Unnatural Configuration Research Articles

Configuration-sensitive face-body interactions in primate visual cortex

Traditionally, the neural processing of faces and bodies is studied separately, although they are encountered together, as parts of an agent. Despite its social importance, it is poorly understood how faces and bodies interact, particularly at the single-neuron level. Here, we examined the interaction between faces and bodies in the macaque inferior temporal (IT) cortex, targeting an fMRI-defined patch. We recorded responses of neurons to monkey images in which the face was in its natural location (natural face-body configuration), or in which the face was mislocated with respect to the upper body (unnatural face-body configuration). On average, the neurons did not respond stronger to the natural face-body configurations compared to the summed responses to their faces and bodies, presented in isolation. However, the neurons responded stronger to the natural compared to the unnatural face-body configurations. This configuration effect was present for face- and monkey-centered images, did not depend on local feature differences between configurations, and was present when the face was replaced by a small object. The face-body interaction rules differed between natural and unnatural configurations. In sum, we show for the first time that single IT neurons process faces and bodies in a configuration-specific manner, preferring natural face-body configurations.

Keep the head in the right place: Face-body interactions in inferior temporal cortex

In primates, faces and bodies activate distinct regions in the inferior temporal (IT) cortex and are typically studied separately. Yet, primates interact with whole agents and not with random concatenations of faces and bodies. Despite its social importance, it is still poorly understood how faces and bodies interact in IT. Here, we addressed this gap by measuring fMRI activations to whole agents and to unnatural face-body configurations in which the head was mislocated with respect to the body, and examined how these relate to the sum of the activations to their corresponding faces and bodies. First, we mapped patches in the IT of awake macaques that were activated more by images of whole monkeys compared to objects and found that these mostly overlapped with body and face patches. In a second fMRI experiment, we obtained no evidence for superadditive responses in these “monkey patches”, with the activation to the monkeys being less or equal to the summed face-body activations. However, monkey patches in the anterior IT were activated more by natural compared to unnatural configurations. The stronger activations to natural configurations could not be explained by the summed face-body activations. These univariate results were supported by regression analyses in which we modeled the activations to both configurations as a weighted linear combination of the activations to the faces and bodies, showing higher regression coefficients for the natural compared to the unnatural configurations. Deeper layers of trained convolutional neural networks also contained units that responded more to natural compared to unnatural monkey configurations. Unlike the monkey fMRI patches, these units showed substantial superadditive responses to the natural configurations. Our monkey fMRI data suggest configuration-sensitive face-body interactions in anterior IT, adding to the evidence for an integrated face-body processing in the primate ventral visual stream, and open the way for mechanistic studies using single unit recordings in these patches.

The Recurring Roles of Chlorine in Synthetic and Biological Studies of the Lissoclimides

Halogenated natural products number in the thousands, but only in rare cases are the evolutionary advantages conferred by the halogens understood. We set out to investigate the lissoclimide family of cytotoxins, which includes several chlorinated members, because of our long-standing interest in the synthesis of chlorinated secondary metabolites.Our initial success in this endeavor was a semisynthesis of chlorolissoclimide (CL) from the commercially available sesquiterpenoid sclareolide. Featuring a highly selective and efficient-and plausibly biomimetic-C-H chlorination, we were able to access enough CL for collaborative studies, including X-ray cocrystallography with the eukaryotic ribosome. Through this experiment, we learned that CL's chlorine atom engages in a novel halogen-π dispersion interaction with a neighboring nucleobase in the ribosome E-site.Owing to the limitations of our semisynthesis approach, we established an analogue-oriented approach to access numerous lissoclimide compounds to both improve our understanding of structure-activity relationships and to learn more about the halogen-π interaction. In the course of these studies, we made over a dozen lissoclimide-like compounds, the most interesting of which contained chlorine-bearing carbons with unnatural configurations. Rationalizing the retained potency of these compounds that appeared to be a poor fit for the lissoclimide binding pocket, we came to realize that the chlorine atoms would engage in these same halogen-π interactions even at the expense of a chair to twist-boat conformational change, which also permitted the compounds to fit in the binding site.Finally, because neither of the first two approaches could easily access the most potent natural lissoclimides, we designed a synthesis that took advantage of rarely used terminal epoxides to initiate polyene cyclizations. In this case, the chlorine atom was incorporated early and helped control the stereochemical outcome of the key step.Over the course of this project, three different synthesis approaches were designed and executed, and our ability to access numerous lissoclimides fueled a range of collaborative biological studies. Further, chlorine played impactful roles throughout various aspects of both synthesis and biology. We remain inspired to learn more about the mechanism of action of these compounds and to deeply investigate the potentially valuable halogen-π dispersion interaction in the context of small molecule/nucleic acid binding. In that context, our work offers an instance wherein we might have gained a rudimentary understanding of the evolutionary importance of the halogen in a halogenated natural product.

