Vertebrate left and right: Finally a cascade,but first a flow?

Vertebrate development gives rise to systematic, normally reliably coordinated left-right asymmetries of body structure. This “handed asymmetry” of anatomy must take its ultimate origin from some chiral molecular assembly (one exhibiting no planes of symmetry and thus, having an intrinsic “handedness”) within the early embryo's cells. But which molecules are involved, how is their chiral property coordinately aligned among many cells, and how does it “seed” the differential cascades of gene expression that characterise right and left halves of the embryo? Recent molecular characterisations of mouse mutations that randomise or reverse body asymmetries have offered tantalising clues to the chiral initiator molecules, but the findings in a subsequent Cell paper (Nonaka S, Yosuke T, Okada Y, Takeda S, Harada K, Kanai Y, Kido M, Hirokawa N. Randomisation of left-right asymmetry due to loss of nodal cilia generating a leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 1998;95:829–837. [Reference 1]) may help us understand how the first gene expression asymmetries occur. BioEssays 21:537–541, 1999. © 1999 John Wiley & Sons, Inc.     

Chirality as a primary switch of hierarchical levels in molecular biological systems

A synergetic law, being of common physicochemical and biological sense, is formulated: any evolving system that possesses an excess of free energy and elements with chiral asymmetry, while being within one hierarchical level, is able to change the type of symmetry in the process of self-organization increasing its complexity but preserving the sign of prevailing chirality (left — L or right — D twist). The same system tends to form spontaneously a sequence of hierarchical levels with alternating chirality signs of de novo formed structures and with an increase of the structures’ relative scales. In living systems, the hierarchy of conjugated levels of macromolecular structures that begins from the “lowest” asymmetric carbon serves as an anti-entropic factor as well as the structural basis of “selected mechanical degrees of freedom” in molecular machines. During transition of DNA to a higher level of structural and functional organization, regular alterations of the chirality sign D-L-D-L and L-D-L-D for DNA and protein structures, respectively, are observed. Sign-alternating chiral hierarchies of DNA and protein structure, in turn, form a complementary conjugated chiral pair that represents an achiral invariant that “consummates” the molecular-biological block of living systems. The ability of a carbon atom to form chiral compounds is an important factor that determined the carbon basis of living systems on the Earth as well as their development though a series of chiral bifurcations. The hierarchy of macromolecular structures demarcated by the chirality sign predetermined the possibility of the “block” character of biological evolution.     

Strategies to establish left/right asymmetry in vertebrates and invertebrates

Left/right (L/R) asymmetry is essential during embryonic development for organ positioning, looping and handed morphogenesis. A major goal in the field is to understand how embryos initially determine their left and right hand sides, a process known as symmetry breaking. A number of recent studies on several vertebrate and invertebrate model organisms have provided a more complex view on how L/R asymmetry is established, revealing an apparent partition between deuterostomes and protostomes. In deuterostomes, nodal cilia represent a conserved symmetry-breaking process; nevertheless, growing evidence shows the existence of pre-cilia L/R asymmetries involving active ion flows. In protostomes like snails and Drosophila, symmetry breaking relies on different mechanisms, involving, in particular, the actin cytoskeleton and associated molecular motors.     

Morphology and Development of Mirror-Image Doublets of Stylonychia mytilus

This paper describes the cortical anatomy and development of mirror-image doublets of Stylonychia mytilus, analyzed using the protargol technique. The reversed, or “left-handed” (LH) component of these doublets is a mirror image of the normal or “right handed” (RH) component with regard to the arrangement of cortical structures. The mirror-image patterning is imperfect, however, as the individual ciliary structures of the LH component all are of normal internal asymmetry, and the orientation of membranelles is inverted. Certain structures that would be expected to form near the line of symmetry are absent. During cell division and cortical reorganization, ciliary primordia arise and become arranged in a mirror-image pattern that is more perfect than that exhibited by the mature structures. Deviations from a mirror-image pattern appear at late stages when organelle sets differentiate within ciliary primordia: for example, the membranelle set differentiates within the oral primordium of the LH component in a sequence that is an inversion rather than a mirror image of the corresponding sequence of the RH component. This mixed control of oral development by different cortical “informational systems” accounts for some of the characteristic abnormalities of the mature oral structures of the LH component.     

