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In this study, we demonstrated that both the expression of most ribosomal protein genes and the amount of ribosomes were decreased in the Δaa3 mutant of Mycobacterium smegmatis, in which the major terminal oxidase (aa3 cytochrome c oxidase) of the respiratory electron transport chain (ETC) is inactivated, compared to those in the wild-type strain. Deletion of the rel gene encoding the major (p)ppGpp synthetase in the background of the Δaa3 mutant restored the reduced expression of ribosomal protein genes, suggesting that inhibition of the respiratory ETC leads to the Rel-dependent stringent response (SR) in this bacterium. Both a decrease in the expression of ribosomal protein genes by overexpression of rel and the increased expression of rel in the Δaa3 mutant relative to the wild-type strain support the Rel-dependent induction of SR in the Δaa3 mutant. We also demonstrated that the expression of ribosomal protein genes was decreased in M. smegmatis exposed to respiration-inhibitory conditions, such as KCN and bedaquiline treatment, null mutation of the cytochrome bcc1 complex, and hypoxia. The MprBA-SigE-SigB regulatory pathway was implicated in both the increased expression of rel and the decreased expression of ribosomal protein genes in the Δaa3 mutant of M. smegmatis.

Cannabis (Cannabis sativa) is a versatile crop belonging to the Cannabaceae family, and is dioecious, typically with separate male and female plants. The flowers of female plants, especially the trichomes, accumulate relatively higher contents of cannabinoids compared with those of male plants. For this reason, to obtain seeds that are genetically female, it is desirable to induce the development of male flowers on a female plant that produces genetically female haploid gametes. Silver thiosulfate (STS) is a highly effective chemical for male flower induction. We investigated male flower induction in three commercial cultivars of female cannabis (Spectrum303, SuperwomanS1, and CBGambit) regarding the treatment frequency, stage of application, and concentration of STS applied as a foliar spray. All three cultivars showed adequate induction of male flowers in response to 1.5 mM STS applied at the early reproductive stage. In particular, SuperwomanS1 was most highly responsive to induction of male flowers, even when treated with 0.3 mM STS at the early reproductive stage. Treatment with three applications of STS was more effective compared with a single application, but a single application of 1.5 mM STS at the early reproductive stage was sufficient for male flower induction. A single STS application during the middle stage of reproductive growth was inadequate for induction of male flowers. However, 6 weeks after three applications of STS, CBGambit exhibited approximately 54% male flower induction at 0.3 mM STS, Spectrum303 showed approximately 56% induction at 3 mM STS, and SuperwomanS1 yielded approximately 26% induction at 1.5 mM (expressed as percentage of total number of individuals with the induced male flowers). Pollen stainability tests using KI-I2 solution and Alexander’s staining showed high pollen viability with over 65% at different single STS concentrations, indicating that pollen grains induced by STS have sufficient viability for the self-pollination. This study demonstrated that different cultivars of cannabis respond diversely to different STS concentrations and highlighted the potential benefits of three STS applications during the middle reproductive stage for cannabis breeding.

Enhancements to the analytical method for the determination of tricyclazole in rice samples have been applied to monitor residues during unmanned aerial spraying. The acetonitrile extraction technique QuEChERS was improved by the incorporation of ethyl acetate and 0.1% formic acid, which significantly elevated the recovery rates. Furthermore, the purification process was refined by integrating both primary–secondary amine (PSA) and C18 in the dSPE method, achieving a substantial improvement in reducing matrix effects (MEs) and increasing recovery efficiency. The optimized method demonstrated an impressive % ME value at −3.1%, with a limit of quantitation (LOQ) established at 0.01 mg/kg, and recovery rates between 94.7 and 95.6% at 0.01, 0.1, and 2 mg/kg. Using two types of adjuvants (stickers) during multi-copter spraying markedly improved the initial tricyclazole deposition on rice panicles, with residue levels initially increasing from 0.35 mg/kg to between 0.68 and 1.60 mg/kg. Residues in hulled rice at harvest (10 days post-application) remained well below the maximum residue limit (MRL) of 0.7 mg/kg, ranging from 0.02 to 0.11 mg/kg, thus affirming the safety and efficacy of adjuvants in residue management.

