Enhancement of Magneto-Chiral Dichroism Intensity by Chemical Design: The Key Role of Magnetic-Dipole Allowed Transitions.

Here we report on the strong magneto-chiral dichroism (MChD) detected through visible and near-infrared light absorption up to 5.0 T on {Er5Ni6} metal clusters obtained by reaction of enantiopure chiral ligands and NiII and ErIII precursors. Single-crystal diffraction analysis reveals that these compounds are 3d-4f heterometallic clusters, showing helical chirality. MChD spectroscopy reveals a high gMChD dissymmetry factor of ca. 0.24 T-1 (T = 4.0 K, B = 1.0 T) for the 4I13/2 ← 4I15/2 magnetic-dipole allowed electronic transition of the ErIII centers. This record value is 1 or 2 orders of magnitude higher than that of the d-d electronic transitions of the NiII ions and the others f-f electric-dipole induced transitions of the ErIII centers. These findings clearly show the key role that magnetic-dipole allowed transitions have in the rational design of chiral lanthanide systems showing strong MChD.

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Strengthened Interficial Adhesive Fracture Energy by Young's Modulus Matching Degree Strategy in Carbon-Based HTM Free MAPbI3 Perovskite Solar Cell with Enhanced Mechanical Compatibility.

Carbon-based hole transport layer-free perovskite solar cells (PSCs) based on methylammonium lead triiodide (MAPbI3 ) have become one of the research focus due to low cost, easy preparation, and good optoelectronic properties. However, instability of perovskite under vacancy defects and stress-strain makes it difficult to achieve high-efficiency and stable power output. Here, a soft-structured long-chain 2D pentanamine iodide (abbreviated as "PI") is used to improve perovskite quality and interfacial mechanical compatibility. PI containing CH3 (CH2 )4 NH3 + and I- ions not only passivate defects at grain boundaries, but also effectively alleviate residual stress during high temperature annealing via decreasing Young's modulus of perovskite film. Most importantly, PI effectively increases matching degree of Young's modulus between MAPbI3 (47.1 GPa) and carbon (6.7 GPa), and strengthens adhesive fracture energy (Gc ) between perovskite and carbon, which is helpful for outward release of nascent interfacial stress generated under service conditions. Consequently, photoelectric conversion efficiency (PCE) of optimal device is enhanced from 10.85% to 13.76% and operational stability is also significantly improved. 83.1% output is maintained after aging for 720 h at room temperature and 25-60% relative humidity (RH). This strategy of regulation from chemistry and physics provides a strategy for efficient and stable carbon-based PSCs.

Phenanthrothiophene-Triazine Star-Shaped Discotic Liquid Crystals: Synthesis, Self-Assembly, and Stimuli-Responsive Fluorescence Properties.

Lipophilic biphenylthiophene- and phenanthrothiophene-triazine compounds, BPTTn and CPTTn, respectively, were prepared by a tandem procedure involving successive Suzuki-Miyaura coupling and Scholl cyclodehydrogenation reactions. These compounds display photoluminescence in solution and in thin film state, solvatochromism with increasing solvent's polarity, as well as acidochromism and metal ion recognition stimuli-responsive fluorescence. Protonation of BPTT10 and CPTT10 by trifluoroacetic acid results in fluorescence quenching, which is reversibly restored once treated with triethylamine (ON-OFF switch). DFT computational studies show that intramolecular charge transfer (ICT) phenomena occurs for both molecules, and reveal that protonation enhances the electron-withdrawing ability of the triazine core and reduces the band gap. This acidochromic behavior was applied to a prototype fluorescent anti-counterfeiting device. They also specifically recognize Fe3+ through coordination, and the recognition mechanism is closely related to the photoinduced electron transfer between Fe3+ and BPTT10/CPTT10. CPTTn self-assemble into columnar rectangular (Colrec) mesophase, which can be modulated by oleic acid via the formation of a hydrogen-bonded supramolecular liquid crystal hexagonal Colhex mesophase. Finally, CPTTn also form organic gels in alkanes at low critical gel concentration (3.0 mg/mL). Therefore, these star-shaped triazine molecules possess many interesting features and thus hold great promises for information processing, liquid crystal semiconductors and organogelators.

