Search

Abstract Spt5 is a well-conserved factor that manipulates multiple stages of transcription from promoter-proximal pausing (PPP) to termination. Recent studies have revealed an unexpected increase of antisense transcripts near promoters in cells expressing mutant Spt5. Here, we identify Spt5p-restricted intragenic antisense transcripts and their close relationship with sense transcription in yeast. We confirm that Spt5 CTR phosphorylation is also important to retain Spt5’s facility to regulate antisense transcription. The genes whose antisense transcription is strongly suppressed by Spt5p share strong endogenous sense transcription and weak antisense transcription, and this pattern is conserved in humans. Mechanistically, we found that Spt5p depletion increased histone acetylation to initiate intragenic antisense transcription by altering chromatin structure. We additionally identified termination factors that appear to be involved in the ability of Spt5p to restrict antisense transcription. By unveiling a new role of Spt5 in finely balancing the bidirectionality of transcription, we demonstrate that Spt5-mediated suppression of DSIF complex regulated-unstable transcripts (DUTs) is essential to sustain the accurate transcription by RNA polymerase II.

Background By analyzing small bowel capsule endoscopy (SBCE) performed in two large hospitals in Kazakhstan, we aimed to explore the characteristics of patients representative of Central Asia and the technical characteristics of SBCE. Methods SBCE cases were retrospectively analyzed. A descriptive analysis was conducted on the patients’ demographic data, diagnosis, and clinical symptoms. The results of SBCE, such as the lesions found, transit time and retention rate in the stomach and small bowel, and bowel visualization quality, were analyzed. Complications related to SBCE were investigated. Results SBCE was performed in 123 patients. Abdominal pain (81.3%) and chronic diarrhea (66.7%) were the most common symptoms, followed by weight loss (25.2%) and gastrointestinal bleeding (15.4%). The most common disease was Crohn’s disease (52.0%). Definite lesions, such as ulcers, polyps, and bleeding, were identified in 55.3% of patients. SBCE was successfully completed in all cases except for 11 (9.1%). The average small bowel transit time was 4 hours and 28 minutes. Excellent visualization (>75% of mucosa) was reported in 82.5% of patients. No patients experienced complications. Conclusions SBCE performed in Kazakhstan showed a high diagnostic yield with high-quality patient selection and no complications.

Abstract Background BRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance compromises their therapeutic efficacy. Diverse genomic and transcriptomic alterations are found in BRAF inhibitor resistant melanoma, posing a pressing need for convergent, druggable target that reverse therapy resistant tumor with different resistance mechanisms. Methods CRISPR-Cas9 screens were performed to identify novel target gene whose inhibition selectively targets A375VR, a BRAF V600E mutant cell line with acquired resistance to vemurafenib. Various in vitro and in vivo assays, including cell competition assay, water soluble tetrazolium (WST) assay, live-dead assay and xenograft assay were performed to confirm synergistic cell death. Liquid Chromatography-Mass Spectrometry analyses quantified polyamine biosynthesis and changes in proteome in vemurafenib resistant melanoma. EIF5A hypusination dependent protein translation and subsequent changes in mitochondrial biogenesis and activity were assayed by O-propargyl-puromycin labeling assay, mitotracker, mitoSOX labeling and seahorse assay. Bioinformatics analyses were used to identify the association of polyamine biosynthesis with BRAF inhibitor resistance and poor prognosis in melanoma patient cohorts. Results We elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings. Conclusions Our findings delineate the molecular mechanisms involving polyamine-EIF5A hypusination-mitochondrial respiration pathway conferring BRAF inhibitor resistance in melanoma. These targets will serve as effective therapeutic targets that can maximize the therapeutic efficacy of existing BRAF inhibitors.

