Geometric frustration of Jahn-Teller order in the infinite-layer lattice.

The Jahn-Teller effect, in which electronic configurations with energetically degenerate orbitals induce lattice distortions to lift this degeneracy, has a key role in many symmetry-lowering crystal deformations1. Lattices of Jahn-Teller ions can induce a cooperative distortion, as exemplified by LaMnO3 (refs. 2,3). Although many examples occur in octahedrally4 or tetrahedrally5 coordinated transition metal oxides due to their high orbital degeneracy, this effect has yet to be manifested for square-planar anion coordination, as found in infinite-layer copper6,7, nickel8,9, iron10,11 and manganese oxides12. Here we synthesize single-crystal CaCoO2 thin films by topotactic reduction of the brownmillerite CaCoO2.5 phase. We observe a markedly distorted infinite-layer structure, with ångström-scale displacements of the cations from their high-symmetry positions. This can be understood to originate from the Jahn-Teller degeneracy of the dxz and dyz orbitals in the d7 electronic configuration along with substantial ligand-transition metal mixing. A complex pattern of distortions arises in a [Formula: see text] tetragonal supercell, reflecting the competition between an ordered Jahn-Teller effect on the CoO2 sublattice and the geometric frustration of the associated displacements of the Ca sublattice, which are strongly coupled in the absence of apical oxygen. As a result of this competition, the CaCoO2 structure forms an extended two-in-two-out type of Co distortion following 'ice rules'13.

Archaic chaperone-usher pili self-secrete into superelastic zigzag springs.

Adhesive pili assembled through the chaperone-usher pathway are hair-like appendages that mediate host tissue colonization and biofilm formation of Gram-negative bacteria1-3. Archaic chaperone-usher pathway pili, the most diverse and widespread chaperone-usher pathway adhesins, are promising vaccine and drug targets owing to their prevalence in the most troublesome multidrug-resistant pathogens1,4,5. However, their architecture and assembly-secretion process remain unknown. Here, we present the cryo-electron microscopy structure of the prototypical archaic Csu pilus that mediates biofilm formation of Acinetobacter baumannii-a notorious multidrug-resistant nosocomial pathogen. In contrast to the thick helical tubes of the classical type 1 and P pili, archaic pili assemble into an ultrathin zigzag architecture secured by an elegant clinch mechanism. The molecular clinch provides the pilus with high mechanical stability as well as superelasticity, a property observed for the first time, to our knowledge, in biomolecules, while enabling a more economical and faster pilus production. Furthermore, we demonstrate that clinch formation at the cell surface drives pilus secretion through the outer membrane. These findings suggest that clinch-formation inhibitors might represent a new strategy to fight multidrug-resistant bacterial infections.

Single-photon nonlinearity at room temperature.

The recent progress in nanotechnology1,2 and single-molecule spectroscopy3-5 paves the way for emergent cost-effective organic quantum optical technologies with potential applications in useful devices operating at ambient conditions. We harness a π-conjugated ladder-type polymer strongly coupled to a microcavity forming hybrid light-matter states, so-called exciton-polaritons, to create exciton-polariton condensates with quantum fluid properties. Obeying Bose statistics, exciton-polaritons exhibit an extreme nonlinearity when undergoing bosonic stimulation6, which we have managed to trigger at the single-photon level, thereby providing an efficient way for all-optical ultrafast control over the macroscopic condensate wavefunction. Here, we utilize stable excitons dressed with high-energy molecular vibrations, allowing for single-photon nonlinear operation at ambient conditions. This opens new horizons for practical implementations like sub-picosecond switching, amplification and all-optical logic at the fundamental quantum limit.

Implementation of machine learning protocols to predict the hydrolysis reaction properties of organophosphorus substrates using descriptors of electron density topology.

