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Category: Cell Biology

Cells know when to separate at mitosis

How do cells know when to separate during mitosis? A molecule called BubR1 was found to regulate the timing of the division of a parent cell into two progeny cells. Researchers who identified the role of BubR1 were optimistic that their discovery could lead to a potential cancer treatment by inducing cancer cells to undergo premature mitosis.

 

 

 

Phases of mitosis

When a cell enters the Synthesis phase (S phase) of the cell cycle, it is likely that it will subsequently go through the sequential phases of mitosis in which a single cell ultimately gives rise to two cells, each with its own copy of chromosomes. Firstly, the cell enters prophase, which is the phase of mitosis largely characterized by the condensation of chromatin (becoming distinct chromosomes), the beginning of spindle fiber formation, and the disintegration of the nucleolus, nuclear membrane, and organelles. This is then followed by a phase, called metaphase, wherein the chromosomes align along the metaphase plate and the microtubules attach to the kinetochores. Then, the chromosomes are pulled apart toward the opposite poles of the cell during anaphase. In the last phase of mitosis called telophase, the chromosomes have completely moved to the opposite poles of the cell resulting in two sets of nuclei. The cytoplasm divides ultimately giving rise to two new cells.

 

 

 

Delaying strategy of BubR1 during mitosis

Mitotic checkpoint complex.1

 

Researchers from Institute of Cancer Research reported in their paper published in Molecular Cell the role of BubR1 in mitosis.  Accordingly, the spindle assembly checkpoint (SAC) prevents the separation of sister chromatids until all chromosomes are properly attached to the spindle. It also catalyzes the formation of the Mitotic Checkpoint Complex (MCC).1 The BubR1 is part of this molecular complex that regulates the Anaphase Promoting Complex/Cyclosome (APC/C). In particular, the BubR1 is part of the molecular machinery that delays the onset of anaphase during mitosis. The delay is crucial as it ensures the chromosomes to be properly positioned before they will be segregated.2

 

The researchers further reported that the N-terminal half of BubR1 contains two ABBA motifs. When they mutated these BubR1motifs, the cells become unable to normally delay mitosis. Moreover, the two resulting cells following mitosis had unevenly divided chromosomes. They explained that without the normal ABBA sequences of BubR1, the MCC failed to bind to the APC/C. Consequently, mitosis progressed despite the chromosomes not yet being properly positioned.

 

 

 

Premature mitosis for cancer cells

The researchers made note of the importance of the ABBA sequence of BubR1. It served as a “safety catch” – preventing the machinery from progressing prematurely. Accordingly, cancer cells rely on this safety catch much more than normal cells as they usually have extra chromosomes to be put into place, and thereby need more time for mitosis.2 This could therefore be used to design cancer treatment, such as a drug that could switch off the “safety catch” of BubR1, and forcing cancer cells to divide prematurely with an unevenly divided chromosomes following mitosis.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

1 Fiore, B.D.,  Wurzenberger, C., Davey, N.E., & Pines, J. (2018).Molecular Cell. https://doi.org/10.1016/j.molcel.2016.11.006

2 Institute of Cancer Research. (2016, December 8). Scientists reveal ‘safety catch’ within all dividing cells: Major discovery could lead to new cancer treatments. ScienceDaily. Retrieved August 7, 2018 from www.sciencedaily.com/releases/2016/12/161208143306.htm

Parental chromosomes are together but still apart at first mitosis

A recent finding by a team of researchers from European Molecular Biology Laboratory on the parental chromosomes during the first mitosis of an embryo implicates a possible revision in biology textbooks. What they observed during the first mitotic division after the supposed “union” of gametes in mouse models apparently invalidates what is currently believed. Biologists assume that there is only one spindle apparatus that works to separate the two parental chromosomes during the first cell division of a mammalian zygote. It turns out that there are two. Their finding could also help explicate the common errors occurring during the first divisions in the early embryos of mammals, and possibly of humans.

 

 

Early model of mitosis in mammalian zygote

Mitosis of a human cell. In this image, the microtubules are shown in green, chromosomes (DNA) in blue, and kinetochores in red.

 

The first mitosis in mammals occurs during the union of male and female chromosomes. Upon fertilization, the zygote holds two parental chromosomes that unite, and then separated, triggering the formation of two cells (each with own nucleus) after the first mitosis. This marks the two-cell stage embryo.

