Our brains are made up of billions of incredibly diverse neurons. They first arise in the developing brain when stem cells stop self-renewing and differentiate into a particular type of neuron. This process, called neurogenesis, is precisely regulated to give rise to the enormous complex structure that is our brain. It is thought that small differences in the way neural stem cells generate neurons are at the origin of the dramatic increase in the size and complexity of our brain.
To gain insight in this complex process, prof. Pierre Vanderhaeghen (VIB-KU Leuven, ULB) and his colleagues examined the mitochondria, small organelles that provide energy in every cell in the body, including the developing brain.
“Diseases caused by defects in mitochondria lead to developmental problems in many organs, in particular the brain,” explains Vanderhaeghen, a specialist in stem cell and developmental neurobiology. “We used to think that this was related to the crucial function of mitochondria to provide energy to the cells, but this is only part of the story: recent work in stem cells suggests that mitochondria have a direct influence on organ development. We have tested whether and how this could be the case in the brain.”
Fission and fusion
Together with his team, he explored whether and how mitochondrial remodeling is coupled with neuronal fate commitment during neurogenesis. “Mitochondria are highly dynamic organelles, that can join together (fusion) or split up (fission), and we know these dynamics are associated with fate changes in various types of stem cells,” says Vanderhaeghen.
Ryohei Iwata, a postdoctoral researcher in the Vanderhaeghen lab, developed a new method to watch mitochondria in great detail as the neural stem cells are ‘caught in the act’ to become neurons. “We found that shortly after stem cells divide, the mitochondria in daughter cells destined to self-renew will fuse, while those in daughter cells that become neurons show high levels of fission instead,” says Ryohei Iwata.
But this was not just a coincidence: indeed, the researchers could show that increased mitochondrial fission in fact promotes differentiation to a neuronal fate, while mitochondrial fusion after mitosis redirects daughter cells towards self-renewal.
So mitochondrial dynamics are important to become a neuron—but there is more.
“We found that the influence of mitochondrial dynamics on cell fate choice is limited to a very specific time window, right after cell division,” says Pierre Casimir, a PhD student in Vanderhaeghen’s lab. “Interestingly, the restricted time window is twice as long in humans compared to mice.”
“Previous findings were primarily focused on fate decision of neural stem cells before they divide, but our data reveal that cell fate can be influenced for a much longer period, even after neural stem cell division,” says Vanderhaeghen. This may have interesting implications in the emerging field of cell reprogramming, where scientists try to convert non-neuronal cells directly in neuronal cells for therapeutic purposes for instance.
“Since this period of plasticity is much longer in human cells compared to mouse cells, it is tempting to speculate that it contributes to the increased self-renewal capacity of human progenitor cells, and thus to the uniquely developed brain and cognitive abilities of our species. It is fascinating to think that mitochondria, small organelles that have evolved in cells more than a billion years ago, might have contributed to the recent evolution of the human brain.”
Pluripotent stem cells have the ability to self-renew and give rise to all other types of cells and organs in the body. The developmental patterns and characteristics are controlled by a network of regulatory genes and molecules, but little is known about how this network has evolved across mammals.
The recent study by Kyoto University researchers across 48 mammalian species published in the journal Genome Biology and Evolution. The study group observed that the genes regulating pluripotent stem cells in mammals are surprisingly similar.
In the study conducted by Ken-ichiro Kamei of Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS), with Miho Murayama and Yoshinori Endo of the Wildlife Research Center, compared 134 gene sets belonging to the pluripotency gene regulatory networks of 48 mammalian species. They found that this network has been highly conserved across species, meaning genetic sequences have remained relatively unchanged over the course of evolution. This high degree of conservation explains why human genetic sequences can reprogram other mammalian tissue cells to turn into pluripotent stem cells. However, since it is also evident that the regulating networks differ across mammals, there might be more efficient combinations of reprogramming factors for each species. Improving techniques for deriving induced pluripotent stem (iPS) cells from mammalian cells, including those from endangered species, could provide a big boost to research and conservation.
“We have been trying to generate induced pluripotent stem cells from various mammalian species, such as the endangered Grévy’s zebra and the bottlenose dolphin,” says Kamei.
Interestingly, the team found relatively high evolutionary changes in genes just downstream of one of the core gene regulatory networks. “This could indicate that mammalian pluripotent stem cells have diversified more than we thought,” says Inoue-Murayama.
The differences between gene regulatory networks in mammalian pluripotent stem cells might also be associated with unique adaptions. For example, the naked mole rat has been positively selected for a pluripotency regulatory gene that could be involved in giving it its extraordinary longevity and cancer resistance. The gene might also be involved in the development of the extremely sensitive hairs that help them navigate underground.
The researchers also found evidence of positive selection for certain pluripotency gene regulatory network genes involved in the adaptation of large animals, such as the minke whale, the African elephant and the flying fox, to their environments. Surprisingly, these same genes are associated with cancer in other mammals. Since these large animals are known for being relatively resistant to cancer, the researchers suggest that the adaptive alterations these genes underwent in these animals somehow also changed some of their functions, thus giving this group a degree of cancer resistance.
The researchers say the study is among the first to compare the pluripotency gene regulatory networks across major taxa, and could be applicable to evolutional biology studies and for facilitating and improving the generation of induced pluripotent stem cells from new species.
Recent findings by researchers at Yale points towards a host of genetic risk factors that explains susceptibility to the debilitating symptoms of post-traumatic stress disorder (PTSD) in veterans.
The Yale-led study published on Sept. 30 in the journal Biological Psychiatry has now identified a social factor that can mitigate these genetic risks: the ability to form loving and trusting relationships with others.
The study is one of the first to explore the role of nurture as well as nature in its investigation of the biological basis of PTSD.
“We exist in a context. We are more than our genes,” said Yale’s Robert H. Pietrzak, associate professor of psychiatry and public health, and senior author of the study.
Pietrzak is also director of the Translational Psychiatric Epidemiology Laboratory of the U.S. Department of Veterans Affairs National Center for PTSD.
Like many genetic studies on mental disorders such as depression, anxiety, and schizophrenia, PTSD studies have revealed numerous genetic risk factors that contribute to the severity of the disorder. For instance, a previous study of more than 165,000 U.S. military veterans led by Yale’s Joel Gelernter, the Foundations Fund Professor of Psychiatry and professor of genetics and of neuroscience, found variants in eight separate regions of the genome that help predict who is most likely to experience the repeated disturbing memories and flashbacks that are hallmark symptoms of PTSD.
In the new study, Pietrzak, Gelernter, and colleagues looked at psychological as well as genetic data collected from the National Health and Resilience in Veterans Study, a national sample of U.S. military veterans supported by the National Center for PTSD. The researchers specifically focused on a measure of attachment style — the ability or inability to form meaningful relations with others — as a potential moderator of genetic risk for PTSD symptoms.
Individuals with a secure attachment style perceive relationships as stable, feel that they are worthy of love and trust, and are able to solicit help from others. Those with an insecure attachment style report an aversion to or anxiety about intimacy with others, and have difficulty asking for help from others.
They found that the ability to form secure attachments essentially neutralized the collective effects of genetic risk for PTSD symptoms. The impact was particularly pronounced in a variant of the IGSF11 gene, which has been linked to synaptic plasticity or the ability of the brain to form new connections between brain cells.
Pietrzak noted that deficits in synaptic plasticity have also been linked to PTSD, depression, and anxiety, among other mental disorders. The findings illustrate the importance of integrating environmental and social as well as genetic factors in the study of PTSD and other mental disorders, the authors said.
“Social environmental factors are critical to informing risk for PTSD and should be considered as potential moderators of genetic effects,” he said. “The ability to form secure attachments is one of the strongest protective factors for PTSD and related disorders.”
The attachment styles may moderate polygenic risk for PTSD symptoms, along with the effects of a novel locus implicated in synaptic transmission and plasticity which may serve as a possible biological mediator of this association.
These findings may help inform interpersonally-oriented treatments for PTSD for individuals with high polygenic risk for this disorder and will help predict who is at greater risk of experiencing severe symptoms of PTSD, the study also suggest that psychological treatments targeting interpersonal relationships may help mitigate PTSD symptoms in veterans with elevated genetic risk for this disorder .
