A potent, broadly neutralizing human monoclonal antibody that efficiently protects hACE2-transgenic mice from infection with the Wuhan, BA.5, and XBB.1.5 SARS-CoV-2 variants.

The COVID-19 pandemic has uncovered the high genetic variability of the SARS-CoV-2 virus and its ability to evade the immune responses that were induced by earlier viral variants. Only a few monoclonal antibodies that have been reported to date are capable of neutralizing a broad spectrum of SARS-CoV-2 variants. Here, we report the isolation of a new broadly neutralizing human monoclonal antibody, iC1. The antibody was identified through sorting the SARS-CoV-1 RBD-stained individual B cells that were isolated from the blood of a vaccinated donor following a breakthrough infection. In vitro, iC1 potently neutralizes pseudoviruses expressing a wide range of SARS-CoV-2 Spike variants, including those of the XBB sublineage. In an hACE2-transgenic mouse model, iC1 provided effective protection against the Wuhan strain of the virus as well as the BA.5 and XBB.1.5 variants. Therefore, iC1 can be considered as a potential component of the broadly neutralizing antibody cocktails resisting the SARS-CoV-2 mutation escape.

Assessment of environmental impacts from authorized discharges of tritiated water from the Fukushima site to coastal and offshore regions.

In August 2023, the long-planned discharging of radioactive wastewater from the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) started after the confirmation of its feasibility and safety. As this water contains elevated amounts of tritium even after being diluted, a lot of resources have been invested in the monitoring of the Fukushima coastal region where the discharge outlet is located. We compare the first 3H surface activity concentrations from these measurements (up to the end of November 2023) with the available background values to evaluate a possible impact of the long-term discharging on humans and environmental levels of the radionuclide of interest in the same or nearby area. From our results, we can conclude that the joint effect of horizontal and vertical mixing has been significant enough to reduce tritium concentrations at the monitored locations in the region close to the FDNPP port two days after the end of the respective phase of the discharging beyond the detection limit of the applied analytical methods (∼0.3 Bq L-1) which is by five orders of magnitude lower than safety limit for drinking water set by the World Health Organization (WHO). Moreover, the distant correlation analysis showed that tritium concentrations at stations located further than 1.4 km were very close to pre-discharge levels (∼0.4 Bq L-1). We also estimated that the 3H activity concentration in the offshore Fukushima region would be elevated by 0.01 Bq L-1 at maximum over a year of continuous discharging, which is in concordance with the already published modeling papers and much less than the impact of the FDNPP accident in 2011.

Contributions of fossil and non-fossil fractions to total carbon in urban aerosols in Bratislava (Slovakia).

Radiocarbon measurements of total carbon (TC) fraction of aerosol samples collected at the campus of the Comenius University in Bratislava (Slovakia) during 2022-2023 were carried out. Based on radiocarbon activity of these samples and a source apportionment model we have determined the relative proportion of fossil and non-fossil carbon in collected atmospheric aerosols. The carbon from non-fossil sources (biomass burning and biogenic emissions) was dominant in this time period, on average it formed 72% of carbon present in the aerosols from the atmosphere of Bratislava. The whole range of determined non-fossil fraction was relatively small as it varied only from 0.67 (August-September) to 0.82 (December-January). These changes do not exhibit any significant seasonal variation as was previously observed in Bratislava during 2017-2018 in the elemental carbon (EC) aerosol fraction.

Relationship between Hypoxia and Hypercapnia Tolerance and Life Expectancy.

The review discusses the potential relationship between hypoxia resistance and longevity, the influence of carbon dioxide on the mechanisms of aging of the mammalian organism, and intermittent hypercapnic-hypoxic effects on the signaling pathways of aging mechanisms. In the article, we focused on the potential mechanisms of the gero-protective efficacy of carbon dioxide when combined with hypoxia. The review summarizes the possible influence of intermittent hypoxia and hypercapnia on aging processes in the nervous system. We considered the perspective variants of the application of hypercapnic-hypoxic influences for achieving active longevity and the prospects for the possibilities of developing hypercapnic-hypoxic training methods.

The last ceratosaur of Asia: a new noasaurid from the Early Cretaceous Great Siberian Refugium.