Selective response of the nucleus taeniae of the amygdala to a naturalistic social stimulus in visually naive domestic chicks

The detection of animate beings at the onset of life is important for phylogenetically distant species, such as birds and primates. Naïve chicks preferentially approach a stimulus resembling a conspecific (a stuffed fowl) over a less naturalistic one (a scrambled version of the stuffed fowl, presenting the same low-level visual features as the fowl in an unnatural configuration). The neuronal mechanisms underlying this behavior are mostly unknown. However, it has been hypothesized that innate social predispositions may involve subpallial brain areas including the amygdala. Here we asked whether a stuffed hen would activate areas of the arcopallium/amygdala complex, in particular the nucleus taeniae of the amygdala (TnA) or septum. We measured brain activity by visualizing the immediate early gene product c-Fos. After exposure to the hen, TnA showed higher density of c-Fos expressing neurons, compared to chicks that were exposed to the scrambled stimulus. A similar trend was present in the lower portion of the arcopallium, but not in the upper portion of the arcopallium or in the septum. This demonstrates that at birth the TnA is already engaged in responses to social visual stimuli, suggesting an important role for this nucleus in the early ontogenetic development of social behavior.

Control of the Stereochemical Course of [4+2] Cycloaddition during trans‐Decalin Formation by Fsa2‐Family Enzymes

Enzyme-catalyzed [4+2] cycloaddition has been proposed to be a key transformation process in various natural product biosynthetic pathways. Recently Fsa2 was found to be involved in stereospecific trans-decalin formation during the biosynthesis of equisetin, a potent HIV-1 integrase inhibitor. To understand the mechanisms by which fsa2 determines the stereochemistry of reaction products, we sought an fsa2 homologue that is involved in trans-decalin formation in the biosynthetic pathway of an enantiomerically opposite analogue, and we found phm7, which is involved in the biosynthesis of phomasetin. A decalin skeleton with an unnatural configuration was successfully constructed by gene replacement of phm7 with fsa2, thus demonstrating enzymatic control of all stereochemistry in the [4+2] cycloaddition. Our findings highlight enzyme-catalyzed [4+2] cycloaddition as a stereochemically divergent step in natural product biosynthetic pathways and open new avenues for generating derivatives with different stereochemistry.

Control of the Stereochemical Course of [4+2] Cycloaddition during trans‐Decalin Formation by Fsa2‐Family Enzymes

AbstractEnzyme‐catalyzed [4+2] cycloaddition has been proposed to be a key transformation process in various natural product biosynthetic pathways. Recently Fsa2 was found to be involved in stereospecific trans‐decalin formation during the biosynthesis of equisetin, a potent HIV‐1 integrase inhibitor. To understand the mechanisms by which fsa2 determines the stereochemistry of reaction products, we sought an fsa2 homologue that is involved in trans‐decalin formation in the biosynthetic pathway of an enantiomerically opposite analogue, and we found phm7, which is involved in the biosynthesis of phomasetin. A decalin skeleton with an unnatural configuration was successfully constructed by gene replacement of phm7 with fsa2, thus demonstrating enzymatic control of all stereochemistry in the [4+2] cycloaddition. Our findings highlight enzyme‐catalyzed [4+2] cycloaddition as a stereochemically divergent step in natural product biosynthetic pathways and open new avenues for generating derivatives with different stereochemistry.

Experimental evidence of structural representation of hands in early infancy

Hands convey important social information, such as an individual’s emotions, goals, and desires, are used to direct attention through pointing, and are a major organ for haptic perception. However, very little is known about infants’ representation of human hands. In Experiment 1, infants tested in a familiarization/novelty preference task discriminated between images of intact hands and images that contained first-order structure distortions (i.e., with locations of fingers altered to result in an unnatural configuration). In Experiment 2, infants tested in a spontaneous preference task exhibited a preference for scrambled hand images over intact images, indicating that 3.5-month-olds have gained sufficient sensitivity to the configural properties of hands to discriminate between intact versus scrambled images without any training in the laboratory. In both procedures, infants’ performance was disrupted by the inversion of images, suggesting that infants’ performance in upright conditions was not based on low-level features. These results indicate that sensitivity to the structure of hands develops early in life. This may lay the foundation for the development of the functional use of hand information for social communication.