Amanda Tamman, formerly of Yale and now a Ph.D. student in clinical psychology at St. John’s University, is first author of the paper.
Yale News bulletin written by By Bill Hathaway. Article modified for style and clarity, Image source: Wikimedia Commons
Amanda J.F. Tamman, Frank R. Wendt, Gita A. Pathak, John H. Krystal, Janitza L. Montalvo-Ortiz, Steven M. Southwick, Lauren M. Sippel, Joel Gelernter, Renato Polimanti, Robert H. Pietrzak. Attachment style moderates polygenic risk for posttraumatic stress in United States military veterans: Results from the National Health and Resilience in Veterans Study. Biological Psychiatry, 2020; DOI: 10.1016/j.biopsych.2020.09.018
In biology all of us share a basic question in biology, what properties are shared among organisms? Comparative genomics and genome sequencing allows comparison of organisms at DNA and protein levels, and sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences.
The sequence Comparisons can be used to:
- Find evolutionary relationships between organisms
- Identify functionally conserved sequences
- Identify corresponding genes in human and model
- organisms: develop models for human diseases
Thus, sequence alignment is an important first step toward structural and functional analysis of newly determined sequences to draw functional and evolutionary inference. The sequence alignment is made between a known sequence and unknown sequence or between two unknown sequences. The known sequence is called reference sequence, and the unknown sequence is called query sequence. To proceed with the alignment process the sequences are either aligned in group of two which is called pair-wise alignment) or more than two known as, multiple sequence alignment) sequences by searching for a series of individual characters or character patterns that are in the same order in the sequences. Identical or similar characters are placed in the same column, and non-identical characters can either be placed in the same column as a mismatch or opposite a gap in the other sequence. In an optimal alignment, non-identical characters and gaps are placed to bring as many identical or similar characters as possible into vertical register. Depending upon the region of comparison, alignments are divided into two types of viz. global and local.
Global alignment program is based on Needleman-Wunsch algorithm In global alignment, two sequences to be aligned are assumed to be generally similar over their entire length. Alignment is carried out from beginning to end of both sequences to find the best possible alignment across the entire length between the two sequences.
The two sequences are treated as potentially equivalent.
Goal for Global alignment: Identify conserved regions and differences, and it is applied for either comparing two genes with same function. or for comparing two sequences for conserved regions.
Local alignment program are based on Smith-Waterman, algorithm. Local alignment does not assume that the two sequences in question have similarity over the entire length, rather, it only finds local regions with the highest level of similarity between the two sequences and aligns these regions without regard for the alignment of the rest of the sequence regions. There are three primary methods of producing local alignments, dot-matrix methods, dynamic programming, and word or k-tuple method.
Goal for local alignment: The goal for local alignment is to check whether a substring in one sequence aligns well with a substring in the other, and it is applied for searching local regions of similarities in large sequences (e.g., newly sequenced genomes). or for searching conserved domains or motifs.
Significance of sequence alignment
Sequence alignment is useful for discovering functional, structural, and evolutionary information in biological sequences. However, it is important to obtain the best possible or “optimal” alignment to discover this information. Sequences that are very much alike, or “similar” in the parlance of sequence analysis, probably have the same function or there may have been a common ancestor sequence, and thus, the sequences are then defined as being homologous. The alignment indicates the changes that could have occurred between the two homologous sequences during the course of evolution.
Now let us learn more about sequence alignment using this video tutorial.
BLAST (basic local alignment search tool) is an algorithm and program for comparing primary biological sequence information, such as the amino-acid sequences of proteins or the nucleotides of DNA or RNA sequences. BLAST performs “local” alignments, and this is particularly helpful when working with one or more functional domains occurring within a protein. The BLAST algorithm is tuned to find these domains or shorter stretches of sequence similarity. Moreover, the local alignment approach also means that an mRNA can be aligned with a piece of genomic DNA, as its is frequently required in genome assembly and analysis.
BLAST works by finding regions of local similarity between sequences comparing nucleotide or protein sequences to sequence databases and it also calculates the statistical significance of matches, and displays a “expect value” or e-value that estimates how many matches would have occurred at a given score by chance, which can aid a user in judging how much confidence to have in an alignment.
Uses of BLAST
BLAST can be used for several purposes such as identification of species, locating domains, establishing phylogeny, DNA mapping, and Sequence comparisons.
Identification of species: With the use of BLAST, we can correctly identify a species or find homologous species. This can be useful, for example, when you are working with a DNA sequence from an unknown species.
Locating domains: When working with a protein sequence you can input it into BLAST, to locate known domains within the sequence of interest.
Establishing phylogeny: Using the results received through BLAST you can create a phylogenetic tree using the BLAST web-page. Phylogenies based on BLAST alone are less reliable than other purpose-built computational phylogenetic methods, so should only be relied upon for "first pass" phylogenetic analyses.
DNA mapping: When working with a known species, and looking to sequence a gene at an unknown location, BLAST can compare the chromosomal position of the sequence of interest, to relevant sequences in the database(s). NCBI has a "Magic-BLAST" tool built around BLAST for this purpose.
Sequence Comparison: When working with genes, BLAST can locate common genes in two related species, and can be used to map annotations from one organism to another.
Therefore BLAST has proven itself to be an important tool for studying functional and evolutionary relationships between sequences as well as help identify members of gene families.
One of the aim of biologiks is to make learning concepts of biology interesting and working on that line it brings me immense pleasure to share few of the educational resources that I have created for my student friends in the form of YouTube videos at our official YouTube channel. Do check them out, share with your friends and leave your comments, if you find it helpful, as you, the students and learners, are always my inspiration to bring up better content every time.
Transposable elements (TEs), so-called selfish DNA sequences, are known to be capable of moving around the genome through cut-and-paste or copy-and-paste mechanisms, and our human genome contains approx 4.5 million copies of these TEs.
This can not be termed as one obscure event as they account for 30-50% of mammalian DNA.
The trnasposable elements have been traditionally considered as genetic freeloaders hitchhiking along in the genome without providing any benefit to the host organism. More recently, however, scientists have begun to uncover cases in which TE sequences have been co-opted by the host to provide a useful function, such as encoding part of a host protein. In a recent study published in the journal Nucleic Acids Research, Professor Hidenori Nishihara from Department of Life Science and Technology, Tokyo Institute of Technology, who has undertaken one of the most comprehensive analyses of TE sequence co-option to date, uncovers tens of thousands of potentially co-opted TE sequences and the findings suggest that the TEs might have played a key role in mammalian evolution.
Talking about his research Professor Nishihara says that "I was specifically interested in the potential influence of TE sequences on the evolution of the mammary gland, an organ that is responsible for producing milk and is, as the name suggests, a key distinguishing feature of mammals." To identify potentially co-opted TE sequences, Dr. Nishihara used four proteins—ERα, FoxA1, GATA3, and AP2γ—that bind to DNA to regulate the production of proteins involved in mammary gland development, and located all of the DNA sequences in the genome to which these proteins bind. Surprisingly, 20–30% of all of the binding sites across the genome were located in TEs, with as many as 38,500 TEs containing at least one binding site. The majority of these were in a copy-and-paste type of TE known as a retrotransposon, which duplicates itself, leaving a new copy in a new location.
The TE-derived binding site sequences were more conserved across species than expected, indicating that they are being preserved by evolution because they serve some important function. Dr. Nishihara believes that these TE sequences have been co-opted to serve as enhancers, DNA elements that increase the transcription of nearby genes (Fig. 1). By binding to one of the four master regulators of mammary gland development, these enhancers ultimately increase the production of proteins involved in mammary gland development.
Dr. Nishihara then investigated when in mammalian evolution these TE sequences were acquired and found two distinct phases of acquisition: roughly 60–70% were acquired in the ancestor of all placental mammals (Eutheria), while 10–20% could be traced back to the ancestor of New World monkeys (Simiiformes) (Fig. 2, left). In addition, there appeared to be another wave of acquisition of ERα binding sites in the ancestor of mice and rats (Muridae) (Fig. 2, right). Thus, by providing a vast number of potential regulatory element binding sites throughout the genome, TEs may have had a substantial impact on the emergence of the mammary gland and its evolution within mammals.