The noasaurid ceratosaur Kiyacursor longipes gen. et sp. nov. is described based on a fragmentary skeleton including cervical vertebra, pectoral girdle, humerus and hind limbs from the Lower Cretaceous (Aptian) Ilek Formation at Shestakovo 1 locality in Western Siberia, Russia. This is the first ceratosaur from the Early Cretaceous of Asia, extending the stratigraphic range of Ceratosauria by 40 Myr on that continent. Kiyacursor shares unique hind limb proportions with Elaphrosaurus and Limusaurus, suggesting improved cursorial ability. These taxa show an ostrich-like specialization of the pes, with a large third metatarsal and greatly reduced second metatarsal. By contrast, all other fast running non-avian theropod dinosaurs have an arctometatarsalian pes, with the third metatarsal strongly reduced proximally. The new taxon lived in the Early Cretaceous ecosystem containing a number of other Jurassic relics, such as stem salamanders, protosuchian and shartegosuchid crocodyliforms, tritylodontid synapsids and docodontan mammaliaforms.

Radiosensitizing effects of heparinized magnetic iron oxide nanoparticles in colon cancer.

The combination of radiation treatment and chemotherapy is currently the standard for management of cancer patients. However, safe doses do not often provide effective therapy, then pre-treated patients are forced to repeat treatment with often already increased tumor resistance to drugs and irradiation. One of the solutions we suggest is to improve primary course of radiation treatment via enhancing radiosensitivity of tumors by magnetic-guided iron oxide nanoparticles (magnetite). We obtained spherical heparinized iron oxide nanoparticles (hIONPs, ∼20 nm), characterized it by TEM, Infrared spectroscopy and DLS. Then hIONPs cytotoxicity was assessed for colon cancer cells (XTT assay) and cellular uptake of nanoparticles was analyzed with X-ray fluorescence. Combination of ionizing radiation (IR) and hIONPs in vitro caused an increase of G2/M arrest of cell cycle, mitotic errors and decrease in survival (compared with samples exposed to IR and hIONPs separately). The promising results were shown for magnetic-guided hIONPs in CT26-grafted BALB/C mice: the combination of intravenously administrated hIONPs and IR showed 20,8% T/C ratio (related to non-treated mice), while single radiation had no shown significant decrease in tumor growth (72,4%). Non-guided by magnets hIONPs with IR showed 57,9% of T/C. This indicates that ultra-small size and biocompatible molecule are not the key to successful nano-drug design, in each case, delivery technologies need to be improved when transferred to in vivo model.

Reliability Study of Metal-Oxide Semiconductors in Integrated Circuits.

This paper is devoted to the study of CMOS IC parameter degradation during reliability testing. The paper presents a review of literature data on the issue of the reliability of semiconductor devices and integrated circuits and the types of failures leading to the degradation of IC parameters. It describes the tests carried out on the reliability of controlled parameters of integrated circuit TPS54332, such as quiescent current, quiescent current in standby mode, resistance of the open key, and instability of the set output voltage in the whole range of input voltages and in the whole range of load currents. The calculated values of activation energies and acceleration coefficients for different test temperature regimes are given. As a result of the work done, sample rejection tests have been carried out on the TPS54332 IC under study. Experimental fail-safe tests were carried out, with subsequent analysis of the chip samples by the controlled parameter quiescent current. On the basis of the obtained experimental values, the values of activation energy and acceleration coefficient at different temperature regimes were calculated. The dependencies of activation energy and acceleration coefficient on temperature were plotted, which show that activation energy linearly increases with increasing temperature, while the acceleration coefficient, on the contrary, decreases. It was also found that the value of the calculated activation energy of the chip is 0.1 eV less than the standard value of the activation energy.

Hypercapnic hypoxia as a rehabilitation method for patients after ischemic stroke.

