Human embryo implantation.

Embryo implantation in humans is interstitial, meaning the entire conceptus embeds in the endometrium before the placental trophoblast invades beyond the uterine mucosa into the underlying inner myometrium. Once implanted, embryo survival pivots on the transformation of the endometrium into an anti-inflammatory placental bed, termed decidua, under homeostatic control of uterine natural killer cells. Here, we examine the evolutionary context of embryo implantation and elaborate on uterine remodelling before and after conception in humans. We also discuss the interactions between the embryo and the decidualising endometrium that regulate interstitial implantation and determine embryo fitness. Together, this Review highlights the precarious but adaptable nature of the implantation process.

Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors.

Evidence is mounting that the major histocompatibility complex (MHC) molecule HLA-F (human leukocyte antigen F) regulates the immune system in pregnancy, infection, and autoimmunity by signaling through NK cell receptors (NKRs). We present structural, biochemical, and evolutionary analyses demonstrating that HLA-F presents peptides of unconventional length dictated by a newly arisen mutation (R62W) that has produced an open-ended groove accommodating particularly long peptides. Compared to empty HLA-F open conformers (OCs), HLA-F tetramers bound with human-derived peptides differentially stained leukocytes, suggesting peptide-dependent engagement. Our in vitro studies confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F. The complex structure of peptide-loaded ß2m-HLA-F bound to the inhibitory LIR1 revealed similarities to high-affinity recognition of the viral MHC-I mimic UL18 and a docking strategy that relies on contacts with HLA-F as well as ß2m, thus precluding binding to HLA-F OCs. These findings provide a biochemical framework to understand how HLA-F could regulate immunity via interactions with NKRs.

Elephants as an animal model for self-domestication.

Humans are unique in their sophisticated culture and societal structures, their complex languages, and their extensive tool use. According to the human self-domestication hypothesis, this unique set of traits may be the result of an evolutionary process of self-induced domestication, in which humans evolved to be less aggressive and more cooperative. However, the only other species that has been argued to be self-domesticated besides humans so far is bonobos, resulting in a narrow scope for investigating this theory limited to the primate order. Here, we propose an animal model for studying self-domestication: the elephant. First, we support our hypothesis with an extensive cross-species comparison, which suggests that elephants indeed exhibit many of the features associated with self-domestication (e.g., reduced aggression, increased prosociality, extended juvenile period, increased playfulness, socially regulated cortisol levels, and complex vocal behavior). Next, we present genetic evidence to reinforce our proposal, showing that genes positively selected in elephants are enriched in pathways associated with domestication traits and include several candidate genes previously associated with domestication. We also discuss several explanations for what may have triggered a self-domestication process in the elephant lineage. Our findings support the idea that elephants, like humans and bonobos, may be self-domesticated. Since the most recent common ancestor of humans and elephants is likely the most recent common ancestor of all placental mammals, our findings have important implications for convergent evolution beyond the primate taxa, and constitute an important advance toward understanding how and why self-domestication shaped humans' unique cultural niche.

A Method for Rigorously Selective Capture and Simultaneous Fluorescent Labeling of N-Terminal Glycine Peptides.

Although chemical methods for the selective derivatization of amino acid (AA) side chains in peptides and proteins are available, selective N-terminal labeling is challenging, especially for glycine, which has no side chain at the α-carbon position. We report here a double activation at glycine's α-methylene group that allows this AA to be differentiated from the other 19 AAs. A condensation reaction of dibenzoylmethane with glycine results in the formation of an imine, and subsequent tautomerization is followed by intramolecular cyclization, leading to the formation of a fluorescent pyrrole ring. Additionally, the approach exhibits compatibility with AAs possessing reactive side chains. Further, the method allows for selective pull-down assays of N-terminal glycine peptides from mixtures without prior knowledge of the N-terminal peptide distribution.

Nanographene-Fused Expanded Carbaporphyrin Tweezers.

