Testing quantum electrodynamics in extreme fields using helium-like uranium.

Quantum electrodynamics (QED), the quantum field theory that describes the interaction between light and matter, is commonly regarded as the best-tested quantum theory in modern physics. However, this claim is mostly based on extremely precise studies performed in the domain of relatively low field strengths and light atoms and ions1-6. In the realm of very strong electromagnetic fields such as in the heaviest highly charged ions (with nuclear charge Z ≫ 1), QED calculations enter a qualitatively different, non-perturbative regime. Yet, the corresponding experimental studies are very challenging, and theoretical predictions are only partially tested. Here we present an experiment sensitive to higher-order QED effects and electron-electron interactions in the high-Z regime. This is achieved by using a multi-reference method based on Doppler-tuned X-ray emission from stored relativistic uranium ions with different charge states. The energy of the 1s1/22p3/2 J = 2 → 1s1/22s1/2 J = 1 intrashell transition in the heaviest two-electron ion (U90+) is obtained with an accuracy of 37 ppm. Furthermore, a comparison of uranium ions with different numbers of bound electrons enables us to disentangle and to test separately the one-electron higher-order QED effects and the bound electron-electron interaction terms without the uncertainty related to the nuclear radius. Moreover, our experimental result can discriminate between several state-of-the-art theoretical approaches and provides an important benchmark for calculations in the strong-field domain.

Cold-responsive adipocyte progenitors couple adrenergic signaling to immune cell activation to promote beige adipocyte accrual.

The full array of cold-responsive cell types within white adipose tissue that drive thermogenic beige adipocyte biogenesis remains undefined. We demonstrate that acute cold challenge elicits striking transcriptomic changes specifically within DPP4+ PDGFRß+ adipocyte precursor cells, including a ß-adrenergic receptor CREB-mediated induction in the expression of the prothermogenic cytokine, Il33 Doxycycline-inducible deletion of Il33 in PDGFRß+ cells at the onset of cold exposure attenuates ILC2 accumulation and beige adipocyte accrual. These studies highlight the multifaceted roles for adipocyte progenitors and the ability of select mesenchymal subpopulations to relay neuronal signals to tissue-resident immune cells in order to regulate tissue plasticity.

Machine learning identifies activation of RUNX/AP-1 as drivers of mesenchymal and fibrotic regulatory programs in gastric cancer.

Gastric cancer (GC) is the fifth most common cancer worldwide and is a heterogeneous disease. Among GC subtypes, the mesenchymal phenotype (Mes-like) is more invasive than the epithelial phenotype (Epi-like). Although gene expression of the epithelial-to-mesenchymal transition (EMT) has been studied, the regulatory landscape shaping this process is not fully understood. Here we use ATAC-seq and RNA-seq data from a compendium of GC cell lines and primary tumors to detect drivers of regulatory state changes and their transcriptional responses. Using the ATAC-seq data, we developed a machine learning approach to determine the transcription factors (TFs) regulating the subtypes of GC. We identified TFs driving the mesenchymal (RUNX2, ZEB1, SNAI2, AP-1 dimer) and the epithelial (GATA4, GATA6, KLF5, HNF4A, FOXA2, GRHL2) states in GC. We identified DNA copy number alterations associated with dysregulation of these TFs, specifically deletion of GATA4 and amplification of MAPK9 Comparisons with bulk and single-cell RNA-seq data sets identified activation toward fibroblast-like epigenomic and expression signatures in Mes-like GC. The activation of this mesenchymal fibrotic program is associated with differentially accessible DNA cis-regulatory elements flanking upregulated mesenchymal genes. These findings establish a map of TF activity in GC and highlight the role of copy number driven alterations in shaping epigenomic regulatory programs as potential drivers of GC heterogeneity and progression.

Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury.

OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). RESULT: We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. CONCLUSION: Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.

Methionine gamma lyase fused with S3 domain VGF forms octamers and adheres to tumor cells via binding to EGFR.

