Gómez-Valdés et al. Lack of Support for the Association between Facial Shape and Aggression: A Reappraisal Based on a Worldwide Population Genetics Perspective. PLoS ONE, 2013; 8 (1)

It is a common misconception that some people are profiled to be angry or aggressive because of their physical appearances, particularly their craniofacial shapes. In addition, there have been some studies suggesting that men with certain facial traits (round-shaped faces) are more likely to develop aggressive and unethical behavior. A new study using a sample of around 5000 individuals from 94 different countries has found no correlation between facial shape and aggressive/criminal behaviors. Researchers analyzed fWHRs (facial width-to-height ratio) and 2D/3D craniofacial landmark coordinates to estimate any possible correlation between skull shape and aggressive behaviors in men. First, they utilized the famous skull collection in Hallstatt/Austria to investigate any potential correlation between skull features and life history parameters of individuals, such as their overall fitness. Second, they analyzed the male prisoners convicted of crimes like inter-personal aggression (homicide, robbery etc.) from Mexico City Federal Penitentiary to see whether there is any relation between skull shape traits and aggressive crimes. Analyses of both databases have found no significant correlation between skull shape traits either with the fitness of males or with their aggressiveness. This study has very important social and political implications in today’s societies, as we unfortunately see many ethnical, racial and even physical prejudices. This comprehensive study has undoubtedly showed once more that physical traits cannot be a reliable predictor of complex human behaviors, which are mostly shaped by external factors such as education and socio-cultural practices.

Biggest Structure in the Universe Discovered

Clowe et al. A structure in the early Universe at z ∼ 1.3 that exceeds the homogeneity scale of the R-W concordance cosmology. Monthly Notices of the Royal Astronomical Society, January 11, 2013

Throughout history, mankind has been trying to answer the questions of “how big” or “how far,” when looking into the vast expanse of the universe. As new technologies are developed, bigger discoveries and consequently bigger numbers are brought to light. An international team of astronomers recently discovered a collection of 73 quasars which form a single structure; the largest structure ever observed in the entire universe. A quasar, short for quasi-stellar object, is the luminous center of a galaxy that surrounds a super massive black hole. The distance of these newly large quasar groups to the earth is about 9 billion light years (1 light year is approximately 9.5 trillion kilometers). The size of these structures is simply mind-blowing. Even if we have a spacecraft that travels at the speed of light, it would still take about 4 billion years to cross. If we put this overwhelming size into perspective, the Milky Way—earth’s home galaxy—is only about 100,000 light-years wide and our neighbor galaxy Andromeda is only 2.5 million light-years away from the Milky Way. So these quasars are 1600 times larger than the distance from the Milky Way to Andromeda. This discovery seriously challenges the size calculations based on the widely accepted Cosmological Principle which assumes that the universe is essentially homogeneous when viewed at a sufficiently large scale. Cosmological Principle predicts that there should not be any structure in the universe larger than 1.2 billion light-years. A four billion light-years wide structure would obviously be an outlier when compared to other structures in the universe and it might contradict with the homogeneity of the universe. However, scientists think that such contradiction would not necessarily falsify the Cosmological Principle originally established by Albert Einstein. It might only change the assumptions of the theory that define at which scale the universe can sufficiently be viewed.

More Twists on Double Helix

Biffi et al. Quantitative visualization of DNA G-quadruplex structures in human cells. Nature Chemistry, 20 January 2013.

About 60 years ago, on April 25th 1953, James Watson and Francis Crick published a one-page paper where they described the “double helix” structure of the DNA, the molecule that carries genetic information from parent to offspring. This discovery not only revolutionized the biological sciences and medicine but also dramatically changed the way we perceive life, nature and most importantly ourselves. Yet, new findings on DNA structure keep surprising us. Scientists from Cambridge University discovered the first quadruple helix—a four-stranded DNA structure in human cells which they named “G-quadruplex.” These structures were previously observed in test tubes but they were never found in cells. The building blocks of DNA molecules consist of four different bases: Adenine (A), Guanine (G), Cytosine (C) and Thymine (T). G-quadruplexes (G stands for Guanine) are formed by four guanine bases that forms a square DNA helix. Researchers found that these structures are enriched in rapidly-dividing cancer cells, specifically at the ends of chromosomes called telomeres. When researchers targeted and trapped these quadruple DNA structures with synthetic molecules, they found that DNA replication slows down and cell division is blocked. Researchers suspect that these quadruple DNA structures in telomeres of cancer cells could explain why cancer cells rapidly proliferate and divide. It is still not clear whether G-quadruplexes exist in healthy cells but targeting these structures in cancerous cells with pharmacology seems to be a promising method to stop the spread of cancer.

