Halide Anions Tuning of Lead-Free Perovskite-Type Ferroelectric Semiconductors with Inverse High-Temperature Symmetry Breaking.

There is a noticeable gap in the literature regarding research on halogen-substitution-regulated ferroelectric semiconductors featuring multiple phase transitions. Here, a new category of 1D perovskite ferroelectrics (DFP)2 SbX5 (DFP+ = 3,3-difluoropyrrolidium, X- = I- , Br- , abbreviated as I-1 and Br-2) with twophase transitions (PTs) is reported. The first low-temperature PT is a mmmFmm2 ferroelectric PT, while the high-temperature PT is a counterintuitive inverse temperature symmetry-breaking PT. By the substitution of iodine with bromine, the Curie temperature (Tc) significantly increases from 348 K of I-1 to 374 K of Br-2. Their ferroelectricity and pyroelectricity are improved (Ps value from 1.3 to 4.0 µC cm-2 , pe value from 0.2 to 0.48 µC cm-2  K-1 for I-1 and Br-2), while their optical bandgaps increased from 2.1 to 2.7 eV. A critical slowing down phenomenon is observed in the dielectric measurement of I-1 while Br-2 exhibits the ferroelastic domain. Structural and computational analyses elucidate that the order-disorder movement of cations and the distortion of the chain perovskite [SbX5 ]2- anions skeleton lead to PT. The semiconductor properties are determined by [SbX5 ]2- anions. The findings contribute to the development of ferroelectric semiconductors and materials with multiple PTs and provide materials for potential applications in the optoelectronic field.

Human Exposure to Ambient Atmospheric Microplastics in a Megacity: Spatiotemporal Variation and Associated Microorganism-Related Health Risk.

Microplastics are found in various human tissues and are considered harmful, raising concerns about human exposure to microplastics in the environment. Existing research has analyzed indoor and occupational scenarios, but long-term monitoring of ambient atmospheric microplastics (AMPs), especially in highly polluted urban regions, needs to be further investigated. This study estimated human environmental exposure to AMPs by considering inhalation, dust ingestion, and dermal exposure in three urban functional zones within a megacity. The annual exposure quantity was 7.37 × 104 items for children and 1.06 × 105 items for adults, comparable with the human microplastic consumption from food and water. Significant spatiotemporal differences were observed in the characteristics of AMPs that humans were exposed to, with wind speed and rainfall frequency mainly driving these changes. The annual human AMP exposure quantity in urban green land spaces, which were recognized as relatively low polluted zones, was comparable with that in public service zones and residential zones. Notably, significant positive correlations between the AMP characteristics and the pathogenicity of the airborne bacterial community were discovered. AMP size and immune-mediated disease risks brought by atmospheric microbes showed the most significant relationship, where Sphingomonas might act as the potential key mediator.

Potential environmental risks of field bio/non-degradable microplastic from mulching residues in farmland: Evidence from metagenomic analysis of plastisphere.

The plastisphere may act as reservoir of antibiotic resistome, accelerating global antimicrobial resistance dissemination. However, the environmental risks in the plastisphere of field microplastics (MPs) in farmland remain largely unknown. Here, antibiotic resistance genes (ARGs) and virulence factors (VFs) on polyethylene microplastics (PE-MPs) and polybutylene adipate terephthalate and polylactic acid microplastics (PBAT/PLA-MPs) from residues were investigated using metagenomic analysis. The results suggested that the profiles of ARG and VF in the plastisphere of PBAT/PLA-MPs had greater number of detected genes with statistically higher values of diversity and abundance than soil and PE-MP. Procrustes analysis indicated a good fitting correlation between ARG/VF profiles and bacterial community composition. Actinobacteria was the major host for tetracycline and glycopeptide resistance genes in the soil and PE-MP plastisphere, whereas the primary host for multidrug resistance genes changed to Proteobacteria in PBAT/PLA-MP plastisphere. Besides, three human pathogens, Sphingomonas paucimobilis, Lactobacillus plantarum and Pseudomonas aeruginosa were identified in the plastisphere. The PE-MP plastisphere exhibited a higher transfer potential of ARGs than PBAT/PLA-MP plastisphere. This work enhances our knowledge of potential environmental risks posed by microplastic in farmland and provides valuable insights for risk assessment and management of agricultural mulching applications.