To prevent pesticides from exceeding maximum residue limits (MRLs) in crops during export and shipment, it is necessary to manage residue levels during the pre-harvest stages. Therefore, the Republic of Korea establishes pre-harvest residue limits (PHRLs) per crop and pesticide. This study was conducted to set PHRLs for penthiopyrad and tebufenpyrad in angelica leaves, where the exceedance rates of MRLs are expected to be high. The LOQ of the analytical method used was 0.01 mg/kg and it demonstrated good linearity, with a correlation coefficient of 0.999 or higher within the quantitation range of 0.005 to 0.5 mg/kg. The recovery and storage stability accuracy values were in the range of 94.5–111.1%, within the acceptable range (70–120%, RSD ≤ 20%). The matrix effect for both pesticides was in the medium-to-strong range, and it did not significantly impact the quantitative results as a matrix-matched calibration method was employed. Using the validated method, residue concentrations of penthiopyrad 20 (%) EC and tebufenpyrad 10 (%) EC were analyzed. Both pesticides exhibited a decreasing residue trend over time. In Fields 1–3 and their integrated results, the biological half-life was within 2.6–4.0 days for penthiopyrad and 3.0–4.2 days for tebufenpyrad. The minimum value of the regression coefficient in the dissipation curve regression equation was selected as the dissipation constant. The selected dissipation constants for penthiopyrad in Fields 1–3 and their integration were 0.1221, 0.2081, 0.2162, and 0.1960. For tebufenpyrad, the dissipation constants were 0.1451, 0.0960, 0.1725, and 0.1600, respectively. The dissipation constant was used to calculate PHRL per field. Following the principles of the PHRL proposal process, residue levels (%) on PHI dates relative to MRLs were calculated, and fields for proposing PHRLs were selected. For penthiopyrad, since the residue level (%) was less than 20%, the PHRL for Field 3 with the largest dissipation constant was proposed. For tebufenpyrad, as the residue level (%) exceeded 80%, the PHRL proposal could not established. It is deemed necessary to reassess the MRL and ‘guidelines for safe use’ for tebufenpyrad in angelica leaves.

Rapeseed (Brassica napus L.) holds significant commercial value as one of the leading oil crops, with its agronomic features and oil quality being crucial determinants. In this investigation, 73,226 single nucleotide polymorphisms (SNPs) across 95 rapeseed mutant lines induced by gamma rays, alongside the original cultivar (‘Tamra’), using genotyping-by-sequencing (GBS) analysis were examined. This study encompassed gene ontology (GO) analysis and a genomewide association study (GWAS), thereby concentrating on agronomic traits (e.g., plant height, ear length, thousand-seed weight, and seed yield) and oil traits (including fatty acid composition and crude fat content). The GO analysis unveiled a multitude of genes with SNP variations associated with cellular processes, intracellular anatomical structures, and organic cyclic compound binding. Through GWAS, we detected 320 significant SNPs linked to both agronomic (104 SNPs) and oil traits (216 SNPs). Notably, two novel candidate genes, Bna.A05p02350D (SFGH) and Bna.C02p22490D (MDN1), are implicated in thousand-seed weight regulation. Additionally, Bna.C03p14350D (EXO70) and Bna.A09p05630D (PI4Kα1) emerged as novel candidate genes associated with erucic acid and crude fat content, respectively. These findings carry implications for identifying superior genotypes for the development of new cultivars. Association studies offer a cost-effective means of screening mutants and selecting elite rapeseed breeding lines, thereby enhancing the commercial viability of this pivotal oil crop.

