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Category: Cell Biology

Mitochondrial DNA not just from moms but also from dads?

If one wants to trace down lineage, that person could turn to the cell’s powerhouse, the mitochondrion. This organelle contains its own special set of DNA believed as inherited solely from mothers across generations.  Thus, looking at the mitochondrial DNA (by mtDNA genealogical DNA testing) could help track down lineage, and for this reason, help determine ancestral or familial connection. Recently though, a team of scientists reported that the mitochondrial DNA is not solely inherited from the mothers. New empirical evidence of biparental inheritance of mitochondrial DNA implicates the need to rectify the long-held notion that the inheritance of mitochondrial genome is exclusively matrilineal or female line.

 

 

Mitochondrial DNA

The mitochondrion (plural: mitochondria), reckoned as the powerhouse of the cell, generates metabolic energy, especially the form of adenosine triphosphate (ATP). And it does so through the process referred to as cellular respiration. Apart from that, the organelle is also described as semi-autonomous since it has its own genetic material distinct from that found in the nucleus. The nucleus contains more genes organized into chromosomes and in charge for almost all of the metabolic processes in the body. On the contrary, the genetic material in the mitochondrion – referred to as mitochondrial DNA – is relatively fewer in number. It carries the genetic code for the manufacturing of RNAs and proteins necessary to the various functions of the mitochondrion, such as energy production.

 

(Recent news on the evolutionary origin of mitochondria, read: Prokaryotic Ancestor of Mitochondria: on the hunt)

 

(You may also want to read: Mitochondrial DNA – hallmark of psychological stress)

 

Mitochondrial inheritance

In humans, the mitochondrial DNA is believed to be inherited solely from the mother. This notion stems from the events that happen at fertilization. The sperm contains on its neck a helix of mitochondria that power up the tail to swim toward the ovum. And when the sperm finally makes its way into the ovum, it leaves its neck and tail on the cell surface of the ovum. Mitochondria that are brought into the ovum would eventually be inactivated and disintegrated. Thus, the mitochondria in the ovum are the only ones that the zygote eventually inherits. A human ovum has an average of 200,000 mtDNA molecules.1 For this, certain traits and diseases involving mitochondrional DNA implicate maternal origin.

 

 

 

Inheritance of mitochondrial DNA– not exclusive

mitochondrial dna eve
The theory of Mitochondrial Eve is based on the exclusivity of human mitochondrial DNA inheritance to the female line, which when traced would lead to only one most recent woman, “Eve”. (Image credit: Ludela, Creative Commons Attribution-Share Alike 3.0 Unported)

 

The theory of Mitochondrial Eve holds that tracing the matrilineal lineage of all recent human beings would lead to all lines converging to one woman referred to as “Eve“. The theory is based on the exclusivity of human mitochondrial DNA inheritance to female line. Nevertheless, independent empirical findings and clinical studies challenge this precept.

 

For instance, Schwartz and Vissing2 reported the case of a 28-year-old man with mitochondrial myopathy. Accordingly, the patient had a mutation (a novel 2-bp mtDNA deletion in ND2 gene). Normally, the gene encodes for a subunit of the enzyme complex I of the mitochondrial respiratory chain. Thus, the faulty gene affected the production of such enzyme, which, in turn, led to the patient’s severe, lifelong exercise intolerance. Furhter, Schwartz and Vissing2 pointed out that the patient’s mitochondrial myopathy was paternal in origin.

 

Recently, a team of researchers observed paternal inheritance of mitochondrial DNA, but this time, on 17 people from three different families.3 They sequenced their mitochondrial DNAs and they discovered father-to-offspring transmission.

 

 

Conclusion

The mitochondrial DNA is said to be a mother’s legacy to her offspring. However, recent studies indicate that the father could also transmit it to his progeny. Somehow, paternal mitochondrial DNA gets into the ovum. Rather than disintegrated or inactivated, it gets expressed. Mitochondrial DNA from the fathers may not be as rare as once thought.  If more studies will corroborate soon, this could debunk Mitochondrial Eve theory. It might also render mtDNA genealogical DNA testing questionable. And, we may also need to start looking to the other side of our lineage to fathom hereditary diseases arising from faulty mitochondrial DNA.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1 Mitochondrial DNA. (2018). Biology-Online Dictionary. Retrieved from https://www.biology-online.org/dictionary/Mitochondrial_DNA

 

2 Schwartz, M. & Vissing, J. (2002). “Paternal Inheritance of Mitochondrial DNA”. New England Journal of Medicine. 347 (8): 576–580.

