Exome Sequencing for the Diagnostics of Osteogenesis Imperfecta in Six Russian Patients.

Osteogenesis imperfecta (OI) is a group of inherited disorders of connective tissue that cause significant deformities and fragility in bones. Most cases of OI are associated with pathogenic variants in collagen type I genes and are characterized by pronounced polymorphisms in clinical manifestations and the absence of clear phenotype-genotype correlation. The objective of this study was to conduct a comprehensive molecular-genetic and clinical analysis to verify the diagnosis of OI in six Russian patients with genetic variants in the COL1A1 and COL1A2 genes. Clinical and laboratory data were obtained from six OI patients who were observed at the Medical Genetics Center in Saint Petersburg from 2016 to 2023. Next-generation sequencing on MGISEQ G400 (MGI, China) was used for DNA analysis. The GATK bioinformatic software (version 4.5.0.0) was used for variant calling and hard filtering. Genetic variants were verified by the direct automatic sequencing of PCR products using the ABI 3500X sequencer. We identified six genetic variants, as follows pathogenic c.3505G>A (p. Gly1169Ser), c.769G>A (p.Gly257Arg), VUS c.4123G>A (p.Ala1375Thr), and c.4114A>T (p.Asn1372Tyr) in COL1A1; and likely pathogenic c.2035G>A (p.Gly679Ser) and c.739-2A>T in COL1A2. In addition, clinical cases are presented due to the presence of the c.4114A>T variant in the COL1A2 gene. Molecular genetics is essential for determining different OI types due to the high similarity across various types of the disease and the failure of unambiguous diagnosis based on clinical manifestations alone. Considering the variable approaches to OI classification, an integrated strategy is required for optimal patient management.

Human Exome Sequencing and Prospects for Predictive Medicine: Analysis of International Data and Own Experience.

Today, whole-exome sequencing (WES) is used to conduct the massive screening of structural and regulatory genes in order to identify the allele frequencies of disease-associated polymorphisms in various populations and thus detect pathogenic genetic changes (mutations or polymorphisms) conducive to malfunctional protein sequences. With its extensive capabilities, exome sequencing today allows both the diagnosis of monogenic diseases (MDs) and the examination of seemingly healthy populations to reveal a wide range of potential risks prior to disease manifestation (in the future, exome sequencing may outpace costly and less informative genome sequencing to become the first-line examination technique). This review establishes the human genetic passport as a new WES-based clinical concept for the identification of new candidate genes, gene variants, and molecular mechanisms in the diagnosis, prediction, and treatment of monogenic, oligogenic, and multifactorial diseases. Various diseases are addressed to demonstrate the extensive potential of WES and consider its advantages as well as disadvantages. Thus, WES can become a general test with a broad spectrum pf applications, including opportunistic screening.

Progress in Carbon Nanostructures: From Synthesis to Applications.

Significant progress in carbon nanostructures has been achieved in the past 20 years; however, there is plenty of room for further study [...].

Advanced Carbon Nanostructures: Synthesis, Properties, and Applications.

Carbon nanomaterials are a class of materials that include allotropic modifications of carbon [...].

Host-Guest Chemistry in Boron Nitride Nanotubes: Interactions with Polyoxometalates and Mechanism of Encapsulation.

Boron nitride nanotubes (BNNTs) are an emerging class of molecular container offering new functionalities and possibilities for studying molecules at the nanoscale. Herein, BNNTs are demonstrated as highly effective nanocontainers for polyoxometalate (POM) molecules. The encapsulation of POMs within BNNTs occurs spontaneously at room temperature from an aqueous solution, leading to the self-assembly of a POM@BNNT host-guest system. Analysis of the interactions between the host-nanotube and guest-molecule indicate that Lewis acid-base interactions between W═O groups of the POM (base) and B-atoms of the BNNT lattice (acid) likely play a major role in driving POM encapsulation, with photoactivated electron transfer from BNNTs to POMs in solution also contributing to the process. The transparent nature of the BNNT nanocontainer allows extensive investigation of the guest-molecules by photoluminescence, Raman, UV-vis absorption, and EPR spectroscopies. These studies revealed considerable energy and electron transfer processes between BNNTs and POMs, likely mediated via defect energy states of the BNNTs and resulting in the quenching of BNNT photoluminescence at room temperature, the emergence of new photoluminescence emissions at cryogenic temperatures (<100 K), a photochromic response, and paramagnetic signals from guest-POMs. These phenomena offer a fresh perspective on host-guest interactions at the nanoscale and open pathways for harvesting the functional properties of these hybrid systems.