Prediction of catalytic reaction efficiency is one of the most intriguing and challenging applications of machine learning (ML) algorithms in chemistry. In this study, we demonstrated a strategy for utilizing ML protocols applied to Quantum Theory of Atoms In Molecules (QTAIM) parameters to predict the ability of the A17 L47K catalytic antibody to covalently capture organophosphate pesticides. We found that the novel "composite" DFT functional B97-3c could be effectively employed for fast and accurate initial geometry optimization, aligning well with the input dataset creation. QTAIM descriptors proved to be well-established in describing the examined dataset using density-based and hierarchical clustering algorithms. The obtained clusters exhibited correlations with the chemical classes of the input compounds. The precise physical interpretation of the QTAIM properties simplifies the explanation of feature impact for both supervised and unsupervised ML protocols. It also enables acceleration in the search for entries with desired properties within large databases. Furthermore, our findings indicated that Ridge Regression with Laplacian kernel and CatBoost Regressor algorithms demonstrated suitable performance in handling small datasets with non-trivial dependencies. They were able to predict the actual reaction barrier values with a high level of accuracy. Additionally, the CatBoost Classifier proved reliable in discriminating between "active" and "inactive" compounds.

3-Substituted 6-Azabicyclo[3.1.1]heptanes: Nonclassical Piperidine Isosteres for Drug Discovery.

Advanced analogs of piperidine and smaller homologues of tropane─3-substituted 6-azabicyclo[3.1.1]heptanes─were synthesized on a large scale using readily available bulk reagents. The key step of the approach involved the double alkylation reaction of malonate with cis-2,4-bis(mesyloxymethyl)azetidine-1-carboxylate, in turn easily prepared on up to 1 kg scale. After hydrolysis, N-Boc-6-azabicyclo[3.1.1]heptane-3,3-dicarboxylic acid was obtained (up to 400 g in a single run), which was used as a common intermediate for the preparation of all the title building blocks. In particular, Pb(OAc)4-mediated oxidative decarboxylation of this intermediate gave 2,6-methanopiperidone derivative (up to 400 g scale), while monodecarboxylation gave N-Boc-6-azabicyclo[3.1.1]heptane-3-carboxylic acids as an easily separatable mixture of cis and trans diastereomers (up to 100 g scale). Further functional group transformations gave diastereopure cis- and trans-N-Boc-monoprotected diamines and amino alcohols. Molecular structure analysis using exit vector parameters (EVP) revealed that cis isomers of 3-substituted 6-azabicyclo[3.1.1]heptanes are three-dimensional analogs of common 1,4-disubstituted piperidine chair conformer, whereas trans isomers can be considered as unusual "boat" piperidines.

Proton Sponge Zwitterions with Positively and Negatively Charged Hydrogen Bonds: Extremely Polar Organic Compounds and Interplay of [NHN]+ and [NHN]- Properties.

Six previously unknown zwitterions with positively and negatively charged [NHN] hydrogen bonds were synthesized by acylation of 4,5-bis(dimethylamino)-1-tosylamino-8-aminonaphthalene with subsequent alkaline treatment of the resulting 8-acylamino derivatives. Using NMR and XRD measurements in conjunction with quantum chemical DFT/PBE1PBE/6-311++G(d,p) calculations, it was shown that the negatively charged [NHN]- bond in such compounds commonly differs from the [NHN]+ bond by significantly lower linearity, higher asymmetry, and moderate to strong paramagnetic shift of the chelated NH proton signal. Among other remarkable findings, the most important are (1) unusually high polarity (µ = 21-26 D) of the obtained zwitterions, (2) sharp difference in structures of the solid 1,8-bis(tosylated) zwitterion (BTZ) grown from MeCN or DMF, and (3) registration for one of the stereoisomers of BTZ with the record short [NHN]- hydrogen bridge (N···N = 2.510 Å) almost reaching the theoretical limit (2.50 Å) for the [NHN]+ hydrogen bond.

Three-component cascade reaction of 3-ketonitriles, 2-unsubstituted imidazole N-oxides, and aldehydes.

A three-component condensation of 2-unsubstituted imidazole N-oxides, 3-ketonitriles, and aldehydes is described. The reaction proceeds via sequential Knoevenagel condensation/Michael addition under mild, catalyst-free conditions with various substrates. Furthermore, the corresponding 2-functionalized imidazole N-oxides can be further dehydrated to (Z)-2-aroyl-3-(1H-imidazol-2-yl)-acrylonitriles, which may also be directly prepared by changing the reaction conditions as a cascade of Knoevenagel condensation/Michael addition/dehydration.

7,8-Dihydro-8-oxo-1,N6-ethenoadenine: an exclusively Hoogsteen-paired thymine mimic in DNA that induces A→T transversions in Escherichia coli.