The first mitosis is thought to proceed initially by the break-down of the nuclear envelope. This enabled the two parental chromosomes to unite thereafter. A single spindle assembly then forms. The spindles attach to the chromosomes, align them at metaphase, and then pull them apart during anaphase. The first mitosis ends at telophase where the cell divides into two cells, each with its own nucleus.

 

 

Viewing first mitosis through light-sheet microscopy

Researchers from European Molecular Biology Laboratory found out that there is not one but two spindle apparatus at work during the first mitosis of the mouse embryo. Using a light-sheet microscopy approach, they were able to conduct real-time, 3D imaging of the mouse embryo.1 Without this innovative technology, capturing an image at this stage will not be feasible because embryos are sensitive to light. With it, the researchers were able to track the chromosomes during the supposed union and saw differently what has long been held. They were surprised to find out that (1) the maternal and the paternal chromosomes assembled their own autonomous spindle structure and (2) the parental chromosomes remain in separate regions and did not mix prior to and during the first mitosis.1,2

 

 

Current model of first mitosis

Based on the current mouse embryo model, what transpires at first mitosis after the nuclear envelope disintegration post-fertilization event is that both the maternal and the paternal chromosomes form their own spindle apparatus. The mitotic spindles then attach to the chromosomes. Even so, the maternal and the paternal chromosomes remain in separate regions of the spindle. The spindles align them in a way that the maternal chromosomes align juxtapose to where the paternal chromosomes align. The two spindle apparatus then autonomously pull them apart towards opposite poles. The cell finally divides into two, where each has only one nucleus. Conversely, an erroneous axis alignment of paternal chromosomes during metaphase was observed to lead to the formation of one of the cells with multiple nuclei after the first mitosis.

The recent findings could help explain certain errors (e.g. multiple-nucleated cell) following the first mitosis. If this mechanism holds true to humans as well it could lead to new targets for treatment (particularly an erring first mitotic spindle apparatus) in a developing embryo. It might also provide an insight as to when life can be assumed to first exist — is it during the first meet-up of the male and the female chromosomes that do not mix yet… or is it that point at which they unite — but apparently occurs only after the first mitosis.

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:

1 Reichmann, J., Nijmeijer, B., Hossain, M. J., Eguren, M., Schneider, I., Politi, A.Z., Roberti, M.J., Hufnagel, L., Hiiragi, T. & Ellenberg, J. (2018). Dual-spindle formation in zygotes keeps parental genomes apart in early mammalian embryosScience. DOI: 10.1126/science.aar7462

2 Zielinska, A.P. & Schuh, M. (2018). Double trouble at the beginning of life. Science  361 (6398): 128-129. DOI: 10.1126/science.aau3216

Colon cancer : Independent prognostic genes and mechanisms

Colon Cancer is the third most deadly cancer worldwide. There were more than 1.4 million cases each year and 694,000 deaths globally. The treatment of colon cancer includes chemotherapy, surgery and radiation therapy. However, advances in diagnosis and treatment leads to development and improvement in survival. Numerous data point out that genetic changes function as vital role in the development of colon and rectal cancer. In which regulatory molecules mRNA affects various molecular and cellular target including cancer cells. That is why, development in research used mRNA as based diagnostic biomarkers for colon cancer in human. Furthermore, certain kind of mRNA used to predict survival in colon cancer patients. As well as a better knowledge of molecular mechanisms and associated gene is important for early diagnosis and treatment.

 

ULBP2 a novel prognostic biomarker in Colon Cancer

ULBP2 is a potential biomarker in colon cancer survival. Previous study shows that matrix metalloproteinase-9 reveals as an important marker for postoperative prognosis in colorectal cancer patients. Also extracellular matrix plays a vital role in cancer progression in which it provides structural and biochemical support in cells.  Despite from all of these, digestion is also considered to have a major role related to cancer preventive activity. Additionally, an in vitro of peptides gastrointestinal digestion can inhibit colon cancer cells proliferation and inflammation. Moreover, recent study showed that up and down regulated mRNAs are largely amass in extracellular matrix and digestion. As a result, it would entails that abnormality of extracellular matrix and digestion takes part in colon cancer progression.

 

Furthermore, the Wnt signaling pathway gives clinical importance on various diseases including colon cancer. Since alteration of this pathway are mostly observed in colorectal cancer with microsatellite instability. So, inhibiting this pathway might be helpful strategy for targeting chemotherapy-resistance cells. Also drug metabolism determined resistance of colorectal cancer resorcinol-based heat shock protein 90 inhibitors. Therefore, Wnt signaling and drug metabolism are both important pathway enriched by up and down regulated mRNAs.