Identification of Genetic Risk Factors of Severe COVID-19 Using Extensive Phenotypic Data: A Proof-of-Concept Study in a Cohort of Russian Patients.

The COVID-19 pandemic has drawn the attention of many researchers to the interaction between pathogen and host genomes. Over the last two years, numerous studies have been conducted to identify the genetic risk factors that predict COVID-19 severity and outcome. However, such an analysis might be complicated in cohorts of limited size and/or in case of limited breadth of genome coverage. In this work, we tried to circumvent these challenges by searching for candidate genes and genetic variants associated with a variety of quantitative and binary traits in a cohort of 840 COVID-19 patients from Russia. While we found no gene- or pathway-level associations with the disease severity and outcome, we discovered eleven independent candidate loci associated with quantitative traits in COVID-19 patients. Out of these, the most significant associations correspond to rs1651553 in MYH14p = 1.4 × 10-7), rs11243705 in SETX (p = 8.2 × 10-6), and rs16885 in ATXN1 (p = 1.3 × 10-5). One of the identified variants, rs33985936 in SCN11A, was successfully replicated in an independent study, and three of the variants were found to be associated with blood-related quantitative traits according to the UK Biobank data (rs33985936 in SCN11A, rs16885 in ATXN1, and rs4747194 in CDH23). Moreover, we show that a risk score based on these variants can predict the severity and outcome of hospitalization in our cohort of patients. Given these findings, we believe that our work may serve as proof-of-concept study demonstrating the utility of quantitative traits and extensive phenotyping for identification of genetic risk factors of severe COVID-19.

Magnetic nanoribbons with embedded cobalt grown inside single-walled carbon nanotubes.

Molecular magnetism and specifically magnetic molecules have recently gained plenty of attention as key elements for quantum technologies, information processing, and spintronics. Transition to the nanoscale and implementation of ordered structures with defined parameters is crucial for advanced applications. Single-walled carbon nanotubes (SWCNTs) provide natural one-dimensional confinement that can be implemented for encapsulation, nanosynthesis, and polymerization of molecules into nanoribbons. Recently, the formation of atomically precise graphene nanoribbons inside SWCNTs has been reported. However, there have been only a limited amount of approaches to form ordered magnetic structures inside the nanotube channels and the creation of magnetic nanoribbons is still lacking. In this work we synthesize and reveal the properties of cobalt-phthalocyanine based nanoribbons (CoPcNRs) encapsulated in SWCNTs. Raman spectroscopy, transmission electron microscopy, absorption spectroscopy, and density functional theory calculations allowed us to confirm the encapsulation and to reveal the specific fingerprints of CoPcNRs. The magnetic properties were studied by transverse magnetooptical Kerr effect measurements, which indicated a strong difference in comparison with the pristine unfilled SWCNTs due to the impact of Co incorporated atoms. We anticipate that this approach of polymerization of encapsulated magnetic molecules inside SWCNTs will result in a diverse class of protected low-dimensional ordered magnetic materials for various applications.

Basic Predictive Risk Factors for Cytokine Storms in COVID-19 Patients.