Right‐ and left‐handed three‐helix proteins. I. Experimental and simulation analysis of differences in folding and structure

Despite the large number of publications on three‐helix protein folding, there is no study devoted to the influence of handedness on the rate of three‐helix protein folding. From the experimental studies, we make a conclusion that the left‐handed three‐helix proteins fold faster than the right‐handed ones. What may explain this difference? An important question arising in this paper is whether the modeling of protein folding can catch the difference between the protein folding rates of proteins with similar structures but with different folding mechanisms. To answer this question, the folding of eight three‐helix proteins (four right‐handed and four left‐handed), which are similar in size, was modeled using the Monte Carlo and dynamic programming methods. The studies allowed us to determine the orders of folding of the secondary‐structure elements in these domains and amino acid residues which are important for the folding. The obtained data are in good correlation with each other and with the experimental data. Structural analysis of these proteins demonstrated that the left‐handed domains have a lesser number of contacts per residue and a smaller radius of cross section than the right‐handed domains. This may be one of the explanations of the observed fact. The same tendency is observed for the large dataset consisting of 332 three‐helix proteins (238 right‐ and 94 left‐handed). From our analysis, we found that the left‐handed three‐helix proteins have some less‐dense packing that should result in faster folding for some proteins as compared to the case of right‐handed proteins.Proteins 2013; © 2013 Wiley Periodicals, Inc.     

Rechts vor links?

Handedness of life: Right over left? Many organisms display an asymmetry in respect to body plan and behavior which discriminates between “right” and “left”. Flatfish, snails, lobsters and walruses show us, that the preference of a specific body side is often genetically determined. The exact functioning of the so-called left-right-organisator (LRO) helps to understand, how the definition of the body sides is achieved during embryogenesis. The selection between “left” and “right” already takes place on a molecular level. The key-to-lock-principle is regarded to be the bridge between molecular chirality and the phenotypical asymmetry of organisms. There is a connection between the accuracy of fit of metabolical partners, the following signal cascade within cells and the macroscopic displacement of organs. This culminates in the preference of the extremities of one body-side – in most humans there is a dominance of the right side.     

The development of asymmetry: the sidedness of drug-induced limb abnormalities is reversed in situs inversus mice

We are studying the development of handedness, in particular the relationships between handed structures with bilateral symmetry, for example the limbs, and those with lateral asymmetry, such as the heart, lungs and gut. Asymmetric (unilateral) developmental limb abnormalities can be induced by chemical treatment of mouse embryos, either in utero by acetazolamide, or in culture by misonidazole. We have examined these effects in mice homozygous for the iv gene. The development of bilateral symmetry in iv/iv mice is normal, but the control of asymmetry appears to be random, that is 50% develop normally (situs solitus), 50% with laterally inverted viscera (situs inversus). We find that the handedness of induced asymmetric limb defects is highly correlated with embryonic visceral situs. Right limb defects are induced in situs solitus embryos, left-sided defects in situs inversus. This suggests that the mechanism of induction of asymmetric defects is not related to any intrinsic difference between the development of left and right limbs, but is connected to visceral asymmetry. In addition, the high correlation of limb defects with situs was observed in culture as well as in utero suggesting that the maternal environment plays no role in the development of asymmetry.     

The development of handedness in left/right asymmetry

The development of handed asymmetry requires a special mechanism for consistently specifying a difference between left and right sides. This is to be distinguished from both random asymmetry, and from those left/right differences that are mirror symmetrical. We propose a model for the development of handedness in bilateral animals, comprising three components. (i) A process termed conversion, in which a molecular handedness is converted into handedness at the cellular level. A specific model for this process is put forward, based on cell polarity and transport of cellular constituents by a handed molecule. (ii) A mechanism for random generation of asymmetry, which could involve a reaction-diffusion process, so that the concentration of a molecule is higher on one side than the other. The handedness generated by conversion could consistently bias this mechanism to one side. (iii) A tissue-specific interpretation process which responds to the difference between the two sides, and results in the development of different structures on the left and right. There could be direct genetic control of the direction of handedness in this model, most probably through the conversion process. Experimental evidence for the model is considered, particularly the iv mutation in the mouse, which appears to result in loss-of-function in biasing, and so asymmetry is random. The model can explain the abnormal development of handedness observed in bisected embryos of some mammalian, amphibian and sub-vertebrate species. Spiral asymmetry, as seen in spiral cleavage and in ciliates, involves only conversion of molecular asymmetry to the cellular and multicellular level, with no separate interpretation step.     

