Stacked or Folded? Impact of Chelate Cooperativity on the Self-Assembly Pathway to Helical Nanotubes from Dinucleobase Monomers.

Self-assembled nanotubes exhibit impressive biological functions that have always inspired supramolecular scientists in their efforts to develop strategies to build such structures from small molecules through a bottom-up approach. One of these strategies employs molecules endowed with self-recognizing motifs at the edges, which can undergo either cyclization-stacking or folding-polymerization processes that lead to tubular architectures. Which of these self-assembly pathways is ultimately selected by these molecules is, however, often difficult to predict and even to evaluate experimentally. We show here a unique example of two structurally related molecules substituted with complementary nucleobases at the edges (i.e., G:C and A:U) for which the supramolecular pathway taken is determined by chelate cooperativity, that is, by their propensity to assemble in specific cyclic structures through Watson-Crick pairing. Because of chelate cooperativities that differ in several orders of magnitude, these molecules exhibit distinct supramolecular scenarios prior to their polymerization that generate self-assembled nanotubes with different internal monomer arrangements, either stacked or coiled, which lead at the same time to opposite helicities and chiroptical properties.

Childhood maltreatment disrupts HPA-axis activity under basal and stress conditions in a dose-response relationship in children and adolescents.

BACKGROUND: This study investigates the impact of childhood maltreatment (CM) on hypothalamic-pituitary-adrenal (HPA)-axis functioning and on anxiety perception. Moreover, the influence of CM severity and frequency was also explored. METHODS: In total, 187 participants aged 7-17 were assessed for CM history using validated questionnaires and ad hoc interviews to be classified according to the criteria of the Tool for Assessing the Severity of Situations in which Children are Vulnerable (TASSCV). Psychopathology was ascertained using the K-SADS-PL5. To assess HPA-axis functioning, salivary cortisol samples were collected throughout a normal day and during an acute psychosocial stressor, the Trier Social Stress Test for children (TSST-C). Subjective anxiety was evaluated using STAI/-C. RESULTS: Youth with a CM history had higher overall diurnal cortisol levels (p = 0.001), blunted cortisol response to acute psychosocial stress (p = 0.002) and greater perceived anxiety (p = 0.003), than those without CM. Specifically, participants exposed to moderate/severe or often/frequent CM showed the greater diurnal cortisol output (pseverity = 0.002; pfrequency = 0.003), and blunted cortisol response during the TSST-C (pseverity = 0.006; pfrequency = 0.008). Meanwhile, youth with low CM severity/frequency exhibited a similar cortisol response to those without CM. However, perceived anxiety was higher in those exposed to CM (p < 0.001), regardless of its severity/frequency. CONCLUSIONS: Disturbances in HPA-axis functioning are already evident early after CM exposure, while psychological and physiological responses to an acute stressor are dissociated in youth exposed to CM. The dose-response relationship described in this paper highlights the need to comprehensively evaluate CM so that vulnerable children can be identified and assigned to proper interventions.

Imaging Follow-Up of Nonsurgical Therapies for Lung Cancer: AJR Expert Panel Narrative Review.

Lung cancer continues to be the most common cause of cancer-related death worldwide. In the past decade, with the implementation of lung cancer screening programs and advances in surgical and nonsurgical therapies, the survival of patients with lung cancer has increased, as has the number of imaging studies that these patients undergo. However, most patients with lung cancer do not undergo surgical re-section, because they have comorbid disease or lung cancer in an advanced stage at diagnosis. Nonsurgical therapies have continued to evolve with a growing range of systemic and targeted therapies, and there has been an associated evolution in the imaging findings encountered at follow-up examinations after such therapies (e.g., with respect to posttreatment changes, treatment complications, and recurrent tumor). This AJR Expert Panel Narrative Review describes the current status of nonsurgical therapies for lung cancer and their expected and unexpected imaging manifestations. The goal is to provide guidance to radiologists regarding imaging assessment after such therapies, focusing mainly on non-small cell lung cancer. Covered therapies include systemic therapy (conventional chemotherapy, targeted therapy, and immunotherapy), radiotherapy, and thermal ablation.