Methods for targeting enzymes exhibiting anticancer properties, such as methionine γ-lyase (MGL), have not yet been sufficiently developed. Here, we present the data describing the physico-chemical properties and cytotoxic effect of fusion protein MGL-S3 - MGL from Clostridium sporogenes translationally fused to S3 domain of the viral growth factor of smallpox. MGL-S3 has methioninase activity comparable to native MGL. In solution, MGL-S3 protein primarily forms octamers, whereas native MGL, on the contrary, usually forms tetramers. MGL-S3 binds to the surface of the neuroblastoma SH-SY5Y and epidermoid carcinoma A431 cells and, unlike native MGL, remains there and retains its cytotoxic effect after media removal. In HEK293T cells lacking EGFRs, no adhesion was recorded. Confocal fluorescence microscopy confirms the preferential adhesion of MGL-S3 to tumor cells, while it avoids getting into lysosomes. Both MGL and MGL-S3 arrest cell cycle of SH-SY5Y cells mainly in the G1 phase, while only MGL-S3 retains this ability after washing the cells.

Measurement of the Isolated Nuclear Two-Photon Decay in

The nuclear two-photon or double-gamma (2γ) decay is a second-order electromagnetic process whereby a nucleus in an excited state emits two gamma rays simultaneously. To be able to directly measure the 2γ decay rate in the low-energy regime below the electron-positron pair-creation threshold, we combined the isochronous mode of a storage ring with Schottky resonant cavities. The newly developed technique can be applied to isomers with excitation energies down to ∼100 keV and half-lives as short as ∼10 ms. The half-life for the 2γ decay of the first-excited 0^{+} state in bare ^{72}Ge ions was determined to be 23.9(6) ms, which strongly deviates from expectations.

Measurement of the Pion Form Factor with CMD-3 Detector and Its Implication to the Hadronic Contribution to Muon (g-2).

The cross section of the process e^{+}e^{-}→π^{+}π^{-} has been measured in the center-of-mass energy range from 0.32 to 1.2 GeV with the CMD-3 detector at the electron-positron collider VEPP-2000. The measurement is based on an integrated luminosity of about 88 pb^{-1}, of which 62 pb^{-1} represent a complete dataset collected by CMD-3 at center-of-mass energies below 1 GeV. In the dominant region near the ρ resonance a systematic uncertainty of 0.7% was achieved. The implications of the presented results for the evaluation of the hadronic contribution to the anomalous magnetic moment of the muon are discussed.

Feasibility study of the multishot gradient-echo planar imaging sequence in non-enhanced and free-breathing whole-heart magnetic resonance coronary angiography.

AIM: To investigate the feasibility of non-enhanced and free-breathing whole-heart magnetic resonance coronary angiography (MRCA) using multishot gradient-echo planar imaging (MSG-EPI). MATERIALS AND METHODS: In total, 29 healthy volunteers were recruited for free-breathing whole-heart MRCA acquisition using the MSG-EPI sequence and fast gradient echo (GRE) sequence. After the examination, the actual scanning times, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) of the left main (LM) coronary artery, subjective quality scores for each segment, and evaluable length of the coronary artery were recorded and statistically analysed. RESULTS: There was no significant difference between the SNRLM of the MSG-EPI sequence and fast GRE sequence (p=0.130), but the CNRLM of the MSG-EPI sequence was higher (p=0.001). The subjective quality score of the mid- and distal left anterior descending branch as well as the distal circumflex branch of the coronary artery in the MSG-EPI sequence was higher than that in the fast GRE sequence (p=0.003, 0.001, and 0.003, respectively). The evaluable length of the left anterior descending branch and the circumflex branch was better using the MSG-EPI sequence than that of the fast GRE sequence (p=0.015 and < 0.001, respectively). Moreover, the scanning time of the MSG-EPI sequence was 54.5% less than that of the fast GRE sequence (p<0.001). CONCLUSION: The MSG-EPI sequence improves the subjective and objective image quality of MRCA as well as reduces the scanning time.