 

3 Luo, S.,  Valencia, C.A.,  Zhang, J., Lee, N., Slone, J., Gui, B., Wang, X.,  Li, Z.,  Dell, S., Brown, J., Chen, S.M.,  Chien, Y., Hwu, W., Fan, P.,  Wong, L.,  Atwal, P.S., & Huang, T. (2018). Biparental Inheritance of Mitochondrial DNA in Humans. Proceedings of the National Academy of Sciences 201810946. DOI:10.1073/pnas.1810946115

Pathobiology of allergy and its most severe form, anaphylaxis

When allergy season looms, some people with serious hypersensitivity to allergens tend to be apprehensive of what may come. Some would rather stay indoors than risking the odds of sucking up triggers that could instigate severe allergic reactions. Apart from triggers from the environment, other common factors for allergy include food, medication, certain toxins, venom from insect stings or bites, stress, and heredity. How does an allergy manifest? Which cells are involved in forming an allergic reaction?

 

 

 

The immune system

allergy
How does an allergy occur? The pathobiological mechanism involves several white blood cells that play a role in mounting an allergic reaction.

 

The immune system protects the body from foreign substances (generally referred to as antigens) that could pose a threat to our well-being.  It prevents harmful bacteria, viruses, parasites, etc. from invading and causing harm. The white blood cells (also called leukocytes) constantly scout for antigens in order to destroy or disable them. The white blood cells include lymphocytes, neutrophils, basophils, eosinophils, monocytes, macrophages, mast cells, and dendritic cells.

 

 

 

Allergy – overview

 

allergy pathway
The allergy pathway.
Image (by Sari Sabban) distributed under the CC 3.0 Unported license.

 

An allergy is a state of hypersensitivity of the immune system in response to an allergen (i.e. a substance capable of inciting an allergic reaction). In this regard, several white blood cells play a role in mounting an allergic reaction.

In summary, the entry of an allergen into the body triggers an antigen-presenting cell, such as a dendritic cell. The dendritic cell takes up the allergen, process it, and then present its epitopes through its MHC II receptor on its cell surface. It, then, migrates to a nearby lymph node, waiting for a T lymphocyte to recognize it.

Upon recognition, the T lymphocyte may differentiate into a Th2 cell (type 2 helper T cells), which is capable of activating B lymphocyte. B lymphocyte, when activated, matures into a plasma cell that could synthesize and release IgE antibody in the bloodstream. Some of the circulating IgE may bind to mast cell and basophil. Thus, re-entry of such allergen could incite the IgE on mast cells and basophils to recognize its epitope. In effect, this activates the mast cell or basophil to release inflammatory substances (e.g. histamine, cytokines, proteases, chemotactic factors) into the bloodstream.

 

 

 

Anaphylaxis – a dreadful allergic reaction

The allergic reaction mounted by the immune system is supposed to protect the body. However, the allergens perceived by the body as a threat are generally harmless. The body tends to overly react to the allergens, and so leads to symptoms. Histamine, for instance, brings about the common symptoms of allergy: pain, heat, swelling, erythema, and itchiness.

 

Anaphylaxis is the most severe form of allergic reaction. It can occur rapidly and it affects more than one body system, such as respiratory, cardiovascular, cutaneous, and gastrointestinal systems. It occurs as a result of the release of inflammatory substances from mast cells and basophils upon exposure to an allergen. Within minutes to an hour, symptoms could manifest as a red rash, swelling, wheezing, lowered blood pressure, and in severe cases, anaphylactic shock.

 

In the presence of breathing difficulties, racing heart, weak pulse, and/or a change in voice, the situation is precarious. It calls for an immediate medical attention.

 

Why does anaphylaxis occur? IgE-mediated anaphylaxis is the common form of anaphylaxis. Initial exposure to an allergen leads to the release of IgE so that re-exposure to the allergen leads to its identification and the eventual activation of mast cells and basophils.  Apart from immunologic factors, though, other causes of anaphylaxis are non-immunologic. For example, temperature (hot or cold), exercise, and vibration may cause anaphylaxis. In this case, IgE is not involved. Rather, these agents directly cause the mast cells and the basophils to degranulate.

 

 

 

Novel mechanism identified

Recently, a team of researchers1,2 found a novel mechanism that could explicate the hasty allergic reaction during anaphylaxis. They were first to uncover a mechanism involving the dendritic cells. Accordingly, a set of dendritic cells seem to “fish” allergens from the blood vessel using their dendrites. The dendritic cell near the blood vessel takes up the blood-borne allergen. Rather than initially processing it, and then presenting the epitope on its surface, it hands over the allergen inside a micro-vesicle to the adjacent mast cells.

