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To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3' base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma.

Multiple myeloma (MM) is a hematological malignancy caused by malignant proliferation of plasma cells in bone marrow. Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents. However, MM remains an incurable neoplastic plasma cell disorder. In addition, almost all MM patients inevitably relapse due to drug resistance. Chimeric antigen receptor (CAR)-modified NK cells represent a promising immunotherapeutic modality for cancer treatment. In this study, NK92 cells were engineered to express the third generation of BCMA CAR. In vitro, BCMA CAR-engineered NK92 cells displayed higher cytotoxicity and produced more cytokines such as IFN-γ and granzyme B than NK92 cells when they were co-cultured with MM cell lines. Furthermore, BCMA CAR-engineered NK92 cells released significantly higher amounts of cytokines and showed higher cytotoxicity when they were exposed to primary cells isolated from MM patients. The cytotoxicity of BCMA CAR NK92 cells was enhanced after MM cells were treated with bortezomib. Additionally, BCMA CAR NK92 cells exhibited potent antitumor activities in subcutaneous tumor models of MM. These results demonstrate that regional administration of BCMA CAR NK92 cells is a potentially promising strategy for treating MM.

Mitogen-activated protein kinase (MAPK) and AKT pathways are frequently co-activated in melanoma through overexpression of receptor tyrosine kinases, mutations in their signaling surrogates, such as RAS and BRAF, or loss of negative regulators such as PTEN. As RAS can be a positive upstream regulator of PI3-K, it has been proposed that the loss of PTEN and the activation of RAS are redundant events in melanoma pathogenesis. Here, in genetically engineered mouse models of cutaneous melanomas, we sought to better understand the genetic interactions between HRAS activation and PTEN inactivation in melanoma genesis and progression in vivo . We showed that HRAS activation cooperates with Pten +/− and Ink4a/Arf −/− to increase melanoma penetrance and promote metastasis. Correspondingly, gain- and loss-of-function studies established that Pten loss increases invasion and migration of melanoma cells and non-transformed melanocytes, and such biological activity correlates with a shift to phosphorylation of AKT2 isoform and E-cadherin down-regulation. Thus, Pten inactivation can drive the genesis and promote the metastatic progression of RAS activated Ink4a/Arf deficient melanomas.

Functional analysis of genes from Saccharomyces cerevisiae has been the major goal after determination of genome sequences. Even though several tools for molecular-genetic analyses have been developed, only a limited number of reliable genetic tools are available to support functional assay at protein level. Epitope tagging is a powerful tool for detecting, purifying, and functional studying of proteins. But systematic tagging systems developed with integration vectors are not available. Here, we have constructed a set of integration vectors allowing a translational fusion of interested proteins to the four different epitope tags (HA, Myc, Flag, and GFP). To confirm function and expression of C-terminal-tagged proteins, we used Cdc11, a component of the septin filament that encircles the mother bud neck and consists of five major proteins: Cdc3, Cdc10, Cdc11, Cdc12, and Sep7. The tagged version of Cdc11 expressed under its endogenous promoter was found to be physiologically functional, as evidenced by localization at the neck and suppression of the growth defect associated with the temperature-sensitive mutation of cdc11-6. The expressed proteins were efficiently detected with antibodies against Cdc11 or the epitopes. When immunoprecipitated with anti-Myc antibody, each septin protein tagged with Myc was effectively copurified with other septin components, indicating formation of a stable septin complex. Because the modules of the tags were located under the same array of eighteen restriction sites on integration vectors containing four different markers ( HIS3, TRP1, LEU2, or URA3), this tagging system provides efficient multiple tagging and stable expression of a gene of interest.