Self-Sorting Governed by Chelate Cooperativity.

Self-sorting phenomena are the basis of manifold relevant (bio)chemical processes where a set of molecules is able to interact with no interference from other sets and are ruled by a number of codes that are programmed in molecular structures. In this work, we study, the relevance of chelate cooperativity as a code for achieving high self-sorting fidelities. In particular, we establish qualitative and quantitative relationships between the cooperativity of a cyclic system and the self-sorting fidelity when combined with other molecules that share identical geometry and/or binding interactions. We demonstrate that only systems displaying sufficiently strong chelate cooperativity can achieve quantitative narcissistic self-sorting fidelities either by dictating the distribution of cyclic species in complex mixtures or by ruling the competition between the intra- and intermolecular versions of a noncovalent interaction.

Secretory immunoglobulin A (s-IgA) reactivity to acute psychosocial stress in children and adolescents: The influence of pubertal development and history of maltreatment.

BACKGROUND: Mucosal secretory immunoglobulin A (s-IgA) is an antibody protein-complex that plays a crucial role in immune first defense against infection. Although different immune biomarkers have been associated with stress-related psychopathology, s-IgA remains poorly studied, especially in youth. OBJECTIVES: The present study investigated how s-IgA behaves in front of acute psychosocial stress in children and adolescents, including possible variability associated with developmental stage and history of childhood maltreatment (CM). METHODS: 94 children and adolescents from 7 to 17 years (54 with a current psychiatric diagnostic and 40 healthy controls) drawn from a larger Spanish study were explored (EPI-Young Stress Project). To assess biological reactivity, participants provided five saliva samples during an acute laboratory-based psychosocial stressor, the Trier Social Stress Test for Children (TSST-C). Samples were assayed for s-IgA, as well as for cortisol. Pubertal development was ascertained by Tanner stage and CM following TASSCV criteria. RESULTS: We observed s-IgA fluctuations throughout the stressor, indicating the validity of TSST-C to stimulate s-IgA secretion (F(4,199) = 6.200, p <.001). Although s-IgA trajectories followed a reactivity and recovery pattern in adolescents, children exhibited no s-IgA response when faced with stress (F(4,197) = 3.406, p =.010). An interaction was found between s-IgA and CM (F(4,203) = 2.643, p =.035). Interestingly, an interaction between developmental stage, CM history and s-IgA reactivity was identified (F(12,343) = 2.036, p =.017); while children non-exposed to maltreatment exhibited no s-IgA changes to acute stress, children with a history of CM showed a similar response to adolescents, increasing their s-IgA levels after the psychosocial stressor. CONCLUSION: Acute psychosocial stress stimulates s-IgA secretion, but only after puberty. However, children with a history of maltreatment exhibited a response resembling that of adolescents, suggesting an early maturation of the immune system. Further studies are needed to clarify the validity of s-IgA as an acute stress biomarker, including additional measures during stress exposure.

Dual-Mode Chiral Self-Assembly of Cone-Shaped Subphthalocyanine Aromatics.

Columnar polymers and liquid crystals obtained from π-conjugated cone-shaped molecules are receiving increasing interest due to the possibility of obtaining unconventional polar organizations that show anisotropic charge transport and unique chiroptical properties. However, and in contrast to the more common planar discotics, the self-assembly of conic or pyramidic molecules in solution remains largely unexplored. Here, we show how a molecular geometry change, from flat to conic, can generate supramolecular landscapes where different self-assembled species, each of them being under thermodynamic equilibrium with the monomer, exist exclusively within distinct regimes. In particular, depending on the solvent nature-aromatic or aliphatic-cone-shaped C3-symmetric subphthalocyanine 1 can undergo self-assembly either as a tail-to-tail dimer, showing monomer-dimer sigmoidal transitions, or as a head-to-tail noncentrosymmetric columnar polymer, exhibiting a nucleation-elongation polymerization mechanism. Moreover, the experimental and theoretical comparison between racemic and enantiopure samples revealed that the two enantiomers (1M and 1P) tend to narcissistically self-sort in the dimer regime, each enantiomer showing a strong preference to associate with itself, but socially self-sort in the polymer regime, favoring an alternate stacking order along the columns.

