for therapy in many diseases including estrogen deficiency-associated osteoporosis, rheumatoid arthritis, Paget’s disease, periodontal disease, bone tumors and malignancies. RANK has been shown to be a key in the thermoregulation signaling in females, which seems to be regulated by ovarian sex hormones. RANK is expressed in key regions of the brain associated with thermoregulation. Inactivation of RANK in these regions causes a loss of fever response to increased levels of RANKL.

It has been shown to be a critical mediator of fever response to lipopolysaccharide-induced fever and pro-inflammatory cytokines IL-1B and TNFa. This key role of the RANK-RANKL system may link the osteoporosis and hot flashes seen as symptoms of hormonal changes in post-menopausal women. RANK is constitutively expressed in mammary epithelial tissues. Calcium transferred from mother to fetus and neonate is provided by the degradation of the female bone by increased osteoclastic activity, regulated by the RANK/RANKL axis. RANKL works through RANK to provide proliferative and survival signals to promote the final stages of lactating mammary gland development. Dysfunctional RANK or RANKL causes the arrest of differentiation and expansion of the alveolar bunds into mature lobulo-alveolar mammary structures, disabling the production of milk. RANK and RANKL have been reported to be expressed in some breast cancer and prostate cancer cell lines. RANKL expression in infiltrating T cells within mammary carcinomas activate RANK-expressing neoplastic mammary epithelial cells which stimulate metastasis.

The expression of RANKL in these cells and the expression of RANK in bone cells may be the biological presentation of Paget’s seed and soil idea. The affinity for RANK of RANKL may be the reason. Once the tumor is seeded in the bone, the tumor cells stimulate bone resorption by secreting factors such as RANKL or prompting the surrounding stroma to express growth factors; these growth factors upregulate production of RANKL which leads to osteoclastogenesis and bone destruction. The destruction of bone releases more growth factors and RANKL which induces more osteoclastogenesis, triggering a vicious cycle of bone destruction, seen in metastatic bone tumors. Most therapies that target the RANK/RANKL/OPG axis aim to either down-regulate expression of RANKL or upregulate the expression of the decoy receptor OPG. For example, denosumab is a human monoclonal antibody, directed against RANKL. In phase I and II trials, denosumab led to a decrease in bone resorption in multiple myeloma, prostate cancer and breast cancer patients.

Another study looked into developing small mimetics based on the structure of OPG that bind to RANK as well as RANKL and cause defective coupling between the two. RANK has been shown to interact with: TRAF1, TRAF2, TRAF3, TRAF5, TRAF6. RANKL Osteoprotegerin Osteoimmunology RANK+Protein at the US National Library of Medicine