 

Mast cells, unlike basophils that are in the bloodstream, are located in tissues, such as connective tissue. Thus, the question as to how the mast cells detect blood-borne allergen could be answered by the recent findings.

 

Rather than being internalized by the dendritic cells for processing, the allergen was merely taken into a micro-vesicle that budded off from the surface of dendritic cells. This, thus, saves time. It cuts the process, leading to a much rapid allergic reaction.

 

However, these findings were observed in mouse models. Therefore, the researchers have yet to observe if this novel mechanism also holds true on humans. If so, this could lead to possible therapeutic regulation of allergies, especially the most dreadful form, anaphylaxis.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

1 Choi, H.W., Suwanpradid, J. Il, Kim, H., Staats, H. F., Haniffa, M., MacLeod, A.S., & Abraham, S. N.. (2018). Perivascular dendritic cells elicit anaphylaxis by relaying allergens to mast cells via microvesiclesScience 362 (6415): eaao0666 DOI: 1126/science.aao0666
2 Duke University Medical Center. (2018, November 8). Using mice, researchers identify how allergic shock occurs so quickly: A newly identified immune cell mines the blood for allergens to directly trigger inflammation. ScienceDaily. Retrieved November 22, 2018 from www.sciencedaily.com/releases/2018/11/181108142440.htm

 

First time! Human blood cell turned into a young sex cell

In essence, our body consists of two major types of cells – one group involved directly in reproducing sexually (called sex cells) and another group that are not (called somatic cells). In particular, the female sex cell is referred to as the ovum (also called egg cell) whereas the male sex cell, the sperm cell. The somatic cells, in turn, are the cells in the body that have varying functions, such as nourishing the sex cells as well as keeping the body thriving and functional.

 

 

 

Origin of sex cells

Our body produces sex cells through the process called gametogenesis. The process is essentially a step-by-step process of meiosis. Oogenesis (i.e. gametogenesis in females) takes place in the ovaries to produce ova or egg cells. In brevity, the oogonium (the female primordial germ cell) undergoes meiosis to produce four haploid egg cells. Conversely, spermatogenesis (i.e. gametogenesis in males) occurs in the testes to yield sperm cells. Quintessentially, the spermatogonium (the male primordial germ cell) will go through meiosis to give rise to four haploid sperm cells.

 

 

 

Sex cells vs somatic cells

In humans, a sex cell may be identified from a somatic cell in being a haploid cell. That means a sex cell would have half the number of chromosomes as that of a somatic cell. Hence, an egg cell or a sperm cell would have 23 chromosomes whereas a somatic cell would have 46. Haploidy in sex cells is important in order to maintain the chromosomal integrity in humans across generations.

 

At fertilization, the sperm cell and the egg cell unite to form a diploid cell (called zygote). The zygote, then, divides mitotically, giving rise to pluripotent stem cells. A pluripotent stem cell is a cell capable of giving rise to various precursors that eventually will acquire specific identity and physiological function via a process called differentiation. A differentiated cell means that the cell has matured and acquired a more specific role, for instance as a skin cell, a blood cell, a liver cell, etc.

 

 

 

Somatic cell converted to sex cell

sex cell
Soon, a somatic cell could be converted into human sex cells.
[Image credit: Karl-Ludwig Poggemann, Flicker.com, CC by 2.0]

 

Intrinsically, a human somatic cell that has “differentiated” could never become a sex cell just as a sex cell could neither become nor give rise to a somatic cell. However, this may no longer hold true in the years to come.

 

Japanese researchers have, for the first time, successfully converted a somatic cell into a sex cell precursor.1 In particular, they had successfully created an oogonium from a human blood cell. They turned blood cells into “induced pluripotent stem cells” (iPS).2 Essentially, the blood cells – turned iPS – appeared to have undergone “molecular amnesia”. It means they forget their initial identity. As a result, they could become any type of cell, even as a sex cell.

 

The researchers transformed human blood cells into oogonia (plural of oogonium). They did so by incubating them for four months in artificial ovaries derived from embryonic mouse cells. They retrieved promising results. Admittedly though, they acknowledged they are still in the early steps of a rather long journey of research. The oogonia, indeed precursors to egg cells, are, at this point, still young, and thereby, unfit for fertilization. The researchers have yet to induce them to become mature, fully differentiated egg cells. Nevertheless, they remain optimistic in having reached this point, and, undeniably, pioneered an important milestone.