Noncovalent Synthesis of Self-Assembled Nanotubes through Decoupled Hierarchical Cooperative Processes.

Because of their wide number of biological functions and potential applications, self-assembled nanotubes constitute highly relevant targets in noncovalent synthesis. Herein, we introduce a novel approach to produce supramolecular nanotubes with defined inner and outer diameters from rigid rod-like monomers programmed with complementary nucleobases through two distinct, decoupled cooperative processes of different hierarchy and acting in orthogonal directions: chelate cooperativity, responsible for the formation of robust Watson-Crick H-bonded cyclic tetramers, and nucleation-growth cooperative polymerization.

PISCOM: a new procedure for epilepsy combining ictal SPECT and interictal PET.

PURPOSE: We present a modified version of the SISCOM procedure that uses interictal PET instead of interictal SPECT for seizure onset zone localization. We called this new nuclear imaging processing technique PISCOM (PET interictal subtracted ictal SPECT coregistered with MRI). METHODS: We retrospectively studied 23 patients (age range 4-61 years) with medically refractory epilepsy who had undergone MRI, ictal SPECT, interictal SPECT and interictal FDG PET and who had been seizure-free for at least 2 years after surgical treatment. FDG PET images were reprocessed (rFDG PET) to assimilate SPECT features for image subtraction. Interictal SPECT and rFDG PET were compared using statistical parametric mapping (SPM). PISCOM and SISCOM images were evaluated visually and using an automated volume of interest-based analysis. The results of the two studies were compared with each other and with the known surgical resection site. RESULTS: SPM showed no significant differences in cortical activity between SPECT and rFDG PET images. PISCOM and SISCOM showed equivalent results in 17 of 23 patients (74%). The seizure onset zone was successfully identified in 19 patients (83%) by PISCOM and in 17 (74%) by SISCOM: in 15 patients (65%) the two techniques showed concordant successful results. The volume of interest-based analysis showed no significant differences between PISCOM and SISCOM in identifying the extension of the seizure onset zone. However, PISCOM showed a lower amount of indeterminate activity due to propagation, background or artefacts. CONCLUSION: Preliminary findings of this initial proof-of-concept study suggest that perfusion and glucose metabolism in the cerebral cortex can be correlated and that PISCOM may be a valid technique for identification of the seizure onset zone. However, further studies are needed to validate these results.

Impact of Conformational Effects on the Ring-Chain Equilibrium of Hydrogen-Bonded Dinucleosides.

Supramolecular ring-versus-chain equilibria are ubiquitous in biological and synthetic systems. Understanding the factors that decide whether a system will fall on one side or the other is crucial to the control of molecular self-assembly. This work reports results with two kinds of dinucleoside monomers, in which the balance between closed cycles and open polymers is found to depend on subtle factors that rule conformational equilibria, such as steric hindrance, intramolecular interactions, or π-conjugation pathways.

Exploiting NH···Cl Hydrogen Bonding Interactions in Cooperative Metallosupramolecular Polymerization.

The self-assembly features of hydrophobic bispyridyldichlorido Pd(II) complexes, equipped with an extended aromatic surface derived from oligophenyleneethynylene (OPE) and polarizable amide functional groups, are reported. The cooperative supramolecular polymerization of these complexes results in bundles of thin fibers in which the monomer units are arranged in a translationally displaced or slipped fashion. Spectroscopic and microscopy studies reveal that these assemblies are held together by simultaneous π-stacking of the OPE moieties and NH···ClPd hydrogen bonds. These unconventional forces are often observed in crystal engineering but remain largely unexploited in supramolecular polymers. Both steric and electronic effects (the presence of bulky and polarizable metal-bound Cl ligands as well as hydrogen bonding donor NH units) prevent the establishment of short Pd-Pd contacts and strongly condition the aggregation mode of the reported complexes, in close analogy to the previously reported amphiphilic Pd(II) complex 4. The results presented herein shed light on the subtle interplay between different noncovalent interactions and their impact on the self-assembly of metallosupramolecular systems.