Restoration of Foxp3+ Regulatory T Cells by HDAC-Dependent Epigenetic Modulation Plays a Pivotal Role in Resolving Pulmonary Arterial Hypertension Pathology.

Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets. Methods: Peripheral blood mononuclear cells were isolated from patients with idiopathic PAH (IPAH) and rodent models of pulmonary hypertension (PH): monocrotaline rats, Sugen5416-hypoxia rats, and Treg-depleted mice. HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) was used to examine the immune modulatory effects in vivo, ex vivo, and in vitro. Measurements and Main Results: Increased HDAC expression was associated with reduced Foxp3+ Tregs and increased PD-1 (programmed cell death-1) signaling in peripheral blood mononuclear cells from patients with IPAH. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3+ Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T-cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25+ Tregs in Sugen5416-hypoxia mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis. Conclusions: Our results indicated HDAC aberration was associated with Foxp3+ Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3+ Tregs by HDAC inhibitors is a promising approach to resolve pulmonary vascular pathology, highlighting the potential benefit of developing epigenetic therapies for PAH.

One-Step Construction of 1,3,4-Oxadiazoles with Anticancer Activity from Tertiary Amines via a Sequential Copper(I)-Catalyzed Oxidative Ugi/aza-Wittig Reaction.

An unparalleled copper(I)-catalyzed synthesis of 1,3,4-oxadiazoles from tertiary amines in one step has been described. The one-pot reactions involving (N-isocyanimine)triphenylphosphorane, tertiary amines, and carboxylic acids resulted in the formation of 1,3,4-oxadiazoles in moderate to good yields through a consecutive oxidative Ugi/aza-Wittig reaction, enabling the direct functionalization of sp3 C-H bonds adjacent to the nitrogen atom. This method offered several notable advantages, including ligands-free, exceptional productivity and a high functional group tolerance. The preliminary biological evaluation demonstrated that compound 4f inhibited hepatoma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.

Novel Metal-Free Synthesis of 3-Substituted Isocoumarins and Evaluation of Their Fluorescence Properties for Potential Applications.

A novel metal-free synthesis of 3-substituted isocoumarins through a sequential O-acylation/Wittig reaction has been established. The readily accessible (2-carboxybenzyl)-triphenylphosphonium bromide and diverse chlorides produced various 1H-isochromen-1-one in the presence of triethylamine, employing sequential O-acylation and an intramolecular Wittig reaction of acid anhydride. Reactions using these facile conditions have exhibited high functional group tolerance and excellent yields (up to 90%). Moreover, the fluorescence properties of isocoumarin derivatives were evaluated at the theoretical and experimental levels to determine their potential application in fluorescent materials. These derivatives have good photoluminescence in THF with a large Stokes shift and an absolute fluorescence quantum yield of up to 14%.

From Helices to Crystals: Multiscale Representation of Chirality in Double-Helix Structures.

Single crystals with chiral shapes aroused the interest of chemists due to their fascinating polarization rotation properties. Although the formation of large-scale spiral structures is considered to be a potential factor in chiral crystals, the precise mechanism behind their formation remains elusive. Herein, we present a rare phenomenon involving the multitransfer and expression of chirality at micro-, meso-, and macroscopic levels, starting from chiral carbon atoms and extending to the double-helical secondary structure, ultimately resulting in the chiral geometry of crystals. The assembly of the chiral double helices is facilitated by the dual characteristics of amide groups derived from amino acids, which serve as both hydrogen bond donors and receptors, similar to the assembly pattern observed in DNA. Crystal face analysis and theoretical morphology reveal two critical factors for the mechanism of the chiral crystal: inherent intrinsically symmetrical distribution of crystal faces and their acquired growth. Importantly, the magnetic circular dichroism (MCD) study reveals the strong magneto-optical response of the hypersensitive f-f transition in the UV-vis-NIR region, which is much stronger than previously observed signals. Remarkably, an external magnetic field can reverse the CD signal. This research highlights the potential of lanthanide-based chiral helical structures as promising magneto-optical materials.

Comparative effectiveness of prophylactic strategies for preeclampsia: a network meta-analysis of randomized controlled trials.

