Neuroimmune transcriptome changes in patient brains of psychiatric and neurological disorders.

Neuroinflammation has been implicated in multiple brain disorders but the extent and the magnitude of change in immune-related genes (IRGs) across distinct brain disorders has not been directly compared. In this study, 1275 IRGs were curated and their expression changes investigated in 2467 postmortem brains of controls and patients with six major brain disorders, including schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD). There were 865 IRGs present across all microarray and RNA-seq datasets. More than 60% of the IRGs had significantly altered expression in at least one of the six disorders. The differentially expressed immune-related genes (dIRGs) shared across disorders were mainly related to innate immunity. Moreover, sex, tissue, and putative cell type were systematically evaluated for immune alterations in different neuropsychiatric disorders. Co-expression networks revealed that transcripts of the neuroimmune systems interacted with neuronal-systems, both of which contribute to the pathology of brain disorders. However, only a few genes with expression changes were also identified as containing risk variants in genome-wide association studies. The transcriptome alterations at gene and network levels may clarify the immune-related pathophysiology and help to better define neuropsychiatric and neurological disorders.

Fabrication of Ni-Polyaniline/Graphene Oxide Composite Electrode with High Capacitance and Water Splitting Activity.

The Ni-PANI@GO composite electrode was fabricated via cost effective electrodeposition technique. According to the XRD, FTIR, Raman, SEM, and XPS analyses revealed that the nickel doped PANI@GO composite has been fabricated on the surface of the nickel foam. Addition of nickel significantly enhanced interaction between graphene with PANI leading to higher degree of polyaniline doping though imine groups. Electrochemical investigation revelated the significant performance of the Ni-PANI@GO composite electrode, boosting an impressive capacitance of 4480 F/g at 40 A/g, surpassing previous Ni-foam-based binder-free electrodes. Notably, Ni-PANI@GO electrode displayed excellent catalytic activity in both oxygen evolution reaction (OER) and hydrogen evolution reaction (HER), generating a considerable volume of the gas bubbles at relatively modest overpotentials of 279 mV and 244 mV respectively. This event allows for the achievement of 20 mA cm-2 current density. Furthermore, in the laboratory-scale water electrolyzer, a low cell voltage of 1.72 V was achieved, facilitating a water-splitting current density of 20 mA cm-2. This study underscores the premising potential for the real-world device's application of the versatile Ni-PANI@GO composite electrode.

Anatomical and morphological changes in Pinus sylvestris and Larix sibirica needles under impact of emissions from a large aluminum enterprise.

Species-specific anatomical and morphological characteristics of Pinus sylvestris and Larix sibirica needles were studied at different levels of tree stand pollution by aluminum smelter emissions. The anatomical characteristics of the needle were studied using light microscopy. The level of tree stand pollution was determined using the cluster analysis outcomes of the pollutant elements content (fluorine, sulfur, and heavy metals) in the needles. Four levels of tree stand pollution were separated: low, moderate, high, and critical, as well as background tree stand in unpolluted areas. It was found that the state of tree phytomass deteriorated with increasing levels of pollution (from low to critical): pine crown defoliation increased to 85%, and larch defoliation increased to 65%. The life span of pine needles was reduced to 2-3 years, with a background value of 6-7 years. The change of morphological parameters was more pronounced in P. sylvestris: the weight and length of the 2-year-old shoot decreased by 2.7-3.1 times compared to the background values; the weight of needles on the shoot and the number of needle pairs on the shoot-by 1.9-2.1 times. The length of the needle and shoot and the number of L. sibirica brachyblasts decreased by 1.8-1.9 times. The anatomical parameters of the needle also changed to a greater extent in P. sylvestris. Up to the high level of tree pollution, we observed a decrease in the cross-sectional area of the needle, central cylinder, vascular bundle, area and thickness of mesophyll, number and diameter of resin ducts by 18-66% compared to background values. At the critical pollution level, when the content of pollutant elements in pine needles reached maximum values, the anatomical parameters of the remaining few green needles were close to background values. In our opinion, this may be due to the activation of mechanisms aimed at maintaining the viability of trees. A reduction in thickness and area of assimilation tissue in the L. sibirica needle was detected only at the critical pollution level. An upward trend in these parameters was found at low, medium, and high pollution levels of tree stand, which may indicate an adaptive nature. The results suggested that at a similar pollution level of trees, the greatest amount of negative anatomical and morphological changes were recorded in pine needles, which indicates a greater sensitivity of this species to technogenic emissions.