Enantioselective Synthesis of the C23–C33 Fragment of Aetheramide A and Its C32 Epimer

The key aetheramide A intermediate with the natural (R,R,R) configuration along with the one having the unnatural (R,S,R) configuration was synthesized. The synthesis of both stereoisomers was accomplished by Suzuki coupling of two advanced chiral building blocks: (R,R)‐ and (R,S)‐vinylboronates and an (R)‐iodoalkene. The former was prepared from (R)‐mandelic acid, and the latter was prepared by enantioselective allylation of 3‐iodoacrylaldehyde.

Characterization of novel small-molecule NRF2 activators: Structural and biochemical validation of stereospecific KEAP1 binding

BackgroundSemi-synthetic oleanane triterpenoid antioxidant inflammation modulators (tpAIMs) are small molecules that interact with KEAP1 cysteine residue 151 (C151) and activate NRF2. Exploration of the structure-activity relationship between the tpAIMs and KEAP1 is limited by the predominantly hydrocarbon nature of the oleanane triterpenoid pentacyclic ring structure. Therefore, we used novel, chemically-tractable, synthetic antioxidant inflammation modulators (sAIMs) to probe the stereoselectivity of the ligand-protein interaction. MethodsWe measured several parameters of NRF2 activation to assess the potency of sAIM enantiomers with natural (tpAIM-like) 4(S),5(S),10(R) or unnatural 4(R),5(R),10(S) configurations. Additionally, we determined the crystal structure of the KEAP1 BTB domain in complex with two different sAIMs. ResultsWe found that the potencies of sAIM enantiomers in the natural configuration were similar to those of the tpAIM, RTA 405. Strikingly, sAIM enantiomers in the unnatural configuration were 10- to 40-fold less potent than their natural counterparts. Crystallographic studies of sAIMs in complex with the KEAP1 BTB domain demonstrated that these ligands form a covalent bond with C151 and revealed the presence of additional hydrogen bonds, Van der Waals interactions, and pi-stacking interactions. ConclusionsAlthough KEAP1 C151 is required for NRF2 activation by tpAIMs and sAIMs, interactions with other KEAP1 residues are critical for the stereospecific recognition and potency of these ligands. General significanceThis work demonstrates that reversible cyanoenone Michael acceptors, such as the tpAIMs and sAIMs, can be specifically tuned to regulate redox sensitive cysteine residues on key signaling molecules, an approach with significant promise for innovative drug development.

Lipid Chirality Revisited: A Change in Lipid Configuration Transforms Membrane-Bound Protein Domains

Since its discovery by Louis Pasteur in 1848 (1), chirality has been—and still is to this day—one major topic for chemists and biochemists alike. Many chirality-related phenomena, from alteration of polarized light to enantioselectivity of enzymes for their substrate, form an integral part of today's university courses in chemical and biological sciences. Similar to the enzymes in charge of their synthesis, phospholipids, glycolipids, and sterols found in biological membranes are chiral. However, even though the effect of chirality on the organization of lipid membranes has been studied (see for example, Weis and McConnell (2)), little is known about the impact of lipid configuration on biological function. In this issue of the Biophysical Journal, Schutte et al. (7) resort to cutting-edge chemical synthesis to generate the unnatural enantiomer of Globotriaosylceramide 3 (Gb3, a glycolipid of established biological importance), and investigate the consequences of changing Gb3 configuration on membrane binding and deformation by Shiga toxin, for which Gb3 is the biological receptor. The Shiga toxin of the bacteria Shigella dysenteriae is a protein that binds Gb3 on the plasma membrane via its B subunit (STxB), and forms membrane-bound protein domains. Importantly, by doing so Shiga toxin induces its own internalization in cells by causing inward curvatures of membranes. This phenomenon is reproduced in vitro by adding STxB to giant unilamellar vesicles (GUVs) containing a small fraction of Gb3, in conditions favoring low membrane tension (3). Like in cells, Gb3 used in in vitro assays is the Gb3-R enantiomer. By replacing Gb3-R with its unnatural enantiomer Gb3-S, Schutte et al. (7) observe that STxB-induced tubulation of GUVs is significantly enhanced, based on experiments with a total of 1253 GUVs. Although the affinity of STxB was the same for Gb3-S as for its natural counterpart, reflectometric interference spectroscopy suggested that the domain height and protein distribution in Gb3-S membranes significantly differed from that in Gb3-R membranes. Those observations were confirmed by atomic force microscopy (AFM) imaging of STxB domains formed in mica-supported planar bila-yers composed of DOPC, DPPC, and Gb3. Taken together, those observation show that, in the words of the authors, .Gb3-R favorably induces large