Terminal effect of chiral residue on helical screw sense in achiral peptides

To understand the terminal effect of chiral residue for determining a helical screw sense, we adopted five kinds of peptides I – V containing N‐ and/or C‐terminal chiral Leu residue(s): Boc–L ‐Leu–(Aib–ΔPhe)₂–Aib–OMe ( I ), Boc–(Aib–ΔPhe)₂–L ‐Leu–OMe ( II ), Boc–L ‐Leu–(Aib–ΔPhe)₂–L ‐Leu–OMe ( III ), Boc–D ‐Leu–(Aib–ΔPhe)₂–L ‐Leu–OMe ( IV ), and Boc–D ‐Leu–(Aib–ΔPhe)₂–Aib–OMe ( V ). The segment –(Aib–ΔPhe)₂– was used for a backbone composed of two “enantiomeric” (left‐/right‐handed) helices. Actually, this could be confirmed by ¹H‐nmr [nuclear Overhauser effect (NOE) and solvent accessibility of NH resonances] and CD spectroscopy on Boc–(Aib–ΔPhe)₂–Aib–OMe, which took a left‐/right‐handed 3₁₀‐helix. Peptides I – V were also found to take 3₁₀‐type helical conformations in CDCl₃, from difference NOE measurement and solvent accessibility of NH resonances. Chloroform, acetonitrile, methanol, and tetrahydrofuran were used for CD measurement. The CD spectra of peptides I – III in all solvents showed marked exciton couplets with a positive peak at longer wavelengths, indicating that their main chains prefer a left‐handed screw sense over a right‐handed one. Peptide V in all solvents showed exciton couplets with a negative peak at longer wavelengths, indicating it prefers a right‐handed screw sense. Peptide IV in chloroform showed a nonsplit type CD pattern having only a small negative signal around 280 nm, meaning that left‐ and right‐handed helices should exist with almost the same content. In the other solvents, peptide IV showed exciton couplets with a negative peak at longer wavelengths, corresponding to a right‐handed screw sense. From conformational energy calculation and the above ¹H‐nmr studies, an N‐ or C‐terminal L ‐Leu residue in the lowest energy left‐handed 3₁₀‐helical conformation was found to take an irregular conformation that deviates from a left‐handed helix. The positional effect of the L ‐residue on helical screw sense was discussed based on CD data of peptides I – V and of Boc–(L ‐Leu–ΔPhe)_n–L ‐Leu–OMe (n = 2 and 3). © 1999 John Wiley & Sons, Inc. Biopoly 49: 551–564, 1999     

P300 topographic asymmetries are present in unmedicated schizophrenics

Our laboratory has repeatedly found a left < right auditory P300 temporal lobe topographic asymmetry in right-handed, medicated schizophrenics. To determine whether this asymmetry was attributable to the effects of antipsychotic medications, we collected auditory “odd-ball” P300 event-related potentials from 14 right-handed, unmediated schizophrenics (withdrawn from medication for an average of 21 days) and 14 right-handed, normal controls. Analysis of normalized P300 amplitudes showed a statistically significant difference in the voltage distributions between groups (a group by temporal electrode site interaction) that was consistent with a left < right temporal voltage asymmetry in schizophrenics but not in the normal controls. We conclude that P300 topographic asymmetries are present in unmedicated schizophrenics. These data are compatible with the growing body of data suggsting left temporal lobe structural abnormalities in schizophrenia.     

Diversity and convergence in the mechanisms establishing L/R asymmetry in metazoa

Differentiating left and right hand sides during embryogenesis represents a major event in body patterning. Left–Right (L/R) asymmetry in bilateria is essential for handed positioning, morphogenesis and ultimately the function of organs (including the brain), with defective L/R asymmetry leading to severe pathologies in human. How and when symmetry is initially broken during embryogenesis remains debated and is a major focus in the field. Work done over the past 20 years, in both vertebrate and invertebrate models, has revealed a number of distinct pathways and mechanisms important for establishing L/R asymmetry and for spreading it to tissues and organs. In this review, we summarize our current knowledge and discuss the diversity of L/R patterning from cells to organs during evolution.     