INTRODUCTION: Experimental studies on animals have demonstrated a higher neuroprotective efficacy of hypercapnic hypoxia compared to normocapnic hypoxia. Respiratory training with hypercapnic hypoxia has shown a positive impact on the functional state of the nervous system in children with cerebral palsy (CP). It can be presumed that the combined effect of moderate hypercapnia and hypoxia will be promising for clinical application within the context of early rehabilitation after ischemic stroke. METHODS: A randomized triple-blind placebo-controlled study was conducted on 102 patients with ischemic stroke, aged 63.07 ± 12.1 years. All patients were diagnosed with ischemic stroke based on neuroimaging criteria and/or clinical criteria within the 48-72 hour timeframe. The experimental group (n = 50) underwent daily respiratory training with hypercapnic hypoxia (FetCO2 5-6%, FetO2 15-16%) using the 'Carbonic' device for 7-11 sessions of 20 minutes each day during the treatment process. The control group (placebo, n = 52) underwent training on a similar device modified for breathing atmospheric air. Neurological examinations were conducted on all patients before the study and on the day after completing the training course. RESULTS: The standard treatment demonstrated effectiveness in terms of neurological status scales in both groups. Intermittent exposure to hypercapnic hypoxia proved more effective in improving neurological function indicators in patients compared to the placebo group: NIHSS scale scores were 40% lower than in the placebo group (p < 0.001); mRS scale scores were 35% lower (p < 0.001); B-ADL-I and RMI indices were higher by 26% (p < 0.01) and 36% (p < 0.001), respectively; MoCA scale results were 13% higher (p < 0.05); HADS and BDI-II scale scores were lower by 35% (p < 0.05) and 25% (p < 0.05), respectively. The increase in MMSE scale scores in the intervention group was 54% higher (p < 0.001), and MoCA scale scores increased by 25% (p < 0.001). CONCLUSION: Respiratory training with hypercapnic hypoxia improves the functional state of the nervous system in patients with ischemic stroke. After conducting further clarifying studies, hypercapnic hypoxia can be considered as an effective method of neurorehabilitation, which can be used as early as 48-72 hours after the onset of stroke.

Molecular Mechanisms of Neuroprotection after the Intermittent Exposures of Hypercapnic Hypoxia.

The review introduces the stages of formation and experimental confirmation of the hypothesis regarding the mutual potentiation of neuroprotective effects of hypoxia and hypercapnia during their combined influence (hypercapnic hypoxia). The main focus is on the mechanisms and signaling pathways involved in the formation of ischemic tolerance in the brain during intermittent hypercapnic hypoxia. Importantly, the combined effect of hypoxia and hypercapnia exerts a more pronounced neuroprotective effect compared to their separate application. Some signaling systems are associated with the predominance of the hypoxic stimulus (HIF-1α, A1 receptors), while others (NF-κB, antioxidant activity, inhibition of apoptosis, maintenance of selective blood-brain barrier permeability) are mainly modulated by hypercapnia. Most of the molecular and cellular mechanisms involved in the formation of brain tolerance to ischemia are due to the contribution of both excess carbon dioxide and oxygen deficiency (ATP-dependent potassium channels, chaperones, endoplasmic reticulum stress, mitochondrial metabolism reprogramming). Overall, experimental studies indicate the dominance of hypercapnia in the neuroprotective effect of its combined action with hypoxia. Recent clinical studies have demonstrated the effectiveness of hypercapnic-hypoxic training in the treatment of childhood cerebral palsy and diabetic polyneuropathy in children. Combining hypercapnic hypoxia with pharmacological modulators of neuro/cardio/cytoprotection signaling pathways is likely to be promising for translating experimental research into clinical medicine.

Application of the intramolecular Diels-Alder vinylarene (IMDAV) reaction for the synthesis of benzo-, carbocyclo-, thienothiopheneisoindolecarboxylic acids and its limitations.

Thienylallylamines, readily accessible from the corresponding thienyl aldehydes, react with maleic and trifluoromethylmaleic anhydrides leading to the formation of acids with a thieno[2,3-f]isoindole core. The reaction sequence involves two successive steps: acylation of the nitrogen atom of the initial allylamine and the intramolecular Diels-Alder vinylarene (IMDAV) reaction. The scope and limitations of the proposed method were thoroughly investigated. It has been revealed with the aid of X-ray analysis and DFT calculations that the key step, the IMDAV reaction, proceeds through an exo-transition state, giving rise to the exclusive formation of a single diastereomer of the target heterocycle. The obtained functionally substituted thieno[2,3-f]isoindole carboxylic acids are potentially useful substrates for further transformations and bioscreening. The antimicrobial evaluation of the obtained compounds revealed that 1-oxo-2-(3-(trifluoromethyl)phenyl)hexahydrobenzo[4,5]thieno[2,3-f]isoindole-10-carboxylic acid is the most active sample in the synthesized library. It exhibits antibacterial activity against sensitive strains of Gram-positive bacteria, including S. aureus, Enterococcus faecium, Bacillus cereus, and Micrococcus luteus, as well as the Gram-negative bacteria E. coli and Pseudomonas fluorescens, with MIC values ranging from 4 to 64 µg mL-1. 9-Oxo-8-phenyloctahydronaphtho[2,1-d]thieno[2,3-f]isoindole-10-carboxylic acid showed antifungal activity against yeast culture C. albicans with a MIC value of 32 µM.