Abstract Objectives Since the enactment of the School Nutrition Act in 1981, school lunch programs in South Korea have grown quantitatively and qualitatively with a current student participation rate of 99.8%. Nonetheless, educational materials are needed to reduce misunderstanding and ignorance about school lunch programs. This study aimed to develop 3 educational videos that help students of various ages (kindergarteners/lower-grade elementary, upper-grade elementary, and secondary school, respectively), understand the school lunch program. Methods A scenario was created, was made, and the opinions on the scenario from experts in foodservice sectors were collected. A survey was conducted to students and parents to determine topics they wanted to know about school foodservice. The final videos were produced using this information and the expert opinions. The data were analyzed using SPSS 27.0 for Mac (IBM Corp., Armonk, NY, USA); a P-value of < 0.05 was considered significant. Results Three videos on school foodservice were developed for various age levels of students: kindergarten/lower-grade elementary, upper-grade elementary, and secondary school. Additionally, English subtitles were included for the multicultural student population. These videos, each lasting about 7 minutes, cover topics such as nutrition, hygiene, and the cultural significance of the school lunch program. The survey results showed that parents and students wanted to know the following topics about the school lunch program: “nutritionally balanced diet” (11.9%), “purchasing safe food ingredients” (10.9%), and “healthy eating habits” (9.9%). Conclusions The developed videos will serve as valuable educational resources on school foodservice, foster a deeper understanding of the school lunch program in parents and students, and potentially address their inquiries regarding production processes, nutrition, hygiene, cultural heritage, and health.

In this study, Ag-impregnated silica aerogel composites were fabricated via wet impregnation. In this approach, silver salt was reduced with ethylene glycol in the presence of polyvinylpyrrolidone (PVP) at reaction temperature 80°C. PVP was used as a capping agent to protect the Ag nanoparticles (NPs) from agglomeration. Wet impregnation was used to synthesize the Ag/SiO2 composite by combining the reduction of AgNO3 with a silica aerogel slurry. Experimental results showed that the AgNO3 concentration and PVP: AgNO3 ratio had an active influence on the growth of Ag NPs on silica surfaces. The X-ray diffraction (XRD) patterns of the composite material showed no imprints of impurities or parasitic materials except for Ag and SiO2. Scanning electron microscopy (SEM) images revealed that the Ag NPs were well impregnated into the porous silica aerogel structure. It was found that SiO2 aerogel surfaces were homogeneously surrounded by the Ag NPs.

In this study, lead-free bismuth sodium titanate (BNT; Bi0.5Na0.5TiO3) powder was synthesized using wet precipitation. The sintering behavior and dielectric properties of the BNT ceramics were investigated in terms of the sintering temperature. Titanium isopropoxide, sodium nitrate, and bismuth nitrate were used as starting materials. A titanium peroxo complex (TPC) solution was synthesized using titanium hydroxide, nitric acid, and hydrogen peroxide. A clear Bi-Na-Ti precursor solution was obtained by mixing the TPC, sodium, and bismuth nitrate solutions. The pH of the precursor solution was increased to 9 using NaOH and a white powder was precipitated. A spherical and pyrochlore phase-free BNT powders were obtained by calcining the white precipitate above 600°C for 3 h. Particle size analysis and SEM observations revealed that the BNT powder calcined at 700°C exhibited homogeneous distribution with particle size less than 300 nm. The sinterability of the BNT ceramic prepared through wet precipitation was significantly enhanced compared to that of the BNT powder prepared via the solid-state reaction of sodium carbonate, bismuth oxide, and titanium oxide powders.

Biological and abiotic stresses in plant growth are associated with reduced crop yields. Therefore, improving plant stress resistance can be a crucial strategy to improve crop production. To overcome these problems, plant growth-promoting bacteria are emphasized as one of the alternative tools for sustainable agriculture. This study found a novel strain (L3T) of a plant growth-promoting bacterium in fermented Liriope platyphylla fruit. Strain L3T showed the ability to promote plant growth. The L3T strain promoted plant growth of D. carota subsp. sativus, increasing the length (increase rate compared to the control group, 36.98%), diameter (47.06%), and weight of carrots (81.5%), ultimately increasing the edible area. In addition, we confirmed that plant growth was improved even in situations that inhibited plant growth, such as salinity and drought stress. Strain L3T performed indole production, siderophore production, phosphate solubilization, and nitrogen fixation, all characteristics of a strain that promotes plant growth. Genome analysis revealed genes involved in the growth promotion effects of strain L3T. Additionally, the properties of exopolysaccharides were identified and characterized using FTIR, TGA, and UHPLC. Our results demonstrated that L3 isolated from fermented L. platyphylla fruit can be used to simultaneously alleviate drought and NaCl stress.