Mechanosensitive Gold Colloidal Membranes Mediated by Supramolecular Interfacial Self-Assembly.

The ability to respond toward mechanical stimuli is a fundamental property of biological organisms at both the macroscopic and cellular levels, yet it has been considerably less observed in artificial supramolecular and colloidal homologues. An archetypal example in this regard is cellular mechanosensation, a process by which mechanical forces applied on the cell membrane are converted into biochemical or electrical signals through nanometer-scale changes in molecular conformations. In this article, we report an artificial gold nanoparticle (Au NP)-discrete π-conjugated molecule hybrid system that mimics the mechanical behavior of biological membranes and is able to self-assemble into colloidal gold nanoclusters or membranes in a controlled and reversible fashion by changing the concentration or the mechanical force (pressure) applied. This has been achieved by rational design of a small π-conjugated thiolated molecule that controls, to a great extent, the hierarchy levels involved in Au NP clustering by enabling reversible, cooperative non-covalent (π-π, solvophobic, and hydrogen bonding) interactions. In addition, the Au NP membranes have the ability to entrap and release aromatic guest molecules reversibly (Kb = 5.0 × 105 M-1) for several cycles when subjected to compression-expansion experiments, in close analogy to the behavior of cellular mechanosensitive channels. Not only does our hybrid system represent the first example of a reversible colloidal membrane, but it also can be controlled by a dynamic mechanical stimulus using a new supramolecular surface-pressure-controlled strategy. This approach holds great potential for the development of multiple colloidal assemblies within different research fields.

How Large Can We Build a Cyclic Assembly? Impact of Ring Size on Chelate Cooperativity in Noncovalent Macrocyclizations.

Self-assembled systems rely on intramolecular cooperative effects to control their growth and regulate their shape, thus yielding discrete, well-defined structures. However, as the size of the system increases, cooperative effects tend to dissipate. We analyze here this situation by studying a set of oligomers of different lengths capped with guanosine and cytidine nucleosides, which associate in cyclic tetramers by complementary Watson-Crick H-bonding interactions. As the monomer length increases, and thus the number of C(sp)-C(sp2 ) σ-bonds in the π-conjugated skeleton, the macrocycle stability decreases due to a notable reduction in effective molarity (EM), which has a clear entropic origin. We determined the relationship between EM or ΔS and the number of σ-bonds, which allowed us to predict the maximum monomer lengths at which cyclic species would still assemble quantitatively, or whether the cyclic species would not able to compete at all with linear oligomers over the whole concentration range.

Control over the Self-Assembly Modes of Pt(II) Complexes by Alkyl Chain Variation: From Slipped to Parallel π-Stacks.

We report the self-assembly of a new family of hydrophobic, bis(pyridyl) Pt(II) complexes featuring an extended oligophenyleneethynylene-derived π-surface appended with six long (dodecyloxy (2)) or short (methoxy (3)) side groups. Complex 2, containing dodecyloxy chains, forms fibrous assemblies with a slipped arrangement of the monomer units (dPt⋅⋅⋅Pt ≈14 Å) in both nonpolar solvents and the solid state. Dispersion-corrected PM6 calculations suggest that this organization is driven by cooperative π-π, C-H⋅⋅⋅Cl and π-Pt interactions, which is supported by EXAFS and 2D NMR spectroscopic analysis. In contrast, nearly parallel π-stacks (dPt⋅⋅⋅Pt ≈4.4 Å) stabilized by multiple π-π and C-H⋅⋅⋅Cl contacts are obtained in the crystalline state for 3 lacking long side chains, as shown by X-ray analysis and PM6 calculations. Our results reveal not only the key role of alkyl chain length in controlling self-assembly modes but also show the relevance of Pt-bound chlorine ligands as new supramolecular synthons.