Assessment of the effects of amphiphilic poly (N­vinylpyrrolidone) nanoparticles loaded with bortezomib on glioblastoma cell lines and zebrafish embryos.

Proteasome inhibitor bortezomib is an anticancer agent approved for treatment of multiple myeloma and mantle cell lymphoma. However, its application in other types of cancer, primarily in solid tumors, is limited due to poor pharmacokinetics, inefficient tissue penetration, low stability and frequent adverse effects. In the present study, a novel micellar nano-scaled delivery system was manufactured, composed of amphiphilic poly(N-vinylpyrrolidone) nanoparticles loaded with bortezomib. Similar nanoparticles loaded with prothionamide, a drug without anticancer effect, were used as control. The size and zeta potential of the obtained polymeric micelles were measured by dynamic light scattering. Bortezomib-loaded micelles exhibited significant cytotoxic activity in vitro in monolayer tumor cell cultures (IC50 ~6.5 µg/ml) and in 3D multicellular tumor spheroids (IC50 ~8.5 µg/ml) of human glioblastoma cell lines U87 and T98G. Additionally, the toxic effects in vivo were studied in zebrafish Danio rerio embryos, with an estimated 50% lethal concentration of 0.1 mg/ml. Considering that bortezomib and other molecules from the class of proteasome inhibitors are potent antitumor agents, nanodelivery approach can help reduce adverse effects and expand the range of its applications for treatment of various oncological diseases.

Serial Llama Immunization with Various SARS-CoV-2 RBD Variants Induces Broad Spectrum Virus-Neutralizing Nanobodies.

The emergence of SARS-CoV-2 mutant variants has posed a significant challenge to both the prevention and treatment of COVID-19 with anti-coronaviral neutralizing antibodies. The latest viral variants demonstrate pronounced resistance to the vast majority of human monoclonal antibodies raised against the ancestral Wuhan variant. Less is known about the susceptibility of the evolved virus to camelid nanobodies developed at the start of the pandemic. In this study, we compared nanobody repertoires raised in the same llama after immunization with Wuhan's RBD variant and after subsequent serial immunization with a variety of RBD variants, including that of SARS-CoV-1. We show that initial immunization induced highly potent nanobodies, which efficiently protected Syrian hamsters from infection with the ancestral Wuhan virus. These nanobodies, however, mostly lacked the activity against SARS-CoV-2 omicron-pseudotyped viruses. In contrast, serial immunization with different RBD variants resulted in the generation of nanobodies demonstrating a higher degree of somatic mutagenesis and a broad range of neutralization. Four nanobodies recognizing distinct epitopes were shown to potently neutralize a spectrum of omicron variants, including those of the XBB sublineage. Our data show that nanobodies broadly neutralizing SARS-CoV-2 variants may be readily induced by a serial variant RBD immunization.

Synthesis of Zinc Nanoparticles by the Gas Condensation Method in a Non-Contact Crucible and Their Physical-Chemical Characterization.

This work explored the zinc nanoparticles obtained by the one-stage induction flow levitation method. A 10 kW tube generator with an operating frequency of 440 kHz was used. The process used 8 mm diameter zinc granules (2 g weight) with a purity of 99.9%. Zinc wire was fed to replace the evaporated metal from the granule surface. This method productivity was 30 g/h of nanoparticles. In addition, various methods were used to characterize the resulting nanoparticles: scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-Ray fluorescence analysis (XRF), dynamic light scattering (DLS), porosimetry and inductively coupled plasma atomic emission spectroscopy (ICP-MS). The resulting nanoparticle size, determined by SEM and porosimetry, was 350 nm, while the size of the primary crystallites was 21 nm. The amount of impurities in the resulting nanoparticles did not exceed 1000 ppm.