 

Prognostic biomarkers are very important and have the power to change the course of disease if only knew beyond prognostic factors. In this research ULBP2 gene that encodes cell surface glycoprotein located at chromosome 6 demonstrates prognostic biomarker for colon cancer. High level of ULBP2 is deemed independent indicator for overall survival and identified as the sole outstanding mRNA.

 

Source: Prepared by Joan Tura from BMC Biological Research

Volume 51:10 March 29, 2018

Permanent Tattoo Means Permanent Immune Action Of Macrophages

Have you ever wondered why a permanent tattoo seemed to last forever? A simple assumption would be is that the ink could have seeped so deep into the skin that it would not have any other way out. However, this is not the case. Studies on the biological aspect of permanent tattoo reveal that the macrophages are engaged in an endless scavenging effort to remove the ink as non-self particles from the skin.

 

 

 

Permanent tattoo and the essence of permanence

People with a permanent tattoo could have cited multifarious reasons for getting one — from a brazen expression of love and art to aesthetic resolves. Behind those multifarious reasons, though, is the enticing essence of the “permanence” it hails. There seems to be no other better way to behold something worth everlasting than getting a permanent tattoo on the skin. Thus, despite the potential long-term medical risks involved (e.g. tattoo-related rash, severe itching, and chronic swelling)1 and the possible regrets after getting inked, some people would not waver going under the needle.

 

 

 

The biology of permanent tattoo

Permanent tattoo also means a permanent immune action of the macrophages.

 

What makes a permanent tattoo “permanent”? Why does it last? The ink used in tattoo is composed of colorants (typically, pigments) combined with a carrier. The carrier (e.g. a distilled water or an alcohol) acts as a solvent of the colorants. An alcohol-based carrier has an added advantage of increasing the permeability of the skin to the colorant. Using a mechanized needle, the ink is injected deep down to the skin all the way through the epidermis. The ink reaches the dermal layer just beneath the epidermis by way of a capillary action.2 The ink does not stay in the spaces between the cells. Rather, different cells in the skin, such as keratinocytes (cells in the epidermis) and fibroblasts (cells in the dermis), take in the pigment molecules. Apart from these cells, the macrophages in the dermis gobble them up as well. These macrophages do so as part of their job as large “eating cells”. The ink is considered as a non-self particle and therefore it must be removed from the body. Some macrophages bring with them the pigment to the lymph nodes.3 Others are trapped in the dermis with the fibroblasts for as long as they live. Nevertheless, the keratinocytes that have taken in the pigment are shed to be replaced with the new ones while ink-laden dermal macrophages die eventually. Thus, one may ask: “how does a permanent tattoo stay put despite the periodic shedding of the skin and the eventual death of ink-laden cells such as macrophages?”

 

 

 

Permanent tattoo and cyclic scavenging of the macrophages

A scanning electron micrograph of a macrophage.
(Credit: NIAID)

 

The permanent tattoo in the skin can be considered as a wound. Similar to any other wounds, it leads to the activation of inflammatory pathways as part of the healing process. During the inflammatory phase, the macrophages move to the injured site to scavenge for foreign particles and cellular debris. When the ink for a permanent tattoo is injected into the skin the macrophages gobble them up. Thus, even if the keratinocytes in the epidermis are replaced with new ones a large chunk of the ink remains because some of the macrophages that engulfed the ink stay there for good. These ink-laden macrophages, though, would also eventually die and wither. When this happens, new macrophages are presumed to arrive to the site to engulf withered old macrophages as well as the released ink particles.4

 

 

 

The engulfing, releasing, and re-engulfing of pigments from a permanent tattoo is an indication how macrophages remain loyal to their role. Perhaps, a deeper understanding in this regard could lead to improved tattoo removal methods. But for those who are keeping their permanent tattoo as it is, knowing that the macrophages in incessant immune action as the reason behind its permanence can be quite fascinating.