Figure 2. Transposable element-derived binding sites were acquired during distinct phases in mammalian evolution. Left: Among the TE-derived binding sites identified, 60–70% were acquired in the ancestor of placental mammals (Eutheria), while 10–20% were acquired in the ancestor of New World monkeys (Simiiformes). Right: Many ERα binding sites were also acquired in the ancestor of mice and rats (Muridae).
Dr. Nishihara's study sheds light on the deep involvement of TEs in the evolution of mammary gland regulatory elements. However, it remains unclear how common this mode of TE-mediated regulatory network evolution is. Dr. Nishihara, at least, believes that the mammary gland is not unique in this respect. He notes that, "in addition to mammary glands, mammals share many features, such as the neocortex, closed secondary palate, and hair. I expect future research to uncover many additional kinds of TEs that have been similarly involved in the evolution of these features in mammals."
One of the oldest desire of man kind is to increase its life expectancy and if possible be immortal. In pursuit of this dream countless have spent their lives searching for elixir of immortality to fountains of youth, often leading to pain and animosity between fellow humans.
Japan, a country owing to its cultural, behavioral and numerous genetic factors has been blessed with many centenarians and currently has the greatest number of known centenarians of any nation with 67,824 according to their 2017 census, along with the highest proportion of centenarians at 34.85 per 100,000 people. Thus Japan becomes the primal choice for conducting studies reflecting on the secrets of longer life and it can be performed with accuracy and a larger statistical sample size compared to other nations.
In a latest set of findings research teams of scientists from the RIKEN Center for Integrative Medical Science (IMS) and Keio University School of Medicine in Japan have shown us that all the while we have been looking in the wrong direction and the solution and clue to long life was within our body's own defense / the immune system.
Supercentenarians -- meaning people over the age of 110 --as their study interest the teams have discovered an interesting finding that the supercentenarians proved to be an unique group of people having a higher count of specific immune cells cytotoxic CD4+ T-cells, when they compared their cell count with a group of supercentenarians and younger controls. They acquired a total of 41,208 cells from seven supercentenarians (an average of 5,887 per subject) and 19,994 cells for controls (an average of 3,999 per subject) from five controls aged in their fifties to eighties.
The study revealed two interesting findings:
Kosuke Hashimoto of IMS, the first author of the paper, expressed the team's stand as "We were especially interested in studying this group of people, because we consider them to be a good model of healthy aging, and this is important in societies like Japan where aging is proceeding rapidly."
IMS Deputy Director Piero Carninci, one of the leaders of the groups, says, "This research shows how single-cell transcription analysis can help us to understand how individuals are more or less susceptible to diseases. CD4-positive cells generally work by generating cytokines, while CD8-positive cells are cytotoxic, and it may be that the combination of these two features allows these individuals to be especially healthy. We believe that this type of cells, which are relatively uncommon in most individuals, even young, are useful for fighting against established tumors, and could be important for immunosurveillance. This is exciting as it has given us new insights into how people who live very long lives are able to protect themselves from conditions such as infections and cancer."
Their research, is published in journal of Proceedings of the National Academy of Sciences (PNAS), and the study was performed by a collaboration including scientists from the RIKEN Center for Integrative Medical Sciences and Keio University School of Medicine.
Pain is one of those feelings which if not all, most of us would never like to encounter and forget our previous encounters as well. However pain has been a necessary evil as it enables our bodies to recognize the occurrence of injuries or other problems which may not be always visible to our eyes, thus preventing further damage.
The International Association for the Study of Pain's widely used definition defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage".
Before discovery of neurons responsible for pain by Charles Scott Sherrington in 1906 and the role of nociceptors, various theories were proposed to explain the origin of pain. Ancient Greeks including Hippocrates believed that it was due to an imbalance in vital fluids.
Now a team of researchers from Karolinska Institutet have now discovered a new sensory receptor organ in the skin that is sensitive to hazardous environmental irritation.
Conventionally pain has been thought to be initiated by activation of free nerve endings without end organs in the skin. In contrast to this paradigm, Abdo et al. discovered a previously unknown meshlike organ covering the skin that senses dangerous environmental stimuli. This organ is built from specialized glial cells with multiple long protrusions and which collectively go to make up a mesh-like organ within the epidermal-dermal border of skin. This organ is sensitive to painful mechanical damage such as pricks and pressure.
The present study describes what the new pain-sensitive organ looks like, how it is organised together with pain-sensitive nerves in the skin and how activation of the organ results in electrical impulses in the nervous system that result in reflex reactions and an experience of pain. In their experiments, the researchers also blocked the organ and saw a resultant decreased ability to feel mechanical pain.
"Our study shows that sensitivity to pain does not occur only in the skin's nerve fibres, but also in this recently-discovered pain-sensitive organ. The discovery changes our understanding of the cellular mechanisms of physical sensation and it may be of significance in the understanding of chronic pain," says Prof. Patrik Ernfors, professor at Karolinska Institutet's Department of Medical Biochemistry and Biophysics and chief investigator for the study.
The research was carried out with financial assistance from ERC, the Swedish Research Council, the Knut and Alice Wallenberg Foundation and Welcome Trust.
1. Abdo H, Calvo-Enrique L, Martinez Lopez J, Song J, Zhang MD, Usoskin D, El Manira A, Adameyko I, Hjerling-Leffler J, Ernfors P. Specialized cutaneous Schwann cells initiate pain sensation. Science, 2019 DOI: 10.1126/science.aax6452
2. Image source: Karolinska Instituet
3. Source article: Karolinska Instituet
The Blue planet of ours is still the only place in universe where we know life exists! However life's journey in this planet was no less than an adventurous journey when it started 4 billion years ago when the first cells formed within a primordial soup of complex, carbon-rich chemical compounds. The primitive life forms or coacervates faced a molecular conundrum as they needed charged ions to perform their basic functions however these ions could de-stabilize and disrupt the simple membranes that encapsulated the cells.
This puzzle has been solved by a team of researchers at University of Washington and their findings were published Aug. 12 in the Proceedings of the National Academy of Sciences. The team solved this puzzle using only molecules that would have been present on the early Earth. Using cell-sized, fluid-filled compartments surrounded by membranes made of fatty acid molecules, the team discovered that amino acids, the building blocks of proteins, can stabilize membranes against magnesium ions. Their results set the stage for the first cells to encode their genetic information in RNA, a molecule related to DNA that requires magnesium for its production, while maintaining the stability of the membrane. Beside explaining the mechanism how amino acid could stabilize the membranes in unfavorable condition they went beyond and demonstrated how the individual building blocks of cellular structures — membranes, proteins and RNA — could have co-localized within watery environments on the ancient Earth.
“Cells are made up of very different types of structures with totally different types of building blocks, and it has never been clear why they would come together in a functional way,” said co-corresponding author Roy Black, a UW affiliate professor of chemistry and bioengineering. “The assumption was just that — somehow — they did come together.”
Prof. Black teamed up with Sarah Keller, a UW professor of chemistry and an expert on membranes. Black had been inspired by the observation that fatty acid molecules can self-assemble to form membranes, and hypothesized that these membranes could act as a favorable surface to assemble the building blocks of RNA and proteins.“You can imagine different types of molecules moving within the primordial soup as fuzzy tennis balls and hard squash balls bouncing around in a big box that is being shaken,” said Keller, who is also co-corresponding author on the paper. “If you line one surface inside the box with Velcro, then only the tennis balls will stick to that surface, and they will end up close together. Roy had the insight that local concentrations of molecules could be enhanced by a similar mechanism.”
The team previously had shown that the building blocks of RNA preferentially attach to fatty acid membranes and, surprisingly, also stabilize the fragile membranes against detrimental effects of salt, a common compound on Earth past and present.
The team hypothesized that amino acids might also stabilize membranes. Using variety of experimental techniques — including light microscopy, electron microscopy and spectroscopy — to test how 10 different amino acids interacted with membranes. Their experiments revealed that certain amino acids bind to membranes and stabilize them. Some amino acids even triggered large structural changes in membranes, such as forming concentric spheres of membranes — much like layers of an onion.