OBJECTIVE: Preeclampsia is a common disease during pregnancy that leads to fetal and maternal adverse events. Few head-to-head clinical trials are currently comparing the effectiveness of prophylactic strategies for preeclampsia. In this network meta-analysis, we aimed to compare the efficacy of prophylactic strategies for preventing preeclampsia in pregnant women at risk. DATA SOURCES: Articles published in or before September 2021 from PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov, references of key articles, and previous meta-analyses were manually searched. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing prophylactic strategies preventing preeclampsia with each other or with negative controls were included. METHODS: Two reviewers independently extracted data, assessed the risk of bias, and assessed evidence certainty. The efficacy of prophylactic strategies was estimated by frequentist and Bayesian network meta-analysis models. The primary composite outcome was preeclampsia/ pregnancy-induced hypertension. RESULTS: In total, 130 trials with a total of 112,916 patients were included to assess 13 prophylactic strategies. Low-molecular-weight heparin (0.60; 95% confidence interval, 0.42-0.87), vitamin D supplementation (0.65; 95% confidence interval, 0.45-0.95), and exercise (0.68; 95% confidence interval, 0.50-0.92) were as efficacious as calcium supplementation (0.71; 95% confidence interval, 0.62-0.82) and aspirin (0.79; 95% confidence interval, 0.72-0.86) in preventing preeclampsia/pregnancy-induced hypertension, with a P score ranking of 85%, 79%, 76%, 74%, and 61%, respectively. In the head-to-head comparison, no differences were found between these effective prophylactic strategies for preventing preeclampsia and pregnancy-induced hypertension, except with regard to exercise, which tended to be superior to aspirin and calcium supplementation in preventing pregnancy-induced hypertension. Furthermore, the prophylactic effects of aspirin and calcium supplementation were robust across subgroups. However, the prophylactic effects of low-molecular-weight heparin, exercise, and vitamin D supplementation on preeclampsia and pregnancy-induced hypertension varied with different risk populations, dosages, areas, etc. The certainty of the evidence was moderate to very low. CONCLUSION: Low-molecular-weight heparin, vitamin D supplementation, exercise, calcium supplementation, and aspirin reduce the risk of preeclampsia/pregnancy-induced hypertension. No significant differences between effective prophylactic strategies were found in preventing preeclampsia. These findings raise the necessity to reevaluate the prophylactic effects of low-molecular-weight heparin, vitamin D supplementation, and exercise on preeclampsia.

Synthetic Nuclease-Producing Microbiome Achieves Efficient Removal of Extracellular Antibiotic Resistance Genes from Wastewater Effluent.

Antibiotic resistance gene (ARG) transmission poses significant threats to human health. The effluent of wastewater treatment plants is demonstrated as a hotspot source of ARGs released into the environment. In this study, a synthetic microbiome containing nuclease-producing Deinococcus radiodurans was constructed to remove extracellular ARGs. Results of quantitative polymerase chain reaction (qPCR) showed significant reduction in plasmid RP4-associated ARGs (by more than 3 orders of magnitude) and reduction of indigenous ARG sul1 and mobile genetic element (MGE) intl1 (by more than 1 order of magnitude) in the synthetic microbiome compared to the control without D. radiodurans. Metagenomic analysis revealed a decrease in ARG and MGE diversity in extracellular DNA (eDNA) of the treated group. Notably, whereas eight antibiotic-resistant plasmids with mobility risk were detected in the control, only one was detected in the synthetic microbiome. The abundance of the nuclease encoding gene exeM, quantified by qPCR, indicated its enrichment in the synthetic microbiome, which ensures stable eDNA degradation even when D. radiodurans decreased. Moreover, intracellular ARGs and MGEs and pathogenic ARG hosts in the river receiving treated effluent were lower than those in the river receiving untreated effluent. Overall, this study presents a new approach for removing extracellular ARGs and further reducing the risk of ARG transmission in receiving rivers.

Melatonin ameliorates bleomycin-induced pulmonary fibrosis via activating NRF2 and inhibiting galectin-3 expression.