A particularly interesting class of all these non-coding RNAs comprises riboswitches. Riboswitches are structured mRNA elements that regulate gene expression upon binding of a specific small metabolite. These biosensors were first discovered in 2002 in bacteria. Later, it was shown that plants, green algae and fungi also posses riboswitches. Although, only one type of riboswitch is found in plants and none has beeen detected in mammals yet, metabolite-sensing riboswitches are commonly used for the regulation of fundamental biochemical pathways in bacteria. Riboswitches help cells monitor the environmental conditions and determine if a compound is present at sufficient levels or not. Based on this decision, production, degradation or transport of the related metabolite is either turned on or off.

Architecture of a Riboswitch

A standard riboswitch is divided into two parts: a ligand-binding domain and a gene expression domain (Figure 1). Small molecular metabolites bind to the ligand-binding domain, which is called aptamer, of riboswitches with astonishing specificity. For instance, purine riboswitches differentiate guanine from adenine by at least 10,000-fold based on the identity of a single pyrimidine (thymine or cytosine) that binds to the ligand (1). When a ligand binds to aptamer, conformational changes of the RNA’s structure occur at the gene expression domain. Eventually, this leads to the modulation of gene expression. Some of the riboswitch mechanisms to regulate the expression of genes include formation of stem-loops, lollipop-like RNA structures, which lead to the blocking of transcription or translation, which are the processes where proteins are synthesized using the mature mRNA, self cleavage or mRNA destabilization (Figure 2).

Classes of Riboswitches

The numerous distinct classes of riboswitches discovered so far are differentiated by their ligands and remarkably, the same class of riboswitches can control gene expression through different mechanisms in various organisms. For example, a riboswitch that recognizes and binds thiamin pyrophosphate (TPP), a derivative of vitamin B1, is called as TPP riboswitch (2). In plant cells, when TPP levels are high, excess TPP binds to a TPP riboswitch located in one of the TPP biosynthesis genes. As a result of TPP binding, conformation of that RNA segment changes, which leads to the formation of an unstable mRNA product which degrades quickly. Although, a very little amount of stable mRNA is also produced, it is not enough for the protein synthesis of an important component of TPP biosynthesis. Therefore, TPP biosynthesis can not be completed and consequently TPP levels drop in the cell. On the other hand, when TPP levels are low in plants, more stable mRNA is formed because there is not enough TPP that can bind to the riboswitch and cause structural changes which will result in the formation of unstable mRNA. The stable mRNA produced in the absence of excess TPP is used for the protein biosynthesis of TPP metabolism successfully and thus TPP levels increase in the cell. Unlike plants in bacteria, when TPP concentration is high, riboswitches down-regulate expression of thiamin biosynthesis genes by either blocking the formation of any type of mRNA (both stable and unstable) or preventing the mRNA process rather than destabilizing the mRNA. Some of the other riboswitches that bind vitamin derived compounds are adenosylcobalamin, the coenzyme form of vitamin B12, and flavin mononucleotide, a biomolecule produced from vitamin B2, riboswitches. There are also riboswitches that can bind to amino acids such as lysine riboswitch. The cyclic diguanylate (c-di-GMP) riboswitch is the first known example of an RNA that binds a second messenger, which carries signals from receptors on the cell surface to target molecules inside the cell (3). Purine riboswitches selectively recognize guanine or adenine and regulate purine biosynthesis and transport, which is important for DNA/RNA synthesis. Another interesting type of riboswitch is the glmS riboswitch. It modulates gene expression by undergoing self-cleavage when there is a sufficient concentration of glucosamine-6-phosphate, an important amino sugar. The spectrum of ligands that can be recognized by riboswitches also includes a metal ion, as well. Mg(2+) riboswitches control Mg(2+) transportation when cells are grown in high Mg(2+) environments. In brief, the growing list of studies on riboswitches shows how novel mechanisms are which they use to regulate the gene expression of many fundamental metabolic pathways.