 

 

 

 

Ethical issues

If, in the future, research on the conversion of a somatic cell into a sex cell pushes through to completion, it could lead to significant resolves to infertility issues. However, ethical concerns shall, likely, surface as well. For instance, a possibility could occur in time. A mere hair cell or a skin cell from an unsuspecting person could be turned into an egg or a sperm cell. And from there, an offspring could come into existence.

 

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1 Yamashiro, C., Sasaki, K., Yabuta, Y., Kojima, Y., Nakamura, T., Okamoto, I., Yokobayashi, S., Murase, Y., Ishikura, Y., Shirane, K., Sasaki, H., Yamamoto, T., & Saitou, M. (2018 Oct 19).Generation of human oogonia from induced pluripotent stem cells in vitro. Science, 362(6412):356-360. doi: 10.1126/science.aat1674.

 

2 Solly, M. (2018 Sept. 24). Scientists create immature Human Eggs Out of Blood Cells For the First Time. Retrieved from [link]

 

Mitochondrial DNA – hallmark of psychological stress

We often hear that stress can be unsettling as it could make us ill when it becomes chronic and overwhelming. However, is there really a biological ratification behind it? Is it scientifically founded? Apparently, independent studies hinted a biological connection indicating how stress can cause biological damage, and eventually lead to certain ailments. And, the mitochondrial DNA — the genome in the mitochondrion appears to play a role.

 

 

 

Biological features of mitochondria

mitochondrial process
Mitochondrial processes that lead to the generation of ATP.
Credit: Boumphreyfr, under the Creative Commons Attribution-Share Alike 3.0 Unported license

 

The mitochondrion (plural: mitochondria) is an organelle that supplies molecular energy for various biological activities. In essence, this rod-shaped structure found within the cell accounts for the generation of ATP, the cell’s major energy source. Thus, the mitochondrion is known to be the “powerhouse of the cell“.

 

Through the process of cellular respiration, glucose (a monosaccharide) is “churned” to extract energy, primarily, in the form of ATP. Firstly, a series of reactions leads to the conversion of glucose to pyruvate. Then, it uses pyruvate, converting it into acetyl coenzyme A for oxidation via enzyme-driven cyclic reaction called Krebs cycle. Finally, a cascade of reactions (redox reactions) involving the electron transport chain leads to the production of ATPs (via chemiosmosis).

 

The mitochondria have their own genetic material, called mitochondrial DNA. Because of this, the mitochondrion is regarded as semi-autonomous and self-reproducing organelle. It means it can manufacture its own RNAs and proteins.  Generally, we inherit the mitochondrial genome maternally, as opposed to the nuclear genome that we inherit from both parents.

mitochondrial DNA
Mitochondrial DNA.
Credit: National Institutes of Health

 

 

 

Mitochondrial fate during stress

mitochondrial DNA and stress
Psychological stress can cause biological damage, such as the release of mitochondrial DNA from damaged and worn-out mitochondria.

 

When confronted with a stressful situation, our body responds intrinsically. We tend to breathe fast. The heartbeat goes wild. Our muscles tense up. And, we sweat profusely. All these responses (so-called “fight-or-flight“) can be an arduous task as they abruptly demand energy. When triggered for so long, eventually, we feel exhausted.  Sooner or later, stress sets in and it takes its toll on our health.

 

The mitochondria work for an extended time just to meet up the spike of demand for energy. In effect, they become vulnerable to damage from too much work.  Inopportunely, the mitochondria have limited repair mechanisms unlike the nucleus.1 And in the end, it results in the disruption of the organelle, thereby, releasing the mitochondrial DNA into the cytoplasm. Eventually, the genetic material reaches the bloodstream where they become genetic cast-offs.