A nanographene-fused expanded carbaporphyrin (5) and its BF2 complex (6) were synthesized. Single-crystal X-ray structures revealed that 5 and 6 are connected by two hexa-peri-hexabenzocoronene (HBC) units and two dipyrromethene or BODIPY units, respectively. As prepared, 5 and 6 both show nonaromatic character with figure-of-eight carbaoctaphyrin (1.1.1.0.1.1.1.0) cores and adopt tweezers-like conformations characterized by a partially confined space between the two constituent HBC units. The distance between the HBC centers is >10 Å, while the dihedral angles between the two HBC planes are 30.5 and 35.2° for 5 and 6, respectively. The interactions between 5 and 6 and fullerene C60 were studied both in organic media and in the solid state. Proton NMR spectral titrations of 5 and 6 with C60 revealed a 1:1 binding mode for both macrocycles. In toluene-d8, the corresponding binding constants were determined to be 1141 ± 17 and 994 ± 10 M-1 for 5 and 6, respectively. Single-crystal X-ray diffraction structural analyses confirmed the formation of 1:1 fullerene inclusion complexes in the solid state. The C60 guests in both complexes are found within triangular pockets composed of two HBC units from the tweezers-like receptor most closely associated with the bound fullerene, as well as an HBC unit from an adjacent host. Femtosecond transient absorption measurements revealed subpicosecond ultrafast charge separation between 5 (and 6) and C60 in the complexes. To the best of our knowledge, the present report provides the first example wherein a nanographene building block is incorporated into the core of a porphyrinic framework.

Cu-Catalyzed Three-Component Alkene Carboamination: Mechanistic Insights and Rational Design to Overcome Limitations.

Herein, we report mechanistic investigations into the Cu-catalyzed three-component carboamination of alkenes with α-halo carbonyls and aryl amines via an oxocarbenium intermediate. Monitoring the reaction reveals the formation of transient atom transfer radical addition (ATRA) intermediates with both electron-neutral and deficient vinyl arenes as well as unactivated alkenes. Based on our experimental studies and density functional theory calculations, the oxocarbenium is generated through atom transfer and subsequent intramolecular substitution. Further, mechanistic factors that dictate the regioselectivity of the nucleophilic attack onto the oxocarbenium to afford the γ-amino ester, γ-iminolactone, or γ-lactone are discussed. A strategy to overcome scope limitation with respect to unactivated alkenes is developed using the mechanistic insights gained herein. Finally, we demonstrate that under modified conditions, our Cu catalyst enables the ATRA reaction between a variety of alkyl halides and vinyl arenes/α-olefins, and we present a one-pot, two-step carbofunctionalization with an array of nucleophiles through ATRA/SN2.

Interpreting the Evolutionary Echoes of a Protein Complex Essential for Inner-Ear Mechanosensation.

The sensory epithelium of the inner ear, found in all extant lineages of vertebrates, has been subjected to over 500 million years of evolution, resulting in the complex inner ear of modern vertebrates. Inner-ear adaptations are as diverse as the species in which they are found, and such unique anatomical variations have been well studied. However, the evolutionary details of the molecular machinery that is required for hearing are less well known. Two molecules that are essential for hearing in vertebrates are cadherin-23 and protocadherin-15, proteins whose interaction with one another acts as the focal point of force transmission when converting sound waves into electrical signals that the brain can interpret. This "tip-link" interaction exists in every lineage of vertebrates, but little is known about the structure or mechanical properties of these proteins in most non-mammalian lineages. Here, we use various techniques to characterize the evolution of this protein interaction. Results show how evolutionary sequence changes in this complex affect its biophysical properties both in simulations and experiments, with variations in interaction strength and dynamics among extant vertebrate lineages. Evolutionary simulations also characterize how the biophysical properties of the complex in turn constrain its evolution and provide a possible explanation for the increase in deafness-causing mutants observed in cadherin-23 relative to protocadherin-15. Together, these results suggest a general picture of tip-link evolution in which selection acted to modify the tip-link interface, although subsequent neutral evolution combined with varying degrees of purifying selection drove additional diversification in modern tetrapods.

Deferasirox Derivatives: Ligands for the Lanthanide Series.