Collagen IVα345 dysfunction in glomerular basement membrane diseases. III. A functional framework for α345 hexamer assembly.

We identified a genetic variant, an 8-residue appendage, of the α345 hexamer of collagen IV present in patients with glomerular basement membrane diseases, Goodpasture's disease and Alport syndrome, and determined the long-awaited crystal structure of the hexamer. We sought to elucidate how variants cause glomerular basement membrane disease by exploring the mechanism of the hexamer assembly. Chloride ions induced in vitro hexamer assembly in a composition-specific manner in the presence of equimolar concentrations of α3, α4, and α5 NC1 monomers. Chloride ions, together with sulfilimine crosslinks, stabilized the assembled hexamer. Furthermore, the chloride ion-dependent assembly revealed the conformational plasticity of the loop-crevice-loop bioactive sites, a critical property underlying bioactivity and pathogenesis. We explored the native mechanism by expressing recombinant α345 miniprotomers in the cell culture and characterizing the expressed proteins. Our findings revealed NC1-directed trimerization, forming protomers inside the cell; hexamerization, forming scaffolds outside the cell; and a Cl gradient-signaled hexamerization. This assembly detail, along with a crystal structure, provides a framework for understanding hexamer dysfunction. Restoration of the native conformation of bioactive sites and α345 hexamer replacement are prospective approaches to therapeutic intervention.

Activity of low-molecular weight components of Larix sibirica antioxidant system under exposure to technogenic pollution.

Changes in the antioxidant protection system of Larix sibirica Ledeb at different pollution levels caused by emissions from a large aluminum smelter (BrAS) have been studied. We revealed that the content of peroxide (H2O2) in the needles is a reliable marker of oxidative stress in the trees under pollution. The crucial role of non-enzymatic components, in particular, proline, phenolic compounds, ascorbic acid, glutathione, in reducing the level of free radicals in the needles cells was found. Proline concentration in the needles significantly rises with the increase in pollution levels from low to high. Under critical level pollution, it decreases by 40% compared to the background. The total content of ascorbic acid (ASC) in the needles of polluted trees varies slightly; however, there are significant changes in its various forms. With an increase in pollution to a high level, the content of the reduced form of ASC in the needles increases by 1.5-2.9 times compared to the background content. At a critical level of pollution, the total level of ascorbic acid and its reduced form falls, the content of the oxidized form reaches minimum values. The total content of phenolic compounds in the needles increased by 50-55%, concentration of flavonoids by 1.5-1.8 times, catechins by 1.9-2.5 times, proanthocyanidins by 45% compared to the background level under low, moderate, high pollution, whereas under critical pollution their content decreased. The absolute concentration of the reduced form glutathione in the needles falls by 1.9-3.0 times, the oxidized form increases by 1.5-2.0 times compared to the background. The ratio of reduced glutathione to oxidized glutathione decreased, especially during critical pollution. The data obtained show significant activation of Siberian larch biochemical protection at low, moderate and high levels of pollution by the aluminum smelter emissions. At a critical levels of contamination, a significant depletion of the pool of low-molecular antioxidants was observed.

Comparison of the Safety, Efficacy, and Procedural Characteristics Associated with Proximal and Distal Radial Access for Diagnostic Cerebral Angiography.