 

 

 

Mitochondrial DNA cast-offs

The ejected mitochondrial DNA, apparently, becomes genetic wastes and stress might have something to do with this outcome. This theory came about based on a series of studies. Firstly, Gong et al. found that chronic mild stress resulted in mitochondrial damage in hippocampus, hypothalamus, and cortex in mouse brains.2

 

Secondly, another team of researchers (Lindqvist et al.) reported that individuals who had recent suicide attempt had higher plasma level of freely circulating mitochondrial DNA in blood than those of healthy individuals.3

 

Thirdly, Martin Picard (a psychobiologist at Columbia University), together with his team, observed similar findings in their participants exposed to a stressful situation. Accordingly, their participants – healthy men and women – were asked to defend themselves against a false accusation. Their blood samples were taken before and after the interview. The researchers found that the mitochondrial DNA in the serum of the participants increased twice 30 minutes after the test. 1 Picard explained that the mitochondrial DNA might have acted like a hormone. Furthermore, he theorized that the ejection of these genetic cast-offs might have mimicked the adrenal gland cells releasing cortisol in response to stress. 1

 

 

 

Mitochondrial DNA as an inflammatory factor

Zhang et al. observed that circulating mitochondrial DNA triggered inflammatory responses. Accordingly, the genetic cast-offs can bind to TLR9 (a receptor) on the immune cell. This binding might have incited the immune cell to respond the same way as they do when reacting with antigens. It might have stimulated the cell to release cytokines that call for other immune cells to the site. 1

 

 

 

So far, these conjectures from independent studies disclose the possible direct biological damage due to stress. There could be a biological insinuation that stress could play a part in the manifestation of ill-health conditions. And, the upsurge of circulating mitochondrial DNA cast-offs is one of them. More information and studies on mitochondrial DNA are delineated on a report on mental health published in Scientific American.

 

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1 Sheikh, K. (2018 Sept 13). Brain’s Dumped DNA May Lead to Stress, Depression. Scientific American. Retrieved from https://www.scientificamerican.com/article/brain-rsquo-s-dumped-dna-may-lead-to-stress-depression/
2 Gong, Y. Chai, Y., Ding, J. H., Sun, X. L., & Hu, G. (2011).Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neuroscience Letters, 488 (1): 76-80. https://doi.org/10.1016/j.neulet.2010.11.006
3 Lindqvist, D., Fernström, J., Grudet, C., Ljunggren, L., Träskman-Bendz, L., Ohlsson, L., & Westrin, Å. (2016). Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity. Translational Psychiatry, 6 (12), e971–. http://doi.org/10.1038/tp.2016.236

Porphyromonas gingivalis: Periodontitis bacterium induces memory impairment and neuroinflammation

Porphyromonas gingivalis is a bacterium commonly associated in periodontitis a chronic inflammatory disease in the oral cavity.  Periodontium is composed of periodontal ligament, cementum, alveolar bone and gingiva. Porphyromonas gingivalis is a gram-negative bacterium that contains toxic components. It is characterized by the presence of edema and destruction of tissue supporting the teeth. In which periodontal bacteria enters into circulation that leads to bacteremia and system dissemination of bacterial products. Moreover, Porphyromonas gingivalis can promotes systemic effects through expression of inflammatory mediators like pro-inflammatory cytokines. As a consequence it is confirmed to be associated with systemic diseases such as diabetes, respiratory disease and cardiovascular disease.

Potential effects of Porphyromonas gingivalis

Neurodegenerative diseases have been recognized as the major cause of cognitive and behavioral damage. It is known that peripheral infections could activate microglial cells within the nervous system enhancing development of neurodegeneration. Thus, the inflammatory molecules in the brain could be enhanced by periodontitis that increase inflammatory levels promoting the development of Alzheimer’s disease. In this particular research Porphyromonas gingivalis infection may impair cognition by elevating expression of pro-inflammatory cytokines. It is also shown that the infected mice displayed impaired memory and learning abilities. Elevated levels of pro-inflammatory mediators in the blood can lead to direct or indirect transport to the brain.

 

Periodontal infection caused by Porphyromonas gingivalis promotes neuro-inflammatory response via releasing pro-inflammatory cytokines. In which inflammation induces alterations in neurovascular functions causing increased in blood brain barrier permeability and aggregation of toxins. In brain trauma, infection and presence of endogenic abnormal protein aggregates can activate secretions of TNF-α. That plays a pivotal role in the development and functions of central nervous system. Moreover, aging is also associated to chronic inflammation which exerts additional stress to the brain nerve cells. Additionally, during systemic inflammation the functions of the blood-cerebrospinal fluid barrier were also significantly affected.

 

Therefore, Porphyromonas gingivalis periodontal infection may induce age-dependent brain inflammation. Also periodontitis can cause memory impairment which has a similar effect on the development of Alzheimer’s disease. Furthermore, aging is the major risk factor of Alzheimer’s disease and is correlated with elevated glial responsiveness. And in due course might increase the brain’s susceptibility to injury and disease.

 

Source: Prepared by Joan Tura from BMC Immunity and Aging

Volume 15:6, January 30, 2018

 

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