The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models.

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × âˆ¼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

A high-resolution protein architecture of the budding yeast genome.

The genome-wide architecture of chromatin-associated proteins that maintains chromosome integrity and gene regulation is not well defined. Here we use chromatin immunoprecipitation, exonuclease digestion and DNA sequencing (ChIP-exo/seq)1,2 to define this architecture in Saccharomyces cerevisiae. We identify 21 meta-assemblages consisting of roughly 400 different proteins that are related to DNA replication, centromeres, subtelomeres, transposons and transcription by RNA polymerase (Pol) I, II and III. Replication proteins engulf a nucleosome, centromeres lack a nucleosome, and repressive proteins encompass three nucleosomes at subtelomeric X-elements. We find that most promoters associated with Pol II evolved to lack a regulatory region, having only a core promoter. These constitutive promoters comprise a short nucleosome-free region (NFR) adjacent to a +1 nucleosome, which together bind the transcription-initiation factor TFIID to form a preinitiation complex. Positioned insulators protect core promoters from upstream events. A small fraction of promoters evolved an architecture for inducibility, whereby sequence-specific transcription factors (ssTFs) create a nucleosome-depleted region (NDR) that is distinct from an NFR. We describe structural interactions among ssTFs, their cognate cofactors and the genome. These interactions include the nucleosomal and transcriptional regulators RPD3-L, SAGA, NuA4, Tup1, Mediator and SWI-SNF. Surprisingly, we do not detect interactions between ssTFs and TFIID, suggesting that such interactions do not stably occur. Our model for gene induction involves ssTFs, cofactors and general factors such as TBP and TFIIB, but not TFIID. By contrast, constitutive transcription involves TFIID but not ssTFs engaged with their cofactors. From this, we define a highly integrated network of gene regulation by ssTFs.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Toward New Horizons in Verdazyl-Nitroxide High-Spin Systems: Thermally Robust Tetraradical with Quintet Ground State.

High-spin organic tetraradicals with significant intramolecular exchange interactions have high potential for advanced technological applications and fundamental research, but examples reported to date exhibit limited stability and processability. In this work, we designed the first tetraradical based on an oxoverdazyl core and nitronyl nitroxide radicals and successfully synthesized it using a palladium-catalyzed cross-coupling reaction of an oxoverdazyl radical bearing three iodo-phenylene moieties with a gold(I) nitronyl nitroxide-2-ide complex in the presence of a recently developed efficient catalytic system. The molecular and crystal structures of the tetraradical were confirmed by single crystal X-ray diffraction analysis. The tetraradical possesses good thermal stability with decomposition onset at ∼125 °C in an inert atmosphere; in a toluene solution upon prolonged heating at 90 °C in air, no decomposition was observed. The resulting unique verdazyl-nitroxide conjugate was thoroughly studied using a range of experimental and theoretical techniques, such as SQUID magnetometry of polycrystalline powders, EPR spectroscopy in various matrices, cyclic voltammetry, and high-level quantum chemical calculations. All collected data confirm the high thermal stability of the resulting tetraradical and quintet multiplicity of its ground state, which makes the synthesis of this important paramagnet a new milestone in the field of creating high-spin systems.

Coronary Artery Calcium Scoring Using Virtual Versus True Noncontrast Images From Photon-Counting Coronary CT Angiography.