“Amino acids were not just protecting vesicles from disruption by magnesium ions, but they also created multilayered vesicles — like nested membranes,” said lead author Caitlin Cornell, a UW doctoral student in the Department of Chemistry.
The researchers also discovered that amino acids stabilized membranes through changes in concentration. Some scientists have hypothesized that the first cells may have formed within shallow basins that went through cycles of high and low concentrations of amino acids as water evaporated and as new water washed in.
The new findings that amino acids protect membranes — as well as prior results showing that RNA building blocks can play a similar role — indicate that membranes may have been a site for these precursor molecules to co-localize, providing a potential mechanism to explain what brought together the ingredients for life.
Keller, Black and their team will turn their attention next to how co-localized building blocks did something even more remarkable: They bound to each other to form functional machines. "That is the next step,” said Prof. Black.
The study was co-authored by Gary Drobny, UW professor of chemistry; Kelly Lee, UW associate professor of medicinal chemistry; UW postdoctoral researchers Mengjun Xue and Helen Litz in the Department of Chemistry, and James Williams in the Department of Medicinal Chemistry; UW graduate students Zachary Cohen in the Department of Chemistry and Alexander Mileant in the Biological Structure, Physics and Design Graduate Program; and UW undergraduate alumni Andrew Ramsay and Moshe Gordon. The research was funded by NASA, the National Institutes of Health and the National Science Foundation.
1. Original article byJames Urton UW news. Note: Content may be edited for style and length.
2. Image resource: Alex Mileant/Caitlin Cornell, University of Washington.
In the whole world of love and affection, there is no love that beats the love of a mother for her children. Earlier exclusively attributed to humans only due to their improved cognitive functions and social structures, it is now a well documented fact that all mother's irrespective of their taxonomic position show a high level of caring for their children.
To understand it better now lets go back to our childhood, somehow our mothers always knew when we were hungry or when we experienced a agony. Mothers seem to have an instinct related to their children and if not all most of the time mothers are correct! How this happens?
A recent discovery carried out by Ryoichi Teruyama and a team of student researchers at Louisiana State University (LA, USA) may have given scientists a more complete understanding of the mechanisms underpinning maternal instinct. The study has revealed differences in the distribution of neurons sensitive to oxytocin in female brains compared with male brains. Oxytocin is a neurotransmitter and hormone found in a variety of species. It is known as the love hormone, and plays a pivotal role in regulating maternal behavior, as well as being responsible for modulating a variety of social behaviors including: maternal care, sexual behavior in both sexes, bonding and anxiety.
“Many researchers have attempted to investigate the difference between the oxytocin system in females versus males, but no one has successfully found conclusive evidence until now. Our discovery was a big surprise,” Teruyama commented.
The team concentrated on the medial preoptic area (MPOA), an area of the brain that forms part of the essential neural circuit that regulates maternal behavior. Using oxytocin receptor (OXTR)-Venus knock-in mice, in which a yellow fluorescent protein is directly inserted into the locus where OXTR is usually located, scientists had the ability to image where OXTR was being expressed.
Whilst there were no significant differences in the amount of OXTR cells located in the MPOA between male and females, it was demonstrated that neurons expressing OXTR were found in the anteroventral periventricular nucleus (AVPV) of the MPOA in females almost exclusively.
When the female OXTR-Venus mice received ovariectomies, OXTR was no longer expressed in the AVPV. However, expression could be restored upon receiving estrogen replacement therapy. This finding denotes estrogen dependence and the female-specific nature of OXTR expression in the AVPV, indicating that these neurons play a role in the induction of maternal responses.
Previous studies have shown a link between altered expression of OXTR and postpartum depression, which is associated with poor maternal health and substandard child development. This work has the potential to contribute to future treatments and pharmaceuticals for postpartum depression where the OXTR cells are targeted.
1. The original article published inBiotechniques. Note: Content edited for style and length.
2. Image courtesy: Pxhere.com.
Stanford University researchers have discovered a new cellular signal that cancer cells seem to use to evade detection and destruction by the cells of the immune system, and macrophages in particular. Studies by the team of researchers in mice model paved a way for development of new therapeutic strategies. The scientists have shown that blocking this signal in mice implanted with human cancers allows immune cells to attack the cancers.
Cancer cells have shown in earlier studies, that they choose to evade destruction by macrophages by overexpressing anti-phagocytic surface proteins called ‘don’t eat me’ signals such as CD471, programmed cell death ligand 1 (PD-L1) and the beta-2 microglobulin subunit of the major histocompatibility class I complex (B2M). Antibodies that block CD47 are in clinical trials. Cancer treatments that target PD-L1 are already being used in the clinics.
The study lead by Amira Barkal, an MD-PhD student, (lead author). Irving Weissman, MD, professor of pathology and of developmental biology and director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine (senior author), showed that CD24 can be the dominant innate immune checkpoint in ovarian cancer and breast cancer, and is a promising target for cancer immunotherapy.Looking for additional signalsThe scientists began by looking for proteins that were produced more highly in cancers than in the tissues from which the cancers arose. “You know that if cancers are growing in the presence of macrophages, they must be making some signal that keeps those cells from attacking the cancer,” Barkal said. “You want to find those signals so you can disrupt them and unleash the full potential of the immune system to fight the cancer.”
The search showed that many cancers produce an abundance of CD24 compared with normal cells and surrounding tissues. In further studies, the scientists showed that the macrophage cells that infiltrate the tumor can sense the CD24 signal through a receptor called SIGLEC-10. They also showed that if they mixed cancer cells from patients with macrophages in a dish, and then blocked the interaction between CD24 and SIGLEC-10, the macrophages would start gorging on cancer cells like they were at an all-you-can-eat buffet. “When we imaged the macrophages after treating the cancers with CD24 blockade, we could see that some of them were just stuffed with cancer cells,” Barkal said.
Lastly, they implanted human breast cancer cells in mice. When CD24 signaling was blocked, the mice’s scavenger macrophages of the immune system attacked the cancer.
Of particular interest was the discovery that ovarian and triple-negative breast cancer, both of which are very hard to treat, were highly affected by blocking the CD24 signaling. “This may be a vulnerability for those very dangerous cancers,” Barkal said.
Complementary to CD47?The other interesting discovery was that CD24 signaling often seems to operate in a complementary way to CD47 signaling. Some cancers, like blood cancers, seem to be highly susceptible to CD47-signaling blockage, but not to CD24-signaling blockage, whereas in other cancers, like ovarian cancer, the opposite is true. This raises the hope that most cancers will be susceptible to attack by blocking one of these signals, and that cancers may be even more vulnerable when more than one “don’t eat me” signal is blocked.
“There are probably many major and minor ‘don’t eat me’ signals, and CD24 seems to be one of the major ones,” Barkal said The researchers now hope that therapies to block CD24 signaling will follow in the footsteps of anti-CD47 therapies, being tested first for safety in preclinical trials, followed by safety and efficacy clinical trials in humans.
For Weissman, the discovery of a second major “don’t eat me” signal validates a scientific approach that combines basic and clinical research. “These features of CD47 and CD24 were discovered by graduate students in MD-PhD programs at Stanford along with other fellows,” Weissman said. “These started as fundamental basic discoveries, but the connection to cancers and their escape from scavenger macrophages led the team to pursue preclinical tests of their potential. This shows that combining investigation and medical training can accelerate potential lifesaving discoveries.”
1. Original article: Stanford University of Medicine
Note: The article has been edited for style and length
2. Journal article: Amira A. Barkal, Rachel E. Brewer, Maxim Markovic, Mark Kowarsky, Sammy A. Barkal, Balyn W. Zaro, Venkatesh Krishnan, Jason Hatakeyama, Oliver Dorigo, Layla J. Barkal, Irving L. Weissman. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature, 2019; DOI: 10.1038/s41586-019-1456-0
3. Image source: Stanford University of medince
Love affects us all! and when it comes to food there is no greater love than the love for your favorite cuisine. Much like our lives not all love is good for us and some time love cost us more dearly than we expect! No I am not talking about break ups, but one must pay attention to what they put in their plate and " Love is blind" kind of logic do not work here specially if it increases your chances for falling for a deadly disease, which may be avoided by going for healthier life style choices.