This work investigated the structural and biological properties of DNA containing 7,8-dihydro-8-oxo-1,N6-ethenoadenine (oxo-ϵA), a non-natural synthetic base that combines structural features of two naturally occurring DNA lesions (7,8-dihydro-8-oxoadenine and 1,N6-ethenoadenine). UV-, CD-, NMR spectroscopies and molecular modeling of DNA duplexes revealed that oxo-ϵA adopts the non-canonical syn conformation (χ = 65º) and fits very well among surrounding residues without inducing major distortions in local helical architecture. The adduct remarkably mimics the natural base thymine. When considered as an adenine-derived DNA lesion, oxo-ϵA was >99% mutagenic in living cells, causing predominantly A→T transversion mutations in Escherichia coli. The adduct in a single-stranded vector was not repaired by base excision repair enzymes (MutM and MutY glycosylases) or the AlkB dioxygenase and did not detectably affect the efficacy of DNA replication in vivo. When the biological and structural data are viewed together, it is likely that the nearly exclusive syn conformation and thymine mimicry of oxo-ϵA defines the selectivity of base pairing in vitro and in vivo, resulting in lesion pairing with A during replication. The base pairing properties of oxo-ϵA, its strong fluorescence and its invisibility to enzymatic repair systems in vivo are features that are sought in novel DNA-based probes and modulators of gene expression.

α-Umpolung/Michael Addition/Quaternization Tandem Reaction to provide α-Imido-ß-phosphonium Propanoates with Broad Spectrum of Biological Activity.

This paper has been supported by the Kazan Federal University Strategic Academic Leadership Program ('PRIORITY-2030'). HRMS data were obtained in the CSF-SAC FRC KSC RAS by support of the State Assignment of the Federal Research Center "Kazan Scientific Center", Russian Academy of Sciences. A.D.V, conducted studies of anticancer activity with financial support form the government assignment for FRC Kazan Scientific Center of RAS.

Phylogenomics revealed migration routes and adaptive radiation timing of Holarctic malaria mosquito species of the Maculipennis Group.

BACKGROUND: Phylogenetic analyses of closely related species of mosquitoes are important for better understanding the evolution of traits contributing to transmission of vector-borne diseases. Six out of 41 dominant malaria vectors of the genus Anopheles in the world belong to the Maculipennis Group, which is subdivided into two Nearctic subgroups (Freeborni and Quadrimaculatus) and one Palearctic (Maculipennis) subgroup. Although previous studies considered the Nearctic subgroups as ancestral, details about their relationship with the Palearctic subgroup, and their migration times and routes from North America to Eurasia remain controversial. The Palearctic species An. beklemishevi is currently included in the Nearctic Quadrimaculatus subgroup adding to the uncertainties in mosquito systematics. RESULTS: To reconstruct historic relationships in the Maculipennis Group, we conducted a phylogenomic analysis of 11 Palearctic and 2 Nearctic species based on sequences of 1271 orthologous genes. The analysis indicated that the Palearctic species An. beklemishevi clusters together with other Eurasian species and represents a basal lineage among them. Also, An. beklemishevi is related more closely to An. freeborni, which inhabits the Western United States, rather than to An. quadrimaculatus, a species from the Eastern United States. The time-calibrated tree suggests a migration of mosquitoes in the Maculipennis Group from North America to Eurasia about 20-25 million years ago through the Bering Land Bridge. A Hybridcheck analysis demonstrated highly significant signatures of introgression events between allopatric species An. labranchiae and An. beklemishevi. The analysis also identified ancestral introgression events between An. sacharovi and its Nearctic relative An. freeborni despite their current geographic isolation. The reconstructed phylogeny suggests that vector competence and the ability to enter complete diapause during winter evolved independently in different lineages of the Maculipennis Group. CONCLUSIONS: Our phylogenomic analyses reveal migration routes and adaptive radiation timing of Holarctic malaria vectors and strongly support the inclusion of An. beklemishevi into the Maculipennis Subgroup. Detailed knowledge of the evolutionary history of the Maculipennis Subgroup provides a framework for examining the genomic changes related to ecological adaptation and susceptibility to human pathogens. These genomic variations may inform researchers about similar changes in the future providing insights into the patterns of disease transmission in Eurasia.

