TNF-α differentially modulates subunit levels of respiratory electron transport complexes of ER/PR +ve/−ve breast cancer cells to regulate mitochondrial complex activity and tumorigenic potential

Background Tumor necrosis factor-α (TNF-α) is an immunostimulatory cytokine that is consistently high in the breast tumor microenvironment (TME); however, its differential role in mitochondrial functions and cell survival in ER/PR +ve and ER/PR −ve breast cancer cells is not well understood. Methods In the current study, we investigated TNF-α modulated mitochondrial proteome using high-resolution mass spectrometry and identified the differentially expressed proteins in two different breast cancer cell lines, ER/PR positive cell line; luminal, MCF-7 and ER/PR negative cell line; basal-like, MDA-MB-231 and explored its implication in regulating the tumorigenic potential of breast cancer cells. We also compared the activity of mitochondrial complexes, ATP, and ROS levels between MCF-7 and MDA-MB-231 in the presence of TNF-α. We used Tumor Immune Estimation Resource (TIMER) webserver to analyze the correlation between TNF-α and mitochondrial proteins in basal and luminal breast cancer patients. Kaplan-Meier method was used to analyze the correlation between mitochondrial protein expression and survival of breast cancer patients. Results The proteome analysis revealed that TNF-α differentially altered the level of critical proteins of mitochondrial respiratory chain complexes both in MCF-7 and MDA-MB-231, which correlated with differential assembly and activity of mitochondrial ETC complexes. The inhibition of the glycolytic pathway in the presence of TNF-α showed that glycolysis is indispensable for the proliferation and clonogenic ability of MDA-MB-231 cells (ER/PR −ve) as compared to MCF-7 cells (ER/PR +ve). The TIMER database showed a negative correlation between the expressions of TNF-α and key regulators of mitochondrial OXPHOS complexes in basal breast vs lobular carcinoma. Conversely, patient survival analysis showed an improved relapse-free survival with increased expression of identified proteins of ETC complexes and survival of the breast cancer patients. Conclusion The evidence presented in our study convincingly demonstrates that TNF-α regulates the survival and proliferation of aggressive tumor cells by modulating the levels of critical assembly factors and subunits involved in mitochondrial respiratory chain supercomplexes organization and function. This favors the rewiring of mitochondrial metabolism towards anaplerosis to support the survival and proliferation of breast cancer cells. Collectively, the results strongly suggest that TNF-α differentially regulates metabolic adaptation in ER/PR +ve (MCF-7) and ER/PR −ve (MDA-MB-231) cells by modulating the mitochondrial supercomplex assembly and activity.This work was supported by the Department of Science and Technology, Govt. of India, grant number INT/Korea/P-39 to Prof. Rajesh Singh. Global Infrastructure Program through the NRF funded by the Ministry of Science and ICT (NRF-2017K1A3A1A19071651 to ECY) and National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (NRF-2016R1A5A1010764 and NRF-2015M3A9B6073835 to ECY) to Prof. Eugene C. Yi

The assessment of memes as digital multimodal composition in L2 classrooms

Digital multimodal writing has become predominant in our students’ lives in and outside the L2 classrooms. While many L2 educators integrate various multimodal projects into their curriculum, internet memes and their assessment have not been explored in depth in L2 settings, although memes have potential to be valuable multimodal writing tasks. The purpose of this study is to better understand how memes can be incorporated and assessed in L2 classrooms. Twenty-seven student-created memes in a low-intermediate Korean as a Foreign Language course at a large university were collected and analyzed. The findings indicated that the student-created memes successfully addressed the multimodal aspect of the meme genre, universal and specific cultural references, and language aspects specific to the genre of memes. Our analyses of the memes suggest three key components to assess this multimodal writing project in addition to its overall task/functions: 1) multimodal aspects that include understanding the interplay between multiple modes for an effective message in a given context; 2) cultural aspects, demonstrating cultural knowledge and its application, recognizing the semiotic importance of multimodal expression in the target community; and 3) language aspects as an effective communication medium, demonstrating genre knowledge of the specific task and language accuracy.24 month embargo; available online: 13 August 2022This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Exploring Foreign Language Students’ Perceptions of the Guided Use of Machine Translation (GUMT) Model for Korean Writing