A recent study published in the journal of Cancer Epidemiology by Jamie J. Lo et, al reveals that red meat consumption may increase the risk of breast cancer, whereas poultry consumption may confer protection against breast cancer risk. For the study the team of researchers collected information on consumption of different meat categories and meat cooking practice behaviors was obtained from 42,012 Sister Study participants for a duration of over 7.6 years and exposure to meat type and meat mutagens was calculated, and estimated for associations with invasive breast cancer risk using multivariable Cox proportional hazards regression. During follow‐up 1,536 invasive breast cancers were diagnosed at least 1 year after enrollment. The study revealed that women who consumed the highest amount of red meat had a 23% higher risk compared with women who consumed the lowest amount. Conversely, increasing consumption of poultry was associated with decreased invasive breast cancer risk: women with the highest consumption had a 15% lower risk than those with the lowest consumption. Breast cancer was reduced even further for women who substituted poultry for meat. Their findings remained consistent even when analyses controlled for known breast cancer risk factors or potential confounding factors such as race, socioeconomic status, obesity, physical activity, alcohol consumption, and other dietary factors. No associations were observed for cooking practices or chemicals formed when cooking meat at high temperature. Senior author Dale P. Sandler, PhD, of the National Institute of Environmental Health Sciences. commented that "While the mechanism through which poultry consumption decreases breast cancer risk is not clear, our study does provide evidence that substituting poultry for red meat may be a simple change that can help reduce the incidence of breast cancer."
Note: Content edited for style and length
1. Jamie J. Lo, Yong‐Moon Mark Park, Rashmi Sinha, Dale P. Sandler. Association between meat consumption and risk of breast cancer: Findings from the Sister Study. International Journal of Cancer, 2019; DOI: 10.1002/ijc.32547
2. Image courtesy: Pixabay
Scientists at Tokyo Institute of Technology have imaged live T cells to reveal the role of CLIP-170 in T-cell activation, a critical process in the immune response.
When bacteria or viruses enter the body, proteins on their surfaces are recognized and processed to activate T cells, white blood cells with critical roles in fighting infections. During T-cell activation, a molecular complex known as the microtubule-organizing center (MTOC) moves to a central location on the surface of the T-cell. Microtubules have several important functions, including determining cell shape and cell division. Thus, MTOC repositioning plays a critical role in the immune response initiated by activated T cells.
In a recent publication in Scientific Reports, the first authors Lim Wei Ming and Yuma Ito, along with their colleagues at Tokyo Institute of Technology (Tokyo Tech), provide compelling evidence that a key protein responsible for the relocation of the MTOC in activated T cells is a molecule known as CLIP-170, a microtubule-binding protein.
The researchers used live-cell imaging to uncover the mechanism of MTOC relocation. “The use of dual-color fluorescence microscopic imaging of live T cells allowed us to visualize and quantify the molecular interactions and dynamics of proteins during MTOC repositioning,” notes Dr. Sakata-Sogawa. This technque allowed them to confirm that phosphorylation of CLIP-170 is involved in movement of the MTOC to the center of the contacted cell surface (Fig. 1); the findings were confirmed using both cells with phosphodeficient CLIP-170 mutant and cells in which AMPK, the molecule that phosphorylates and activates CLIP-170, was impaired. Further imaging showed that CLIP-170 is essential for directing dynein, a motor protein, to the plus ends of microtubules and for anchoring dynein in the center of the cell surface (Fig. 2). Dynein then pulls on the microtubules to reposition the MTOC to its new location in the center.
“These findings shed new light on microtubule binding proteins and microtubule dynamics,” explains Dr. Tokunaga. Such research is critical, as a deeper understanding of T cell activation in the immune response, and could lead to the development of safer methods for cancer immunotherapy because presentation of CTLA-4, which is found by a 2018 Novel Prize laureate and used as a target of the therapy, is also regulated by MTOC reposition
Figure 1. CLIP-170 phosphorylation regulates MTOC repositioning and full activation of T cells.
Fluorescence live-cell imaging of the wild-type CLIP-170-TagRFP-T (a,b) or a phosphodeficient S312A mutant CLIP-170-TagREP-T (c) and dynein light chain (DLC)-mEGFP co-expressed in T cells. Increased dynein relocation to the center, which is responsible for MTOC repositioning, requires both stimulation and CLIP-170 phosphorylation. The boxed regions in the merged images are enlarged (right). Scale bars: 5 μm (left, 2nd left, merged) and 2 μm (right)
Figure 2: Schematic model for the keyrole of CLIP-170 in MTOC repositioning during T cell activation by regulating dynein relocation.
In resting T cells, the majority of dynein is immobile on the contacted cell surface and is located at the periphery region. T cell stimulation increases the fraction of dynein undergoing minus-end-directed motility (“mobilise”), which is a “weakly processive” state. Then, the dynein is anchored to the surface (“anchor”). Alongside this, stimulation induces some fraction of dynein to colocalize with CLIP-170 and dynactin and follow plus-end tracking (“recruit”). After tracking of one or two micrometers, the dynein is released from the complex and anchored (“release”). As a result, dynein relocation increases to the center region of the contact surface, the immunological synapse, where “anchored” dynein molecules are immobile and or weakly processive at a velocity in good agreement with the velocity of MTOC repositioning. “Anchored” and weakly processive dynein pulls the microtubules and the MTOC (“pull”), which causes MTOC repositioning near the immunological synapse and full activation of T cells. Phosphorylation of CLIP-170 is essential for dynein recruitment to the plus-end and for dynein relocation.
1. Original article source: School of Life Science and Technology, Tokyo Institute of Technology
2. Research Paper: Wei Ming Lim, Yuma Ito, Kumiko Sakata-Sogawa* & Makio Tokunaga* CLIP-170 is essential for MTOC repositioning during T cell activation by regulating dynein localisation on the cell surface Nature Scientific Reports DOI : 10.1038/s41598-018-35593-z
3. Image source: School of Life Science and Technology, Tokyo Institute of Technology
New research demonstrates antiparasitic drug turns lethal for malaria-carrying mosquitoes showing promising future for the drug. Preliminary analysis showed that the drug reduced malaria cases in children under 5 by 16%. The trends are encouraging for the drug and it might become part of national malaria control programs.
Ivermectin a well known antiparasitic drug for treatment of a wide range of parasite infestations from head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, and lymphatic filariasis, may have another hidden benefit.
Mosquitoes of the genus Anopheles and only females of the species are capable of transmitting the malaria pathogen a protozoa, of genus Plasmodium, which undergoes a series of infection steps before arriving at the mosquito’s salivary gland, from where it ultimately gets transmitted to the human host during blood meal.
Malaria has been a well known killer in the tropical regions of the globe killing more peoples combined who died from outer causes. The data for malaria infection and transmission is staggering as each year, the disease infects more than 200 million people, causing 429,000 deaths — and the situation seems to get worse as despite spending billions on malaria eradication programs, we seem to have reached a plateau. Meanwhile mosquitoes are becoming increasingly resistant to insecticides, which is forcing researchers to think of all sorts of new solutions like a malaria vaccine, genetically engineering mosquitoes so they wipe themselves out and many more.
Previous studies have found that malaria-carrying mosquitoes would die after sucking the blood from individuals who had taken ivermectin, researchers have known for decades that the drug also kills insects if they ingest it. Brian Foy, a medical entomologist at Colorado State University, Fort Collins, believes that makes it a prime candidate in the fight against malaria. If enough people in an area have ivermectin in their blood, says Foy, some of the female mosquitoes that bite them will die, whereas others will be too weakened to pass on the malaria parasite. Foy has shown in lab studies that the approach holds promise, and co-founded a research network last year to study the concept further, to show that ivermectin actually has an impact on malaria in the field, Foy teamed up with Roch Dabiré, a researcher at the Institute of Health Studies in Bobo-Dioulasso, Burkina Faso. The scientists went to eight villages near the town of Diébougou, in the southwest of the country. At the start of the trial, in July, the population of all villages received one dose of ivermectin and another drug, albendazole; this standard combination is given twice yearly around Burkina Faso to control elephantiasis and soil-transmitted worms. In four of the villages, this was followed by ivermectin tablets every 3 weeks for the entire population except pregnant women and children under 90 centimeters tall, who may be at higher risk of side effects. The four other villages served as controls; they received no drugs after the first dose.