OBJECTIVES: Radial access is an increasingly popular approach for performing cerebral angiography. There are two sites for radial artery puncture: proximal transradial access (pTRA) in the wrist and distal transradial access (dTRA) in the snuffbox. These approaches have not been directly compared. MATERIALS AND METHODS: Consecutive diagnostic cerebral angiograms performed at a single institution were retrospectively reviewed. Outcomes included fluoroscopy time, radiation dose, contrast volume, time to obtain access, procedure duration, and time to discharge home. Success rates as well as minor and major complication rates associated with each approach were also compared. Multivariate linear regression models were used to determine the relationship between access site and outcomes while adjusting for covariates. RESULTS: A total of 287 angiograms on 244 patients met the inclusion criteria. pTRA was associated with shorter fluoroscopy time (ß -2.54, 95% CI -4.18 - -0.9, p = 0.003) and lower radiation dose (ß -242.89, 95% CI -351.55 - -134.24, p < 0.001), but not contrast volume. Time to obtain access, procedure duration, and time to discharge home were similar between approaches. A total of 10 minor complications occurred with similar rates for each approach (8 for dTRA, 2 for pTRA, p = 0.168) and there were no major complications. The conversion rate to femoral access was low (1.05% overall) and did not differ with approach. CONCLUSION: dTRA and pTRA are associated with similarly high rates of safety and efficacy. Procedure duration, time to obtain access, and time to discharge did not differ between approaches.

Src family kinases, adaptor proteins and the actin cytoskeleton in epithelial-to-mesenchymal transition.

Over a century of scientific inquiry since the discovery of v-SRC but still no final judgement on SRC function. However, a significant body of work has defined Src family kinases as key players in tumor progression, invasion and metastasis in human cancer. With the ever-growing evidence supporting the role of epithelial-mesenchymal transition (EMT) in invasion and metastasis, so does our understanding of the role SFKs play in mediating these processes. Here we describe some key mechanisms through which Src family kinases play critical role in epithelial homeostasis and how their function is essential for the propagation of invasive signals. Video abstract.

Changes in the fatty acid composition of pine needle lipids under the aluminum smelter emissions.

Changes in the fatty acid (FA) composition of total lipids of Pinus sylvestris needles at different pollution levels caused by emissions from a large aluminum smelter (BrAS) have been studied. In the needles of trees from unpolluted (background) territories, the FA spectrum is represented by 24 acids with prevalence of unsaturated FAs (71.6%). The main unsaturated FA are represented by oleic (C18: 1ω9), linoleic (C18: 2ω6), and α-linolenic (C18: 3ω3) acids. Under the influence of BrAS emissions, the total amount of identified FAs in the needles and the proportion of unsaturated FAs decrease, while the fraction of saturated FAs, on the contrary, increases from 25.4% in unpolluted needles to 33.2% in polluted ones. The content of palmitic FA (C16:0) in the needles exceeds background values by 1.5 times, behenic acid (C22:0) - by 1.6-2.5 times, arachidic acid (C20:0) - by 1.5 times, palmitic margaric acid (C17:0) - by 1.5-2.3 times. These FAs play the important role in the protection of plant membranes from the effects of abiotic stress factors, making them less permeable. The sum of short-chain saturated FAs (C12:0, C14:0, C15:0) increase by 4.8 times in needles of trees that are highly polluted. Pentadecanoic (C15:0) acid is found in the needles only in the background areas and at the low pollution level. With a more severe pollution, C15:0 is not identified, but lauric acid with the cis-configuration of double bonds in the structure (izo-C12:0) appears. The presence of "relict" ∆5-polymethylene FAs in the composition of pine needle membrane lipids is determined. In the background areas, they account for 12.9% of the total FAs. With the industrial pollution intensification, their total content increases and reaches 14.1%. ∆5-polymethylene FAs are also able to protect membranes against negative influences. Thus, changes in the quantitative and qualitative FA composition of pine needle total lipids indicate the activation of the stabilization mechanisms of membrane lipids due to their tight packing in a bilayer. It is one of the adaptive reactions of Pinus sylvestris in response to the impact of the aluminum industry emissions.

Reassigning stop codons via translation termination: How a few eukaryotes broke the dogma.

The genetic code determines how amino acids are encoded within mRNA. It is universal among the vast majority of organisms, although several exceptions are known. Variant genetic codes are found in ciliates, mitochondria, and numerous other organisms. All revealed genetic codes (standard and variant) have at least one codon encoding a translation stop signal. However, recently two new genetic codes with a reassignment of all three stop codons were revealed in studies examining the protozoa transcriptomes. Here, we discuss this finding and the recent studies of variant genetic codes in eukaryotes. We consider the possible molecular mechanisms allowing the use of certain codons as sense and stop signals simultaneously. The results obtained by studying these amazing organisms represent a new and exciting insight into the mechanism of stop codon decoding in eukaryotes. Also see the video abstract here.