Cancer cells, which divide indefinitely and without control, are frequently exposed to various stress factors but manage to adapt and survive. The mechanisms by which cancer cells maintain cellular homeostasis and exploit stress conditions are not yet clear. Here, we elucidate the roles of diverse cellular metabolism and its regulatory mechanisms, highlighting the essential role of metabolism in cellular composition and signal transduction. Cells respond to various stresses, including DNA damage, energy stress, and oxidative stress, thereby causing metabolic alteration. We provide profound insight into the adaptive mechanisms employed by cancer cells to ensure their survival among internal and external stressors through a comprehensive analysis of the correlation between metabolic alterations and cellular stress. Furthermore, this research establishes a robust framework for the development of innovative therapeutic strategies that specifically target the cellular adaptations of cancer cells.

Recently, the durability of high-performance and multifunctional portable electronic devices such as smartphones and tablets, has become an important issue. Electronic device housing, which protects internal components from external stimuli, such as vibration, shock, and electrical hazards, is essential for resolving durability issues. Therefore, the materials used for electronic device housing must possess good mechanical and electrical insulating properties. Herein, we propose a novel high-strength polymer nanocomposite based on 3D-aligned aluminum borate nanowhisker (ABOw) structures. ABOw was synthesized using a facile hydrothermal method, and 3D-aligned ABOw structures were fabricated using a freeze-casting process. The 3D-aligned ABOw/epoxy composites consist of repetitively layered structures, and the microstructures of these composites are controlled by the filler content. The developed 3D-aligned ABOw/epoxy composite had a compressive strength 56.72% higher than that of pure epoxy, indicating that it can provide high durability when applied as a protective material for portable electronic devices.

Maternal asthma status, prenatal exposures, and infant gut microbiota perturbation are associated with heightened risk of atopy and asthma risk in childhood, observations hypothetically linked by intergenerational microbial transmission. Using maternal vaginal (n = 184) and paired infant stool (n = 172) samples, we identify four compositionally and functionally distinct Lactobacillus-dominated vaginal microbiota clusters (VCs) that relate to prenatal maternal health and exposures and infant serum immunoglobulin E (IgE) status at 1 year. Variance in bacteria shared between mother and infant pairs relate to VCs, maternal allergy/asthma status, and infant IgE levels. Heritable bacterial gene pathways associated with infant IgE include fatty acid synthesis and histamine and tryptophan degradation. In vitro, vertically transmitted Lactobacillus jensenii strains induce immunosuppressive phenotypes on human antigen-presenting cells. Murine supplementation with L. jensenii reduces lung eosinophils, neutrophilic expansion, and the proportion of interleukin-4 (IL-4)+ CD4+ T cells. Thus, bacterial and atopy heritability are intimately linked, suggesting a microbial component of intergenerational disease transmission.

Abstract Herein, a novel extracellular matrix (ECM) hydrogel is proposed fabricated solely from decellularized, human fibroblast‐derived matrix (FDM) toward advanced wound healing. This FDM‐gel is physically very stable and viscoelastic, while preserving the natural ECM diversity and various bioactive factors. Subcutaneously transplanted FDM‐gel provided a permissive environment for innate immune cells infiltration. Compared to collagen hydrogel, excellent wound healing indications of FDM‐gel treated in the full‐thickness wounds are noticed, particularly hair follicle formation via highly upregulated β‐catenin. Sequential analysis of the regenerated wound tissues disclosed that FDM‐gel significantly alleviated pro‐inflammatory cytokine and promoted M2‐like macrophages, along with significantly elevated vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) level. A mechanistic study demonstrated that macrophages‐FDM interactions through cell surface integrins α5β1 and α1β1 resulted in significant production of VEGF and bFGF, increased Akt phosphorylation, and upregulated matrix metalloproteinase‐9 activity. Interestingly, blocking such interactions using specific inhibitors (ATN161 for α5β1 and obtustatin for α1β1) negatively affected those pro‐healing growth factors secretion. Macrophages depletion animal model significantly attenuated the healing effect of FDM‐gel. This study demonstrates that the FDM‐gel is an excellent immunomodulatory material that is permissive for host cells infiltration, resorbable with time, and interactive with macrophages, where it thus enables regenerative matrix remodeling toward a complete wound healing.