Paper is a popular platform material in all areas of sensor research due to its porosity, large surface area, and biodegradability, to name but a few. Many paper-based nanocomposites have been reported in the last decade as novel substrates for surface-enhanced Raman spectroscopy (SERS). However, there are still limiting factors, like the low density of hot spots or loss of wettability. Herein, we designed a process to fabricate a silver–chitosan nanocomposite layer on paper celluloses by a layer-by-layer method and pH-triggered chitosan assembly. Under microscopic observation, the resulting material showed a nanoporous structure, and silver nanoparticles were anchored evenly over the nanocomposite layer. In SERS measurement, the detection limit of 4-aminothiophenol was 5.13 ppb. Furthermore, its mechanical property and a strategy toward further biosensing approaches were investigated.

The impact of fermented concentrate on the growth and rumen health of beef cattle remains an area of emerging research. This study aimed to assess the influence of a fermented concentrate (TRT) compared to a conventional concentrate (CON) on the growth, rumen fermentation characteristics, and microbiota composition in Korean cattle. Using a crossover design, eight cattle were alternately fed TRT and CON diets, with subsequent analysis of feed components, rumen fermentation parameters, and microbial profiles. TRT and CON diets did not differ significantly in their effect on animal growth metrics. However, the TRT diet was associated with reduced digestibility of rapidly degradable carbohydrates and modified rumen fermentation patterns, as evidenced by an elevated pH and increased acetate-to-propionate ratio (p < 0.05). Furthermore, the TRT diet increased the abundance of lactic acid bacteria, Bacillus, and yeast and organic acid levels in the rumen (p < 0.05). Moreover, Lachnospiraceae and Bacteroidales populations in the rumen and fecal Akkermansia abundance increased in the TRT group compared to the CON group. These microbial changes suggest a potential enhancement of the immune system and overall health of the host. Further research on the long-term implications of incorporating fermented concentrate into cattle diets is warranted.

The widespread adoption of mobile work, driven by advancements in information and communication technology, has increasingly blurred the boundaries between work and personal life. This phenomenon can increase job stress, potentially leading to sleep deprivation, which affects not only employees’ health and well-being but also organizational performance. Grounded in Conservation of Resources theory, this study examines the pathway through which mWork contributes to sleep deprivation, focusing on the mediating role of job stress, and investigates the moderating effects of gender and number of children on this relationship. Data were collected using a stratified random sampling method across three waves with 4-week intervals, involving 325 employees in South Korea engaged in diverse occupations, including the administrative, technical, service, and sales sectors. The findings reveal that mWork increases sleep deprivation through the mediation of job stress. Furthermore, the relationship between mWork and job stress was found to vary depending on gender and number of children, with stronger moderating effects observed among women and employees with children. This study underscores the need for organizations to develop tailored management strategies that address the unique challenges posed by mWork, taking particular note of employees’ gender and family responsibilities. By mitigating the negative effects of mWork on job stress and sleep deprivation, organizations can enhance employee well-being and promote sustainable long-term performance.

To establish an efficient plant regeneration system from cell suspension cultures of Euonymus alatus , embryogenic callus formation from immature embryos was investigated. The highest frequency of embryogenic callus formation reached 50% when the immature zygotic embryos were incubated on Murashige and Skoog (MS) medium supplemented with 1 mg/L 2,4-dichlorophenoxy acetic acid (2,4-D). At higher concentrations of 2,4-D (over 2 mg/L), the frequency of embryogenic callus formation declined significantly. The total number of somatic embryos development was highest with the 3% (w/v) sucrose treatment, which was found to be the optimal concentration for somatic embryo formation. Activated charcoal (AC) and 6-benzyladenine (BA) significantly increased the frequency of plantlet conversion from somatic embryos, but gibberellic acid (GA 3 ) had a negative effect on plantlet conversion and subsequent development from somatic embryos. Even though the cell suspension cultures were maintained for more than 1 year, cell aggregates from embryogenic cell suspension cultures were successfully converted into normal somatic embryos with two cotyledons. To our knowledge, this is the first successful report of a plant regeneration system of E. alatus via somatic embryogenesis. Thus, the embryogenic cell line and plant regeneration system established in this study can be applied to mass proliferation and production of pharmaceutical metabolite in E. alatus .