On the utmost importance of the geometry factor of accuracy in the quantum chemical calculations of 31P NMR chemical shifts: New efficient pecG-n (n = 1, 2) basis sets for the geometry optimization procedure.

31P nuclear magnetic resonance (NMR) chemical shifts were shown to be very sensitive to the basis set used at the geometry optimization stage. Commonly used energy-optimized basis sets for a phosphorus atom containing only one polarization d-function were shown to be unable to provide correct equilibrium geometries for the calculations of phosphorus chemical shifts. The use of basis sets with at least two polarization d-functions on a phosphorus atom is strongly recommended. In this paper, an idea of creating the basis sets purposed for the geometry optimization that provide the least possible error coming from the geometry factor of accuracy in the resultant NMR shielding constants is proposed. The property-energy consisted algorithm with the target function in the form of the molecular energy gradient relative to P-P bond lengths was applied to create new geometry-oriented pecG-n (n = 1, 2) basis sets for a phosphorus atom. New basis sets have demonstrated by far superior performance as compared to the other commonly used energy-optimized basis sets in massive calculations of 31P NMR chemical shifts carried out at the gauge-including atomic orbital-coupled cluster singles and doubles/pecS-2 level of the theory by taking into account solvent, vibrational, and relativistic corrections.

Repeatability and agreement of two swept-source optical coherence tomographers and scheimpflug imaging for measurements of corneal curvature.

PURPOSE: To evaluate the repeatability and agreement of two swept-source optical coherence tomographers and Scheimpflug imaging for corneal curvature in healthy subjects to obtain data on the clinical application of a new device. METHODS: This prospective study was conducted in January and February 2021 with 100 healthy subjects at the Eye Hospital of Wenzhou Medical University. Simulated keratometry (Sim-K), posterior keratometry (Kp), total corneal power (TCP), and total corneal astigmatism (TCA) were measured with CASIA2, Anterion, and Pentacam. Within-subject standard deviation (Sw), repeatability coefficient (RC), coefficient of variation (CoV), and intraclass correlation coefficient (ICC) were used to assess inter-device repeatability. Bland-Altman analysis was performed to determine inter-device agreement. RESULTS: The three devices showed good repeatability for Sim-K, Kp, and TCP with all ICC > 0.980. Pentacam showed the highest repeatability (ICC ≥ 0.993; ICC ≥ 0.993) while the CASIA2 demonstrated the lowest repeatability (ICC: ≥ 0.986; ICC: ≥ 0.985) for Sim-K and TCP. Anterion and CASIA2 revealed better repeatability (ICC ≥ 0.998; ICC ≥ 0.981) for Kp than Pentacam (ICC ≥ 0.980). Pentacam and Anterion showed good repeatability for TCA (ICC: 0.935 and 0.916), whereas the CASIA2 showed moderate repeatability (ICC: 0.836). Three instruments demonstrated good agreement with the maximum absolute 95% Limits of agreement (LoA) of 1.00 D for Sim-K, Kp, and TCP. Wide LoA were found for TCA with the maximum absolute 95% LoA ≥ 0.66 D between the three devices. CONCLUSIONS: In healthy subjects, the three devices (Pentacam, Anterion and CASIA2) displayed comparable repeatability and accuracy for SimK, Kp, and TCP, and could be used interchangeably for these parameters. However, TCA measured by the three devices was not interchangeable. TRIAL REGISTRATION: Chinese Clinical Trial Registry Center (10/10/2020, ChiCTR2000038959).

Regulation of cold-induced thermogenesis by the RNA binding protein FAM195A.