Taxifolin inhibits melanoma proliferation/migration impeding USP18/Rac1/JNK/ß-catenin oncogenic signaling.

BACKGROUND: Metastatic melanoma is a fatal cancer. Despite the advances in targeted therapy and immunotherapy for patients with melanoma, drug resistance and low response rates pose a considerable challenge. Taxifolin is a multifunctional natural compound with emerging antitumor potentials. However, its utility in melanoma treatment remains unclear. PURPOSE: The study aimed to investigate the effect of purified Taxifolin from Larix olgensis roots (Changbai Mountain, China) on melanoma and explore the underlying mechanism. METHODS: Purified Taxifolin from Larix olgensis roots was evaluated for its antimelanoma effects in vitro and in vivo settings. RNA-seq analysis was performed to explore the underlying mechanism. RESULTS: Purified Taxifolin (> 99 %) from Larix olgensis roots inhibited the proliferation and migration of B16F10 melanoma cells at 200 and 400 µM, and of A375 cells at 100 and 200 µM. Taxifolin administered at 60 mg/kg suppressed tumor growth and metastasis in mouse models without causing significant toxicity. Taxifolin modulated USP18/Rac1/JNK/ß-catenin axis to exert its antitumor effect. CONCLUSION: These findings indicate that Taxifolin derived from Larix olgensis roots may be a promising antimelanoma therapy.

Enhanced Electrocaloric Effect of Lead Scandium Tantalate by Zirconium Doping.

The electrocaloric effect (ECE) is a novel technology that offers high efficiency and environmental friendliness, making it suitable for solid-state refrigeration applications. Among the extensively studied ECE materials, lead scandium tantalate (PST) stands out for its excellent performance. However, its applications are restricted by its narrow working temperature range. To overcome this limitation, we explore the enhancement of the ECE through zirconium ion doping. We synthesized PbSc0.5-0.5xTa0.5-0.5xZrxO3 samples (x = 0, 0.025, 0.05, 0.075). The introduction of zirconium ions led to an increase in the Curie temperature from 28.9 °C (x = 0) to 55.5 °C (x = 0.075). Additionally, the relaxation factor γ of the ceramics increased from 1.40 (x = 0) to 1.59 (x = 0.075). The temperature span (Tspan) exhibited a rising trend with increasing x, reaching 10.9 K at x = 0.075. The maximum temperature change (ΔTmax) was observed at x = 0.025, with a value of 1.94 K. X-ray diffraction (XRD) patterns revealed that zirconium ion doping influenced the B-site ordering degree, thereby regulating the ECE. To further validate the results, we employed direct measurements and thermodynamic calculations. Overall, the regulation of ionic ordering through zirconium doping effectively enhances the ECE performance. These findings contribute to the development of advanced materials for solid-state refrigeration technologies.

Plastic substrate and residual time of microplastics in the urban river shape the composition and structure of bacterial communities in plastisphere.

The widespread secondary microplastics (MPs) in urban freshwater, originating from plastic wastes, have created a new habitat called plastisphere for microorganisms. The factors influencing the structure and ecological risks of the microbial community within the plastisphere are not yet fully understood. We conducted an in-site incubation experiment in an urban river, using MPs from garbage bags (GB), shopping bags (SB), and plastic bottles (PB). Bacterial communities in water and plastisphere incubated for 2 and 4 weeks were analyzed by 16S high-throughput sequencing. The results showed the bacterial composition of the plastisphere, especially the PB, exhibited enrichment of plastic-degrading and photoautotrophic taxa. Diversity declined in GB and PB but increased in SB plastisphere. Abundance analysis revealed distinct bacterial species that were enriched or depleted in each type of plastisphere. As the succession progressed, the differences in community structure was more pronounced, and the decline in the complexity of bacterial community within each plastisphere suggested increasing specialization. All the plastisphere exhibited elevated pathogenicity at the second or forth week, compared to bacterial communities related to natural particles. These findings highlighted the continually evolving plastisphere in urban rivers was influenced by the plastic substrates, and attention should be paid to fragile plastic wastes due to the rapidly increasing pathogenicity of the bacterial community attached to them.