Background Coronary artery calcium scoring (CACS) for coronary artery disease requires true noncontrast (TNC) CT alongside contrast-enhanced coronary CT angiography (CCTA). Photon-counting CT provides an algorithm (PureCalcium) for reconstructing virtual noncontrast images from CCTA specifically for CACS. Purpose To assess CACS differences based on PureCalcium images derived from contrast-enhanced photon-counting CCTA compared with TNC images and evaluate the impact of these differences on the clinically relevant classification of patients into plaque burden groups. Materials and Methods Photon-counting CCTA images acquired between August 2022 and May 2023 were retrospectively identified. Agatston scores were derived from both TNC and PureCalcium images and tested for differences with use of the Wilcoxon signed-rank test. The agreement was assessed with use of equivalence tests, Bland-Altman analysis, and intraclass correlation coefficient. Plaque burden groups were established based on Agatston scores, and agreement was evaluated using weighted Cohen kappa. The dose-length product was analyzed. Results Among 170 patients (mean age, 63 years ± 13 [SD]; 92 male), 111 had Agatston scores higher than 0. Median Agatston scores did not differ between TNC and PureCalcium images (4.8 [IQR, 0-84.4; range, 0.0-2151.8] vs 2.7 [IQR, 0-90.7; range, 0.0-2377.1]; P = .99), with strong correlation (intraclass correlation coefficient, 0.98 [95% CI: 0.97, 0.99]). The equivalence test was inconclusive, with a 95% CI of 0.90, 1.19. Bland-Altman analysis showed wide repeatability limits, indicating low agreement between the two scores. With use of the PureCalcium algorithm, 125 of 170 patients (74%) were correctly classified into plaque burden groups (excellent agreement, κ = 0.88). Patients without plaque burden were misclassified at higher than normal rates (P < .001). TNC image acquisition contributed a mean of 19.7% ± 8.8 of the radiation dose of the entire examination. Conclusion PureCalcium images show potential to replace TNC images for measuring Agatston scores, thereby reducing radiation dose in CCTA. There was strong correlation in calcium scores between TNC and PureCalcium, but limited agreement. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Sakuma in this issue.

A Nitronyl Nitroxide-Substituted Benzotriazinyl Tetraradical.

High-spin organic tetraradicals with significant intramolecular exchange interactions have high potential for advanced technological applications and fundamental research, but those synthesized to date possess limited stability and processability. In this work, we have designed a tetraradical based on the Blatter's radical and nitronyl nitroxide radical moieties and successfully synthesized it by using the palladium-catalyzed cross-coupling reaction of a triiodo-derivative of the 1,2,4-benzotriazinyl radical with gold(I) nitronyl nitroxide-2-ide complex in the presence of a newly developed efficient catalytic system. The molecular and crystal structure of the tetraradical was confirmed by X-ray diffraction analysis. The tetraradical possesses good thermal stability with decomposition onset at ∼150 °C under an inert atmosphere and exhibits reversible redox waves at -0.54 and 0.45 V versus Ag/AgCl. The magnetic properties of the tetraradical were characterized by SQUID magnetometry of polycrystalline powders and EPR spectroscopy in various matrices. The collected data, analyzed by using high-level quantum chemical calculations, confirmed that the tetraradical has a triplet ground state and a nearby excited quintet state. The unique high stability of the prepared triazinyl-nitronylnitroxide tetraradical is a new milestone in the field of creating high-spin systems.

Differences in Metabolomic Profiles Between Black and White Women and Risk of Coronary Heart Disease: an Observational Study of Women From Four US Cohorts.

BACKGROUND: Racial differences in metabolomic profiles may reflect underlying differences in social determinants of health by self-reported race and may be related to racial disparities in coronary heart disease (CHD) among women in the United States. However, the magnitude of differences in metabolomic profiles between Black and White women in the United States has not been well-described. It also remains unknown whether such differences are related to differences in CHD risk. METHODS: Plasma metabolomic profiles were analyzed using liquid chromatography-tandem mass spectrometry in the WHI-OS (Women's Health Initiative-Observational Study; 138 Black and 696 White women), WHI-HT trials (WHI-Hormone Therapy; 156 Black and 1138 White women), MESA (Multi-Ethnic Study of Atherosclerosis; 114 Black and 219 White women), JHS (Jackson Heart Study; 1465 Black women with 107 incident CHD cases), and NHS (Nurses' Health Study; 2506 White women with 136 incident CHD cases). First, linear regression models were used to estimate associations between self-reported race and 472 metabolites in WHI-OS (discovery); findings were replicated in WHI-HT and validated in MESA. Second, we used elastic net regression to construct a racial difference metabolomic pattern (RDMP) representing differences in the metabolomic patterns between Black and White women in the WHI-OS; the RDMP was validated in the WHI-HT and MESA. Third, using conditional logistic regressions in the WHI (717 CHD cases and 719 matched controls), we examined associations of metabolites with large differences in levels by race and the RDMP with risk of CHD, and the results were replicated in Black women from the JHS and White women from the NHS. RESULTS: Of the 472 tested metabolites, levels of 259 (54.9%) metabolites, mostly lipid metabolites and amino acids, significantly differed between Black and White women in both WHI-OS and WHI-HT after adjusting for baseline characteristics, socioeconomic status, lifestyle factors, baseline health conditions, and medication use (false discovery rate <0.05); similar trends were observed in MESA. The RDMP, composed of 152 metabolites, was identified in the WHI-OS and showed significantly different distributions between Black and White women in the WHI-HT and MESA. Higher RDMP quartiles were associated with an increased risk of incident CHD (odds ratio=1.51 [0.97-2.37] for the highest quartile comparing to the lowest; Ptrend=0.02), independent of self-reported race and known CHD risk factors. In race-stratified analyses, the RDMP-CHD associations were more pronounced in White women. Similar patterns were observed in Black women from the JHS and White women from the NHS. CONCLUSIONS: Metabolomic profiles significantly and substantially differ between Black and White women and may be associated with CHD risk and racial disparities in US women.