 

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1 NYU Langone Medical Center. (2015, May 27). Tattoos may come with long-term medical risks, physicians warn. ScienceDaily. Retrieved from www.sciencedaily.com/releases/2015/05/150527213601.htm
2 Feltman, R. (2018). Tattoos are permanent, but the science behind them just shifted. Popsci.com. Retrieved from https://www.popsci.com/how-tattoos-work
3 European Synchrotron Radiation Facility. (2017). Nanoparticles from tattoos travel inside the body, scientists find. ScienceDaily. Retrieved from www.sciencedaily.com/releases/2017/09/170912093105.htm
4 Baranska, A., Shawket, A., Jouve, M., Baratin, M., Malosse, C., Voluzan, O., Vu Manh, T.P., Fiore, F., Bajénoff, M., Benaroch, P., Dalod, M., Malissen, M., Henri, S., & Malissen, B. (2018). Unveiling skin macrophage dynamics explains both tattoo persistence and strenuous removal. The Journal of Experimental Medicine. DOI: 10.1084/jem.20171608

Oxytocin – Of Love, Fear, and Anxiety

Oxytocin has long had a reputation of being the “love hormone”. It engenders social bonding, attachment, intimacy, and affection. It is the chemical that gives people that warm, fuzzy, jolly feeling when they are with someone they love or care about. Recently, though, oxytocin may gain yet another moniker as the “fear and anxiety hormone”. It seems to perpetuate bad memories like an undying echo.

 

 

 

Oxytocin – love in the brain

CPK model of the Oxitocin molecule

 

Oxytocin, biochemically, is a neuropeptide hormone. Apart from the brain, it is also produced in other non-neural cells such as those in the corpus luteum and the placenta of females and the Leydig cells of males. In the brain, it is synthesized in the hypothalamus and then released into the bloodstream by the pituitary gland. The amount of oxytocin, especially coming from the neural sources, is linked to the various prosocial behaviors in humans. The more oxytocin there is, the more prosocial behavior is reinforced, and hence, the more the oxytocin underpins itself as a potent love elixir.

 

 

 

Oxytocin as a love hormone

Oxytocin, the love hormone

 

Prosocial behaviors pertain to the various acts and demeanor of a person that can meaningly well be sorted out as beneficial towards other people or society as a whole. They are manifested in the form of helping, sharing, and other empathetic acts of altruism. Oxytocin has been associated with the fostering of these prosocial behaviors, and thus, has been called the love hormone. Several studies have implicated it as a chemical that helped people to be more trusting1, empathetic, and generous2, and to connect with others they favour 3. In a romantic relationship, the oxytocin is reputed as the love chemical because it is produced in great amounts during the couple’s most intimate moments.

 

 

 

Two-faced oxytocin

Oxytocin is also the hormone linked to feelings of fear and anxiety.

 

While oxytocin is regarded by many as the love hormone, it may as well be taken as a crisis chemical.4 While oxytocin makes us feel better by reducing our anxieties while we are with those we love, it may also trigger our fear and anxieties over an impending social tension.5 The anxiety or fear we feel may be rooted to the oxytocin. It does so biochemically by activating the extracellular signal regulated kinases that are involved in the stimulation of the fear pathway in the brain.5 Not only does it act when we are threatened, it also strengthens bad memories from a tragic or a heart-breaking experience. 4

 

 

 

When it comes to relationships, oxytocin is a chemical that gives us that ecstatic feeling associated with love and it is also the one that triggers us to feel concerned over things that may go wrong. Fear is a strong emotion as love. It is ingrained in us like an instinct. Our response to it may vary. We may respond to it either by revivifying a relationship with additional effort — or by saving ourselves from a looming bucket of heartache caused by a failed relationship. Oxytocin is not just a love hormone but also a crisis chemical that helps us to be more prudent and cautious as we toggle between love and anxiety.

 

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1 Lane, A., Luminet, O., Rimé, B., Gross, J.J., de Timary, P., & Mikolajczak, M. (2013). “Oxytocin increases willingness to socially share one’s emotions”. International Journal of Psychology. 48 (4): 676–81. doi:10.1080/00207594.2012.677540
2 Hurlemann, R., Patin, A., Onur, O.A., Cohen, M.X., Baumgartner, T., Metzler, S., Dziobek, I., Gallinat, J., Wagner, M., Maier, W., & Kendrick, K.M. (April 2010). “Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans”. The Journal of Neuroscience. 30 (14): 4999–5007. doi:10.1523/JNEUROSCI.5538-09.2010
3 Sheng, F., Liu, Y., Zhou, B., Zhou, W., & Han, S. (February 2013). “Oxytocin modulates the racial bias in neural responses to others’ suffering”. Biological Psychology. 92 (2): 380–6. doi:10.1016/j.biopsycho.2012.11.018
4 Norwegian University of Science and Technology. (2017, May 18). Love hormone is released during crises: When you notice your partner is less interested than you are, your brain may send out a hormone that can help you fix the relationship. ScienceDaily. Retrieved from www.sciencedaily.com/releases/2017/05/170518104023.htm
5Northwestern University. (2013, July 22). ‘Love hormone’ is two-faced: Oxytocin strengthens bad memories and can increase fear and anxiety. ScienceDaily. Retrieved from www.sciencedaily.com/releases/2013/07/130722123206.htm