Pulmonary fibrosis (PF) is a chronic interstitial lung disease with no effective therapies. Galectin-3 (Gal-3), a marker of oxidative stress, plays a key role in the pathogenesis of PF. Fibroblast-myofibroblast differentiation (FMD) is an important source of fibrotic cells in PF. Previous studies showed that melatonin (MT) exerted anti-fibrotic effect in many diseases including PF through its antioxidant activity. In the present study we investigated the relationships among Gal-3, NRF2, ROS in FMD and their regulation by MT. We established an in vitro model of FMD in TGF-ß1-treated human fetal lung fibroblast1 (HFL1) cells and a PF mouse model via bleomycin (BLM) intratracheal instillation. We found that Gal-3 expression was significantly increased both in vitro and in vivo. Knockdown of Gal-3 in HFL1 cells markedly attenuated TGF-ß1-induced FMD process and ROS accumulation. In TGF-ß1-treated HFL1 cells, pretreatment with NRF2-specific inhibitor ML385 (5 µM) significantly increased the levels of Gal-3, α-SMA and ROS, suggesting that the expression of Gal-3 was regulated by NRF2. Treatment with NRF2-activator MT (250 µM) blocked α-SMA and ROS accumulation accompanied by reduced Gal-3 expression. In BLM-induced PF model, administration of MT (5 mg·kg-1·d-1, ip for 14 or 28 days) significantly attenuated the progression of lung fibrosis through up-regulating NRF2 and down-regulating Gal-3 expression in lung tissues. These results suggest that Gal-3 regulates TGF-ß1-induced pro-fibrogenic responses and ROS production in FMD, and MT activates NRF2 to block FMD process by down-regulating Gal-3 expression. This study provides a useful clue for a clinical strategy to prevent PF. Graphic abstract of the mechanisms. MT attenuated BLM-induced PF via activating NRF2 and inhibiting Gal-3 expression.

Double resonance induced by group coupling with quenched disorder.

Results show that the astrocytes can not only listen to the talk of large assemble of neurons but also give advice to the conversations and are significant sources of heterogeneous couplings as well. In the present work, we focus on such regulation character of astrocytes and explore the role of heterogeneous couplings among interacted neuron-astrocyte components in a signal response. We consider reduced dynamics in which the listening and advising processes of astrocytes are mapped into the form of group coupling, where the couplings are normally distributed. In both globally coupled overdamped bistable oscillators and an excitable FitzHugh-Nagumo (FHN) neuron model, we numerically and analytically demonstrate that two types of bell-shaped collective response curves can be obtained as the ensemble coupling strength or the heterogeneity of group coupling rise, respectively, which can be seen as a new type of double resonance. Furthermore, through the bifurcation analysis, we verify that these resonant signal responses stem from the competition between dispersion and aggregation induced by heterogeneous group and positive pairwise couplings, respectively. Our results contribute to a better understanding of the signal propagation in coupled systems with quenched disorder.

[Application of Rapid Detection Method Based on NG-Test® CARBA 5 in Bloodstream Infections Associated With Carbapenem-Resistant Enterobacterales].

Objective: To compare the consistency and accuracy of a rapid test method and a traditional test method for pathogen identification, antimicrobial susceptibility and carbapenemase type identification of positive blood culture samples. Methods: A total of 51 positive blood culture samples of bloodstream infection (BSI) were collected between March 2022 and May 2022. All samples were found to be "positive for Gram-negative bacilli" according to the blood smear results. The rapid method was adopted to perform rapid antimicrobial susceptibility test (RAST) and analysis of the positive blood culture samples. According to the RAST result interpretation standards, NG-Test® CARBA 5 was used for rapid carbapenemase detection of the imipenem-resistant strains and the results were confirmed by PCR. In addition, mass spectrometry, VITEK 2 Compact drug sensitivity analysis, and carbapenemase type identification were performed with the colonies cultured with positive samples according to the traditional method. Results: In the identification of bacteria, the rapid method and the traditional method had 100% consistency rate in the identification results of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. In the antimicrobial susceptibility test, the consistency rate between the results of the two methods was high and the consistency rate for results for susceptibility to imipenem was 100%. In the identification of carbapenemase type, 18 serinase-producing strains and 3 metal-ß-lactamase-producing strains of Enterobacterales were detected by the traditional method. With the rapid method, 18 Klebsiella pneumoniae carbapenemase (KPC)-producing strains, 2 New Delhi metallo-betalactamase (NDM)-producing strains, and 1 imipenem enzyme (IMP)-producing strain were identified in the blood culture samples by using a testing kit. Compared with the PCR results, the sensitivity and specificity of the rapid test for determining carbapenemase types were 100%. In this study, we investigated a rapid method for bacteria and carbapenemase type identification of positive blood culture specimens and found that the turnaround time (TAT) of the rapid method was reduced by 1.94 days on average in comparison with the TAT of the traditional method. Conclusion: The rapid method established in the study can effectively shorten the TAT for pathogenic microorganism identification and antimicrobial susceptibility test of blood culture samples, and the joint report of colloidal gold carbapenemase type identification results can provide a reference for clinicians to use antibiotics appropriately and accurately manage multi-drug resistant bacterial infections.