Efficacy and safety of innate and adaptive immunotherapy combined with standard of care in high-grade gliomas: a systematic review and meta-analysis.

Background: Malignant glioma is the most common intracranial malignant tumor with the highest mortality. In the era of immunotherapy, it is important to determine what type of immunotherapy provides the best chance of survival. Method: Here, the efficacy and safety of immunotherapy in high-grade glioma (HGG) were evaluated by systematic review and meta-analysis. The differences between various types of immunotherapy were explored. Retrieved hits were screened for inclusion in 2,317 articles. We extracted the overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) as two key outcomes for examining the efficacy of immunotherapy. We also analyzed data on the reported corresponding adverse events to assess the safety of immunotherapy. This study was registered with PROSPERO (CRD42019112356). Results: We included a total of 1,271 patients, of which 524 received a combination of immunotherapy and standard of care (SOC), while 747 received SOC alone. We found that immunotherapy extended the OS (HR = 0.74; 95% confidence interval [CI], 0.56-0.99; Z = -2.00, P = 0.0458 < 0.05) and PFS (HR = 0.67; 95% CI, 0.45-0.99; Z = -1.99, P = 0.0466 < 0.05), although certain adverse events occurred (proportion = 0.0773, 95% CI, 0.0589-0.1014). Our data have demonstrated the efficacy of the dendritic cell (DC) vaccine in prolonging the OS (HR = 0.38; 95% CI, 0.21-0.68; Z = -3.23; P = 0.0012 < 0.05) of glioma patients. Oncolytic viral therapy (VT) only extended patient survival in a subgroup analysis (HR = 0.60; 95% CI, 0.45-0.80; Z = -3.53; P = 0.0004 < 0.05). By contrast, immunopotentiation (IP) did not prolong OS (HR = 0.69; 95% CI, 0.50-0.96; Z = -2.23; P = 0.0256). Conclusion: Thus, DC vaccination significantly prolonged the OS of HGG patients, however, the efficacy of VT and IP should be explored in further studies. All the therapeutic schemes evaluated were associated with certain side effects. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=112356.

The oil price-macroeconomy dependence.

This paper investigates the relationship between the price of oil and real output in the United States in the context of a Markov regime switching, identified, structural GARCH-in-Mean VAR model with copulas. We use the copula method to investigate the nonlinear dependence structure, as well as (upper and lower) tail dependence, between the price of oil and real output growth, and Markov regime switching to account for changing oil price dynamics over the sample period. We find an asymmetric negative dependence structure between oil price and output growth shocks and that oil price uncertainty has a negative and statistically significant effect on real output growth.

Maternal body mass index and risk of fetal overgrowth in women with gestational diabetes Mellitus in Southeast China: a retrospective cohort study.

BACKGROUND: To investigate the relationship between body mass index (BMI) changes and large for gestational age (LGA) in women with gestational diabetes mellitus (GDM). METHODS: A retrospective cohort study including 10,486 women with GDM was conducted. A dose‒response analysis of BMI changes and the occurrence of LGA was performed. Binary logistic regressions were performed to assess crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Receiver operating characteristic (ROC) curves and areas under the curve (AUCs) were used to assess the ability of BMI changes to predict LGA. RESULTS: The probability of LGA increased with increasing BMI. The risk of LGA increased across the BMI change quartiles. The BMI change remained positively associated with the risk of LGAafter stratification analysis. The AUC was 0.570 (95% CI: 0.557 ~ 0.584)in the entire study population, and the best optimal predictive cut-off value was 4.922, with a sensitivity of 0.622 and a specificity of 0.486. The best optimal predictive cut-off value decreased from the underweight group to the overweight and obese group. CONCLUSIONS: BMI changes are related to the risk of LGA and may be a useful predictor of the incidence of LGA in singleton pregnant women with GDM.

Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance.

Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following recombination-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.

Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance.

Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following homology-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.

Stat3 shRNA delivery with folate receptor-modified multi-functionalized graphene oxide particles for combined infrared radiation and gene therapy in hepatocellular carcinoma.