Role of the Gut Microbiome and Bacterial Amyloids in the Development of Synucleinopathies.

Less than ten years ago, evidence began to accumulate about association between the changes in the composition of gut microbiota and development of human synucleinopathies, in particular sporadic form of Parkinson's disease. We collected data from more than one hundred and thirty experimental studies that reported similar results and summarized the frequencies of detection of different groups of bacteria in these studies. It is important to note that it is extremely rare that a unidirectional change in the population of one or another group of microorganisms (only an elevation or only a reduction) was detected in the patients with Parkinson's disease. However, we were able to identify several groups of bacteria that were overrepresented in the patients with Parkinson's disease in the analyzed studies. There are various hypotheses about the molecular mechanisms that explain such relationships. Usually, α-synuclein aggregation is associated with the development of inflammatory processes that occur in response to the changes in the microbiome. However, experimental evidence is accumulating on the influence of bacterial proteins, including amyloids (curli), as well as various metabolites, on the α-synuclein aggregation. In the review, we provided up-to-date information about such examples.

Studying of psycholinguistic features of doctors' professional communication under war conditions.

OBJECTIVE: Aim: Studying of psycholinguistic features of doctors' communication competence in Ukraine under war conditions. PATIENTS AND METHODS: Materials and Methods: Bibliosemantic method; method of system analysis, comparison and generalization; empirical methods - direct observation of the doctors' and patients' living language, typology of empirical data according to socio-demographic indicators. RESULTS: Results: Within the study, 286 dialogues were collected. With voluntary consent, they were recorded in video and audio formats in compliance with ethical, bioethical, and legal norms. Next, initial typology of dialogues, their lexical and semantic analysis with identification of typical positive and negative communicative strategies were carried out. With the help of the ≪Textanz≫ specialized computer software, 48 dialogues were subjected to the content analysis procedure for two separate ≪Doctors≫ and ≪Patients≫ samples. CONCLUSION: Conclusions: The results of the analysis of ≪Doctor-Patient≫ dialogues enabled identifying and describing psycholinguistic markers of typical physiological, mental, social, and spiritual states of individuals seeking medical help under martial law. Thus, the markers of positive emotional states (optimism, confidence, empathy, etc.) and affective, negative emotional processes (anxiety, fear, anger, aggression, sadness, depression, etc.) were identified.

Chromium-Lanthanide Complexes Containing the Cr═P═Cr Fragment: Synthesis, Characterization, and Computational Study.