2-Hydroxy Fatty Acid Enantiomers of Gb3 Impact Shiga Toxin Binding and Membrane Organization

Shiga toxin subunit B (STxB) binding to its cellular receptor Gb3 leads to the formation of protein-lipid clusters and bending of the membrane. A newly developed synthetic route allowed synthesizing the biologically most relevant Gb3-C24:1 2OH species with both, the natural (Gb3-R) as well as the unnatural (Gb3-S) configuration of the 2OH group. The derivatives bind STxB with identical nanomolar affinity, while the propensity to induce membrane tubules in giant unilamellar vesicles is more pronounced for Gb3-S. Fluorescence and atomic force microscopy images of phase-separated supported membranes revealed differences in the lateral organization of the protein on the membrane. Gb3-R favorably induces large and tightly packed protein clusters, while a lower protein density is found on Gb3-S doped membranes.

Complete Spectroscopy of negative parity states in208Pb with Ex< 6.3 MeV

Using the Q3D magnetic spectrograph at the Maier-Leibnitz-Laboratorium, Garching, experiments with the 208 Pb(p, p 0 ) reaction via isobaric analog resonances and using the 207 Pb(d, p) reaction have been performed with a HWHM of 1.5 keV on the low energy side. All 70 particle-hole states with negative parity predicted by the schematic shell model without residual interaction below Ex = 6.3 MeV are identified. Except for the states with spins 1 − and 2 − , more than 80% of the strength in each state can be described by at most four configurations; for spins 0 − , 4 − , 6 − , 7 − , and 8 − two configura- tions or even one configuration describe more than 95% of the strength. Natural parity configurations are more strongly mixed than unnatural parity configurations.

A novel synthetic approach to (20 R)- and (20 S)-21-hydroxy steroids. Synthesis of a marine sterol 21-hydroxycholesterol

A short and efficient synthesis of steroid synthons, di( tert-butyldimethylsilyl) ethers of 3,21-dihydroxy-24-nor-chol-5-en-23-al ( 8 and 10) and of ethyl 3,21-dihydroxy-25-homo-chola-5,23-dien-25-oate ( 9 and 11), having natural (20 R) and unnatural (20 S) configuration from 3β-( tert-butyldimethylsilyloxy)-14α,20ξ-card-5-enolide ( 2) is reported. Further elongation of the side chain of these synthons provides a new method for the synthesis of (20 R) and (20 S)-21-hydroxy steroids. The utility of the method was exemplified by the synthesis of a natural marine sterol – 21-hydroxycholesterol ( 18).

Saturation of curvature‐induced secondary flow, energy losses, and turbulence in sharp open‐channel bends: Laboratory experiments, analysis, and modeling

The paper investigates the influence of relative bend curvature on secondary flow, energy losses, and turbulence in sharp open‐channel bends. These processes are important in natural streams with respect to sediment transport, the bathymetry and planimetry, mixing and spreading of pollutants, heat, oxygen, nutrients and biological species, and the conveyance capacity. Laboratory experiments were carried out in a configuration with rectangular cross section, consisting of a 193° bend of constant radius of curvature, preceded and followed by straight reaches. This somewhat unnatural configuration allows investigating the adaptation of mean flow and turbulence to curvature changes in open‐channel bends, without contamination by other effects such as a mobile bed topography. Experiments were carried out for three different values of the curvature ratio, defined as the ratio of centerline radius of curvature over flow depth, which is the principal curvature parameter for hydrodynamic processes. Commonly used so‐called linear models predict secondary flow to increase linearly with the curvature ratio. The reported experiments show that the secondary flow hardly increases in the investigated very sharp bends when the curvature ratio is further increased. This phenomenon is called saturation. Similar saturation is observed for the energy losses and the turbulence. This paper focuses on the analysis and modeling of the saturation of energy losses and turbulence. Secondary flow is found to be the dominant contribution to the curvature‐induced increase in turbulence production, which leads to increased energy losses. The curvature‐induced turbulence is explained by the fact that the turbulence dissipation lags behind the turbulence production, in agreement with the concept of the turbulence energy cascade. A 1‐D model is proposed for the curvature‐induced energy losses and turbulence. It could extend 1‐D or depth‐averaged 2‐D models that are commonly used in long‐term (scale of a flood event to geological scales) or large‐scale (scale of a river basin) investigations on flood propagation, hazard mapping, water quality modeling, and planimetric river evolution.