As a vital oncogene, a variety of inhibitors targeting Stat3 and its various upstream signaling pathways has been explored. Since small molecules, peptidomimetics and other peptide inhibitors usually lead to side effects and difficult administration, gene therapeutics that have characteristics of low toxicity and high targeting, make them an attractive alternative for targeting Stat3. A major challenge to this approach is the lack of safe delivery systems for in-vivo applications. Among the various siRNA delivery systems, nanoparticles emerge as a new tool for gene delivery with high biocompatibility, low cost, and minimal toxicity. In this study, we developed a graphene oxide (GO)-based nanocarrier, GO-polyethyleneimine (PEI)-polyethylene glycol (PEG)-folic acid (FA), as a tool targeting for Stat3-specific shRNA to mouse hepatoma cells in vitro and in vivo . Infrared photothermal therapy was combined in vivo since GO has the characteristic of infrared absorbability. Our results suggest a significant tumor growth inhibition after treatment with GO-PEI-PEG-FA- sh-Stat3 combined with infrared photothermal therapy. Thus, GO-PEI-PEG-FA appears to be a novel nano-transformer that could be used in the clinics in future.

The plastisphere of biodegradable and conventional microplastics from residues exhibit distinct microbial structure, network and function in plastic-mulching farmland.

The inhomogeneity of plastisphere and soil may result in different microbial communities, thus potentially affecting soil functions. Biodegradable plastics offer an alternative to conventional plastics, nevertheless, the inadequate end-of-life treatment of biodegradable plastics may release more microplastics. Herein, we collected PE and PBAT/PLA microplastics in plastic-mulching farmland in Hebei, China. The bacterial communities of soil, PE and PBAT/PLA plastisphere were investigated using 16 S high-throughput sequencing. We found that the structure of bacterial communities in PBAT/PLA plastisphere were significantly distinct from PE plastisphere and soil. The alpha diversities in PBAT/PLA plastisphere were significantly lower than PE plastisphere and soil. Statistical analysis of differentially ASVs suggested that PBAT/PLA microplastics act as a filter, enriching taxa with the capability to degrade plastic polymers such as Proteobacteria and Actinobacteria. Compared to PE plastisphere, PBAT/PLA plastisphere has networks of less complexity, lower modularity, and more competitive interactions. Predicted metabolic pathways involved in human diseases, carbohydrate metabolism, amino acid metabolism, and xenobiotic biodegradation and metabolism were promoted in PBAT/PLA plastisphere, along with the facilitation in abundance of genes associated with carbon and nitrogen cycling. Our results highlighted the uniqueness of plastisphere of biodegradable microplastics from conventional microplastics and their potential impact on soil functions.

RSL3 triggers glioma stem cell differentiation via the Tgm2/AKT/ID1 signaling axis.

RSL3 is a synthetic molecule that inactivates glutathione peroxidase 4 to induce ferroptosis. However, its effect on glioma stem cells (GSC) remains unclear. In this study, we found that RSL3 significantly suppressed GSC proliferation and induced their differentiation into astrocytes, which was accompanied by the downregulation of stemness-related markers, including Nestin and Sox2. Combined transcriptome and proteome analyses further revealed that RSL3 promoted GSC differentiation by suppressing transglutaminase 2 (Tgm2), but not by ferroptosis-related pathways. Tgm2 overexpression in CSC2078 cells rescued the changes in stemness-related markers and differentiation caused by RSL3, which was mediated by inhibitor of DNA binding 1 (ID1) activation. Further studies identified ID1 as a downstream signaling target of Tgm2. Blocking the phosphoinositide-3 kinase (PI3K)/Akt pathway with LY294002 suppressed PI3K, p-Akt, and ID1 levels but not Tgm2. Tgm2 overexpression abrogated the changes in PI3K, p-Akt, and ID1 levels caused by LY294002. Taken together, we demonstrate that RSL3 does not induce ferroptosis; instead, it inhibits GSC proliferation and triggers their differentiation by suppressing the Tgm2/Akt/ID1 signaling axis.

The lag-effects of meteorological factors and air pollutants on child respiratory diseases in Fuzhou, China.