Heterometallic complexes [Cp*2Ln(µ-isoCO)2{Cr2(µ-P)Cp2(CO)2}] [Ln = Yb (1), Sm (2)] were obtained in reactions of [Cp*2Ln(thf)2] (Ln = Sm, Yb) with [{CpCr(CO)2}2(µ,η2:2-P2)] (4). An analogous yttrium compound [Cp*2Y(µ-isoCO)2{Cr2(µ-P)Cp2(CO)2}] (3) was synthesized using a three-component reaction between [Cp*2Y(BPh4)], 4, and KC8. Compounds 1-3 were isolated as solvent-free crystalline phases; in the case of 2, the 2·0.5C7H8 solvate was also obtained. The structures of all crystalline phases were determined by single-crystal X-ray diffraction analysis. All compounds contain a unique {((CO)2CpCr═P═CrCp(CO)2)}- unit, which is linked to Ln3+ ions through CO ligands in the isocarbonyl mode. Compounds 1 and 3 have a molecular structure, while compound 2 contains polymeric chains of triangular [Cp*2Sm(µ-isoCO)2{Cr2(µ-P)Cp2(CO)2}] units linked by µ-isoCO-ligands. 31P NMR studies demonstrated similar dramatic downfield shifts for complexes 1-3. To realize the electronic structure of 1-3 and to elucidate the nature of the high downfield chemical 31P shift, quantum chemical calculations were performed both for 1-3 and for related Cr- and Fe-phosphido complexes. Calculations show that the anomalously high downfield chemical shifts for 1-3 are due to the anisotropic effect of the Cr═P double bonds.

Two Discoveries in One Crystal: σ-Type Oxime Radical as an Unforeseen Building Block in Molecular Magnetics and Its Spatial Structure.

In the present work, the study of the unusual interaction between copper hexafluoroacetylacetonate and the diacetyliminoxyl radical resulted in two discoveries from different fields: the determination of the oxime radical spatial structure and the introduction of an oxime radical into the field of molecular magnetic material design. Oxime radicals are key plausible intermediates in the processes of oxidative CH-functionalization and in the synthesis of functionalized isoxazolines from oximes. Due to the lack of X-ray diffraction data for oxime radicals, the knowledge about their structure is based mainly on indirect approaches, spectroscopic methods (electron paramagnetic resonance and IR), and quantum chemical calculations. The structure of the oxime radical was determined for the first time by stabilizing the diacetyliminoxyl radical in the form of its complex with copper (II) hexafluoroacetylacetonate (Cu(hfac)2), followed by single-crystal X-ray diffraction analysis. Although oxime radicals are known to undergo oxidative coupling with acetylacetonate ligands in transition-metal complexes, a complex is formed with intact hfac ligands. X-ray diffraction studies have shown that the oxime radical is coordinated with copper ions through the oxygen atoms of the carbonyl groups without the direct involvement of the C═N-O• radical moiety. The structure of the coordinated diacetyliminoxyl is in good agreement with the density functional theory (DFT) prediction for free diacetyliminoxyl due to the very weak interaction of the radical molecule with copper ions. Remarkably, both weak ferromagnetic and antiferromagnetic interactions between Cu (II) and oxime radicals have been revealed by modeling the temperature dependence of magnetic susceptibility and confirmed by DFT calculations, rendering diacetyliminoxyl a promising building block for the design of molecular magnets.

Brain structural and functional connectivity and network organization in cerebral palsy: A scoping review.

AIM: To explore altered structural and functional connectivity and network organization in cerebral palsy (CP), by clinical CP subtype (unilateral spastic, bilateral spastic, dyskinetic, and ataxic CP). METHOD: PubMed and Embase databases were systematically searched. Extracted data included clinical characteristics, analyses, outcome measures, and results. RESULTS: Sixty-five studies were included, of which 50 investigated structural connectivity, and 20 investigated functional connectivity using functional magnetic resonance imaging (14 studies) or electroencephalography (six studies). Five of the 50 studies of structural connectivity and one of 14 of functional connectivity investigated whole-brain network organization. Most studies included patients with unilateral spastic CP; none included ataxic CP. INTERPRETATION: Differences in structural and functional connectivity were observed between investigated clinical CP subtypes and typically developing individuals on a wide variety of measures, including efferent, afferent, interhemispheric, and intrahemispheric connections. Directions for future research include extending knowledge in underrepresented CP subtypes and methodologies, evaluating the prognostic potential of specific connectivity and network measures in neonates, and understanding therapeutic effects on brain connectivity.