Objective: A critical role in coronavirus disease 2019 (COVID-19) pathogenesis is played by immune dysregulation that leads to a generalized uncontrolled multisystem inflammatory response, caused by overproduction of proinflammatory cytokines, known as "a cytokine storm" (CS), strongly associated with a severe course of disease. The aim of this study is to identify prognostic biomarkers for CS development in COVID-19 patients and integrate them into a prognostic score for CS-associated risk applicable to routine clinical practice. Materials and Methods: The authors performed a review of 458 medical records from COVID-19 patients (241 men and 217 women aged 60.0 ± 10.0) who received treatment in the St. Petersburg State Budgetary Institution of Healthcare City Hospital 40 (City Hospital 40, St. Petersburg), from Apr. 18, 2020 to Nov. 21, 2020. The patients were split in two groups: one group included 100 patients with moderate disease symptoms; the other group included 358 patients with progressive moderately severe, severe, and extremely severe disease. The National Early Warning Score (NEWS) score was used alongside with clinical assessment, chest computed tomographic (CT) scans, electrocardiography (ECG), and lab tests, like ferritin, C-reactive protein (CRP), interleukin (IL)-6, lactate dehydrogenase (LDH), and D-dimer. Results: The basic risk factors for cytokine storms in COVID-19 patients are male gender, age over 40 years, positive test result for replicative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA, absolute lymphocyte count, dynamics in the NEWS score, as well as LDH, D-dimer, ferritin, and IL-6 levels. These clinical and instrumental findings can be also used as laboratory biomarkers for diagnosis and dynamic monitoring of cytokine storms. The suggested prognostic scale (including the NEWS score dynamics; serum IL-6 greater than 23 pg/ml; serum CRP 50 mg/L or greater; absolute lymphocyte count less than 0.72 × 109/L; positive test result for replicative coronavirus (SARS-CoV-2) RNA; age 40 years and over) is a useful tool to identify patients at a high risk for cytokine storm, requiring an early onset of anti-inflammatory therapy.

Tunneling current modulation in atomically precise graphene nanoribbon heterojunctions.

Lateral heterojunctions of atomically precise graphene nanoribbons (GNRs) hold promise for applications in nanotechnology, yet their charge transport and most of the spectroscopic properties have not been investigated. Here, we synthesize a monolayer of multiple aligned heterojunctions consisting of quasi-metallic and wide-bandgap GNRs, and report characterization by scanning tunneling microscopy, angle-resolved photoemission, Raman spectroscopy, and charge transport. Comprehensive transport measurements as a function of bias and gate voltages, channel length, and temperature reveal that charge transport is dictated by tunneling through the potential barriers formed by wide-bandgap GNR segments. The current-voltage characteristics are in agreement with calculations of tunneling conductance through asymmetric barriers. We fabricate a GNR heterojunctions based sensor and demonstrate greatly improved sensitivity to adsorbates compared to graphene based sensors. This is achieved via modulation of the GNR heterojunction tunneling barriers by adsorbates.

Analysis of the Spectrum of ACE2 Variation Suggests a Possible Influence of Rare and Common Variants on Susceptibility to COVID-19 and Severity of Outcome.

OBJECTIVES: In March 2020, the World Health Organization declared that an infectious respiratory disease caused by a new severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2, causing coronavirus disease 2019 (COVID-19)] became a pandemic. In our study, we have analyzed a large publicly available dataset, the Genome Aggregation Database (gnomAD), as well as a cohort of 37 Russian patients with COVID-19 to assess the influence of different classes of genetic variants in the angiotensin-converting enzyme-2 (ACE2) gene on the susceptibility to COVID-19 and the severity of disease outcome. RESULTS: We demonstrate that the European populations slightly differ in alternative allele frequencies at the 2,754 variant sites in ACE2 identified in the gnomAD database. We find that the Southern European population has a lower frequency of missense variants and slightly higher frequency of regulatory variants. However, we found no statistical support for the significance of these differences. We also show that the Russian population is similar to other European populations when comparing the frequencies of the ACE2 variants. Evaluation of the effect of various classes of ACE2 variants on COVID-19 outcome in a cohort of Russian patients showed that common missense and regulatory variants do not explain the differences in disease severity. At the same time, we find several rare ACE2 variants (including rs146598386, rs73195521, rs755766792, and others) that are likely to affect the outcome of COVID-19. Our results demonstrate that the spectrum of genetic variants in ACE2 may partially explain the differences in severity of the COVID-19 outcome.

All-dielectric magnetic metasurface for advanced light control in dual polarizations combined with high-Q resonances.