Background: The effects of meteorological factors and air pollutants on respiratory diseases (RDs) were various in different populations according to the demographic characteristics, and children were considered a vulnerable population. Previous studies were mainly based in cities with serious air pollution. This study aimed to qualify the lag effects of meteorological factors and air pollution on respiratory diseases among children under 18 years old in Fuzhou. Methods: Meteorological data, air pollutants concentrations and hospital admission data of Fujian Maternity and Child Health Hospital between 2015 and 2019 were collected. A Distributed Lag Nonlinear Model (DLNM) was used to evaluate the nonlinear and lagged effect of meteorological factors and air pollutants on daily RDs number. A subgroup analysis was also conducted to evaluate the effect on different sex groups and age groups. Results: A total number of 796 125 RDs visits was included during the study period. For meteorological factors, lower mean temperature and relative humidity were significantly associated with daily RDs number (peak relative risk (RR) = 1.032 (95% confidence interval (CI) = 1.011-1.053) and 1.021 (95% CI = 1.013-1.029)), while lower wind speed showed a significant association at low range (peak RR = 0.995 (95% CI = 0.992-0.999)). Temperature warming was a significant protective factor for RDs (peak RR = 0.989 (95% CI = 0.986-0.993)). For air pollutants, SO2, NO2, PM10 and PM2.5 were all significantly associated with RDs (peak RR = 1.028 (95% CI = 1.022-1.035), 1.024 (95% CI = 1.013-1.034), 1.036 (95% CI = 1.025-1.047), 1.028 (95% CI = 1.019-1.037)), and the relationship had no threshold. The estimated RR and peak lag day did not change extremely between subgroups. Conclusions: The findings provide statistical evidence for the prevention of child RDs. In addition, our findings suggested that even at low concentrations, air pollutants still have negative effects on the respiratory system.

Automated identification and quantification of invisible microplastics in agricultural soils.

Microplastics in agricultural soils have become the research hotspot in recent years, however, the quantitative methods based on the traditional visual inspection may have a high false detection rate. Here we combined the laser direct infrared (LDIR) and Fourier-transform infrared (FTIR) methods to investigate the microplastics in farmland with long-term agricultural activities. The results showed that the total abundance of microplastics reached 1.98 ± 0.41 × 105, 1.57 ± 0.28 × 105, 1.78 ± 0.27 × 105, and 3.20 ± 0.41 × 105 particles/kg soil in cotton fields with film mulching of 5, 10, 20, and >30 years, respectively. LDIR results indicated that microplastics ranging from 10 to 500 µm accounted for 96.5-99.9 % of the total microplastic amounts in the soils. Additionally, a total of 26 polymer types of microplastics were detected, among which polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC), polyamide (PA), and polytetrafluoroethylene (PTFE) were dominantly observed. For the microplastics detected by FTIR (500 µm-5 mm), PE polymer was majorly observed (88.0-98.9 %). Most microplastics were films (88.2 %), while fibers and pellets were also found. The reclaimed water from sewage treatment plants, the drip irrigation utilities, and the residual plastic film are the potential sources of microplastics in the farmland soils. By using the automated quantitative and identifiable approaches, this study suggested that the commonly used visual counting method may underestimate the microplastic contamination in agricultural soils.

Intervertebral Disc Degeneration and Low Back Pain Depends on Duration and Magnitude of Axial Compression.

Purpose: The pathological role of axial stress in intervertebral disc degeneration (IDD) is controversial, and there was no quantified study until now. Here, we tried to clarify the correlation between IDD or low back pain (LBP) and axial stress at different duration and magnitude in vitro and in vivo. Method: In vitro, the gene expression of aggrecan, matrix metalloproteinase-3 (MMP3), calcitonin gene-related peptide (CGRP), and substance P (SP) was measured when nucleus pulposus cells (NPCs) were compressed under gradual severity. In vivo, a measurable Ilizarov-type compression apparatus was established for single coccygeal (Co) intervertebral disc (IVD) compression of Co7-8 in mouse. Gradient stress was placed at 0.4 Mpa (mild), 0.8 Mpa (moderate), and 1.2 Mpa (severe) for three days to investigate the effect of the magnitude of axial stress. Additionally, mild compression with 3, 7, and 14 days was used to determine the effect of the duration of axial stress. Subsequently, we evaluated the severity of IDD and LBP by radiological X-ray film; histological examination with H&E staining; immunohistochemical analysis with collagen II, aggrecan, and CGRP staining; and western blot analysis with collagen II, aggrecan, MMP-3, and interleukin-1ß (IL-1ß). Results: When NPCs suffered gradual increased mechanical stress, the cells exhibited gradual downregulated expression of extracellular matrix (ECM)-related gene of aggrecan, upregulated expression of IDD-related gene of MMP3, and LBP-related gene of CGRP and SP. In the meantime, with different magnitudes of axial stress, the IVD showed progressively severe IDD and LBP, with gradual narrowing intervertebral height, destruction of IVD anatomy, decreased ECM, and increased catabolic factors and proalgesic peptides. Conclusion: Axial compression is one of the critical pathological factors to cause IDD and LBP, and there was a strong positive correlation depended on the duration and magnitude of compression.