The trial is still ongoing and will conclude in November. But an interim analysis presented today by Foy and Dabiré at the annual meeting of the American Society of Tropical Medicine and Hygiene suggests that the drug is already having an impact. Among children under the age of 5—the group at the highest risk of severe disease and death from malaria—there were 16% fewer cases in the villages that received ivermectin at 3-week intervals. That translates to 94 cases averted so far this season in the four villages.
The full results will take some time to analyze, and the study will need to be repeated at a larger scale to see if the findings hold up, Dabiré says. If they do, ivermectin could be another weapon in the antimalaria arsenal, Foy says. He adds that it wouldn’t replace other measures, such as insecticide-treated bed nets.
It’s an interesting approach that should be explored further, says Michel Boussinesq, who studies ivermectin at the Institute of Research for Development in Montpellier, France. But the need to give ivermectin every 3 weeks could be a logistical problem, he says. Boussinesq and his colleagues are working on an ivermectin implant for animals that instead releases the drug slowly and offers long-term protection.
Such implants aren’t likely to be acceptable for use in humans, Foy says—but he points out that ivermectin would only be given during the rainy season, when malaria mosquitoes are active. The season lasts about 6 months in the region where the study took place and even less than that farther north, in the Sahel region. “I think that’s feasible,” Foy says.
Willem Takken, a medical entomologist at Wageningen University and Research Centre in the Netherlands, sees another, fundamental problem: Mosquitoes have developed resistance against almost any chemical that humans have thrown at them. He says that’s bound to happen with ivermectin, too. That’s why, despite the encouraging data, “I find it hard to get enthusiastic about this,” Takken says. He believes that nonchemical approaches, such as mosquito traps or bacteria that render mosquitoes unable to transmit pathogens, hold more long-term promise.
Recent study by a group of scientists from Intermountain Healthcare Heart Institute in Salt Lake City, identified eight new gene mutations that may contribute to idiopathic dilated cardiomyopathy, a form of heart disease not caused by known external influences.
In a new study from the Intermountain Healthcare Heart Institute in Salt Lake City, led by Dr. Jeffrey L. Anderson, MD, the researchers have identified eight new gene mutations that may cause or contribute to idiopathic dilated cardiomyopathy, a form of heart disease not caused by known external influences, such as high blood pressure, obesity, smoking, or diseased coronary arteries. The study observed that for at least 40 percent of the enrolled patients, the disease had an underlying genetic cause that leads to the muscle in the major pumping chamber of the heart (left ventricle) being too weak and thin to function properly, causing heart failure.
“Although many mutations contributing to non-ischemic dilated cardiomyopathy have been identified, there remains a large gap in our knowledge of its heritability. The more we can learn about what’s causing the condition, the better we can identify and treat it,” said Jeffrey L. Anderson, MD, principal investigator of the study, and a researcher at the Intermountain Healthcare Heart Institute. “If it’s passed on in families, we’ll be able to identify those who might be at risk for developing heart disease and work to prevent it, diagnose it, and begin treatment earlier.”
The study team is going to present the findings from the study at the American College of Cardiology’s Annual Scientific Session in New Orleans on March 18, 2019.
A quarter to one-third of idiopathic dilated cardiomyopathy patients will need a mechanical support device, a heart transplant, or will die within five years, Dr. Anderson noted, so this is a very serious condition.
In the study, researchers looked at genetic samples of 231 patients with idiopathic dilated cardiomyopathy, evaluated in an Intermountain Medical Center Specialty Clinic who volunteered to enter blood samples into the Intermountain Healthcare INSPIRE Registry and DNA Bank, which is the system’s collection of biological samples, clinical information, and laboratory data from consenting patients who are diagnosed with any of a number of healthcare-related conditions.
In collaboration with Intermountain’s Precision Genomics laboratory, researchers sequenced patients’ DNA, focusing on the TITIN (TNN) gene, which codes the body’s largest protein.
“That protein acts as a spring in your heart muscle,” said Dr. Anderson. “It enhances the passive elasticity of the muscle and also limits how much you can stretch it.” Previous studies have already observed variants of TTN in patients with idiopathic dilated cardiomyopathy, but the story has been incomplete.
Now, in this new study, Intermountain researchers identified 24 patients with TTN variants, and eight of those variants hadn’t been seen or documented before. They also confirmed the presence of seven variants that had been discovered and reported previously. The new variants all are of the “truncating” variety, that is, they lead to a shortening of the protein and in doing so it is predicted to cause the protein to malfunction in its role of maintaining the integrity of heart muscle function.
These new variants, Dr. Anderson said, still will require functional testing and clinical validation, but they likely will lead to further expansion of the known spectrum of genes that predispose to idiopathic dilated cardiomyopathy.
The addition of these variants to the current list of known pathological heart muscle protein mutations will help to close the still large gap in our knowledge of the heritability of heart muscle disease and in doing so can lead to earlier diagnosis and more effective prevention and treatment.
The study was funded by the Intermountain Foundation and an in-kind grant from Intermountain Precision Genomics.
The compounds in frying oils that are repeatedly reheated to high temperatures may trigger cell proliferation and metastases in breast tumors, scientists in food science and human nutrition at the University of Illinois found in a new study of mice model.
A common scene we observe in our roadside food stalls is that the cooking oil used for frying eatables is often reused, the prime reason being cost effectiveness, however its risks are often discussed in closed circles but no concrete steps are ever taken. However now a consciousness is seen to be arising and some regulatory bodies like FSSAI of India issued directive against reusing cooking oil.
In the present study published in the journal of Cancer Prevention Research the scientists observed that, thermally abused frying oil ( cooking oil that has been repeatedly reheated to high temperatures) may act as a toxicological trigger that promotes tumor cell proliferation, metastases and changes in lipid metabolism. The study conducted in mice also suggests that consuming the chemical compounds found in thermally abused cooking oil may trigger genetic changes that promote the progression of late-stage breast cancer.
In this study the mice were divided into two groups consuming a low-fat diet for one week, one group of the mice was fed unheated fresh soybean oil, while another group consumed thermally abused oil for the next 16 weeks. Soybean oil was used in the study because of its common use by the food service industry in deep frying.
The team of research scientists simulated late-stage breast cancer by injecting 4T1 breast cancer cells into a tibia of each mouse. The 4T1 cells are an aggressive form of the disease that can spontaneously metastasize to multiple distant sites in the body, including the lungs, liver and lymph nodes, according to the study.
Twenty days after inoculation with the tumor cells, the primary tumors in the tibias of the mice that consumed the thermally abused oil had more than four times as much metastatic growth as the mice that consumed the fresh soybean oil. And when the researchers examined the animals’ lungs, they found more metastases among those that consumed the thermally abused oil.
“There were twice as many tumors in the lung, and they were more aggressive and invasive,” said William G. Helferich, a professor of food science and human nutrition, who led the research.
Food chemistry professor Nicki J. Engeseth, the acting head of the department, co-wrote the paper. Graduate student Ashley W. Oyirifi and U. of I. alumnus Anthony Cam were the lead authors.
“I just assumed these nodules in the lungs were little clones – but they weren’t. They’d undergone transformation to become more aggressive. The metastases in the fresh-oil group were there, but they weren’t as invasive or aggressive, and the proliferation wasn’t as extensive,” Helferich said.
In examining both groups of mice, the scientists found that the metastatic lung tumors in those that consumed thermally abused frying oil expressed significantly more of a key protein, Ki-67, which is associated strictly with cell proliferation.
Gene expression in these animals’ livers was altered as well. When the researchers conducted RNA sequencing analysis, they found 455 genes in which expression was at least two times greater – or, conversely, two times lower – than in mice that consumed the fresh oil.
The altered gene pathways were associated with oxidative stress and the metabolism of foreign substances, Oyirifi said. When oil is repeatedly reused, triglycerides are broken apart, oxidizing free fatty acids and releasing acrolein, a toxic chemical that has carcinogenic properties. Scientists have long known that thermally abused oil contains acrolein, and studies have linked the lipid peroxides in it with a variety of health problems, including atherosclerosis and heart disease. As the oil degrades, polymer molecules also accumulate, raising nutritional and toxicological concerns, Engeseth said.