Kenaf (Hibiscus cannabinus L.), in the Malvaceae family, is an important crop for not only fiber production, but also various other industrial materials. We performed phylogenetic analysis and a genome-wide association study (GWAS) of seven agronomic traits: days to flowering, plant height, fresh weight, dry weight, flower color, stem color, and leaf shape, using 96 kenaf genotypes, including gamma-irradiation-derived mutant lines. Genotypes were determined by genotyping-by-sequencing (GBS) and a total of 49,241 single-nucleotide polymorphisms (SNPs) were used in the analysis. Days to flowering, plant height, fresh weight, and dry weight were positively correlated with each other, and stem color was also correlated with fresh weight and dry weight. The phylogenetic analysis divided the 96 lines into nine related groups within two independent groups, and the GWAS analysis detected a total of 49 SNPs for days to flowering, plant height, fresh weight, dry weight, flower color, stem color, and leaf shape with −log10(P) ≥ 4, of which 22 were located in genic regions. The detected SNPs were located in genes with homology ranging from 45% to 96% to plants of the Malvaceae and Betulaceae, and these genes were found to be involved in plant growth and development via various pathways. Our identification of SNP markers related to agronomic traits is expected to help improve the quality of selective breeding programs for kenaf.

The concentration of phenolic compounds in rapeseed is important because they are either anti-nutritional compounds or directly related to antioxidant activity. In this study, single nucleotide polymorphisms (SNPs) were identified using genotyping-by-sequencing (GBS), and an association study was conducted to investigate phenolic content in 95 rapeseed mutant lines derived from gamma rays and their original cultivar. A total of 3,196,318 SNPs were detected, resulting in the identification of a set of 70,208 union SNPs used to perform association studies. Seven compounds were identified, sinapine being the major phenolic compound (91.2–99.2%) in all genotypes. An association study was conducted for seven compounds and total phenolic content (TPC). It identified 241 SNPs that were significantly associated with these compounds, total sinapine content (TSC), and TPC. Based on the SNP markers detected, BnaC02g20420D was associated with dihexose, BnaC08g30570D with progoitrin, BnaA01g06890D with methyl sinapate, BnaA09g16810D with sinapine(4-O-8′)guaiacyl, BnaCnng39930D with trans-sinapine 1, BnaA07g31720D with trans-sinapine 2, BnaC03g31950D with sinapoyl malate, and BnaAnng27700D with TPC. These were selected as candidate genes that may play a key role in rapeseed. The SNP markers associated with these key phenolic compounds can be used as targets in breeding programs to reduce anti-nutritional components.

Sorghum (Sorghum bicolor L.) is a promising biomass crop with high yields of cellulose, hemicellulose, and lignin. Sorghum biomass has emerged as an eco-friendly industrial material useful for producing biofuels and bioplastics. This study conducted genotyping-by-sequencing (GBS)-based genome-wide association studies (GWAS) to establish the genetic basis of traits associated with biomass. Specifically, the researchers evaluated agronomic traits and phenolic compounds using 96 sorghum genotypes. Six phenolic compounds, luteolinidin diglucoside, luteolin glucoside, apigeninidin glucoside, luteolinidin, apigeninidin, and 5-O-Me luteolinidin, were found to be the major phenolic compounds in all genotypes. Out of our six detected phenolic compounds (luteolinidin diglucoside, luteolin glucoside, apigeninidin glucoside, luteolinidin, apigeninidin, and 5-O-Me luteolinidin), luteolinidin was the major phenolic compound in all genotypes. Next, a GWAS analysis was performed to confirm significant associations between 192,040 filtered single-nucleotide polymorphisms (SNPs) and biomass-related traits. The study identified 40 SNPs on 10 chromosomes that were significantly associated with heading date (4 SNPs), plant height (3 SNPs), dry yield (2 SNPs), and phenolic compounds (31 SNPs). The GWAS analysis showed that SbRio.10G099600 (FUT1) was associated with heading date, SbRio.09G149200 with plant height, SbRio.06G211400 (MAFB) with dry yield, SbRio.04G259800 (PDHA1) with total phenolic content and luteolinidin diglucoside, and SbRio.02G343600 (LeETR4) with total phenolic content and luteolinidin, suggesting that these genes could play key roles in sorghum. These findings demonstrate the potential value of sorghum as a biomass resource and the potential for selecting sorghum genotypes with reduced phenolic contents for use in the bioindustry.