Nanostructured magnetic materials provide an efficient tool for light manipulation on sub-nanosecond and sub-micron scales, and allow for the observation of the novel effects which are fundamentally impossible in smooth films. For many cases of practical importance, it is vital to observe the magneto-optical intensity modulation in a dual-polarization regime. However, the nanostructures reported on up to date usually utilize a transverse Kerr effect and thus provide light modulation only for p-polarized light. We present a concept of a transparent magnetic metasurface to solve this problem, and demonstrate a novel mechanism for magneto-optical modulation. A 2D array of bismuth-substituted iron-garnet nanopillars on an ultrathin iron-garnet slab forms a metasurface supporting quasi-waveguide mode excitation. In contrast to plasmonic structures, the all-dielectric magnetic metasurface is shown to exhibit much higher transparency and superior quality-factor resonances, followed by a multifold increase in light intensity modulation. The existence of a wide variety of excited mode types allows for advanced light control: transmittance of both p- and s-polarized illumination becomes sensitive to the medium magnetization, something that is fundamentally impossible in smooth magnetic films. The proposed metasurface is very promising for sensing, magnetometry and light modulation applications.

Photothermal Bottom-up Graphene Nanoribbon Growth Kinetics.

We present laser-induced photothermal synthesis of atomically precise graphene nanoribbons (GNRs). The kinetics of photothermal bottom-up GNR growth are unravelled by in situ Raman spectroscopy carried out in ultrahigh vacuum. We photothermally drive the reaction steps by short periods of laser irradiation and subsequently analyze the Raman spectra of the reactants in the irradiated area. Growth kinetics of chevron GNRs (CGNRs) and seven atoms wide armchair GNRs (7-AGNRs) is investigated. The reaction rate constants for polymerization, cyclodehydrogenation, and interribbon fusion are experimentally determined. We find that the limiting rate constants for CGNR growth are several hundred times smaller than for 7-AGNR growth and that interribbon fusion is an important elementary reaction occurring during 7-AGNR growth. Our work highlights that photothermal synthesis and in situ Raman spectroscopy are a powerful tandem for the investigation of on-surface reactions.

All-Dielectric Nanophotonics Enables Tunable Excitation of the Exchange Spin Waves.

Launching and controlling magnons with laser pulses opens up new routes for applications including optomagnetic switching and all-optical spin wave emission and enables new approaches for information processing with ultralow energy dissipation. However, subwavelength light localization within the magnetic structures leading to efficient magnon excitation that does not inherently absorb light has still been missing. Here, we propose to marriage the laser-induced ultrafast magnetism and nanophotonics to efficiently excite and control spin dynamics in magnetic dielectric structures. We demonstrate that nanopatterning by a 1D grating of trenches allows localization of light in spots with sizes of tens of nanometers and thus launch the exchange standing spin waves of different orders. The relative amplitude of the exchange and magnetostatic spin waves can be adjusted on demand by modifying laser pulse polarization, incidence angle, and wavelength. Nanostructuring of the magnetic media provides a unique possibility for the selective spin manipulation, a key issue for further progress of magnonics, spintronics, and quantum technologies.

A 12-mer Peptide of Tag7 (PGLYRP1) Forms a Cytotoxic Complex with Hsp70 and Inhibits TNF-Alpha Induced Cell Death.

Investigation of interactions between a pro-inflammatory cytokine tumor necrosis factor (TNFα) and its receptor is required for the development of new treatments for autoimmune diseases associated with the adverse effects of TNFα. Earlier, we demonstrated that the innate immunity protein Tag7 (PGRP-S, PGLYRP1) can interact with the TNFα receptor, TNFR1, and block the transduction of apoptotic signals through this receptor. A complex formed between the Tag7 protein and the major heat shock protein Hsp70 can activate TNFR1 receptor and induce tumor cell death via either apoptotic or necroptotic pathway. In this study, we show that a 12-mer peptide, designated 17.1, which was derived from the Tag7 protein, can be regarded as a novel TNFα inhibitor, also is able to form a cytotoxic complex with the heat shock protein Hsp70. This finding demonstrates a new role for Hsp70 protein in the immune response. Also, this new inhibitory 17.1 peptide demonstrates an anti-inflammatory activity in the complete Freund's adjuvant (CFA)-induced autoimmune arthritis model in laboratory mice. It appears that the 17.1 peptide could potentially be used as an anti-inflammatory agent.