Seizure-onset zone localization by statistical parametric mapping in visually normal (18) F-FDG PET studies.

OBJECTIVE: Neuroimaging is crucial in the presurgical evaluation of patients with medically refractory epilepsy. To improve the moderate sensitivity of [(18) F]fluorodeoxyglucose-positron emission tomography ((18) F-FDG-PET), our aim was to evaluate the usefulness of statistical parametric mapping (SPM) to localize the seizure-onset zone (SOZ) in PET studies deemed normal by visual assessment. METHODS: Fifty-five patients with medically refractory epilepsy whose (18) F-FDG-PET was visually evaluated as normal were retrospectively included. Twenty of these patients had undergone surgical intervention. PET images were analyzed by SPM8 using a corrected p-value of p < 0.05 and three uncorrected p-values of p < 0.0001, p < 0.001, and p < 0.005, matched with minimum cluster sizes of k > 0, k > 20, k > 100, and k > 200, respectively. The SPM-identified potential seizure zone (SZ) was compared to the SOZ, which was determined by consensus during patient management meetings in the epilepsy unit, taking into account presurgical tests. Studies in which the SPM-identified potential SZ was concordant with the SOZ were considered "correctly localizing." RESULTS: The SPM threshold combination with the least restrictive p-value and greatest minimum cluster size achieved the highest rate of correctly localizing studies. When p < 0.005/k > 200 was used, 40% (22/55) of studies were correctly localizing, and the concordance obtained in the surgically intervened subgroup was substantial (к = 0.607, 95% confidence interval [CI] 0.258-0.957), which was comparable to the concordance obtained by magnetic resonance imaging (MRI) (к = 0.783, 95% CI 0.509-1.000). SIGNIFICANCE: SPM offers improved SOZ localization in (18) F-FDG-PET studies that are negative on visual assessment. For this purpose, statistical parametric maps could be thresholded with liberal p-values and restrictive cluster sizes.

Role of the Symmetry of Multipoint Hydrogen Bonding on Chelate Cooperativity in Supramolecular Macrocyclization Processes.

Herein, we analyze the intrinsic chelate effect that multipoint H-bonding patterns exert on the overall energy of dinucleoside cyclic systems. Our results indicate that the chelate effect is regulated by the symmetry of the H-bonding pattern, and that the effective molarity is reduced by about three orders of magnitude when going from the unsymmetric ADD-DAA or DDA-AAD patterns to the symmetric DAD-ADA pattern.

Prospective comparison of whole-body (18)F-FDG PET/CT and MRI of the spine in the diagnosis of haematogenous spondylodiscitis.

PURPOSE: To prospectively compare (18)F-FDG PET/CT and MRI in the diagnosis of haematogenous spondylodiscitis METHODS: The study included 26 patients (12 women, 14 men; mean age 59 ± 17 years) with clinical symptoms of infection of the spine. Patients who had had prior spinal surgery or any type of antibiotic therapy in the previous 3 months were excluded from the study. Whole-body PET/CT 60 min after injection of 4.07 MBq/kg of (18)F-FDG and an MRI scan of the spine was performed in all patients. SUVmax in an area surrounding the lesions with the suspicion of infection as well as a background SUVmean in a preserved area of the spine were calculated for quantification. Infection was diagnosed by microbiological documentation in cultures of image-guided spinal puncture fluid or blood. Infection was excluded if symptoms were absent without antimicrobial therapy during a follow-up of at least 6 months. RESULTS: Spondylodiscitis was confirmed in 18 of the 26 patients. Staphylococcus aureus was found in 8 patients, Mycobacterium tuberculosis in 4, Escherichia coli in 2 and other pathogens in 4. Of the remaining 8 patients, the diagnoses were degenerative spondyloarthropathy in 5 and vertebral fracture in 3. The sensitivity, specificity, and positive and negative predictive value were 83%, 88%, 94% and 70% for (18)F-FDG PET/CT, and 94%, 38%, 77% and 75% for MRI, respectively. The accuracies of (18)F-FDG PET/CT and MRI were similar (84% and 81%, respectively). The combination of (18)F-FDG PET/CT and MRI detected the infection in 100% of the patients with spondylodiscitis. (18)F-FDG uptake, quantified in terms of SUVmax corrected by the background SUVmean, was significantly higher in patients with spondylodiscitis than in those without infection (p < 0.001). CONCLUSION: Due to its high specificity, (18)F-FDG PET/CT should be considered as a first-line imaging procedure in the diagnosis of spondylodiscitis. Quantification of uptake in terms of SUVmax was able to discriminate infection of the spine from other processes in this series of patients.