RNA helicase DDX19 stabilizes ribosomal elongation and termination complexes.

The human DEAD-box RNA-helicase DDX19 functions in mRNA export through the nuclear pore complex. The yeast homolog of this protein, Dbp5, has been reported to participate in translation termination. Using a reconstituted mammalian in vitro translation system, we show that the human protein DDX19 is also important for translation termination. It is associated with the fraction of translating ribosomes. We show that DDX19 interacts with pre-termination complexes (preTCs) in a nucleotide-dependent manner. Furthermore, DDX19 increases the efficiency of termination complex (TC) formation and the peptide release in the presence of eukaryotic release factors. Using the eRF1(AGQ) mutant protein or a non-hydrolysable analog of GTP to inhibit subsequent peptidyl-tRNA hydrolysis, we reveal that the activation of translation termination by DDX19 occurs during the stop codon recognition. This activation is a result of DDX19 binding to preTC and a concomitant stabilization of terminating ribosomes. Moreover, we show that DDX19 stabilizes ribosome complexes with translation elongation factors eEF1 and eEF2. Taken together, our findings reveal that the human RNA helicase DDX19 actively participates in protein biosynthesis.

Stabilization of eukaryotic ribosomal termination complexes by deacylated tRNA.

Stabilization of the ribosomal complexes plays an important role in translational control. Mechanisms of ribosome stabilization have been studied in detail for initiation and elongation of eukaryotic translation, but almost nothing is known about stabilization of eukaryotic termination ribosomal complexes. Here, we present one of the mechanisms of fine-tuning of the translation termination process in eukaryotes. We show that certain deacylated tRNAs, remaining in the E site of the ribosome at the end of the elongation cycle, increase the stability of the termination and posttermination complexes. Moreover, only the part of eRF1 recognizing the stop codon is stabilized in the A site of the ribosome, and the stabilization is not dependent on the hydrolysis of peptidyl-tRNA. The determinants, defining this property of the tRNA, reside in the acceptor stem. It was demonstrated by site-directed mutagenesis of tRNA(Val) and construction of a mini-helix structure identical to the acceptor stem of tRNA. The mechanism of this stabilization is different from the fixation of the unrotated state of the ribosome by CCA end of tRNA or by cycloheximide in the E site. Our data allow to reveal the possible functions of the isodecoder tRNAs in eukaryotes.

Antioxidant, anti-inflammatory and epigenetic potential of curcumin in Alzheimer's disease.

Alzheimer's disease (AD) constitutes a multifactorial neurodegenerative pathology characterized by cognitive deterioration, personality alterations, and behavioral shifts. The ongoing brain impairment process poses significant challenges for therapeutic interventions due to activating multiple neurotoxic pathways. Current pharmacological interventions have shown limited efficacy and are associated with significant side effects. Approaches focusing on the early interference with disease pathways, before activation of broad neurotoxic processes, could be promising to slow down symptomatic progression of the disease. Curcumin-an integral component of traditional medicine in numerous cultures worldwide-has garnered interest as a promising AD treatment. Current research indicates that curcumin may exhibit therapeutic potential in neurodegenerative pathologies, attributed to its potent anti-inflammatory and antioxidant properties. Additionally, curcumin and its derivatives have demonstrated an ability to modulate cellular pathways via epigenetic mechanisms. This article aims to raise awareness of the neuroprotective properties of curcuminoids that could provide therapeutic benefits in AD. The paper provides a comprehensive overview of the neuroprotective efficacy of curcumin against signaling pathways that could be involved in AD and summarizes recent evidence of the biological efficiency of curcumins in vivo.

Diversity and negative effect of PM0.3-10.0 adsorbed by needles of urban trees in Irkutsk, Russia.