Background The formation of shoots plays a pivotal role in plant organogenesis and productivity. Despite its significance, the underlying molecular mechanism of de novo regeneration has not been extensively elucidated in Capsicum annuum ‘Dempsey’, a bell pepper cultivar. To address this, we performed a comparative transcriptome analysis focusing on the differential expression in C. annuum ‘Dempsey’ shoot, callus, and leaf tissue. We further investigated phytohormone-related biological processes and their interacting genes in the C. annuum ‘Dempsey’ transcriptome based on comparative transcriptomic analysis across five species. Results We provided a comprehensive view of the gene networks regulating shoot formation on the callus, revealing a strong involvement of hypoxia responses and oxidative stress. Our comparative transcriptome analysis revealed a significant conservation in the increase of gene expression patterns related to auxin and defense mechanisms in both callus and shoot tissues. Consequently, hypoxia response and defense mechanism emerged as critical regulators in callus and shoot formation in C. annuum ‘Dempsey’. Current transcriptome data also indicated a substantial decline in gene expression linked to photosynthesis within regenerative tissues, implying a deactivation of the regulatory system governing photosynthesis in C. annuum ‘Dempsey’. Conclusion Coupled with defense mechanisms, we thus considered spatial redistribution of auxin to play a critical role in the shoot morphogenesis via primordia outgrowth. Our findings shed light on shoot formation mechanisms in C. annuum ‘Dempsey’ explants, important information for regeneration programs, and have broader implications for precise molecular breeding in recalcitrant crops.

Glioblastoma is a highly malignant tumor that easily acquires resistance to treatment. The stem-cell-like character (stemness) has been thought to be closely associated with the treatment resistance of glioblastoma cells. In this study, we determined that farnesyl diphosphate synthase (FDPS), a key enzyme in isoprenoid biosynthesis, plays an important role in maintaining glioblastoma stemness. A comparison of the mRNA expression in patient-derived glioblastoma sphere cells, which maintain stemness, and their differentiated counterparts, which lose stemness, via RNA sequencing showed that most of the altered genes were networked in the cholesterol biosynthesis pathway. We screened Federal Drug Administration (FDA)-approved drugs targeting specific enzymes in the cholesterol biosynthesis pathway for their ability to inhibit glioblastoma sphere formation. Inhibitors of FDPS, such as alendronate and zoledronate, significantly reduced the formation of glioblastoma spheres, and alendronate was effective at a lower molar concentration than zoledronate. Knockdown of FDPS using short hairpin RNA also completely inhibited the formation of secondary spheres. FDPS mRNA in patients with glioblastoma was associated with malignancy in three independent microarray data sets. RNA sequencing showed that alendronate treatment reduced the embryonic stem cell signature and activated development- and necrosis-related pathways in glioblastoma spheres. These results suggest that FDPS is important for the maintenance of glioblastoma stemness and that alendronate, a drug widely used to treat osteoporosis, can be repositioned to treat glioblastoma. Brain cancer: Enzyme target for potential therapy A drug that targets a key enzyme in aggressive brain cancer tumors could help tackle resistance to existing treatments. Glioblastoma is the most aggressive form of brain cancer and remains difficult to treat because the cancer cells can survive chemotherapy and radiotherapy. Certain cells within glioblastoma tumors have ‘stemness’ – unique stem cell-like metabolic characteristics that allow them to rapidly repair DNA damage and trigger relapse. Hyonchol Jang at the National Cancer Center in Goyang, South Korea and co-workers discovered that an enzyme called farnesyl diphosphate synthase (FDPS) helps maintain stemness in glioblastoma. The team then treated patient-derived glioblastoma cells with existing drugs known to inhibit FDPS. One such drug, which is already used to treat osteoporosis, inhibited the formation of secondary glioblastoma and may prove valuble in the treatment of brain cancer.