Nanosecond Freezing of Water at High Pressures: Nucleation and Growth near the Metastability Limit.

The fundamental study of phase transition kinetics has motivated experimental methods toward achieving the largest degree of undercooling possible, more recently culminating in the technique of rapid, quasi-isentropic compression. This approach has been demonstrated to freeze water into the high-pressure ice VII phase on nanosecond timescales, with some experiments undergoing heterogeneous nucleation while others, in apparent contradiction, suggest a homogeneous nucleation mode. In this study, we show through a combination of theory, simulation, and analysis of experiments that these seemingly contradictory results are in agreement when viewed from the perspective of classical nucleation theory. We find that, perhaps surprisingly, classical nucleation theory is capable of accurately predicting the solidification kinetics of ice VII formation under an extremely high driving force (|Δµ/k_{B}T|≈1) but only if amended by two important considerations: (i) transient nucleation and (ii) separate liquid and solid temperatures. This is the first demonstration of a model that is able to reproduce the experimentally observed rapid freezing kinetics.

Intravenously Injected Amyloid-ß Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral ß-Amyloidosis in AßPP/PS1 Transgenic Mice Model of Alzheimer's Disease.

Cerebral ß-amyloidosis, an accumulation in the patient's brain of aggregated amyloid-ß (Aß) peptides abnormally saturated by divalent biometal ions, is one of the hallmarks of Alzheimer's disease (AD). Earlier, we found that exogenously administrated synthetic Aß with isomerized Asp7 (isoD7-Aß) induces Aß fibrillar aggregation in the transgenic mice model of AD. IsoD7-Aß molecules have been implied to act as seeds enforcing endogenous Aß to undergo pathological aggregation through zinc-mediated interactions. On the basis of our findings on zinc-induced oligomerization of the metal-binding domain of various Aß species, we hypothesize that upon phosphorylation of Ser8, isoD7-Aß loses its ability to form zinc-bound oligomeric seeds. In this work, we found that (i) in vitro isoD7-Aß with phosphorylated Ser8 (isoD7-pS8-Aß) is less prone to spontaneous and zinc-induced aggregation in comparison with isoD7-Aß and intact Aß as shown by thioflavin T fluorimetry and dynamic light scattering data, and (ii) intravenous injections of isoD7-pS8-Aß significantly slow down the progression of institutional ß-amyloidosis in AßPP/PS1 transgenic mice as shown by the reduction of the congophilic amyloid plaques' number in the hippocampus. The results support the role of the zinc-mediated oligomerization of Aß species in the modulation of cerebral ß-amyloidosis and demonstrate that isoD7-pS8-Aß can serve as a potential molecular tool to block the aggregation of endogenous Aß in AD.

Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition.

The triggers of late-onset sporadic Alzheimer's disease (AD) are still poorly understood. Impairment of protein phosphorylation with age is well-known; however, the role of the phosphorylation in ß-amyloid peptide (Aß) is not studied sufficiently. Zinc-induced oligomerization of Aß represents a potential seeding mechanism for the formation of neurotoxic Aß oligomers and aggregates. Phosphorylation of Aß by Ser8 (pS8-Aß), localized inside the zinc-binding domain of the peptide, may significantly alter its zinc-induced oligomerization. Indeed, using dynamic light scattering, we have shown that phosphorylation by Ser8 dramatically reduces zinc-induced aggregation of Aß, and moreover pS8-Aß suppresses zinc-driven aggregation of non-modified Aß in an equimolar mixture. We have further analyzed the effect of pS8-Aß on the progression of cerebral amyloidosis with serial retro-orbital injections of the peptide in APPSwe/PSEN1dE9 murine model of AD, followed by histological analysis of amyloid burden in hippocampus. Unlike the non-modified Aß that has no influence on the amyloidosis progression in murine models of AD, pS8-Aß injections reduced the number of amyloid plaques in the hippocampus of mice by one-third. Recently shown inhibition of Na+,K+-ATPase activity by Aß, which is thought to be a major contributor to neuronal dysfunction in AD, is completely reversed by phosphorylation of the peptide. Thus, several AD-associated pathogenic properties of Aß are neutralized by its phosphorylation.