Size and symmetry of sex combs were not related to male mating success in Drosophila melanogaster reared at different temperatures

Temperature is one of the most important climatic factors that may influence different traits (morphological, physiological or behavioral) in Drosophila. In this study, we examined the effects of two developmental temperatures (18°C and 25°C) on the size and the symmetry of sex combs (a male sexual trait) and their importance for male mating success in Drosophila melanogaster. However, the number of sex comb teeth (“size”) and its difference between right and left legs (“symmetry”) were relevant neither to male mating success nor to the growth temperatures.     

A mechanism for molecular asymmetry

Summary The origin of the molecular asymmetry of biological systems has been speculated upon extensively, and has been the object of numerous inconclusive experimental studies. That circularly polarized light (CPL) might have been the cause of this asymmetry was suggested in 1874 (van't Hoff 1897; Le Bel 1874). During the daylight morning (AM) there is a significant component of left (L) CPL in skylight, which reverses to right (R) CPL in the afternoon (PM) (Wolstencroft 1985). The rates or photochemical reactions of LCPL and RCPL are different for the R (right) and S (left) forms of chiral molecules (Flores et al. 1977). At sunset the ambient temperature at the surface of the earth is approximately 10°C higher than at sunrise. Most chemical reactions proceed faster at higher temperatures and for each 10°C rise in temperature chemical reaction rates increase by a factor of 1.8–4.1 (Taylor 1925). It is proposed that the combination of these four factors, LCPL in the AM compared to the RCPL in the PM, the different rates of photochemical reaction of the R and the S forms of an R-S racemic mixture with RCPL (and LCPL), the higher PM temperature, and the faster reaction rates in the PM could lead to a substantial deviation from equality in the degradation and formation of R and S enantiomeric forms of chiral molecules.     

Generation of robust left-right asymmetry in the mouse embryo requires a self-enhancement and lateral-inhibition system

The bilateral symmetry of the mouse embryo is broken by leftward fluid flow in the node. However, it is unclear how this directional flow is then translated into the robust, left side-specific Nodal gene expression that determines and coordinates left-right situs throughout the embryo. While manipulating Nodal and Lefty gene expression, we have observed phenomena that are indicative of the involvement of a self-enhancement and lateral-inhibition (SELI) system. We constructed a mathematical SELI model that not only simulates, but also predicts, experimental data. As predicted by the model, Nodal expression initiates even on the right side. These results indicate that directional flow represents an initial small difference between the left and right sides of the embryo, but is insufficient to determine embryonic situs. Nodal and Lefty are deployed as a SELI system required to amplify this initial bias and convert it into robust asymmetry.     

Actigraphic Investigations On The Activity‐Rest Behavior Of Right‐ and Left‐Handed Students

The aim of this study was to explore differences between left‐and right‐handed subjects in sleep duration. Sleep and activity patterns were continuously registered for 12 days using actometers on 20 left‐handed and 20 right‐handed medical students in Berlin. Handedness was determined by a modified version of the Edinburgh handedness inventory. Each participant wore one actometer on each wrist. Actiwatch® Sleep Analysis Software (CNT, UK) was used to evaluate the data, and statistical calculations were performed with a non‐parametric variance analysis. A significant difference in mean sleep duration between left‐handers (7.9 h) and right‐handers (7.3 h) was determined (p=0.025 for measurement made on the dominant hand and p=0.013 for ones made on the non‐dominant hand). In contrast, the maximal phase of daily activity (acrophase) did not show any difference between the two groups. The difference in sleep duration might be caused by either the greater effort required for left‐handers to cope in a right‐handed world or by structural brain differences.     

Handedness preference and switching of peptide helices. Part I: Helices based on protein amino acids

In this article, we review the relevant results obtained during almost 60 years of research on a specific aspect of stereochemistry, namely handedness preference and switches between right‐handed and left‐handed helical peptide structures generated by protein amino acids or appropriately designed, side‐chain modified analogs. In particular, we present and discuss here experimental and theoretical data on three categories of those screw‐sense issues: (i) right‐handed/left‐handed α‐helix transitions underwent by peptides rich in Asp, specific Asp β‐esters, and Asn; (ii) comparison of the preferred conformations adopted by helical host–guest peptide series, each characterized by an amino acid residue (e.g. Ile or its diastereomer aIle) endowed with two chiral centers in its chemical structure; and (iii) right‐handed (type I)/left‐handed (type II) poly‐(Pro)_n helix transitions monitored for peptides rich in Pro itself or its analogs with a pyrrolidine ring substitution, particularly at the biologically important position 4. The unique modular and chiral properties of peptides, combined with their relatively easy synthesis, the chance to shape them into the desired conformation, and the enormous chemical diversity of their coded and non‐coded α‐amino acid building blocks, offer a huge opportunity to structural chemists for applications to bioscience and nanoscience problems. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.     