Synthesis and biological activity of enantiomeric pairs of 5-[( E)-cycloalk-2-enylidenemethyl]thiolactomycin congeners

The title congeners were synthesized by employing our efficient synthetic route previously explored for preparing enantiomeric pairs of thiolactomycin and its 3-demethyl derivative. While all the synthesized congeners lacked in vitro antibacterial activity, some of the congeners bearing an ( E)-cyclohept-2-enylidenemethyl or an ( E)-cyclooct-2-enylidenemethyl group were found to exhibit more potent type I FAS inhibitory activity than ( S)-3-demethylthiolactomycin having an unnatural configuration.

Synthesis of the ABC-ring models of goniodomin A: preference for the unnatural configuration at C11 of the BC-ring in a non-macrocyclic model system

To confirm the natural relative stereochemistry of the ABC-ring of goniodomin A ( 1), the corresponding three stereoisomeric compounds, (2 R,5 S,6 S,7 S,9 S,11 R,15 S)-, (2 R,5 S,6 S,7 R,9 R,11 S,15 R)-, and (2 R,5 S,6 S,7 R,9 R,11 R,15 S)-isomers ( 2, 3, and 5, respectively), were stereoselectively synthesized using a Nozaki–Hiyama–Kishi reaction as a key step. It was also found that a (2 R,5 S,6 S,7 R,9 R,11 S,15 S)-isomer ( 4), corresponding to the absolute configuration of 1 recently proposed by Sasaki, was not detected during the formation of 5 from a common ketodiol substrate under acid-catalyzed spiroacetalization conditions. This would be attributable to the absence of a macrocyclic framework.

Use of the intramolecular Heck reaction for forming congested quaternary carbon stereocenters. Stereocontrolled total synthesis of (+/-)-gelsemine.

Intramolecular Heck reactions of alpha,beta-unsaturated 2-haloanilides derived from azatricyclo[4.4.0.0(2,8)]decanone 5 efficiently install the congested spirooxindole functionality of gelsemine. Depending upon the Heck reaction conditions and the nature of the beta-substituent, either products having the natural or unnatural configuration of the spirooxindole group are formed predominantly. Efforts to elaborate the hydropyran ring of gelsemine from the endo-oriented nitrile substituent of pentacyclic Heck product 18 were unsuccessful. Important steps in the ultimately successful route to (+/-)-gelsemine (1) are as follows: (a) intramolecular Heck reaction of tricyclic beta-methoxy alpha,beta-unsaturated 2-iodoanilide 68 in the presence of silver phosphate to form pentacyclic product 69 having the unnatural configuration of the spirooxindole fragment, (b) formation of hexacyclic aziridine 80 from the reaction of cyanide with intermediate 79 containing an N-methoxycarbonyl-beta-bromoethylamine fragment, (c) introduction of C17 by ring-opening of the aziridinium ion derived from aziridine 80, and (d) base-promoted skeletal rearrangement of pentacyclic equatorial alcohol 82 to form the oxacyclic ring and invert the spirooxindole functional group to provide hexacyclic gelsemine precursor 83.

Synthesis and PET oxidative cyclization of silyl enol ethers: build-up of quasi-steroidal carbocycles

PET oxidative cyclization of silyl enol ethers carrying suitable side chains with olefinic double bonds results in the stereoselective formation of carbocycles. Two model compounds for investigating the influence of silyl enol ether ring size are synthesized. Furthermore the synthesis of a quasi-steroidal carbocycle with an unnatural configuration is presented.

An Intramolecular Furan−Diene Diels−Alder Approach to 11‐Oxo 10α‐Steroids

The intramolecular cycloaddition of 14, with dimethylaluminium chloride as a catalyst and under kinetic control, yielded the exo adduct 19a. Opening of the oxygen bridge in the reduced adduct 20 gave intermediate 21. Oxidation of the latter made it possible to introduce the methyl group at C-10, which exclusively afforded 23, with the unnatural configuration. Further conversion resulted in the formation of D-homo-10-epi-adrenosterone (25). (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

ChemInform Abstract: Synthesis and Biological Activity of the 1α,25‐Dihydroxyvitamin D3 Diastereomer with Unnatural Configuration at the Rings C/D Side‐Chain Moiety.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.