Giant peak of the Inverse Faraday effect in the band gap of magnetophotonic microcavity.

Optical impact on the spin system in a magnetically ordered medium provides a unique possibility for local manipulation of magnetization at subpicosecond time scales. One of the mechanisms of the optical manipulation is related to the inverse Faraday effect (IFE). Usually the IFE is observed in crystals and magnetic films on a substrate. Here we demonstrate the IFE induced by fs-laser pulses in the magnetic film inside the magnetophotonic microcavity. Spectral dependence of the IFE on the laser pulse wavelength in the band gap of the magnetophotonic microcavity has a sharp peak leading to a significant enhancement of the IFE. This phenomenon is explained by strong confinement of the electromagnetic energy within the magnetic film. Calculated near field distribution of the IFE effective magnetic field indicates its subwavelength localization within 30 nm along the film thickness. These excited volumes can be shifted along the sample depth via e.g. changing frequency of the laser pulses. The obtained results open a way for ultrafast optical control of magnetization at subwavelength scales.

Diagnostics of autoimmune neurodegeneration using fluorescent probing.

The discovery of antibody-mediated catalysis was a breakthrough that showed antibody function is not limited to specific binding interactions, and that immunoglobulins (Igs) may also chemically transform their target antigens. Recently, so-called "natural catalytic antibodies" have been intimately linked with several pathologies, where they either protect the organism or contribute to the development of autoimmune abnormalities. Previously, we showed that myelin-reactive autoantibodies from patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE) exhibit the ability to recognize and hydrolyse distinct epitopes within myelin basic protein (MBP). Further, the antibody-mediated cleavage of encephalitogenic MBP peptide 81-103, flanked by two fluorescent proteins, can serve as a novel biomarker for MS. Here, we report the next generation of this biomarker, based on the antibody-mediated degradation of a novel chemically synthesized FRET substrate, comprising the fluorophore Cy5 and the quencher QXL680, interconnected by the MBP peptide 81-99: Cy5-MBP81-99-QXL680. This substrate is degraded upon incubation with either purified antibodies from MS patients but not healthy donors or purified antibodies and splenocytes from EAE but not from non-immunized mice. Data presented herein suggest the elaboration of potential specific, rapid, and sensitive diagnostic criteria of active progressive MS.

Exposure to the Epstein-Barr Viral Antigen Latent Membrane Protein 1 Induces Myelin-Reactive Antibodies In Vivo.

Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system (CNS). Cross-reactivity of neuronal proteins with exogenous antigens is considered one of the possible mechanisms of MS triggering. Previously, we showed that monoclonal myelin basic protein (MBP)-specific antibodies from MS patients cross-react with Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1). In this study, we report that exposure of mice to LMP1 results in induction of myelin-reactive autoantibodies in vivo. We posit that chronic exposure or multiple acute exposures to viral antigen may redirect B cells from production of antiviral antibodies to antibodies, specific to myelin antigen. However, even in inbred animals, which are almost identical in terms of their genomes, such an effect is only observed in 20-50% of animals, indicating that this change occurs by chance, rather than systematically. Cross-immunoprecipitation analysis showed that only part of anti-MBP antibodies from LMP1-immunized mice might simultaneously bind LMP1. In contrast, the majority of anti-LMP1 antibodies from MBP-immunized mice bind MBP. De novo sequencing of anti-LMP1 and anti-MBP antibodies by mass spectrometry demonstrated enhanced clonal diversity in LMP1-immunized mice in comparison with MBP-immunized mice. We suggest that induction of MBP-reactive antibodies in LMP1-immunized mice may be caused by either Follicular dendritic cells (FDCs) or by T cells that are primed by myelin antigens directly in CNS. Our findings help to elucidate the still enigmatic link between EBV infection and MS development, suggesting that myelin-reactive antibodies raised as a response toward EBV protein LMP1 are not truly cross-reactive but are primarily caused by epitope spreading.