The study was performed in natural forests preserved within the Boreal zone city, Irkutsk, Russia. Test sites were selected in the forests in different districts of the city, where samples of Scots pine (Pinus sylvestris L.) and Siberian larch (Larix sibirica Ledeb.) needles were taken to study the adsorption on their surface of aerosol particles of different sizes, in microns: PM0.3, PM0.5, PM1, PM2.5, PM5, PM10. Scanning electron microscopy was used to obtain high-resolution photographs (magnification 800- × 2000, × 16,000) and aerosol particles (particulate matter-PM) were shown to be intensively adsorbed by the surface of needles, with both size and shape of the particles characterized by a wide variety. Pine needles can be covered with particles of solid aerosol by 50-75%, stomata are often completely blocked. Larch needles often show areas, which are completely covered with aerosol particles, there are often found stomata deformed by the penetration of PMx. X-ray spectral microanalysis showed differences in the chemical composition of adsorbed PMx, the particles can be metallic if metals predominate in their composition, carbonaceous-in case of carbon predominance-or polyelemental if the composition is complex and includes significant quantities of other elements besides metals and carbon (calcium, magnesium, potassium, sodium, sulfur, chlorine, fluorine). Since the particles contain a large proportion of technogenic pollutants, accumulation by the needles of some widespread pollutants was investigated. A direct correlation of a highly significant level between the concentration of PMx in the air and the accumulation of many heavy metals in pine and larch needles, as well as sulfur, fluorine, and chlorine, has been revealed, which indicates a high cleaning capacity of urban forests. At the same time, the negative impact of PMx particles on the vital status of trees is great, which shows in intense disturbance of the parameters of photosynthesis and transpiration, leading to a significant decrease in the growth characteristics of trees and reduction in the photosynthetic volume of the crowns. We consider that the results obtained are instrumental in developing an approach to improvement of urban forests status and creating a comfortable urban environment for the population.

Outcomes After Endovascular Treatment of Direct Carotid Cavernous Fistulas: Systematic Review and Meta-Analysis.

BACKGROUND: Direct carotid cavernous fistulas (dCCF) involve pathologic shunting from the internal carotid artery into the cavernous sinus. We systematically reviewed the methods and outcomes of endovascular therapy for dCCF. METHODS: PubMed, Scopus, and EMBASE were used to identify studies that reported outcomes for patients undergoing embolization of dCCF. Outcomes included rates of occlusion, complications, symptom improvement, and recurrence. Pooled rates for each outcome were obtained with random effects models. The influence of embolization method on outcomes was assessed with meta-regressions. RESULTS: There were 16 studies comprising 270 patients. The mean age was 39.6 years, there were 36.3% females, and the mean follow-up was 19.7 months. Coils were the most common method of embolization (69.3%), followed by Onyx (31.1%), covered stent (22.2%), N-butyl cyanoacrylate (6.7%), and flow diversion (4.8%). The pooled overall occlusion rate was 92.1% (95% confidence interval [CI], 86.3-95.6; I2 = 29.2%). The pooled complication rate was 10.9% (95% CI, 7.3-16; I2 = 0%). Use of coils were associated with a slightly lower odds of overall complications (odds ratio, 0.98; 95% CI, 0.97-0.99) and cranial nerve palsy (odds ratio, 0.98; 95% CI, 0.97-0.99). The pooled fistula recurrence rate was 8.3% (95% CI, 4.3-15.4; I2 = 30.9%). CONCLUSIONS: Endovascular therapy for dCCF is associated with high occlusion and low complication rates. Recurrence is not uncommon, highlighting the need for close follow-up.

Circadian rhythm in systemic autoimmune conditions: Potential of chrono-immunology in clinical practice: A narrative review.