[Chemical reaction mechanism of decoction of traditional Chinese medicines: a review].

Complicated chemical reactions occur in the decoction of traditional Chinese medicines(TCMs) which features complex components, influencing the safety, efficacy, and quality controllability of TCMs. Therefore, it is particularly important to clarify the chemical reaction mechanism of TCMs in the decoction. This study summarized eight typical chemical reactions in the decoction of TCMs, such as substitution reaction, redox reaction, isomerization/stereoselective reaction, complexation, and supramolecular reaction. With the "toxicity attenuation and efficiency enhancement" of aconitines and other examples, this study reviewed the reactions in decoction of TCMs, which was expected to clarify the variation mechanisms of key chemical components in this process and to help guide medicine preparation and safe and rational use of medicine in clinical settings. The current main research methods for chemical reaction mechanisms of decoction of TCMs were also summed up and compared. The novel real-time analysis device of decoction system for TCMs was found to be efficient and simple without the pre-treatment of samples. This device provides a promising solution, which has great potential in quantity evaluation and control of TCMs. Moreover, it is expected to become a foundational and exemplary research tool, which can advance the research in this field.

Rasmussen's encephalitis is characterized by relatively lower production of IFN-ß and activated cytotoxic T cell upon herpes viruses infection.

BACKGROUND: The etiology of Rasmussen's encephalitis (RE), a rare chronic neurological disorder characterized by CD8+ T cell infiltration and unihemispheric brain atrophy, is still unknown. Various human herpes viruses (HHVs) have been detected in RE brain, but their contribution to RE pathogenesis is unclear. METHODS: HHVs infection and relevant immune response were compared among brain tissues from RE, temporal lobe epilepsy (TLE) and traumatic brain injury (TBI) patients. Viral antigen or genome, CD8+ T cells, microglia and innate immunity molecules were analyzed by immunohistochemical staining, DNA dot blot assay or immunofluorescence double staining. Cytokines were measured by multiplex flow cytometry. Cell apoptosis was visualized by TUNEL staining. Viral infection, immune response and the severity of unihemispheric atrophy were subjected to correlation analysis. RESULTS: Antigens of various HHVs were prevalent in RE and TLE brains, and the cumulative viral score of HHVs positively correlated with the unihemispheric atrophy in RE patients. CD8+ T cells infiltration were observed in both RE and TLE brains and showed co-localization with HHV antigens, but their activation, as revealed by Granzyme B (GZMB) release and apoptosis, was found only in RE. In comparison to TLE, RE brain tissues contained higher level of inflammatory cytokines, but the interferon-ß level, which was negatively correlated with cumulative viral score, was relatively lower. In line with this, the DNA sensor STING and IFI16, rather than other innate immunity signaling molecules, were insufficiently activated in RE. CONCLUSIONS: Compared with TBI, both RE and TLE had prevalently HHV infection and immune response in brain tissues. However, in comparison to TLE, RE showed insufficient activation of antiviral innate immunity but overactivation of cytotoxic T cells. Our results show the relatively lower level of antiviral innate immunity and overactivation of cytotoxic T cells in RE cases upon HHV infection, the overactivated T cells might be a compensate to the innate immunity but the causative evidence is lack in our study and need more investigation in the future.

A Carotenoid- and Nuclease-Producing Bacterium Can Mitigate Enterococcus faecalis Transformation by Antibiotic Resistance Genes.