NIAGADS Alzheimer's GenomicsDB: A resource for exploring Alzheimer's disease genetic and genomic knowledge.

INTRODUCTION: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site Alzheimer's Genomics Database (GenomicsDB) is a public knowledge base of Alzheimer's disease (AD) genetic datasets and genomic annotations. METHODS: GenomicsDB uses a custom systems architecture to adopt and enforce rigorous standards that facilitate harmonization of AD-relevant genome-wide association study summary statistics datasets with functional annotations, including over 230 million annotated variants from the AD Sequencing Project. RESULTS: GenomicsDB generates interactive reports compiled from the harmonized datasets and annotations. These reports contextualize AD-risk associations in a broader functional genomic setting and summarize them in the context of functionally annotated genes and variants. DISCUSSION: Created to make AD-genetics knowledge more accessible to AD researchers, the GenomicsDB is designed to guide users unfamiliar with genetic data in not only exploring but also interpreting this ever-growing volume of data. Scalable and interoperable with other genomics resources using data technology standards, the GenomicsDB can serve as a central hub for research and data analysis on AD and related dementias. HIGHLIGHTS: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) offers to the public a unique, disease-centric collection of AD-relevant GWAS summary statistics datasets. Interpreting these data is challenging and requires significant bioinformatics expertise to standardize datasets and harmonize them with functional annotations on genome-wide scales. The NIAGADS Alzheimer's GenomicsDB helps overcome these challenges by providing a user-friendly public knowledge base for AD-relevant genetics that shares harmonized, annotated summary statistics datasets from the NIAGADS repository in an interpretable, easily searchable format.

Temporal changes of 137Cs concentrations in the Far Eastern Seas: partitioning of 137Cs between overlying waters and sediments.

Deep-ocean sediments, similarly to seawater, are important reservoirs of 137Cs, an anthropogenic radionuclide with a relatively long half-live found in the Earth system. To better understand the geochemical behaviour of 137Cs in the ocean, we examined the temporal changes of 137Cs activity concentrations in the overlying waters and in sediments from the Far Eastern Seas (Sea of Japan, SOJ, and Okhotsk Sea, OS) during the period of 1998-2021. The 137Cs activity levels showed exponential changes during the observed period. The decay-corrected change rates of 137Cs in deep waters of SOJ exhibited a slow increase, while 137Cs levels in seawater and sediment in OS decreased gradually. This reflects a topographical difference, as SOJ is a semi-closed sea, whereas OS receives continuously inflow of subarctic waters. It was confirmed that 137Cs released after the Fukushima Dai-ichi Nuclear Power Plant accident was rapidly transported into the deep waters of the SOJ. To elucidate the transfer processes of 137Cs from seawater to sediment, we discussed the temporal changes of the partition coefficients (Kd) of 137Cs between the overlying water and the surface sediment. In shallow areas (< 1500 m water depth), Kd values were almost constant within the sampling periods, although the temporal changes in the Kd values occurred in deeper waters (> 2500 m depth). The Kd values increased with increasing depth, which may reflect a pressure effect as a possible mechanism. These findings suggest that chemical processes may be important factors controlling the transport of 137Cs between seawater and sediment, although more complicated phenomena occurred in deep waters and sediments of the SOJ (> 3000 m depth).

hipFG: high-throughput harmonization and integration pipeline for functional genomics data.

SUMMARY: Preparing functional genomic (FG) data with diverse assay types and file formats for integration into analysis workflows that interpret genome-wide association and other studies is a significant and time-consuming challenge. Here we introduce hipFG (Harmonization and Integration Pipeline for Functional Genomics), an automatically customized pipeline for efficient and scalable normalization of heterogenous FG data collections into standardized, indexed, rapidly searchable analysis-ready datasets while accounting for FG datatypes (e.g. chromatin interactions, genomic intervals, quantitative trait loci). AVAILABILITY AND IMPLEMENTATION: hipFG is freely available at https://bitbucket.org/wanglab-upenn/hipFG. A Docker container is available at https://hub.docker.com/r/wanglab/hipfg.