Probing the Conformational Restraints of DNA Damage Recognition with ß-L-Nucleotides.

The DNA building blocks 2'-deoxynucleotides are enantiomeric, with their natural ß-D-configuration dictated by the sugar moiety. Their synthetic ß-L-enantiomers (ßLdNs) can be used to obtain L-DNA, which, when fully substituted, is resistant to nucleases and is finding use in many biosensing and nanotechnology applications. However, much less is known about the enzymatic recognition and processing of individual ßLdNs embedded in D-DNA. Here, we address the template properties of ßLdNs for several DNA polymerases and the ability of base excision repair enzymes to remove these modifications from DNA. The Klenow fragment was fully blocked by ßLdNs, whereas DNA polymerase κ bypassed them in an error-free manner. Phage RB69 DNA polymerase and DNA polymerase ß treated ßLdNs as non-instructive but the latter enzyme shifted towards error-free incorporation on a gapped DNA substrate. DNA glycosylases and AP endonucleases did not process ßLdNs. DNA glycosylases sensitive to the base opposite their cognate lesions also did not recognize ßLdNs as a correct pairing partner. Nevertheless, when placed in a reporter plasmid, pyrimidine ßLdNs were resistant to repair in human cells, whereas purine ßLdNs appear to be partly repaired. Overall, ßLdNs are unique modifications that are mostly non-instructive but have dual non-instructive/instructive properties in special cases.

Characterizing Aptamer Interaction with the Oncolytic Virus VV-GMCSF-Lact.

Aptamers are currently being investigated for their potential to improve virotherapy. They offer several advantages, including the ability to prevent the aggregation of viral particles, enhance target specificity, and protect against the neutralizing effects of antibodies. The purpose of this study was to comprehensively investigate an aptamer capable of enhancing virotherapy. This involved characterizing the previously selected aptamer for vaccinia virus (VACV), evaluating the aggregation and molecular interaction of the optimized aptamers with the recombinant oncolytic virus VV-GMCSF-Lact, and estimating their immunoshielding properties in the presence of human blood serum. We chose one optimized aptamer, NV14t_56, with the highest affinity to the virus from the pool of several truncated aptamers and built its 3D model. The NV14t_56 remained stable in human blood serum for 1 h and bound to VV-GMCSF-Lact in the micromolar range (Kd ≈ 0.35 µM). Based on dynamic light scattering data, it has been demonstrated that aptamers surround viral particles and inhibit aggregate formation. In the presence of serum, the hydrodynamic diameter (by intensity) of the aptamer-virus complex did not change. Microscale thermophoresis (MST) experiments showed that NV14t_56 binds with virus (EC50 = 1.487 × 109 PFU/mL). The analysis of the amplitudes of MST curves reveals that the components of the serum bind to the aptamer-virus complex without disrupting it. In vitro experiments demonstrated the efficacy of VV-GMCSF-Lact in conjunction with the aptamer when exposed to human blood serum in the absence of neutralizing antibodies (Nabs). Thus, NV14t_56 has the ability to inhibit virus aggregation, allowing VV-GMCSF-Lact to maintain its effectiveness throughout the storage period and subsequent use. When employing aptamers as protective agents for oncolytic viruses, the presence of neutralizing antibodies should be taken into account.

Surgical Treatment of Metatarsalgia and Severe Instability of Lesser Metatarsophalangeal Joints.

The main object of this prospective cohort study was to compare surgical treatment options for primary metatarsalgia and the severe instability of lesser metatarsophalangeal joints. The outcomes of triple Weil osteotomy combined with direct plantar plate repair and triple Weil osteotomy, performed with proximal interphalangeal joint arthrodesis, are analyzed and compared. One hundred thirteen patients (117 feet) were enrolled in the study. They were split into 2 groups. In the first group, undergoing Weil osteotomy, combined with the plantar plate repair, good results, including complete pain reduction, elimination of hyperkeratosis, and American Orthopedic Foot and Ankle Society Score improvement, were achieved in 84.7% of the cases. The second group, where the combination of Weil osteotomy and proximal interphalangeal joint K-wire arthrodesis was used, demonstrated good results in 52.4% of the cases. Weil osteotomy, combined with the plantar plate repair, achieves better results in comparison to osteotomy, performed with the interphalangeal joint arthrodesis.