Countries in Europe and elsewhere regulate the amount of polar materials in frying oil, which are chemically altered triglycerides and fatty acids that are used as chemical markers of oils’ decomposition. Typically, these standards permit restaurants to use oil containing up to 24-27 percent polar material. By contrast, the thermally abused oil used in the current study contained about 15 percent polar material, while fresh oil contains 2-4 percent or less, Helferich said.
“Because there are no regulations in the U.S., it’s really difficult for us to evaluate what’s out there,” Engeseth said. “But the important thing is, the food that’s fried in these oils sucks up quite a bit of oil. Even though we’re not consuming the oil directly, we’re consuming oil that’s brought into the food during the frying process.”
Breast cancer survivors’ biggest fear is recurrence, and the majority of these survivors have dormant tumor cells circulating in their blood, Helferich said.
“What wakes those cells up is anybody’s guess, but I’m convinced that diet activates them and creates an environment in different tissues that’s more fertile for them to grow,” he said.
“Many cancer biologists are trying to understand what’s happening at metastatic sites to prime them for tumor growth,” Oyirifi said. “We’re trying to add to this conversation and help people understand that it might not be just some inherent biological mechanism but a lifestyle factor. If diet provides an opportunity to reduce breast cancer survivors’ risk, it offers them agency over their own health.” Additional co-authors on the study were Urszula T. Iwaniec and Russell T. Turner, both of Oregon State University; and Fureya (Yunxian) Liu, a then-graduate student at the U. of I.
The National Center for Complementary and Integrative Health, the Office of Dietary Supplements, the National Cancer Institute and the National Institute of Environmental Health Sciences funded the research.
Note: The article is edited for style and length
Biological activities of Woolly mammoth nuclei was observed by Japanese scientists, could the prehistoric giants be brought back to life?
The 28,000-year-old remains of a woolly mammoth, named ‘Yuka’, were found in Siberian permafrost. The study group recovered the less-damaged nucleus-like structures from the remains and visualised their dynamics in living mouse oocytes after nuclear transfer (aka cloning). In the reconstructed oocytes, the mammoth nuclei showed the spindle assembly, histone incorporation and partial nuclear formation; however, the full activation of nuclei for cleavage was not confirmed. The scientists hope their work provides a platform to evaluate the biological activities of nuclei in extinct animal species.
Wolly mammoth an ice age giant often found plodding in animated movies like The ice age, actually died out just over 4,000 years ago, and climate change was one of the most probable reason for their death apart from alleged viral infections but could the prehistoric giants be soon back to life? Probably not, however the work by the team led by Dr. Akira Iritani from Institute of Advanced Technology, Kindai University, Wakayama,Japan provides a platform to evaluate the biological activities of nuclei in extinct animal species.
Their results published in the journal Nature Scientific reports indicates that “a part of mammoth nuclei possesses the potential for nuclear reconstitution, while observing possible signs of repair to damaged mammoth DNA.” However despite the successes, the scientists did not observe the further cell division necessary to create a viable egg, “possibly due to the extensive DNA damage in the transferred nuclei”.
Researcher Kei Miyamoto, one of the study’s authors told Japan’s Nikkei news outlet. “We want to move our study forward to the stage of cell division,” he added, but acknowledged “we still have a long way to go”.
The samples of woolly mammoth (named Yuka) used in the present study was found in Siberian permafrost in 2010. The animal, is beleived to be of about seven-years-old at the time of death and it is one of the best preserved mammoths known to science. Dr. Akira’s team extracted tissue samples from the animal’s bone marrow and muscle. It is worth mentioning that most mammoth populations died out between 14,000 and 10,000 years ago. The last mainland population existed in the Kyttyk peninsula of Siberia until 9,650 years ago. But the species is observed to be surviving for another 5,000 years on Siberian islands, which became cut off from the mainland by retreating ice following the last ice age. The last known population remained on Wrangel Island in the Arctic Ocean until 4,000 years ago – well beyond the dawn of human civilisation, but finally becoming extinct around the time of the construction of the pyramids of Giza in Egypt. The real cause for their extinction is still a issue where no scientific consensus has been reached, climate change leading to habitat destruction and hunting by humans are commonly discussed theories and works like that of Dr. Akira might shine some light on the other aspects of their extinction.
Note: The article has been edited for style and length
If you have a sweet tooth and often crave for a cola, I think you need to pay attention what lies ahead. A cola or a carbonated drink is usually our resort to cool off during a hot summer day, however its a well known fact that it packs a lot of false calories and people on diet strictly avoid drinking cola.
The main reason cola is high in calories is a common sweetening agent present in all processed foods, High-fructose corn syrup (HFCS), also known as glucose-fructose, isoglucose and glucose-fructose syrup, is a sweetener made from corn starch. Although extensively used in almost all processed foods HFCS has been found to be closely associated with Obesity, Diabetes. However the present study led by researchers at Baylor College of Medicine and Weill Cornell Medicine published in Science, showed that consuming a daily modest amount of high-fructose corn syrup – the equivalent of people drinking about 12 ounces of a sugar-sweetened beverage daily – accelerates the growth of intestinal tumors in mouse models of the disease, independently of obesity.
The team also discovered the mechanism by which the consumption of sugary drinks can directly feed cancer growth, suggesting potential novel therapeutic strategies.“An increasing number of observational studies have raised awareness of the association between consuming sugary drinks, obesity and the risk of colorectal cancer,” said co-corresponding author Dr. Jihye Yun, assistant professor of molecular and human genetics at Baylor. “The current thought is that sugar is harmful to our health mainly because consuming too much can lead to obesity. We know that obesity increases the risk of many types of cancer including colorectal cancer; however, we were uncertain whether a direct and causal link existed between sugar consumption and cancer. Therefore, I decided to address this important question when I was a postdoc in the Dr. Lewis Cantley lab at Weill Cornell Medicine.
First, Yun and her colleagues generated a mouse model of early-stage colon cancer where APC gene is deleted. “APC is a gatekeeper in colorectal cancer. Deleting this protein is like removing the breaks of a car. Without it, normal intestinal cells neither stop growing nor die, forming early stage tumors called polyps. More than 90 percent of colorectal cancer patients have this type of APC mutation,” Yun said.
Using this mouse model of the disease, the team tested the effect of consuming sugar-sweetened water on tumor development. The sweetened water was 25 percent high-fructose corn syrup, which is the main sweetener of sugary drinks people consume. High-fructose corn syrup consists of glucose and fructose at a 45:55 ratio.
When the researchers provided the sugary drink in the water bottle for the APC-model mice to drink at their will, mice rapidly gained weight in a month. To prevent the mice from being obese and mimic humans’ daily consumption of one can of soda, the researchers gave the mice a moderate amount of sugary water orally with a special syringe once a day. After two months, the APC-model mice receiving sugary water did not become obese, but developed tumors that were larger and of higher-grade than those in model mice treated with regular water.
“These results suggest that when the animals have early stage of tumors in the intestines – which can occur in many young adult humans by chance and without notice – consuming even modest amounts of high-fructose corn syrup in liquid form can boost tumor growth and progression independently of obesity,” Yun said. “Further research is needed to translate these discovery to people; however, our findings in animal models suggest that chronic consumption of sugary drinks can shorten the time it takes cancer to develop. In humans, it usually takes 20 to 30 years for colorectal cancer to grow from early stage benign tumors to aggressive cancers.”
“This observation in animal models might explain why increased consumption of sweet drinks and other foods with high sugar content over the past 30 years is correlating with an increase in colorectal cancers in 25 to 50-year-olds in the United States,” said Cantley, co-corresponding author, former mentor of Yun and professor of cancer biology in medicine and director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
The team then investigated the mechanism by which this sugar promoted tumor growth. They discovered that the APC-model mice receiving modest high-fructose corn syrup had high amounts of fructose in their colons. “We observed that sugary drinks increased the levels of fructose and glucose in the colon and blood, respectively and that tumors could efficiently take up both fructose and glucose via different routes.”