Novel Approaches to the Establishment of Local Microenvironment from Resorbable Biomaterials in the Brain In Vitro Models.

The development of brain in vitro models requires the application of novel biocompatible materials and biopolymers as scaffolds for controllable and effective cell growth and functioning. The "ideal" brain in vitro model should demonstrate the principal features of brain plasticity like synaptic transmission and remodeling, neurogenesis and angiogenesis, and changes in the metabolism associated with the establishment of new intercellular connections. Therefore, the extracellular scaffolds that are helpful in the establishment and maintenance of local microenvironments supporting brain plasticity mechanisms are of critical importance. In this review, we will focus on some carbohydrate metabolites-lactate, pyruvate, oxaloacetate, malate-that greatly contribute to the regulation of cell-to-cell communications and metabolic plasticity of brain cells and on some resorbable biopolymers that may reproduce the local microenvironment enriched in particular cell metabolites.

The Role of microRNAs in Epigenetic Regulation of Signaling Pathways in Neurological Pathologies.

In recent times, there has been a significant increase in researchers' interest in the functions of microRNAs and the role of these molecules in the pathogenesis of many multifactorial diseases. This is related to the diagnostic and prognostic potential of microRNA expression levels as well as the prospects of using it in personalized targeted therapy. This review of the literature analyzes existing scientific data on the involvement of microRNAs in the molecular and cellular mechanisms underlying the development of pathologies such as Alzheimer's disease, cerebral ischemia and reperfusion injury, and dysfunction of the blood-brain barrier.

On the way from Asia to America: eutriconodontan mammals from the Early Cretaceous of Yakutia, Russia.

Eutriconodonta are an important group of early crown mammals with a wide distribution in the Jurassic-Cretaceous of the Northern Hemisphere and few occurrences in the Southern Hemisphere. Three taxa of eutriconodontans are known from the Early Cretaceous high-latitude Teete vertebrate assemblage in Yakutia, Russia: Sangarotherium aquilonium (Eutriconodonta incertae sedis), Gobiconodon sp. A (large), and Gobiconodon sp. B (small) (Gobiconodontidae). These three taxa are based on four specimens and indicate a remarkable taxonomic diversity of eutriconodontans at this locality. The coexistence of two Gobiconodon species, large and small, is characteristic for several Early Cretaceous vertebrate assemblages in Asia. Gobiconodon sp. A from the Teete locality is the largest species of this genus known from Asia, but is smaller than the North American G. ostromi. The spreading of Gobiconodon from Asia to North America likely occurred during the Aptian-Albian faunal dispersal event. The discovery of Gobiconodon in the Teete locality is further evidence for a dispersal route via Beringia from Asia to North America which previously has been postulated based on the occurrence of Asian dinosaur taxa in western North America at this time. The questionable record of Gobiconodon from Europe and its lack from eastern North America make a dispersal from Asia to North America via Europe less probable.

Roving methyltransferases generate a mosaic epigenetic landscape and influence evolution in Bacteroides fragilis group.

Three types of DNA methyl modifications have been detected in bacterial genomes, and mechanistic studies have demonstrated roles for DNA methylation in physiological functions ranging from phage defense to transcriptional control of virulence and host-pathogen interactions. Despite the ubiquity of methyltransferases and the immense variety of possible methylation patterns, epigenomic diversity remains unexplored for most bacterial species. Members of the Bacteroides fragilis group (BFG) reside in the human gastrointestinal tract as key players in symbiotic communities but also can establish anaerobic infections that are increasingly multi-drug resistant. In this work, we utilize long-read sequencing technologies to perform pangenomic (n = 383) and panepigenomic (n = 268) analysis of clinical BFG isolates cultured from infections seen at the NIH Clinical Center over four decades. Our analysis reveals that single BFG species harbor hundreds of DNA methylation motifs, with most individual motif combinations occurring uniquely in single isolates, implying immense unsampled methylation diversity within BFG epigenomes. Mining of BFG genomes identified more than 6000 methyltransferase genes, approximately 1000 of which were associated with intact prophages. Network analysis revealed substantial gene flow among disparate phage genomes, implying a role for genetic exchange between BFG phages as one of the ultimate sources driving BFG epigenome diversity.