Dynamics of 8-Oxoguanine in DNA: Decisive Effects of Base Pairing and Nucleotide Context.

8-Oxo-7,8-dihydroguanine (oxoG), an abundant DNA lesion, can mispair with adenine and induce mutations. To prevent this, cells possess DNA repair glycosylases that excise either oxoG from oxoG:C pairs (bacterial Fpg, human OGG1) or A from oxoG:A mispairs (bacterial MutY, human MUTYH). Early lesion recognition steps remain murky and may include enforced base pair opening or capture of a spontaneously opened pair. We adapted the CLEANEX-PM NMR protocol to detect DNA imino proton exchange and analyzed the dynamics of oxoG:C, oxoG:A, and their undamaged counterparts in nucleotide contexts with different stacking energy. Even in a poorly stacking context, the oxoG:C pair did not open easier than G:C, arguing against extrahelical base capture by Fpg/OGG1. On the contrary, oxoG opposite A significantly populated the extrahelical state, which may assist recognition by MutY/MUTYH.

Quantum Shell in a Shell: Engineering Colloidal Nanocrystals for a High-Intensity Excitation Regime.

Many optoelectronic processes in colloidal semiconductor nanocrystals (NCs) suffer an efficiency decline under high-intensity excitation. This issue is caused by Auger recombination of multiple excitons, which converts the NC energy into excess heat, reducing the efficiency and life span of NC-based devices, including photodetectors, X-ray scintillators, lasers, and high-brightness light-emitting diodes (LEDs). Recently, semiconductor quantum shells (QSs) have emerged as a promising NC geometry for the suppression of Auger decay; however, their optoelectronic performance has been hindered by surface-related carrier losses. Here, we address this issue by introducing quantum shells with a CdS-CdSe-CdS-ZnS core-shell-shell-shell multilayer structure. The ZnS barrier inhibits the surface carrier decay, which increases the photoluminescence (PL) quantum yield (QY) to 90% while retaining a high biexciton emission QY of 79%. The improved QS morphology allows demonstrating one of the longest Auger lifetimes reported for colloidal NCs to date. The reduction of nonradiative losses in QSs also leads to suppressed blinking in single nanoparticles and low-threshold amplified spontaneous emission. We expect that ZnS-encapsulated quantum shells will benefit many applications exploiting high-power optical or electrical excitation regimes.

In Vitro Prostate Cancer Treatment via CRISPR-Cas9 Gene Editing Facilitated by Polyethyleneimine-Derived Graphene Quantum Dots.

CRISPR-Cas9 is a programmable gene editing tool with a promising potential for cancer gene therapy. This therapeutic function is enabled in the present work via the non-covalent delivery of CRISPR ribonucleic protein (RNP) by cationic glucosamine/PEI-derived graphene quantum dots (PEI-GQD) that aid in overcoming physiological barriers and tracking genes of interest. PEI-GQD/RNP complex targeting the TP53 mutation overexpressed in ~50% of cancers successfully produces its double-stranded breaks in solution and in PC3 prostate cancer cells. Restoring this cancer "suicide" gene can promote cellular repair pathways and lead to cancer cell apoptosis. Its repair to the healthy form performed by simultaneous PEI-GQD delivery of CRISPR RNP and a gene repair template leads to a successful therapeutic outcome: 40% apoptotic cancer cell death, while having no effect on non-cancerous HeK293 cells. The translocation of PEI-GQD/RNP complex into PC3 cell cytoplasm is tracked via GQD intrinsic fluorescence, while EGFP-tagged RNP is detected in the cell nucleus, showing the successful detachment of the gene editing tool upon internalization. Using GQDs as non-viral delivery and imaging agents for CRISPR-Cas9 RNP sets the stage for image-guided cancer-specific gene therapy.

Reconfigurable dipole receive array for dynamic parallel imaging at ultra-high magnetic field.