Brain CoA and Acetyl CoA Metabolism in Mechanisms of Neurodegeneration.

The processes of biotransformation of pantothenic acid (Pan) in the biosynthesis and hydrolysis of CoA, key role of pantothenate kinase (PANK) and CoA synthetase (CoASY) in the formation of the priority mitochondrial pool of CoA, with a high metabolic turnover of the coenzyme and limited transport of Pan across the blood-brain barrier are considered. The system of acetyl-CoA, a secondary messenger, which is the main substrate of acetylation processes including formation of N-acetyl aspartate and acetylcholine, post-translational modification of histones, predetermines protection of the neurons against degenerative signals and cholinergic neurotransmission. Biochemical mechanisms of neurodegenerative syndromes in the cases of PANK and CoASY defects, and the possibility of correcting of CoA biosynthesis in the models with knockouts of these enzymes have been described. The data of a post-mortem study of the brains from the patients with Huntington's and Alzheimer's diseases are presented, proving Pan deficiency in the CNS, which is especially pronounced in the pathognomonic neurostructures. In the frontal cortex of the patients with Parkinson's disease, combined immunofluorescence of anti-CoA- and anti-tau protein was detected, reflecting CoAlation during dimerization of the tau protein and its redox sensitivity. Redox activity and antioxidant properties of the precursors of CoA biosynthesis were confirmed in vitro with synaptosomal membranes and mitochondria during modeling of aluminum neurotoxicity accompanied by the decrease in the level of CoA in CNS. The ability of CoA biosynthesis precursors to stabilize glutathione pool in neurostructures, in particular, in the hippocampus, is considered as a pathogenetic protection mechanism during exposure to neurotoxins, development of neuroinflammation and neurodegeneration, and justifies the combined use of Pan derivatives (for example, D-panthenol) and glutathione precursors (N-acetylcysteine). Taking into account the discovery of new functions of CoA (redox-dependent processes of CoAlation of proteins, possible association of oxidative stress and deficiency of Pan (CoA) in neurodegenerative pathology), it seems promising to study bioavailability and biotransformation of Pan derivatives, in particular of D-panthenol, 4'-phospho-pantetheine, its acylated derivatives, and compositions with redox pharmacological compounds, are promising for their potential use as etiopathogenetic agents.

How Big Is the Yeast Prion Universe?

The number of yeast prions and prion-like proteins described since 1994 has grown from two to nearly twenty. If in the early years most scientists working with the classic mammalian prion, PrPSc, were skeptical about the possibility of using the term prion to refer to yeast cytoplasmic elements with unusual properties, it is now clear that prion-like phenomena are widespread and that yeast can serve as a convenient model for studying them. Here we give a brief overview of the yeast prions discovered so far and focus our attention to the various approaches used to identify them. The prospects for the discovery of new yeast prions are also discussed.

Identification of New FG-Repeat Nucleoporins with Amyloid Properties.

Amyloids are fibrillar protein aggregates with a cross-ß structure. More than two hundred different proteins with amyloid or amyloid-like properties are already known. Functional amyloids with conservative amyloidogenic regions were found in different organisms. Protein aggregation appears to be beneficial for the organism in these cases. Therefore, this property might be conservative for orthologous proteins. The amyloid aggregates of the CPEB protein were suggested to play an important role in the long-term memory formation in Aplysia californica, Drosophila melanogaster, and Mus musculus. Moreover, the FXR1 protein demonstrates amyloid properties among the Vertebrates. A few nucleoporins (e.g., yeast Nup49, Nup100, Nup116, and human Nup153 and Nup58), are supposed or proved to form amyloid fibrils. In this study, we performed wide-scale bioinformatic analysis of nucleoporins with FG-repeats (phenylalanine-glycine repeats). We demonstrated that most of the barrier nucleoporins possess potential amyloidogenic properties. Furthermore, the aggregation-prone properties of several Nsp1 and Nup100 orthologs in bacteria and yeast cells were analyzed. Only two new nucleoporins, Drosophila melanogaster Nup98 and Schizosaccharomyces pombe Nup98, aggregated in different experiments. At the same time, Taeniopygia guttata Nup58 only formed amyloids in bacterial cells. These results rather contradict the hypothesis about the functional aggregation of nucleoporins.

Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.

BACKGROUND: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1ß, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. METHODS: We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point. RESULTS: The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1ß, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo. CONCLUSIONS: Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1ß, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.).

Semantic Annotation of Experimental Methods in Analytical Chemistry.

A major obstacle for reusing and integrating existing data is finding the data that is most relevant in a given context. The primary metadata resource is the scientific literature describing the experiments that produced the data. To stimulate the development of natural language processing methods for extracting this information from articles, we have manually annotated 100 recent open access publications in Analytical Chemistry as semantic graphs. We focused on articles mentioning mass spectrometry in their experimental sections, as we are particularly interested in the topic, which is also within the domain of several ontologies and controlled vocabularies. The resulting gold standard dataset is publicly available and directly applicable to validating automated methods for retrieving this metadata from the literature. In the process, we also made a number of observations on the structure and description of experiments and open access publication in this journal.

Exogenous phytohormones in the regulation of growth and development of cereals under abiotic stresses.

Abiotic stresses, among which extreme temperatures, salinity, drought, UV radiation, heavy metal pollution, etc., adversely affect the growth and yield of cereals, the most important group of monocotyledonous plants that have met the nutritional and other needs of mankind for thousands of years. To cope with stress, plants deploy certain adaptive strategies that combine morphological, physiological, and biochemical responses, and on which growth and productivity depend. An important place in the formation of such strategies is occupied by phytohormones - signaling biomolecules of a different chemical structure and physicochemical properties, which act in nanomolar concentrations and regulate most physiological and metabolic processes of plants. In this review, the latest literature data concerning the growth and development regulation by exogenous phytohormones in cereals under abiotic stresses have been analyzed and summarized. The effects of priming and foliar treatment with abscisic acid, gibberellins, auxins, cytokinins, brassinosteroids, jasmonic and salicylic acids on the cultivated cereals tolerance to different abiotic stressors are discussed. Peculiarities of bilateral and multilateral hormonal signaling in the formation of responses of cultivated cereals to abiotic stressors after application of exogenous phytohormones are considered. The issue of exogenous phytohormones effects on molecular mechanisms controlling the synthesis of endogenous hormones, their signaling and activity are singled out. It is emphasized that phytohormonal engineering opens new opportunities to increase yields and is seen as an important promising approach to overcoming the cereal losses caused by adverse external factors.

Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells.

ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers target specific nucleosomes to regulate transcription is unclear. Here we present genome-wide remodeller-nucleosome interaction profiles for the chromatin remodellers Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank micrococcal nuclease (MNase)-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription. Surprisingly, large CpG-rich NFRs that extend downstream of annotated transcriptional start sites are nevertheless bound by non-nucleosomal or subnucleosomal histone variants (H3.3 and H2A.Z) and marked by H3K4me3 and H3K27ac modifications. RNA polymerase II therefore navigates hundreds of base pairs of altered chromatin in the sense direction before encountering an MNase-resistant nucleosome at the 3' end of the NFR. Transcriptome analysis after remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. Whereas at active genes individual remodellers have either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner. These findings indicate that remodellers target specific nucleosomes at the edge of NFRs, where they regulate ES cell transcriptional programs.

Structure and Polymorphism of Amyloid and Amyloid-Like Aggregates.

Amyloids are protein aggregates with the cross-ß structure. The interest in amyloids is explained, on the one hand, by their role in the development of socially significant human neurodegenerative diseases, and on the other hand, by the discovery of functional amyloids, whose formation is an integral part of cellular processes. To date, more than a hundred proteins with the amyloid or amyloid-like properties have been identified. Studying the structure of amyloid aggregates has revealed a wide variety of protein conformations. In the review, we discuss the diversity of protein folds in the amyloid-like aggregates and the characteristic features of amyloid aggregates that determine their unusual properties, including stability and interaction with amyloid-specific dyes. The review also describes the diversity of amyloid aggregates and its significance for living organisms.