Background The remarkable efficacy of osimertinib in non‒small cell lung cancer (NSCLC) with acquired T790M mutation has been widely documented in clinical trials and real-world practice. However, some patients show primary resistance to this drug. Even patients who initially show a favorable response have inconsistent clinical outcomes later. Therefore, the aim of this study was to identify additional clinical predictive factors for osimertinib efficacy. Methods A prospective cohort of patients with acquired T790M positive stage IV lung adenocarcinoma treated with osimertinib salvage therapy in Hallym University Medical Center were analyzed. Results Sixty-one eligible patients were analyzed, including 38 (62%) women and 39 (64%) who never smoked. Their mean age was 63.3 years. The median follow-up after treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) was 36.0 months (interquartile range, 24.7–50.2 months). The majority (n=45, 74%) of patients were deceased. Based on univariate analysis, low baseline neutrophil-to-lymphocyte ratios (NLR), age ≥50 years, never-smoking history, stage IVA at osimertinib initiation, and prolonged response to previous TKIs (≥10 months) were associated with a significantly longer progression-free survival (PFS). Multivariate analysis showed that never-smoking status (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.30–0.98; p=0.041) and a baseline NLR less than or equal to 3.5 (HR, 0.23; 95% CI, 0.12–0.45; p

Abstract Degree of expression of programmed death-ligand 1 (PD-L1) is related with Immune check point inhibitors (ICIs) response but it needs sufficient tumor tissue. There is unmet need for easily accessible and prognostic peripheral blood (PB) biomarkers. We investigated the application of serum peripheral lymphocyte count (PLC) as a predictive PB biomarker for ICI response in patients with NSCLC. We conducted a retrospective study and reviewed the patients with NSCLC who were treated with ICIs from April 1, 2016, to March 31, 2019. The PLC before and after 1 month of immunotherapy was collected. We evaluated the association between PLC and progression-free survival (PFS), overall survival (OS) and adverse events. A total of 231 patients were treated with ICIs for NSCLC. The median follow-up period was 4.7 months and the disease progressed in 138 patients (59.7%). Compared with the lowest quartile (Q1: the lowest 25%), the highest quartile (Q4: the highest 25%) of post-treatment PLC showed a significantly higher PFS (HR 0.28, 95% CI 0.16–0.52) and OS (HR 0.35, 95% CI 0.19–0.65) in the adjusted model. An association between adverse events and PLC was not observed. We revealed that an increased pre- and post-treatment PLC was associated with favorable PFS and OS with NSCLC patients treated with ICIs. PLC could be a helpful for ICI responses in NSCLC.

Background: bronchodilators are the key treatment for chronic obstructive pulmonary disease (COPD), however, inhaled corticosteroids (ICSs)/long-acting β2-agonists (LABA) are widely prescribed. We compared the escalation time to open triple combination therapy between long-acting muscarinic receptor antagonists (LAMA) and ICS/LABA in COPD management. Methods: this retrospective study included COPD patients selected from the National Health Insurance Service of South Korea from January 2005 to April 2015. The primary outcome was the escalation time to triple therapy in patients who initially received LAMA or ICS/LABA. Other outcomes included risk factors predisposing escalation to triple combination therapy. Results: a total of 2444 patients were assigned to the LAMA or ICS/LABA groups. The incidences of triple combination therapy in the LAMA and ICS/LABA groups were 81.0 and 139.8 per 1000 person-years, respectively (p < 0.001); the median times to triple therapy escalation were 281 and 207 days, respectively (p = 0.03). Treatment with ICS/LABA showed a higher risk of triple therapy escalation compared to LAMA (hazard ratio (HR), 1.601; 95% confidence interval (CI), 1.402–1.829). The associated risk factor was male sex. (HR, 1.564; 95% CI, 1.352–1.809). Conclusions: the initiation of COPD treatment with LAMA is associated with a reduced escalation time to triple therapy compared with ICS/LABA.