Dissemination of antibiotic resistance genes (ARGs) through natural transformation is facilitated by factors that stabilize extracellular DNA (eDNA) and that induce reactive oxygen species (ROS) that permeabilize receptor cells and upregulate transformation competence genes. In this study, we demonstrate that Deinococcus radiodurans can mitigate this ARG dissemination pathway by removing both eDNA and ROS that make recipient cells more vulnerable to transformation. We used plasmid RP4 as source of extracellular ARGs (tetA, aphA, and blaTEM-2) and the opportunistic pathogen Enterococcus faecalis as receptor. The presence of D. radiodurans significantly reduced the transformation frequency from 2.5 ± 0.7 × 10-6 to 7.4 ± 1.4 × 10-7 (p < 0.05). Based on quantification of intracellular ROS accumulation and superoxide dismutase (SOD) activity, and quantitative polymerase chain reaction (qPCR) and transcriptomic analyses, we propose two mechanisms by which D. radiodurans mitigates E. faecalis transformation by ARGs: (a) residual antibiotics induce D. radiodurans to synthesize liposoluble carotenoids that scavenge ROS and thus mitigate the susceptibility of E. faecalis for eDNA uptake, and (b) eDNA induces D. radiodurans to synthesize extracellular nucleases that degrade eARGs. This mechanistic insight informs biological strategies (including bioaugmentation) to curtail the spread of ARGs through transformation.

Diversity-induced resonance in a globally coupled bistable system with diversely distributed heterogeneity.

A moderate degree of diversity, in form of quenched noise or intrinsic heterogeneity, can significantly strengthen the collective response of coupled extended systems. As yet, related discoveries on diversity-induced resonance are mainly concentrated on symmetrically distributed heterogeneity, e.g., the Gaussian or uniform distributions with zero-mean. The necessary conditions that guarantee the arise of resonance phenomenon in heterogeneous oscillators remain largely unknown. In this work, we show that the standard deviation and the ratio of negative entities of a given distribution jointly modulate diversity-induced resonance and the concomitance of negative and positive entities is the prerequisite for this resonant behavior emerging in diverse symmetrical and asymmetrical distributions. Particularly, for a proper degree of diversity of a given distribution, the collective signal response behaves like a bell-shaped curve as the ratio of negative oscillator increases, which can be termed negative-oscillator-ratio induced resonance. Furthermore, we analytically reveal that the ratio of negative oscillators plays a gating role in the resonance phenomenon on the basis of a reduced equation. Finally, we examine the robustness of these results in globally coupled bistable elements with asymmetrical potential functions. Our results suggest that the phenomenon of diversity-induced resonance can arise in arbitrarily distributed heterogeneous bistable oscillators by regulating the ratio of negative entities appropriately.

Linking Nonalcoholic Fatty Liver Disease and Brain Disease: Focusing on Bile Acid Signaling.

A metabolic illness known as non-alcoholic fatty liver disease (NAFLD), affects more than one-quarter of the world's population. Bile acids (BAs), as detergents involved in lipid digestion, show an abnormal metabolism in patients with NAFLD. However, BAs can affect other organs as well, such as the brain, where it has a neuroprotective effect. According to a series of studies, brain disorders may be extrahepatic manifestations of NAFLD, such as depression, changes to the cerebrovascular system, and worsening cognitive ability. Consequently, we propose that NAFLD affects the development of brain disease, through the bile acid signaling pathway. Through direct or indirect channels, BAs can send messages to the brain. Some BAs may operate directly on the central Farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) by overcoming the blood-brain barrier (BBB). Furthermore, glucagon-like peptide-1 (GLP-1) and the fibroblast growth factor (FGF) 19 are released from the intestine FXR and GPBAR1 receptors, upon activation, both of which send signals to the brain. Inflammatory, systemic metabolic disorders in the liver and brain are regulated by the bile acid-activated receptors FXR and GPBAR1, which are potential therapeutic targets. From a bile acid viewpoint, we examine the bile acid signaling changes in NAFLD and brain disease. We also recommend the development of dual GPBAR1/FXR ligands to reduce side effects and manage NAFLD and brain disease efficiently.

Evaluation of microleakage and push-out bond strength of various composite resins for sealing the screw-access channel in implant-supported restorations.