Deferasirox is an FDA-approved iron chelator used in the treatment of iron toxicity. In this work, we report the use of several deferasirox derivatives as lanthanide chelators. Solid-state structural studies of three representative trivalent lanthanide cations, La(III), Eu(III), and Lu(III), revealed the formation of 2:2 complexes in the solid state. A 1:1 stoichiometry dominates in DMSO solution, with Ka values of 472 ± 14, 477 ± 11, and 496 ± 15 M-1 being obtained in the case of these three cations, respectively. Under the conditions of competitive precipitation in the presence of triethylamine, high selectivity (up to 80%) for lutetium(III) was observed in competition with La(III), Ce(III), and Eu(III). Theoretical calculations provided support for the observed selective crystallization.

Cyclic Carbaporphyrin Arrays.

Two cyclic carbaporphyrin arrays (trimer 6 and tetramer 7) were synthesized from a dibrominated carbaporphyrin precursor (5) via a one-pot Yamamoto-type coupling. Single-crystal X-ray diffraction analyses revealed that 6 and 7 contain three and four covalently linked carbaporphyrin (formally dicarbacorrole) units, respectively. Trimer 6 adopts a roughly planar conformation and tetramer 7 adopts an up-and-down zig-zag conformation. Both 6 and 7 contain a [n]cyclo-meta-phenylene ([n]CMP) core, namely, [6]- and [8]CMP for 6 and 7, respectively. Transient absorption (TA) anisotropy and pump-power-dependent excited-state decay studies provided evidence for excitation energy transfer (EET) within both trimer 6 and tetramer 7. The exciton energy hopping (EEH) times were estimated to be 18 and 35 ps for 6 and 7, respectively, as inferred from pump-power-dependent TA measurements. Since the center-to-center distances between adjacent carbaporphyrin units are similar in 6 and 7, the different EEH times are attributed to differences in the orientation of the transition dipoles in these two congeneric arrays. The orientation factor κ2, the key parameter defining the Förster resonance energy transfer efficiency, was calculated to be 2.15 and 1.03 for 6 and 7, respectively, a finding that supports the shorter excitation energy hopping time seen in the case of trimer 6. To our knowledge, this is the first time that covalently linked cyclic carbaporphyrin arrays were synthesized using a single carbaporphyrin as the starting point and that EET between carbaporphyrin subunits constrained within a well-defined polycyclic framework has been correlated with structural differences.

Direct Extraction of Sodium Hydroxide by Calix[4]pyrrole-Based Ion-Pair Receptors.

Described in this work are calix[4]pyrrole-based ion-pair receptors, cis/trans-1 and cis/trans-2, designed for the extraction of sodium hydroxide. An X-ray diffraction analysis of a single crystal of the cis-1·NaOH isomer isolated from a mixture of cis/trans-1 revealed a unique dimeric supramolecular structure. An average dimer in toluene-d8 solution was inferred on the basis of diffusion-ordered spectroscopy (DOSY). Support for the proposed stoichiometry came from density functional theory (DFT) calculations. The structural stability of the dimeric cis-1·NaOH complex in toluene solution was further confirmed by ab initio molecular dynamics (AIMD) simulation with explicit representation of solvent. Under conditions of liquid-liquid extraction (LLE), purified receptors cis- and trans-2 were both found to remove NaOH from a pH 11.01 aqueous source phase into toluene with extraction efficiencies (E%) of 50-60% when used equimolar to NaOH. However, in all cases, precipitation was observed. Complexities associated with precipitation could be avoided by immobilization of the receptors onto a chemically inert poly(styrene) resin by means of solvent impregnation. The use of solvent-impregnated resins (SIRs) eliminated precipitation in solution while retaining the extraction efficiency toward NaOH. This allowed both the pH and salinity of the alkaline source phase to be lowered.

Supramolecular Recognition within a Nanosized "Buckytrap" That Exhibits Substantial Photoconductivity.