The circadian rhythm (CR) is a fundamental biological process regulated by the Earth's rotation and solar cycles. It plays a critical role in various bodily functions, and its dysregulation can have systemic effects. These effects impact metabolism, redox homeostasis, cell cycle regulation, gut microbiota, cognition, and immune response. Immune mediators, cycle proteins, and hormones exhibit circadian oscillations, supporting optimal immune function and defence against pathogens. Sleep deprivation and disruptions challenge the regulatory mechanisms, making immune responses vulnerable. Altered CR pathways have been implicated in diseases such as diabetes, neurological conditions, and systemic autoimmune diseases (SADs). SADs involve abnormal immune responses to self-antigens, with genetic and environmental factors disrupting self-tolerance and contributing to conditions like Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Inflammatory Myositis. Dysregulated CR may lead to increased production of pro-inflammatory cytokines, contributing to the systemic responses observed in SADs. Sleep disturbances significantly impact the quality of life of patients with SADs; however, they are often overlooked. The relationship between sleep and autoimmune conditions, whether causal or consequential to CR dysregulation, remains unclear. Chrono-immunology investigates the role of CR in immunity, offering potential for targeted therapies in autoimmune conditions. This paper provides an overview of the connections between sleep and autoimmune conditions, highlighting the importance of recognizing sleep disturbances in SADs and the need for further research into the complex relationship between the CR and autoimmune diseases.

Spatiotemporal specificity of correlated DNA methylation and gene expression pairs across different human tissues and stages of brain development.

DNA methylation (DNAm) that occurs on promoter regions is primarily considered to repress gene expression. Previous studies indicated that DNAm could also show positive correlations with gene expression. Both DNAm and gene expression profiles are known to be tissue- and development-specific. This study aims to investigate how DNAm and gene expression are coordinated across different human tissues and developmental stages, as well as the biological significance of such correlations. By analyzing 2,239 samples with both DNAm and gene expression data in the same human subjects obtained from six published datasets, we evaluated the correlations between gene and CpG pairs (GCPs) at cis-regions and compared significantly correlated GCPs (cGCPs) across different tissues and brains at different age groups. A total of 37,363 cGCPs was identified in the six datasets; approximately 38% of the cGCPs were positively correlated. The majority (>90%) of cGCPs was tissue- or development-specific. We also observed that the correlation direction can be opposite in different tissues and ages. Further analysis highlights the importance of cGCPs for their cellular functions and potential roles in complex traits and human diseases. For instance, the early developmental brain possessed a highly unique set of cGCPs that were associated with neurogenesis and psychiatric disorders. By assessing the epigenetic factors involved in cGCPs, we discovered novel regulatory mechanisms of positive cGCPs distinct from negative cGCPs, which were related to multiple factors, such as H3K27me3, CTCF, and JARD2. The catalogue of cGCPs compiled can be used to guide functional interpretation of genetic and epigenetic studies.

Exploring the role of Nrf2 signaling in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is one of the most aggressive glial cell tumors in adults. Although current treatment options for GBM offer some therapeutic benefit, median survival remains poor and does not generally exceed 14 months. Several genes, such as isocitrate dehydrogenase (IDH) enzyme and O6-methylguanine-DNA methyltransferase (MGMT), have been implicated in pathogenesis of the disease. Treatment is often adapted based on the presence of IDH mutations and MGMT promoter methylation status. Recent GBM cell line studies have associated Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) expression with high-grade tumors. Increased Nrf2 expression is often found in tumors with IDH-1 mutations. Nrf2 is an important transcription factor with anti-apoptotic, antioxidative, anti-inflammatory, and proliferative properties due to its complex interactions with multiple regulatory pathways. In addition, evidence suggests that Nrf2 promotes  GBM cell survival in hypoxic environment,by up-regulating hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Downregulation of Nrf2 has been shown to improve GBM sensitivity to chemotherapy drugs such as Temozolomide. Thus, Nrf2 could be a key regulator of GBM pathways and potential therapeutic target.  Further research efforts exploring an interplay between Nrf2 and major molecular signaling mechanisms could offer novel GBM drug candidates with a potential to significantly improve patients prognosis.

OMICs Technologies for Natural Compounds-based Drug Development.