Molecular chirality and the origin of life

In the living systems L-amino acids and D-sugars are found with almost no exceptions. Although all the molecular chirality must have been established prior to the emergence of life, the origin of the asymmetry of molecules is still an unsolved problem. The time of appearance of the asymmetry of molecules, therefore, was quite problematic during chemical evolution.Since Pasteur's discovery in 1848, a large number of works for solving this problem have been carried out on the basis of mathematics, physics or chemistry. All the proposals which put forth for breaking the symmetry are still considered to be too weak to explain the cause of obtaining the chiral purity as a result of the symmetry breaking of molecules. In order to expand our scope, new sources of the symmetry breaking of molecules should be considered.In this article, some approaches to the achiral-chiral transition are reviewed, which will give an idea for the origin of asymmetry of molecules.     

Intramolecular Enantiomerism in S(+)2,2‐dimethyl ‐1,3‐dioxolane‐4‐methanol: The Interpretation of Raman Optical Activity Intensity

A bond polarizability algorithm was developed and applied to interpret the Raman optical activity (ROA) intensity. It is demonstrated that for the chiral molecule such as S(+)2,2‐dimethyl‐1,3‐dioxolane‐4‐methanol there exists approximate (or symmetry breaking) mirror reflection that reverses the signs of the differential bond polarizabilities of the pair bond coordinates that are related to each other by the mirror reflection, just like that between the right and left enantiomers. The magnitude difference of the differential bond polarizabilities of the pair bond coordinates becomes smaller as they are farther away from the asymmetric atom. Hence, that the asymmetric atom (center) plays a central role in ROA is confirmed from a spectroscopic viewpoint. Meanwhile, the concept of intramolecular enantiomerism is proposed. Chirality 27:820–825, 2015. © 2015 Wiley Periodicals, Inc.     

Atomic coordinates and calculated intensities for a side by side D.N.A. model

A precise conformation of the side-by-side type is proposed for the B-D.N.A. form. In this model the antiparallel chains are related by a dyadic symmetry and binding between complementary bases is realized using Watson-Crick pairing. The elementary unit, comprising 10 nucleotides for one chain, is composed of one segment in a right handed helix, a second segment rotated to the left and two bends. Cylindrical atomic coordinates are given for atoms in the elementary unit and the square of the Fourier transform is calculated for this conformation and compared to the well known double helix and to experimental data.     

Evolution of mirror images by sexually asymmetric mating behavior in hermaphroditic snails

Abstract Directionally asymmetric animals generally exhibit no variation in handedness of whole-body architecture. In contrast, reversed chirality in both coil and entire anatomy has frequently evolved in snails. We demonstrate a nonrandom pattern and deterministic process of chiral evolution, as predicted by the following hypothesis. Bimodal shell shapes are associated with discrete mating behaviors in hermaphroditic pulmonates. Flat-shelled species mate reciprocally, face-to-face. This sexual symmetry prevents interchiral mating because genitalia exposed by a sinistral on its left side cannot be joined with those exposed by a dextral on its right. Thus, selection against the chiral minority, resulting from mating disadvantage, stabilizes chiral monomorphism. Tall-shelled species mate nonreciprocally: the 'male' copulates by mounting the 'female's' shell, mutually aligned in the same direction. This sexual asymmetry permits interchiral copulation with small behavioral adjustments. Therefore, the positive frequency-dependent selection is relaxed, and reversal alleles persist longer in populations of tall-shelled species. We verified both the assumption and the prediction of this hypothesis: significantly lower interchiral mating success in a low-spired species and higher chiral evolution rate in high-spired taxa. Sexual asymmetry is the key to understanding the accelerated chiral evolution in high-spired pulmonates.