Using cutting-edge technologies to trace the fate of glucose and fructose in tumor tissues, the team showed that fructose was first chemically changed and this process then enabled it to efficiently promote the production of fatty acids, which ultimately contribute to tumor growth.
“Most previous studies used either glucose or fructose alone to study the effect of sugar in animals or cell lines. We thought that this approach did not reflect how people actually consume sugary drinks because neither drinks nor foods have only glucose or fructose. They have both glucose and fructose together in similar amounts,” Yun said. “Our findings suggest that the role of fructose in tumors is to enhance glucose’s role of directing fatty acids synthesis. The resulting abundance of fatty acids can be potentially used by cancer cells to form cellular membranes and signaling molecules, to grow or to influence inflammation.”
To determine whether fructose metabolism or increased fatty acid production was responsible for sugar-induced tumor growth, the researchers modified APC-model mice to lack genes coding for enzymes involved in either fructose metabolism or fatty acid synthesis. One group of APC-model mice lacked an enzyme KHK, which is involved in fructose metabolism, and another group lacked enzyme FASN, which participates in fatty acid synthesis. They found that mice lacking either of these genes did not develop larger tumors, unlike APC-model mice, when fed the same modest amounts of high-fructose corn syrup.
“This study revealed the surprising result that colorectal cancers utilize high-fructose corn syrup, the major ingredient in most sugary sodas and many other processed foods, as a fuel to increase rates of tumor growth,” Cantley said. “While many studies have correlated increased rates of colorectal cancer with diet, this study shows a direct molecular mechanism for the correlation between consumption of sugar and colorectal cancer.”
“Our findings also open new possibilities for treatment,” Yun said. “Unlike glucose, fructose is not essential for the survival and growth of normal cells, which suggests that therapies targeting fructose metabolism are worth exploring. Alternatively, avoiding consuming sugary drinks as much as possible instead of relying on drugs would significantly reduce the availability of sugar in the colon.”
While further studies in humans are necessary, Yun and colleagues hope this research will help to raise public awareness about the potentially harmful consequences consuming sugary drinks has on human health and contribute to reducing the risk and mortality of colorectal cancer worldwide.
Other contributors to this work include Drs. Sukjin Yang, Yumei Wang and Justin Van Riper with Baylor, Marcus Goncalves (lead author), Changyuan Lu, Jordan Trautner, Travis Hartman, Seo-Kyoung Hwang, Charles Murphy, Roxanne Morris, Sam Taylor, Quiying Chen, Steven Gross and Kyu Rhee, all with Weill Cornell Medicine, Chantal Pauli with the University Hospital Zurich, Kaitlyn Bosch with the Icahn School of Medicine at Mount Sinai, H Carl Lekaye with Memorial Sloan Kettering Cancer Center, Jatin Roper with Duke University and Young Kim with Chonnam National University.
This study was supported by the National Institutes of Health, Stand Up 2 Cancer, the Cancer Prevention and Research Institute of Texas and the National Cancer Institute.
Note: Content may be edited for style and length.
1. Original article can be accessed here : https://www.bcm.edu/news/molecular-and-human-genetics/high-fructose-corn-syrup-intestinal-tumors
2. Journal Reference: Marcus D. Goncalves, Changyuan Lu, et al, High-fructose corn syrup enhances intestinal tumor growth in mice. Science, 2019; 363 (6433): 1345-1349 DOI: 10.1126/science.aat8515
3. Image source: For representation only, https://goo.gl/images/s4dkKy
Computer scientists at Caltech have designed DNA molecules that can carry out reprogrammable computations, for the first time creating so-called algorithmic self-assembly in which the same "hardware" can be configured to run different "softwares"
I remember during my graduation days early 2005-06 I could lay my hands on a science magazine called junior science refresher, although the magazine was not a top notch but nevertheless it was the only science news available in my state at that time. During my course of reading the magazine I came across the term "DNA computing" which fascinated me as a life-science student that one day the lving molecule could replace our silicon based computers. Now this recent development by Caltech caught my eye so thought of sharing the information with my readers and friends. Here is the original new byte from caltech.
In a paper publishing in Nature on March 21, a team headed by Caltech's Erik Winfree (PhD '98), professor of computer science, computation and neural systems, and bioengineering, showed how the DNA computations could execute six-bit algorithms that perform simple tasks. The system is analogous to a computer, but instead of using transistors and diodes, it uses molecules to represent a six-bit binary number (for example, 011001) as input, during computation, and as output. One such algorithm determines whether the number of 1-bits in the input is odd or even, (the example above would be odd, since it has three 1-bits); while another determines whether the input is a palindrome; and yet another generates random numbers.
"Think of them as nano apps," says Damien Woods, professor of computer science at Maynooth University near Dublin, Ireland, and one of two lead authors of the study. "The ability to run any type of software program without having to change the hardware is what allowed computers to become so useful. We are implementing that idea in molecules, essentially embedding an algorithm within chemistry to control chemical processes."
The system works by self-assembly: small, specially designed DNA strands stick together to build a logic circuit while simultaneously executing the circuit algorithm. Starting with the original six bits that represent the input, the system adds row after row of molecules—progressively running the algorithm. Modern digital electronic computers use electricity flowing through circuits to manipulate information; here, the rows of DNA strands sticking together perform the computation. The end result is a test tube filled with billions of completed algorithms, each one resembling a knitted scarf of DNA, representing a readout of the computation. The pattern on each "scarf" gives you the solution to the algorithm that you were running. The system can be reprogrammed to run a different algorithm by simply selecting a different subset of strands from the roughly 700 that constitute the system.
"We were surprised by the versatility of programs we were able to design, despite being limited to six-bit inputs," says David Doty, fellow lead author and assistant professor of computer science at the University of California, Davis. "When we began experiments, we had only designed three programs. But once we started using the system, we realized just how much potential it has. It was the same excitement we felt the first time we programmed a computer, and we became intensely curious about what else these strands could do. By the end, we had designed and run a total of 21 circuits."
The researchers were able to experimentally demonstrate six-bit molecular algorithms for a diverse set of tasks. In mathematics, their circuits tested inputs to assess if they were multiples of three, performed equality checks, and counted to 63. Other circuits drew "pictures" on the DNA "scarves," such as a zigzag, a double helix, and irregularly spaced diamonds. Probabilistic behaviors were also demonstrated, including random walks, as well as a clever algorithm (originally developed by computer pioneer John von Neumann) for obtaining a fair 50/50 random choice from a biased coin.
Both Woods and Doty were theoretical computer scientists when beginning this research, so they had to learn a new set of "wet lab" skills that are typically more in the wheelhouse of bioengineers and biophysicists. "When engineering requires crossing disciplines, there is a significant barrier to entry," says Winfree. "Computer engineering overcame this barrier by designing machines that are reprogrammable at a high level—so today's programmers don't need to know transistor physics. Our goal in this work was to show that molecular systems similarly can be programmed at a high level, so that in the future, tomorrow's molecular programmers can unleash their creativity without having to master multiple disciplines."
"Unlike previous experiments on molecules specially designed to execute a single computation, reprogramming our system to solve these different problems was as simple as choosing different test tubes to mix together," Woods says. "We were programming at the lab bench."
Although DNA computers have the potential to perform more complex computations than the ones featured in the Nature paper, Winfree cautions that one should not expect them to start replacing the standard silicon microchip computers. That is not the point of this research. "These are rudimentary computations, but they have the power to teach us more about how simple molecular processes like self-assembly can encode information and carry out algorithms. Biology is proof that chemistry is inherently information-based and can store information that can direct algorithmic behavior at the molecular level," he says.
1. Original story scource: https://www.caltech.edu/about/news/computer-scientists-create-reprogrammable-molecular-computing-system
2. Journal reference: Damien Woods, David Doty, Cameron Myhrvold, Joy Hui, Felix Zhou, Peng Yin & Erik Winfree. Diverse and robust molecular algorithms using reprogrammable DNA self-assembly. Nature, 2019 DOI: 10.1038/s41586-019-1014-9
3. Image source: Completed DNA algorithms Credit: Winfree Lab/Caltech
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