Compounds isolated from natural sources have been used for medicinal purposes for many centuries. Some metabolites of plants and microorganisms possess properties that would make them effective treatments against bacterial infection, inflammation, cancer, and an array of other medical conditions. In addition, natural compounds offer therapeutic approaches with lower toxicity compared to most synthetic analogues. However, it is challenging to identify and isolate potential drug candidates without specific information about structural specificity and limited knowledge of any specific physiological pathways in which they are involved. To solve this problem and find a way to efficiently utilize natural sources for the screening of compounds candidates, technologies, such as next-generation sequencing, bioinformatics techniques, and molecular analysis systems, should be adapted for screening many chemical compounds. Molecular techniques capable of performing analysis of large datasets, such as whole-genome sequencing and cellular protein expression profile, have become essential tools in drug discovery. OMICs, as genomics, proteomics, and metabolomics, are often used in targeted drug discovery, isolation, and characterization. This review summarizes technologies that are effective in natural source drug discovery and aid in a more precisely targeted pharmaceutical approach, including RNA interference or CRISPR technology. We strongly suggest that a multidisciplinary effort utilizing novel molecular tools to identify and isolate active compounds applicable for future drug discovery and production must be enhanced with all the available computational tools.

The effect of aluminum smelter emissions on nutritional status of coniferous trees (Irkutsk Region, Russia).

Element contents in assimilation organs of trees are an essential component of a comprehensive forest condition diagnosis. They allow conclusions about the current nutritional status of trees and estimate the main risks for a sustainable forest ecosystem management in the future. The purpose of this research was to study the effect of highly aggressive fluorine-containing emissions from a large aluminum smelter on the nutritional status of coniferous trees Larix sibirica and Pinus sylvestris. Studies carried out in the background areas showed that the both species have the main part of the elements in optimal quantities. A deficiency is noted for potassium. The content of N, K, Mg, Na, S, F, Cu, Co, and Cd in L. sibirica needles was 1.2-5.2 times higher than in P. sylvestris needles. Under the influence of the aluminum smelter emissions, fluorine concentration in the tree needles increases by 13.8-30.0 times; sulfur by 2.9-3.6 times; heavy metals by 2.0-5.1 times; and nitrogen, calcium, magnesium, and sodium by 1.2-3.6 times, especially in the industrial zone and 5 km far from it. With the increasing distance from the smelter, the content of pollutants in the tree needles decreases. Values close to background are observed at a distance of over 40 km. According to index biogeochemical transformation, the elemental composition of P. sylvestris needles undergoes greater changes than L. sibirica ones under the influence emissions from the aluminum smelter. Changes in the element concentration of the tree needles caused by the impact of industrial emissions lead to a restructuring of the elements accumulation rows, as well as to a violation of the element quantitative ratios. Change of N:P:K, Ca:K, Ca:P, P:S, P:F, Mn:F, and Mn:Fe ratios points to serious nutrient imbalances in coniferous trees, which may reduce their vitality and growth in the long run.

Transition from Proximal to Distal Radial Access for Diagnostic Cerebral Angiography: Learning Curve Analysis.

BACKGROUND: Distal transradial access (dTRA) has several advantages compared with proximal transradial access (pTRA) for cerebral angiography. The learning curve for transitioning from pTRA to dTRA has not been described. METHODS: Retrospective analysis of the first 75 diagnostic cerebral angiograms performed with dTRA by a single operator was performed. Outcomes included time for sheath insertion, sheath to first vessel time, procedure duration, fluoroscopy time, radiation dose, and contrast volume. Their associations with procedure number were evaluated with multivariate linear regressions, segmented linear regression, and locally weighted regression (LOESS). RESULTS: The mean age of patients was 56.1 years and 61.3% were female. Seventy-four of 75 angiograms were successfully completed with dTRA. There were 3 minor and no major complications. After adjusting for covariates, sheath to first vessel time (ß = -0.50, P < 0.001) and procedure duration (ß = -0.26, P = 0.002) were associated with procedure number. Time for sheath insertion, fluoroscopy time, radiation dose, and contrast volume were not associated with procedure number. Segmented linear regression identified break-points of 33 for sheath to first vessel time and 11 for procedure duration, which corresponded to the procedure number after which these outcomes trended down. LOESS models for time to sheath placement, procedure duration, fluoroscopy time, and radiation dose predicted minimum values between procedures 40-50. CONCLUSIONS: Transitioning from pTRA to dTRA for diagnostic cerebral angiography is feasible and safe. The learning curve is overcome between procedures 11 and 33, and further refinement in performance occurs through procedures 40-50.