Berberine is a phytocompound from plants viz. Phellodendri cortex and Coptis rhizome, used to treat a variety of diseases. It is effective in preventing osteoporosis, but it is less effective than drugs currently used in clinical practice. In this study, we used a novel berberine derivative, WJCPR11, to promote osteoblast differentiation and to investigate its use in the prevention and treatment of osteoporosis. WJCPR11 at a safe concentration without toxicity increased alkaline phosphatase (ALP) activity induced by bone morphogenetic protein 2 (BMP2) dose-dependently. The mRNA expression of ALP, osteocalcin (OC), runt-related transcription factor 2 (Runx2), and osterix was increased, with the ALP level increasing the most. In addition, the protein abundance of bone sialoprotein (BSP), collagen, type I, alpha 1, Runx2, and osterix were also increased. Moreover, the transcriptional activity of ALP, BSP, and OC was increased by WJCPR11, with OC showing the most significant increase. The results indicate that osteoblast differentiation is promoted by WJCPR11, and it could play a role in the prevention of osteoporosis. [ABSTRACT FROM AUTHOR]

Abstract Background Endobronchial valve (EBV) therapy, a validated method for bronchoscopic lung volume reduction (BLVR) in severe emphysema, has been explored for persistent air-leak (PAL) management. However, its effectiveness and safety in the Asian population require further real-world evaluation. In this study, we assessed the outcomes of treatment with EBV within this demographic. Methods We conducted a retrospective analysis of medical records from 11 Korean centers. For the emphysema cohort, inclusion criteria were patients diagnosed with emphysema who underwent bronchoscopy intended for BLVR. We assessed these patients for clinical outcomes of chronic obstructive pulmonary disease. All patients with PAL who underwent treatment with EBV were included. We identified the underlying causes of PAL and evaluated clinical outcomes after the procedure. Results The severe emphysema cohort comprised 192 patients with an average age of 70.3 years, and 95.8% of them were men. Ultimately, 137 underwent treatment with EBV. Three months after the procedure, the BLVR group demonstrated a significant improvement in forced expiratory volume in 1 s (+160 mL vs. +30 mL; P = 0.009). Radiographic evidence of lung volume reduction 6 months after BLVR was significantly associated with improved survival (adjusted hazard ratio 0.020; 95% confidence interval 0.038–0.650; P = 0.010). Although pneumothorax was more common in the BLVR group (18.9% vs. 3.8%; P = 0.018), death was higher in the no-BLVR group (38.5% vs. 54.5%, P = 0.001), whereas other adverse events were comparable between the groups. Within the subset of 18 patients with PAL, the predominant causes of air-leak included spontaneous secondary pneumothorax (44.0%), parapneumonic effusion/empyema (22.2%), and post-lung resection surgery (16.7%). Following the treatment, the majority (77.8%) successfully had their chest tubes removed. Post-procedural complications were minimal, with two incidences of hemoptysis and one of empyema, all of which were effectively managed. Conclusions Treatment with EBV provides substantial clinical benefits in the management of emphysema and PAL in the Asian population, suggesting a favorable outcome for this therapeutic approach.