Prokaryotic Ancestor of Mitochondria: on the hunt

The alphaproteobacteria have been widely cited as the closest relative– and possibly the prokaryotic ancestor — of the powerhouse of the eukaryotic cell, mitochondria. A team of researchers from Uppsala University in Sweden aimed to identify its prokaryotic ancestral origin. However, their recent findings seemed to contradict this notion.1 The mitochondria may have taken an evolutionary fate that is quite different from the one previously thought. Debates on the endosymbiotic theory remain fierce.

 

 

 

Mitochondria, the cell’s powerhouse

The mitochondrion and its small circular chromosome, mitochondrial DNA.
(Credit by Darryl Leja, NHGRI)

 

The mitochondria are best known as the powerhouse of eukaryotic cells. Through cellular respiration, the mitochondrion (single form of the plural, mitochondria) is the organelle responsible for generating and supplying energy (e.g. adenosine triphosphate) needed in various metabolic activities of the cell. It is semi-autonomous as it has its own genome. Referred to as mitochondrial DNA, the genetic material contained in the mitochondrion enables the manufacturing of its own RNAs and proteins. The genome of the mitochondrion is distinct from the nuclear genome and this paved the idea that this organelle is possibly derived from a prokaryote through endosymbiosis (endosymbiotic theory).

 

 

 

Mitochondria and the endosymbiotic theory

An endosymbiosis is a form of symbiosis wherein the endosymbiont lives within the body of its host. In terms of evolution, endosymbiosis was used as a basis of the origin of semi-autonomic organelles, such as mitochondria. Referred to as the Endosymbiotic theory, this theory suggests that mitochondria within the eukaryotic cell came about as a result of early endosymbiosis between prokaryotic endosymbionts and the eukaryotic host cell. The proponents of this theory posited that the mitochondria arose from the prokaryotes (particularly, alphaproteobacteria). One of the proofs raised is based upon the ability of the mitochondria to reproduce via a process similar to the prokaryotic binary fission. Another is the mitochondrial DNA being more akin to the prokaryotic genome (as a single circular DNA) than the nuclear genome.2

 

 

 

Ancestral endosymbiont of the mitochondria

To lay further evidence to the endosymbiotic theory, the research team from Uppsala University in Sweden aimed to uncover the identity of the mitochondrial ancestor. They analyzed large amounts of environmental sequencing data from the Pacific and the Atlantic Ocean and found several species that had not yet been identified. They were able to reconstruct the genomes of over 40 alphaproteobacteria.1 These bacteria include the Rickettsiales group, which is commonly cited as the closest relative among other alphaproteobacteria based on genomic studies 3, and possibly where the mitochondria originated from. Also, the Rickettsiales is a group of parasitic prokaryotes. As such, they depend highly on their host cell to survive. However, the Uppsala University research team was unable to pinpoint the mitochondrial ancestor from their recent analyses on the present-day alphaproteobacteria, including Rickettsiales. And based on what their current data suggest, the evolutionary position of the mitochondria would lie outside of the alphaproteobacteria. This means that this group is not the closest relative, and the ancestor from where the mitochondria evolved could have also given rise to the presently-identified alphaproteobacteria.1

 

 

 

Laying a firm basis for the endosymbiotic theory remains a challenging feat at this time. Nevertheless, we cannot simply rest the case just because the new data said otherwise. Researchers should not be disheartened in finding more decisive and fully comprehensive evidence as to the ancestral origin of the mitochondria. Reaching a consensus may still be far off. However, a disparity in evidence-based viewpoints is better than a clash of unfounded words.

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1 Uppsala University. (2018, April 25). “Redefining the origin of the cellular powerhouse”. ScienceDaily. Retrieved from www.sciencedaily.com/releases/2018/04/180425131841.htm
2 “Endosymbiotic theory”. (n.d.). Biology-Online.org. Retrieved from https://biology-online.org/dictionary/Endosymbiotic_theory
3 Andersson, S. G., Zomorodipour, A., Andersson, J. O., Sicheritz-Pontén, T., Alsmark, U. C., Podowski, R. M., Näslund, A. K., Eriksson, A. S., Winkler, H. H., and Kurland, C. G. (1998). “The genome sequence of Rickettsia prowazekii and the origin of mitochondria”. Nature 396 (6707): 133–140. doi:10.1038/24094