We report here a nanosized "buckytrap", 1, constructed from two bis-zinc(II) expanded-TTF (exTTF) porphyrin subunits. Two forms, 1a and 1b, differing in the axial ligands, H2O vs tetrahydrofuran (THF), were isolated and characterized. Discrete host-guest inclusion complexes are formed upon treatment with fullerenes as inferred from a single-crystal X-ray structural analyses of 1a with C70. The fullerene is found to be encapsulated within the inner pseudohexagonal cavity of 1a. In contrast, the corresponding free-base derivative (2) was found to form infinite ball-and-socket type supramolecular organic frameworks (3D-SOFs) with fullerenes, (2•C60)n or (2•C70)n. This difference is ascribed to the fact that in 1a and 1b the axial positions are blocked by a H2O or THF ligand. Emission spectroscopic studies supported a 1:1 host-guest binding stoichiometry, allowing association constants of (2.0 ± 0.5) × 104 M-1 and (4.3 ± 0.9) × 104 M-1 to be calculated for C60 and C70, respectively. Flash-photolysis time-resolved microwave conductivity (FP-TRMC) studies of solid films of the Zn-complex 1a revealed that the intrinsic charge carrier transport, i.e., pseudo-photoconductivity (ϕ∑µ), increases upon fullerene inclusion (e.g., ϕ∑µ = 1.53 × 10-4 cm2 V-1 s-1 for C60⊂(1a)2 and ϕ∑µ = 1.45 × 10-4 cm2 V-1 s-1 for C70⊂(1a)2 vs ϕ∑µ = 2.49 × 10-5 cm2 V-1 s-1 for 1a) at 298 K. These findings provide support for the notion that controlling the nature of self-assembly supramolecular constructs formed from exTTF-porphyrin dimers through metalation or choice of fullerene can be used to regulate key functional features, including photoconductivity.

Is there a loophole in Dollo's law? A DevoEvo perspective on irreversibility (of felid dentition).

There is a longstanding interest in whether the loss of complex characters is reversible (so-called "Dollo's law"). Reevolution has been suggested for numerous traits but among the first was Kurtén, who proposed that the presence of the second lower molar (M2 ) of the Eurasian lynx (Lynx lynx) was a violation of Dollo's law because all other Felids lack M2 . While an early and often cited example for the reevolution of a complex trait, Kurtén and Werdelin used an ad hoc parsimony argument to support their. Here I revisit the evidence that M2 reevolved lynx using explicit parsimony and maximum likelihood models of character evolution and find strong evidence that Kurtén and Werdelin were correct-M2 reevolved in E. lynx. Next, I explore the developmental mechanisms which may explain this violation of Dollo's law and suggest that the reevolution of lost complex traits may arise from the reevolution of cis-regulatory elements and protein-protein interactions, which have a longer half-life after silencing that protein coding genes. Finally, I present a developmental model to explain the reevolution M2 in E. lynx, which suggest that the developmental programs required for the establishment of serially homologous characters may never really be lost so long as a single instance of the character remains-thus the gain and loss and regain of serially homologous characters, such mammalian molars, may be developmentally and evolutionarily "simple."

Cooption of polyalanine tract into a repressor domain in the mammalian transcription factor HoxA11.

An enduring problem in biology is explaining how novel functions of genes originated and how those functions diverge between species. Despite detailed studies on the functional evolution of a few proteins, the molecular mechanisms by which protein functions have evolved are almost entirely unknown. Here, we show that a polyalanine tract in the homeodomain transcription factor HoxA11 arose in the stem-lineage of mammals and functions as an autonomous repressor module by physically interacting with the PAH domains of SIN3 proteins. These results suggest that long polyalanine tracts, which are common in transcription factors and often associated with disease, may tend to function as repressor domains and can contribute to the diversification of transcription factor functions despite the deleterious consequences of polyalanine tract expansion.

Diphenylpyrrole-Strapped Calix[4]pyrrole Extractant for the Fluoride and Chloride Anions.