This study examines students’ perceptions of the Guided Use of Machine Translation (GUMT) model and their perceptions of GUMT’s impact on their foreign language (FL) writing. Adapted from O’Neill (2016, 2019b), GUMT model activities were developed and implemented in an upper-elementary Korean as a FL course at a large southwestern U.S. university. At the beginning of the semester, students received an instructional session on how to use machine translation (MT) effectively as the first step of GUMT. The session included 1) the potential strengths and weaknesses of two online Korean MT platforms, Google Translate and Papago; and 2) the combined use of other online resources (e.g., image and news searches) to enhance students’ awareness of pragmatic issues related to MT output. Throughout the semester, students applied the GUMT model to writing assignments and wrote reflections on their GUMT practice. Students also received continuous feedback from instructors on MT use. Analyses of pre- and post-surveys and students’ reflections indicate that the GUMT model played an important role in fostering MT use strategies and improving students’ confidence and self-perceptions of their fluency in FL writing

Study on Verifying the Effectiveness of Non-face-to-face Youth Volunteering in Improving Self-Esteem Among Children of Deaf Adults (CODAs)

The goal of this study is to evaluate the effectiveness of youth volunteering in increasing the self-esteem of hearing children of deaf adults (CODAs), who commonly start taking care of their parents from a young age. To this end, an experimental study based on the non-equal comparison groups design was applied to a experimental group of 4 participants and a control group of 3 participants, selected based on the recommendation from expert social workers from the M General Social Welfare Center in P City. The volunteer programs, conducted non-face-to-face due to COVID-19, were centered on art activities such as drawing one's own dreams, decorating flowers, and customizing pencil cases. Repeated measures analysis of variance (rANOVA) was conducted to verify the effectiveness of volunteering, and the analysis results are as follows. First, in both the experimental group and the control group, CODAs' self esteem increased after the program was carried out. Second, while the growth effect appeared in both groups, the slope of increase in the self-esteem of the experimental group was significantly higher than that of the control group. Accordingly, the effectiveness of volunteering to improve CODAs' self-esteem was verified. This study suggests academic and practical implications based on these findings

Adenylyl cyclase isoform 1 contributes to sinoatrial node automaticity via functional microdomains

Sinoatrial node (SAN) cells are the heart's primary pacemaker. Their activity is tightly regulated by β-adrenergic receptor (β-AR) signaling. Adenylyl cyclase (AC) is a key enzyme in the β-AR pathway that catalyzes the production of cAMP. There are current gaps in our knowledge regarding the dominant AC isoforms and the specific roles of Ca2+-activated ACs in the SAN. The current study tests the hypothesis that distinct AC isoforms are preferentially expressed in the SAN and compartmentalize within microdomains to orchestrate heart rate regulation during β-AR signaling. In contrast to atrial and ventricular myocytes, SAN cells express a diverse repertoire of ACs, with ACI as the predominant Ca2+-activated isoform. Although ACI-KO (ACI-/-) mice exhibit normal cardiac systolic or diastolic function, they experience SAN dysfunction. Similarly, SAN-specific CRISPR/Cas9-mediated gene silencing of ACI results in sinus node dysfunction. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) channels form functional microdomains almost exclusively with ACI, while ryanodine receptor and L-type Ca2+ channels likely compartmentalize with ACI and other AC isoforms. In contrast, there were no significant differences in T-type Ca2+ and Na+ currents at baseline or after β-AR stimulation between WT and ACI-/- SAN cells. Due to its central characteristic feature as a Ca2+-activated isoform, ACI plays a unique role in sustaining the rise of local cAMP and heart rates during β-AR stimulation. The findings provide insights into the critical roles of the Ca2+-activated isoform of AC in sustaining SAN automaticity that is distinct from contractile cardiomyocytes