The cilium is a microtubule-based organelle that plays a pivotal role in embryonic development and maintenance of physiological functions in the human body. In addition to their function as sensors that transduce diverse extracellular signals, including growth factors, fluid flow, and physical forces, cilia are intricately involved in cell cycle regulation and preservation of DNA integrity, as their formation and resorption dynamics are tightly linked to cell cycle progression. Recently, several studies have linked defects in specific ciliary proteins to the DNA damage response. However, it remains unclear whether and how primary cilia contribute to cancer development. Mebendazole (MBZ) is an anthelmintic drug with anticancer properties in some cancer cells. MBZ is continuously being tested for clinical studies, but the precise mechanism of its anticancer activities remains unknown. Here, using Xenopus laevis embryos as a model system, we discovered that MBZ significantly hinders cilia formation and induces DNA damage. Remarkably, primary cilium-bearing cancer cells exhibited heightened vulnerability to combined treatment with MBZ and conventional anticancer drugs. Our findings shed light on the specific influence of MBZ on cilia, rather than cytosolic microtubules, in triggering DNA damage, elucidating a previously unidentified mechanism underlying potential MBZ-mediated cancer therapy.

This study investigates that the subsurface pathways, travel time, and its interannual variability of Fukushima-derived tracers subducted with the North Pacific subtropical mode water (NPSTMW) using 22-year-long (1994–2015) eddy-resolving (1/12°) and eddy-permitting (1/4°) ocean reanalysis. The NPSTMW is a thick subsurface layer with low potential vorticity and relatively uniform potential density, making it a key indicator of the North Pacific oceanic conditions. A series of Lagrangian particle tracking simulations quantitatively revealed that the Fukushima-derived particles moved along the Kuroshio Extension (KE) and spread over the majority of the subtropical region in the northwestern Pacific within 4–5 years. Approximately 36% of the particles flowed eastward in the Kuroshio-Oyashio transition zone (KO) and thereafter re-emerged to the sea surface at the remote area (near dateline), and 30% of particles moved along the KE. The remaining 34% subducted into NPSTMW layer and then widely spread out to the subtropical region along the re-circulation gyre (RG), exhibiting a subsurface pathway during entire particle tracking. When the particles were released, their pathway was immediately determined, whether it flowed along the KO (>36°N), KE (30°–36°N), or RG (

Objective Hydroxychloroquine (HCQ) use for the treatment of dermatomyositis (DM) has been associated with adverse cutaneous reactions. We applied a new user, active comparator, retrospective design to assess differences in adverse cutaneous reactions or hospitalizations between HCQ and methotrexate (MTX) use among patients with DM. Methods We used a national network of data from insurance registries (TriNetX), enrolling patients with two International Classification of Diseases (ICD) codes for DM separated by 6 months or more who had a prescription for either (but not both) HCQ or MTX on or after DM diagnosis. Outcomes were adverse cutaneous reactions (ICD codes) or hospital admission (Current Procedural Terminology (CPT) codes) within 4 months from the prescription dispense date. Logistic regression was used to produce adjusted odds ratios (aORs) and 95% confidence intervals (CIs) comparing outcomes in the HCQ group (n = 1364) and the MTX group (n = 1400), adjusted for age at first DM diagnosis, year of birth, sex, and time from DM diagnosis to first prescription. Results Overall, we found no significant difference in odds of hospitalization in those taking HCQ (aOR 1.05; 95% CI: 0.79‐1.39) compared with those on MTX. Patients with DM on HCQ had 30% higher odds of adverse cutaneous reaction diagnosis compared with patients on MTX (aOR 1.30; 95% CI: 1.02‐1.59). Age at DM diagnosis was an effect modifier of this association, with higher odds of adverse cutaneous reaction among patients taking HCQ who were younger at diagnosis. Conclusion Compared with MTX use, HCQ use, especially in younger patients, may result in higher odds of adverse cutaneous reactions.