Summary: Etomoxir has been used for decades as a popular small molecule inhibitor of carnitine palmitoyltransferase I, Cpt1, to block mitochondrial fatty acid β-oxidation. To test the specificity of etomoxir, we generated click chemistry–enabled reagents to label etomoxir binding proteins in situ. Etomoxir bound to Cpt1, but also bound to a large array of diverse proteins that metabolize and transport fatty acids in the cytoplasm, peroxisome, and mitochondria. Many of the most abundant proteins identified in primary hepatocytes were peroxisomal proteins. The loss of Pex5, required for the import of peroxisomal matrix proteins, eliminated many of these etomoxir-labeled proteins. By utilizing the promiscuous, covalent, and fatty acid mimetic properties of etomoxir, etomoxir targets of fatty acid ω-oxidation were revealed following the loss of Pex5. These data demonstrate that etomoxir is not specific for Cpt1 and is not appropriate as a tool to distinguish the biological effects of fatty acid oxidation.

Summary: YAP/TEAD signaling is essential for organismal development, cell proliferation, and cancer progression. As a transcriptional coactivator, how YAP activates its downstream target genes is incompletely understood. YAP forms biomolecular condensates in response to hyperosmotic stress, concentrating transcription-related factors to activate downstream target genes. However, whether YAP forms condensates under other signals, how YAP condensates organize and function, and how YAP condensates activate transcription in general are unknown. Here, we report that endogenous YAP forms sub-micron scale condensates in response to Hippo pathway regulation and actin cytoskeletal tension. YAP condensates are stabilized by the transcription factor TEAD1, and recruit BRD4, a coactivator that is enriched at active enhancers. Using single-particle tracking, we found that YAP condensates slowed YAP diffusion within condensate boundaries, a possible mechanism for promoting YAP target search. These results reveal that YAP condensate formation is a highly regulated process that is critical for YAP/TEAD target gene expression.

Abstract Rifampicin is an important agent for tuberculosis treatment; however, it is often discontinued because of adverse reactions. The treatment regimen then can be administered as that for rifampicin-resistant tuberculosis, which can be toxic. We retrospectively reviewed 114 patients with drug-susceptible pulmonary tuberculosis who discontinued rifampicin due to adverse reactions during an 18 year period at a tertiary referral center, of which 92 (80.7%) exhibited favorable response. Hepatotoxicity was the leading cause of intolerance. Patients with a favorable response were younger and less likely to have comorbidities. The majority of patients were administered four medications during the intensive phase and three to four during the consolidative phase. For those with a favorable response, the median duration of treatment was 10.2 months and the most common intensive regimen was a combination of isoniazid, ethambutol, pyrazinamide, and fluoroquinolone (25%). The most common consolidation regimen was a combination of isoniazid, ethambutol, and fluoroquinolone (22.8%). Among the patients with a favorable response, two (2.2%) experienced recurrence after a follow-up of 3.4 (interquartile range 1.8–6.8) years. For patients with drug-susceptible pulmonary tuberculosis who do not tolerate rifampicin owing to its toxicity, a shorter regimen may be a useful alternative.

Background Filler injection has become an extremely popular method for facial skin rejuvenation, including the periorbital area. In the recent years, new polynucleotide (PN)-containing filler products have been used for esthetic purposes. Aim We aimed to investigate the efficacy and safety of PN filler injection in the periorbital area. Patients/methods A total of 27 subjects were enrolled in this randomized, pair-matched, and active-controlled study. Each subject received filler injections thrice with two-week intervals, with a PN filler injection on one side and a non-crosslinked hyaluronic acid (HA) filler injection on the contralateral side of the periorbital area. Results Improvements in the visual analog scale and global esthetic improvement scale scores were not significantly different between the PN and HA groups. The improvement rates of skin elasticity and hydration decreased over time in both groups, with the PN group showing a higher improvement rate. The improvement rates of roughness and pore volume were higher in the PN group than in the HA group. The improvement rate of dermal density was not significantly different between the groups. No serious adverse events were reported. Conclusion The PN filler injection is effective and safe for periorbital rejuvenation.