PURPOSE: To extend the concept of 3D dynamic parallel imaging, we developed a prototype of an electronically reconfigurable dipole array that provides sensitivity alteration along the dipole length. METHODS: We developed a radiofrequency array coil consisting of eight reconfigurable elevated-end dipole antennas. The receive sensitivity profile of each dipole can be electronically shifted toward one or the other end by electrical shortening or lengthening the dipole arms using positive-intrinsic-negative-diode lump-element switching units. Based on the results of electromagnetic simulations, we built the prototype and tested it at 9.4 T on phantom and healthy volunteer. A modified 3D SENSE reconstruction was used, and geometry factor (g-factor) calculations were performed to assess the new array coil. RESULTS: Electromagnetic simulations showed that the new array coil was capable of alteration of its receive sensitivity profile along the dipole length. Electromagnetic and g-factor simulations showed closely agreeing predictions when compared to the measurements. The new dynamically reconfigurable dipole array provided significant improvement in geometry factor compared to static dipoles. We obtained up to 220% improvement for 3 × 2 (Ry × Rz ) acceleration compared to the static configuration case in terms of maximum g-factor and up to 54% in terms of mean g-factor for the same acceleration. CONCLUSION: We presented an 8-element prototype of a novel electronically reconfigurable dipole receive array that permits rapid sensitivity modulations along the dipole axes. Applying dynamic sensitivity modulation during image acquisition emulates two virtual rows of receive elements along the z-direction, and therefore improves parallel imaging performance for 3D acquisitions.

Т1 mapping of rat lungs in 19 F MRI using octafluorocyclobutane.

PURPOSE: To demonstrate the feasibility of using octafluorocyclobutane (OFCB, c-C4 F8 ) for T1 mapping of lungs in 19 F MRI. METHODS: The study was performed at 7 T in three healthy rats and three rats with pulmonary hypertension. To increase the sensitivity of 19 F MRI, a bent-shaped RF coil with periodic metal strips structure was used. The double flip angle method was used to calculate normalized transmitting RF field (B1n + ) maps and for correcting T1 maps built with the variable flip angle (VFA) method. The ultrashort TE pulse sequence was applied for acquiring MR images throughout the study. RESULTS: The dependencies of OFCB relaxation times on its partial pressure in mixtures with oxygen, air, helium, and argon were obtained. T1 of OFCB linearly depended on its partial pressure with the slope of about 0.35 ms/kPa in the case of free diffusion. RF field inhomogeneity leads to distortion of T1 maps built with the VFA method, and therefore to high standard deviation of T1 in these maps. To improve the accuracy of the T1 maps, the B1n + maps were applied for VFA correction. This contributed to a 2-3-fold decrease in the SD of T1 values in the corresponding maps compared with T1 maps calculated without the correction. Three-dimensional T1 maps were obtained, and the mean T1 in healthy rat lungs was 35 ± 10 ms, and in rat lungs with pulmonary hypertension - 41 ± 9 ms. CONCLUSION: OFCB has a spin-rotational relaxation mechanism and can be used for 19 F T1 mapping of lungs. The calculated OFCB maps captured ventilation defects induced by edema.

Deuterium metabolic imaging of the human brain in vivo at 7 T.

PURPOSE: To explore the potential of deuterium metabolic imaging (DMI) in the human brain in vivo at 7 T, using a multi-element deuterium (2 H) RF coil for 3D volume coverage. METHODS: 1 H-MR images and localized 2 H MR spectra were acquired in vivo in the human brain of 3 healthy subjects to generate DMI maps of 2 H-labeled water, glucose, and glutamate/glutamine (Glx). In addition, non-localized 2 H-MR spectra were acquired both in vivo and in vitro to determine T1 and T2 relaxation times of deuterated metabolites at 7 T. The performance of the 2 H coil was assessed through numeric simulations and experimentally acquired B1 + maps. RESULTS: 3D DMI maps covering the entire human brain in vivo were obtained from well-resolved deuterated (2 H) metabolite resonances of water, glucose, and Glx. The T1 and T2 relaxation times were consistent with those reported at adjacent field strengths. Experimental B1 + maps were in good agreement with simulations, indicating efficient and homogeneous B1 + transmission and low RF power deposition for 2 H, consistent with a similar array coil design reported at 9.4 T. CONCLUSION: Here, we have demonstrated the successful implementation of 3D DMI in the human brain in vivo at 7 T. The spatial and temporal nominal resolutions achieved at 7 T (i.e., 2.7 mL in 28 min, respectively) were close to those achieved at 9.4 T and greatly outperformed DMI at lower magnetic fields. DMI at 7 T and beyond has clear potential in applications dealing with small brain lesions.