Homeothermic vertebrates produce heat in cold environments through thermogenesis, in which brown adipose tissue (BAT) increases mitochondrial oxidation along with uncoupling of the electron transport chain and activation of uncoupling protein 1 (UCP1). Although the transcription factors regulating the expression of UCP1 and nutrient oxidation genes have been extensively studied, only a few other proteins essential for BAT function have been identified. We describe the discovery of FAM195A, a BAT-enriched RNA binding protein, which is required for cold-dependent thermogenesis in mice. FAM195A knockout (KO) mice display whitening of BAT and an inability to thermoregulate. In BAT of FAM195A KO mice, enzymes involved in branched-chain amino acid (BCAA) metabolism are down-regulated, impairing their response to cold. Knockdown of FAM195A in brown adipocytes in vitro also impairs expression of leucine oxidation enzymes, revealing FAM195A to be a regulator of BCAA metabolism and a potential target for metabolic disorders.

[Expedited program and utilization for anticancer drug approval in China and the United States].

Objective: To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021. Methods: Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison. Results: Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions: Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

Radioprotective Properties of Riboxin (Inosine) and Indralin under External Irradiation.

A comparative assessment of radioprotective properties of inosine nucleoside (riboxin) and recognized radioprotector indralin was carried out. We analyzed survival of male ICR CD-1 mice weighting 32.2±0.2 g exposed to external X-ray radiation at doses 6.5 and 6.75 Gy and receiving indralin at a dose of 100 or 150 µg/g body weight or riboxin (inosine) at a dose of 100 or 200 µg/g body weight before irradiation. The survival analysis was carried out by the Kaplan-Meier method. The significance was assessed by using the log-rank-test. Inosine showed a significant difference from the irradiated control only at a dose of 100 µg/g body weight at a radiation dose of 6.75 Gy. The survival of animals treated with indralin was significantly higher in comparison with not only the irradiated control group, but also with the groups receiving inosine.

Assessment of the Acute Toxicity of Chlorophyllin and Trolox for the Possibility of Studying Their Radioprotective Properties.

The acute toxicity of chlorophyllin and trolox upon intraperitoneal injection of their solutions was studied in male ICR (CD-1) mice. The LD50 of chlorophyllin was found to be 633±37.2 µg/g body weight, which is lower than the LD50 of established radioprotectors. Trolox is technically non-toxic under the conditions of our study. The results obtained highlight the need for a detailed study of the radioprotective properties of trolox and chlorophyllin.

Comparative Evaluation of the Radioprotective Properties of Copper Chlorophyllin, Trolox, and Indralin in an Experiment on Mice.

The radioprotective properties of copper chlorophyllin (100 and 150 µg/g), the standard antioxidant trolox (100 and 200 µg/g), and the standard radioprotector indralin (100 and 150 µg/g) were compared in male ICR mice (CD-1) subjected to whole-body irradiation (X-ray radiation) in doses of 6, 6.5, and 6.75 Gy. Animal survival was analyzed using the Kaplan-Meier method, and the significance of differences was evaluated using the log-rank test method. Dose change factors determined using the Phinney probit analysis were 1.1, 1.0, and 1.8 for chlorophyllin, trolox, and indralin at a dose of 100 µg/g body weight, respectively. The insignificant radioprotective properties of chlorophyllin and their absence in trolox when administered prophylactically do not rule out their possible radioprotective properties like a radiomodulator that protects the body after irradiation.

Stress-Tolerant Dormant Bacterial Forms: Biological and Ultrastructural Properties of Moraxella catarrhalis and Kocuria rhizophila.

Dormant forms of causative agents of healthcare-acquired infections Moraxella catarrhalis and Kocuria rhizophila have been obtained. Dormant forms cells retained viability during long-term storage (≈107 CFU/ml after 2 months) under provocative conditions (lack of nutrient sources; temperature 20°C, oxygen access) were characterized by heat resistance, and acquired special ultrastructural organization typical of dormant forms (compacted nucleoid, thickened cell wall). They were also capable of forming alternative phenotypes (dominant and small colony variants) in a new cycle of germination in a fresh medium. These results demonstrate that the dormant forms can be responsible both for survival in the environment and persistence in the host organism.

Experimental Approaches to Scar Modeling through Mechanical Skin Damage and Chemical Burn in Sprague Dawley Rats.