High-fidelity noncovalent synthesis of hydrogen-bonded macrocyclic assemblies.

A hydrogen-bonded cyclic tetramer is assembled with remarkably high effective molarities from a properly designed dinucleoside monomer. This self-assembled species exhibits an impressive thermodynamic and kinetic stability and is formed with high fidelities within a broad concentration range.

Non-centrosymmetric homochiral supramolecular polymers of tetrahedral subphthalocyanine molecules.

A combination of spectroscopy (UV/Vis absorption, emission, and circular dichroism), microscopy (AFM and TEM), and computational studies reveal the formation of non-centrosymmetric homochiral columnar subphthalocyanine assemblies. These assemblies form through a cooperative supramolecular polymerization process driven by hydrogen-bonding between amide groups, π-π stacking, and dipolar interactions between axial B-F bonds.

H-aggregates of oligophenyleneethynylene (OPE)-BODIPY systems in water: guest size-dependent encapsulation mechanism and co-aggregate morphology.

The synthesis of a new oligophenyleneethynylene (OPE)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) bolaamphiphile 1 and its aqueous self-assembly are reported. Compound 1 forms H-type aggregates in aqueous and polar media, as demonstrated by UV/Vis and fluorescence experiments. Concentration-dependent (1)H NMR studies in CD3CN reveal that the BODIPY units are arranged on top of each other into π-stacks with H-type excitonic coupling, as supported by ROESY NMR and theoretical calculations and visualized by Cryo-SEM studies. A detailed analysis of the spectral changes observed in temperature-dependent UV/Vis studies reveals that 1 self-assembles in a non-cooperative (isodesmic) fashion in water. The hydrophobic interior of these self-assembled structures can be exploited to encapsulate hydrophobic dyes, such as tetracene and anthracene. Both dyes absorb in a complementary region of the UV/Vis spectrum and are small enough to interact with the hydrophobic segments of 1. Temperature-dependent UV/Vis studies reveal that the spectral changes associated to the encapsulation mechanism of tetracene can be fitted to a Boltzmann function, and the initially flexible fibres of 1 rigidify upon guest addition. In contrast, the co-assembly of 1 and anthracene is a highly cooperative process, which suggests that a different class of (more-ordered) aggregates is formed. TEM and Cryo SEM imaging show the formation of uniform spherical nanoparticles, indicating that a subtle change in the guest molecular structure induces a significant change in the encapsulation mechanism and, consequently, the aggregate morphology.

Self-assembly and (hydro)gelation triggered by cooperative π-π and unconventional C-H···X hydrogen bonding interactions.

Weak C-H···X hydrogen bonds are important stabilizing forces in crystal engineering and anion recognition in solution. In contrast, their quantitative influence on the stabilization of supramolecular polymers or gels has thus far remained unexplored. Herein, we report an oligophenyleneethynylene (OPE)-based amphiphilic Pt(II) complex that forms supramolecular polymeric structures in aqueous and polar media driven by π-π and different weak C-H···X (X=Cl, O) interactions involving chlorine atoms attached to the Pt(II) centers as well as oxygen atoms and polarized methylene groups belonging to the peripheral glycol chains. A collection of experimental techniques (UV/Vis, 1D and 2D NMR, DLS, AFM, SEM, and X-Ray diffraction) demonstrate that the interplay between different weak noncovalent interactions leads to the cooperative formation of self-assembled structures of high aspect ratio and gels in which the molecular arrangement is maintained in the crystalline state.