Epigenetic regulation of cancer stem cells: Shedding light on the refractory/relapsed cancers.

The resistance to drugs, ability to enter quiescence and generate heterogeneous cancer cells, and enhancement of aggressiveness, make cancer stem cells (CSCs) integral part of tumor progression, metastasis and recurrence after treatment. The epigenetic modification machinery is crucial for the viability of CSCs and evolution of aggressive forms of a tumor. These mechanisms can also be targeted by specific drugs, providing a promising approach for blocking CSCs. In this review, we summarize the epigenetic regulatory mechanisms in CSCs which contribute to drug resistance, quiescence and tumor heterogeneity. We also discuss the drugs that can potentially target these processes and data from experimental and clinical studies.

Nocathiacin, Thiazomycin, and Polar Analogs Are Highly Effective Agents against Toxigenic Clostridioides difficile.

Clostridioides difficile is a commensal Gram-positive gut bacterium that causes C. difficile-associated diarrhea. Currently available antibacterial therapeutic treatment options are effective except for the repeated recurrences significantly burdening the health care system and causing mortality. The development of new therapeutic modalities including new effective antibiotics with a low rate of recurrence has been unpredictive and exceedingly challenging, requiring continued profiling of many new classes of antibiotics. Nocathiacins and thiazomycins are a class of thiazolyl peptides exhibiting potent and selective broad-spectrum Gram-positive activity including activity against the anaerobe C. difficile. These compounds showed MIC values of 0.015-0.06 µg/mL against C. difficile with more than 100-200-fold selectivity versus commensurate Gram-negative Bacteroides fragilis. Nocathiacin I and one of its analogs exhibited potent in vivo efficacy in the gold-standard hamster model of C. difficile infection, providing 100% protection in this lethal model at 6.25 mg/kg orally twice daily. The efficacy was corroborated by robust reduction of cecum C. difficile burden and proportionate exposure of the compounds in the cecum contents without any systemic absorption. In this paper, details of the results of in vitro, in vivo, pharmacodynamics, and pharmacokinetic studies have been described.

Roles for the methyltransferase SETD8 in DNA damage repair.

Epigenetic posttranslational modifications are critical for fine-tuning gene expression in various biological processes. SETD8 is so far the only known lysyl methyltransferase in mammalian cells to produce mono-methylation of histone H4 at lysine 20 (H4K20me1), a prerequisite for di- and tri-methylation. Importantly, SETD8 is related to a number of cellular activities, impinging upon tissue development, senescence and tumorigenesis. The double-strand breaks (DSBs) are cytotoxic DNA damages with deleterious consequences, such as genomic instability and cancer origin, if unrepaired. The homology-directed repair and canonical nonhomologous end-joining are two most prominent DSB repair pathways evolved to eliminate such aberrations. Emerging evidence implies that SETD8 and its corresponding H4K20 methylation are relevant to establishment of DSB repair pathway choice. Understanding how SETD8 functions in DSB repair pathway choice will shed light on the molecular basis of SETD8-deficiency related disorders and will be valuable for the development of new treatments. In this review, we discuss the progress made to date in roles for the lysine mono-methyltransferase SETD8 in DNA damage repair and its therapeutic relevance, in particular illuminating its involvement in establishment of DSB repair pathway choice, which is crucial for the timely elimination of DSBs.