Creating of a scar model in laboratory animals is the most acceptable option for the preclinical search of scar treatment. However, due to high skin regeneration rate in laboratory rodents, creating an optimal animal model of scar formation is a challenge. Here we describe five methods for modeling a scar tissue in rats that we have tested. These methods allowed achieving different histopathological features and different stages of skin scar formation.

Association of Polymorphic Variants of TCF7L2 and PPARG Genes with Metabolic Markers in Patients with Early Disorders of Carbohydrate Metabolism.

We performed complex analysis of the association of polymorphic variants rs7903146 of the TCF7L2 gene and rs1801282 of the PPARG gene with metabolic parameters, insulin resistance, and ß-cell function in a group of patients with early signs of carbohydrate metabolism disturbances in a sample of Tyumen citizens. The study group consisted of 64 people (39 women, 25 men) aged 40-70 years. The distribution of frequencies of alleles and genotypes of the polymorphic markers rs7903146 and rs1801282 was analyzed and associations of carriage of major homozygous polymorphisms with various phenotypic traits were identified. Genotyping for polymorphic variants of TCF7L2 and PPARG genes was performed using allele-specific PCR with primers provided by Synthol company. Carriers of homozygotes for allele C of the polymorphic marker rs7903146 significantly differed from other respondents by a higher level of C-peptide, as well as by the presence of associations with waist circumference, elevated level of glycated hemoglobin, and arterial hypertension. Carriers of homozygotes for the allele C of the rs1801282 polymorphism of the PPARG gene differed from the group of carriers of homozygotes for the allele G and the group of heterozygote carriers by higher levels of triglycerides, as well as the presence of associations with waist circumference and the level of glycated hemoglobin.

Antibiotic Adjuvant 4-Hexylresorcinol Enhances the Efficiency of Antituberculosis Drugs.

We studied the possibility of using 4-hexylresorcinol to increase the efficiency of anti-mycobacterial chemotherapy. In an in vitro experiment, 4-hexylresorcinol increased the efficiency of rifampicin, kanamycin, and isoniazid against Mycobacterium smegmatis by 3-5 times. Experiments in sanitation of BALB/c mice infected with M. smegmatis showed the best efficacy of the isoniazid and 4-hexylresorcinol combination in comparison with isoniazid monotherapy. The growth-inhibiting activity of the combination of antibiotic rifabutin with 4-hexylresorcinol was shown on 6 strains of M. tuberculosis. A 2-fold decrease in the minimum inhibitory concentration of this antibiotic in the presence of half-minimum inhibitory concentration of 4-hexylresorcinol was demonstrated for monoresistant strain M. tuberculosis 5360/42Hr. On the mouse model of experimental tuberculosis caused by M. tuberculosis H37Rv, a 5-fold decrease in lung contamination and more rapid complete cure were achieved in animals treated with the combination of rifabutin and 4-hexylresorcinol in comparison with rifabutin monotherapy.

Evaluation of the Effect of Dibornol on the Level of DNA Damage in the DNA Comet Test In Vivo.

In male C57BL/6 mice (8-12 weeks) and male Wistar rats (12 weeks), the effect of dibornol (2,6-diisobornyl-4-methylphenol) on the level of spontaneous DNA damage in cells of the bone marrow, liver, kidneys, and rectum of mice (series I) and genotoxic effects in rat testicular cells after administration of cytostatic drugs with different mechanisms of action (series II) were studied using the DNA comet assay. In series I, dibornol was intragastrically administered to mice once at doses of 200, 400, and 2000 mg/kg; in series II, dibornol was intragastrically administered to rats at a dose of 10 mg/kg for 5 days before and 5 days after the cytostatic treatment (methotrexate, doxorubicin). It was found that dibornol in all studied doses did not produce the genotoxic (carcinogenic) effect and reduced the level of spontaneous DNA damage in the bone marrow. After combined administration of cytostatic drugs (doxorubicin, methotrexate) and dibornol, the level of DNA breaks was reduced to 38.5 and 49% of the control, respectively.