The anion binding features of diphenylpyrrole-strapped calix[4]pyrrole 1 have been investigated by means of 1 H NMR spectroscopy and ITC (isothermal titration calorimetry), as well as single crystal X-ray diffraction analyses. Receptor 1 bearing an auxiliary pyrrolic NH donor and solubilizing phenyl groups on the strap was found to bind F- , Cl- , and Br- as their tetrabutylammonium salts with high affinity in DMSO-d6 . In addition, receptor 1 was found to extract the fluoride anion (as both its tetraethylammonium (TEA+ ) and tetrabutylammonium (TBA+ ) salts), as well as the chloride anion into chloroform-d from an aqueous source phase. Cation metathesis using TBAI or the use of a dual host approach involving crown ethers enabled receptor 1 to extract simple alkali metal fluoride or chloride salts from water. Quantitative binding of NaF by receptor 1 was observed in 20 % D2 O-DMSO-d6 allowing for the direct determination of the NaF concentration in an unknown sample.

Optical detection of alcohols with a Cu(I)HETPHEN complex by reversible aldehyde to hemiacetal conversion.

A heteroleptic copper(I) bis(phenanthroline) complex with aldehyde groups at the 4,7 positions of the phenanthroline ligand was synthesized. The complex is responsive to alcohol, resulting in a distinct colour change caused by the facile reaction of the aldehyde group with alcohol, forming a hemiacetal product. The aldehyde species can be regenerated after heating the intermediate at 80 °C for 10 minutes, demonstrating the reusability of the complex for alcohol detection. This work presents a new strategy for applying transition metal complexes in small molecule sensing by installing functional groups in the secondary coordination sphere which reversibly react with analytes.

Changing Directions: Influence of Ligand Electronics on the Directionality and Kinetics of Photoinduced Charge Transfer in Cu(I)Diimine Complexes.

A key challenge to the effective utilization of solar energy is to promote efficient photoinduced charge transfer, specifically avoiding unproductive, circuitous electron-transfer pathways and optimizing the kinetics of charge separation and recombination. We hypothesize that one way to address this challenge is to develop a fundamental understanding of how to initiate and control directional photoinduced charge transfer, particularly for earth-abundant first-row transition-metal coordination complexes, which typically suffer from relatively short excited-state lifetimes. Here, we report a series of functionalized heteroleptic copper(I)bis(phenanthroline) complexes, which have allowed us to investigate the directionality of intramolecular photoinduced metal-to-ligand charge transfer (MLCT) as a function of the substituent Hammett parameter. Ultrafast transient absorption suggests a complicated interplay of MLCT localization and solvent interaction with the Cu(II) center of the MLCT state. This work provides a set of design principles for directional charge transfer in earth-abundant complexes and can be used to efficiently design pathways for connecting the molecular modules to catalysts or electrodes and integration into systems for light-driven catalysis.

Relaxed constraint and functional divergence of the progesterone receptor (PGR) in the human stem-lineage.

The steroid hormone progesterone, acting through the progesterone receptor (PR), a ligand-activated DNA-binding transcription factor, plays an essential role in regulating nearly every aspect of female reproductive biology. While many reproductive traits regulated by PR are conserved in mammals, Catarrhine primates evolved several derived traits including spontaneous decidualization, menstruation, and a divergent (and unknown) parturition signal, suggesting that PR may also have evolved divergent functions in Catarrhines. There is conflicting evidence, however, whether the progesterone receptor gene (PGR) was positively selected in the human lineage. Here we show that PGR evolved rapidly in the human stem-lineage (as well as other Catarrhine primates), which likely reflects an episode of relaxed selection intensity rather than positive selection. Coincident with the episode of relaxed selection intensity, ancestral sequence resurrection and functional tests indicate that the major human PR isoforms (PR-A and PR-B) evolved divergent functions in the human stem-lineage. These results suggest that the regulation of progesterone signaling by PR-A and PR-B may also have diverged in the human lineage and that non-human animal models of progesterone signaling may not faithfully recapitulate human biology.

Behavior-related gene regulatory networks: A new level of organization in the brain.