Applications for Riboswitches as drug targets and chemosensors

Riboswitches are powerful and essential components in all three domains of life which are bacteria, archaea (a group of single-celled microorganisms) and eukaryotes ( organisms whose cells contain complex structures inside membranes such as plants and fungi) functioning as intracellular biosensors and regulators. They regulate gene expression in a highly efficient, precise and fast way. Therefore, they can be engineered for various applications.

First of all, riboswitches are excellent candidates as drug targets since they control many important bacterial and fungal genes. Chemical analogs that mimic the actual ligands of the riboswitches can be designed to silence or regulate the expression of defective genes responsible for disease development or even kill certain bacterial pathogens by turning off the genes that are involved in fundamental metabolic pathways. A great example of this strategy is presented by the Breaker laboratory at Yale University. The Breaker group chose guanine-binding riboswitches as targets for the development of novel antibacterial compounds. They have designed several guanine analogues and tested their ability to be bound by the riboswitch and repress bacterial growth (4). They have been able to inhibit the bacterial growth by inducing guanine riboswitch action. Their approach could be used to discover new antibacterial compounds that specifically target other riboswitch classes.

In addition to being drug targets, riboswitches can open new frontiers in bioremediation, bionanotechnology, and synthetic biology. In 2007 Shana Topp and Justin P. Gallivan from Emory University demonstrated that Escherichia coli can be reprogrammed to detect, follow, and precisely localize to a completely new chemical signal by using a synthetic riboswitch (5). They suggest that the bacteria with synthetic or mutated riboswitches could be used to follow and degrade pollutants in soil or target small-molecule signals of disease. Overall, their work to equip the bacteria which can autonomously follow chemical signals, degrade, synthesize or release compounds can help scientists invent new technologies in bioremediation, drug transport, and synthetic biology.

Furthermore, riboswitches are ideal candidates for use in analytical devices and techniques. Their binding features make them suitable in all specific analytical applications in which selective recognition is required. Therefore, these powerful molecular tools can be utilized in analytical chemistry, molecular biology and biosensor technology (6).

As a result, living systems utilize riboswitches to detect the concentrations of small-molecule metabolites and to modulate the expression of related genes via numerous elegant mechanisms. The use of genetic engineering of riboswitches holds enormous potential for inventing new applications to sense and destroy pathogens, deliver drugs, perform bioremediation, detect chemicals and many others that might have significant impacts on our lives. It is also remarkable that only a couple of decades ago most of the non-coding RNAs were assumed to be useless, and are called junks since they do not provide any information for protein synthesis. Yet riboswitches by themselves are enough to prove that God has created everything with a purpose. He is All-Wise and he does nothing in vain. Riboswitches are not useless at all. They are such complex, and perfectly working systems that they can serve humanity as well-designed on/off switches in numerous applications.

Safiye Arslan is a research fellow in the area of biological chemistry and lives in Nevada.

References

1. Gilbert SD, Reyes FE, Edwards AL, Batey RT. 2009. Adaptive ligand binding by the purine riboswitch in the recognition of guanine and adenine analogs. Structure 17, 857-868

2. Wachter A, Tunc-Ozdemir M, Grove BC, Green PJ, Shintani DK, Breaker RR. 2007. Riboswitch control of gene expression in plants by splicing and alternative 3′ end processing of mRNAs. Plant Cell 19, 3437-3450.

3. Kulshina N, Baird NJ, Ferré-D’Amaré AR. 2009. Recognition of the bacterial second messenger cyclic diguanylate by its cognate riboswitch. Nature Structural & Molecular Biology 16, 1212-1217.

4. Kim JN, Blount KF, Puskarz I, Lim J, Link KH, Breaker RR. 2009. Design and antimicrobial action of purine analogues that bind Guanine riboswitches. ACS Chemical Biology 4, 915-927.

5. Topp S, Gallivan JP. 2007. Guiding bacteria with small molecules and RNA. Journal of the American Chemical Society 129, 6807-6811.

6. Mairal T, Ozalp VC, Lozano Sanchez P, Mir M, Katakis I, O’Sullivan CK. 2008. Aptamers: molecular tools for analytical applications. Analytical and Bioanalytical Chemistry 390, 989-1007.