STATEMENT OF PROBLEM: Microleakage and loss of the composite resin sealing the screw-access channel are frequent complications of screw-retained implant-supported prostheses. How the screw-access channel should be best restored to reduce such complications is unclear. PURPOSE: The purpose of this in vitro study was to evaluate the microleakage and bond strength of 3 types of composite resins (flowable, packable, and bulk-fill) with or without a bonding agent treatment to seal the screw-access channel of 2 types of restorative materials (zirconia and Co-Cr alloy) with or without thermocycling. MATERIAL AND METHODS: In total, 240 yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) specimens (IPS e.max ZirCAD) and 240 Co-Cr alloy (Vera PDS) specimens were prepared with a Ø3×3-mm cylindrical cavity at the center to simulate the screw-access channel. Three types of composite resins (flowable, packable, and bulk-fill resin) (Filtek Z350 XT Flowable Restorative, Filtek Z350 XT Universal Restorative, and Filtek One Bulk Fill Restorative) were applied to restore the access channel of the zirconia and Co-Cr specimens with or without a bonding agent (Single Bond Universal Adhesive). Microleakage and push-out bond strength were determined and compared by dividing the specimens into experimental groups with or without thermocycling (1000 times with 30 seconds at 5 ±2 °C and 55 ±2 °C). The results were analyzed by using a 1-way ANOVA and 4-way ANOVA. Adjustment for multiple comparisons was made with the Tukey Honestly Significant Difference (HSD) test. RESULTS: The specimens subjected to thermocycling showed a lower bond strength (P<.001) and higher microleakage (P<.001) than specimens stored in a constant-temperature water bath. Specimens treated with bonding agents showed a higher bond strength (P<.001) and lower microleakage (P<.001) than specimens not treated with a bonding agent. Higher bond strengths were observed in the order of bulk-fill resin, packable resin, and flowable resin (P<.001). Packable resin showed higher microleakage than flowable resin and bulk-fill resin (P<.05). No significant difference in microleakage was found between the flowable resin and bulk-fill resin (P>.05). CONCLUSIONS: Higher bond strengths were observed in the order of bulk-fill resin, packable resin, and flowable resin. Less microleakage was observed in the flowable resin and bulk-fill resin than in the packable composite resin. Bonding agent treatment was effective in increasing bond strength and decreasing microleakage. Zirconia and Co-Cr showed a bond strength similar to that of composite resins, but zirconia showed higher microleakage than Co-Cr. Restoring the screw-access channel with the bulk-fill resin should increase bond strength and reduce microleakage.

[Sources of Klebsiella pneumoniae Isolated in a Hospital in the Past Decade and Trends and Changes of in vitro Drug Susceptibility].

Objective: To investigate the source of Klebsiella pneumoniae (KP) isolated in a hospital in the past decade and the in vitro drug susceptibility, and to provide clinical references for the treatment of KP-associated infection. Methods: The detection rate, the sources of the specimens, and in vitro susceptibility to antimicrobial agents of KP isolated from clinical specimens in a hospital between January 2012 and December 2021 were retrospectively analyzed. Resistance rate of the extended-spectrum ß-lactamases-producing isolates vs. that of the non-enzyme-producing ones, and the resistance rate of imipenem-resistant strains vs. that of imipenem-susceptible ones were compared and analyzed. Carbapenase inhibitor enhancement test was used to identify the types of the carbapenemases. Results: In total, 34 573 strains of KP were isolated from 1 684 668 clinical specimens, accounting for 14.6% of bacterial isolates. There were 16 888 non-repeated strains of KP. The main specimen sources of the isolates were sputum (10 274/16 888, 60.8%), blood (1 913/16 888, 11.3%) and urine (1 876/16 888, 11.1%). The proportion of extended-spectrum ß-lactamases-producing isolates increased from 29.6% (409/1 382) in 2012 to 38.9% (967/2 487) in 2021, and the resistance rate to antimicrobial agents was higher than that of non-enzyme-producing ones ( P<0.05). The proportion of imipenem-resistant strains increased from 3.2% (44/1 382) in 2012 to 23.4% (583/2 487) in 2021, and the resistance rate to antimicrobial agents was higher than that of imipenem-susceptible strains ( P<0.05). Serine carbapenase-producing strains accounted for 91.1% (920/1010). Conclusion: The resistance to antimicrobial agents of KP strains isolated from clinical specimens increased. It is necessary to monitor the in vitro drug susceptibility and the type of the carbapenemases of the isolates in order to provide guidance for the clinical usage of antibiotics.