Neuronal networks are the standard heuristic model today for describing brain activity associated with animal behavior. Recent studies have revealed an extensive role for a completely distinct layer of networked activities in the brain-the gene regulatory network (GRN)-that orchestrates expression levels of hundreds to thousands of genes in a behavior-related manner. We examine emerging insights into the relationships between these two types of networks and discuss their interplay in spatial as well as temporal dimensions, across multiple scales of organization. We discuss properties expected of behavior-related GRNs by drawing inspiration from the rich literature on GRNs related to animal development, comparing and contrasting these two broad classes of GRNs as they relate to their respective phenotypic manifestations. Developmental GRNs also represent a third layer of network biology, playing out over a third timescale, which is believed to play a crucial mediatory role between neuronal networks and behavioral GRNs. We end with a special emphasis on social behavior, discuss whether unique GRN organization and cis-regulatory architecture underlies this special class of behavior, and review literature that suggests an affirmative answer.

Calix[4]pyrrole-Based Molecular Capsule: Dihydrogen Phosphate-Promoted 1:2 Fluoride Anion Complexation.

A molecular capsule (1) consisting of two calix[4]pyrroles connected via ethylene diamide linkers has been prepared as an anion receptor. 1H NMR spectroscopic studies carried out in CD2Cl2 revealed that receptor 1 recognizes a variety of anions with different binding modes and stoichiometries. For instance, receptor 1 binds fluoride and acetate with 1:2 receptor/anion stoichiometry and other test anions with 1:1 stoichiometry in solution when their respective tetrabutylammonium (TBA+) salts were used. In contrast, with tetraethylammnium (TEA+) salts, receptor 1 forms 1:2 complexes with chloride and bromide in addition to fluoride, overcoming expected Columbic repulsions between the anions co-bound in close proximity. Receptor 1 is also able to bind oxoanions, such as oxalate (C2O42-), dihydrogen phosphate (H2PO4-), sulfate (SO42-), and hydrogen pyrophosphate (HP2O73-), in the form of 1:1 complexes as the result of presumed cooperation between the two calix[4]pyrrole subunits. The selectivity of receptor 1 for fluoride versus dihydrogen phosphate varies depending on their relative concentrations. For instance, in the presence of less than 1.0 equiv of an equimolar mixture of fluoride and dihydrogen phosphate, receptor 1 shows high selectivity for dihydrogen phosphate. In contrast, in the presence of ≥2.0 anion equiv, receptor 1 binds fluoride preferentially, forming a 1:2 complex. Moreover, when treated with F-, the preformed 1:1 H2PO4- complex of receptor 1 is converted to the corresponding 1:2 receptor/fluoride complex with the release of the prebound dihydrogen phosphate anion. As inferred from gas-phase computations, this seemingly counterintuitive behavior is rationalized in terms of the precomplexed dihydrogen phosphate serving to reduce the reorganization energy required to bind two fluoride anions. The presence of a water molecule in addition to the bound fluoride anions may also favor the formation of the 1:2 F- complex. The present study provides a new approach for fine-tuning the binding selectivity of polytopic anion receptors.

Pyrene-Bridged Expanded Carbaporphyrin Nanobelts.

Two belt-like expanded carbaporphyrins (NB1 and NB2) were prepared via a one-pot procedure that involves a [6 + 3] condensation between a pyrene-bearing tetrapyrrole precursor (2) and pentafluorobenzaldehyde, followed by oxidation. Single crystal X-ray diffraction analyses revealed that NB1 and NB2 both contain six dipyrromethene moieties and three bridging pyrene units. In the structure of NB1, there are two vertically orientated pyrene units and one transverse orientated pyrene unit; however, in NB2 all three pyrene units are vertically orientated. The structural differences between NB1 and NB2 are reflected in their respective physical properties as revealed by proton NMR, UV-vis, and fluorescence spectroscopies. In contrast to all-carbon nanobelts, NB1 and NB2 contain multiple pyrrolic nitrogen donors that could serve as potential metal coordination sites. As a test of this possibility, NB2 was used to prepare an unprecedented Zn complex containing 7 Zn2+ metal centers connected by a network of bridging atoms, as confirmed by a single crystal X-ray diffraction analysis. To the best of our knowledge, this is the first example of a belt-like molecular system that can coordinate multiple metal ions both along the backbone and within its central cavity.