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Abstract IscU2 is a scaffold protein that is critical for the assembly of iron–sulfur (Fe–S) clusters and the functions of Fe–S-containing mitochondrial proteins. However, the role of IscU2 in tumor development remains unclear. Here, we demonstrated that IscU2 expression is much higher in human pancreatic ductal adenocarcinoma (PDAC) tissues than in adjacent normal pancreatic tissues. In PDAC cells, activated KRAS enhances the c-Myc-mediated IscU2 transcription. The upregulated IscU2 stabilizes Fe–S cluster and regulates the activity of tricarboxylic acid (TCA) cycle enzymes α-ketoglutarate (α-KG) dehydrogenase and aconitase 2, which promote α-KG catabolism through oxidative and reductive TCA cycling, respectively. In addition to promoting mitochondrial functions, activated KRAS-induced and IscU2-dependent acceleration of α-KG catabolism results in reduced α-KG levels in the cytosol and nucleus, leading to an increase in DNA 5mC due to Tet methylcytosine dioxygenase 3 (TET3) inhibition and subsequent expression of genes including DNA polymerase alpha 1 catalytic subunit for PDAC cell proliferation and tumor growth in mice. These findings underscore a critical role of IscU2 in KRAS-promoted α-KG catabolism, 5mC-dependent gene expression, and PDAC growth and highlight the instrumental and integrated regulation of mitochondrial functions and gene expression by IscU2 in PDAC cells.

ObjectiveWe proposed that the deficit of ACC1 is the cause of patient symptoms including global developmental delay, microcephaly, hypotonia, and dysmorphic facial features. We evaluated the possible disease-causing role of the ACACA gene in developmental delay and investigated the pathogenesis of ACC1 deficiency.MethodsA patient who presented with global developmental delay with unknown cause was recruited. Detailed medical records were collected and reviewed. Whole exome sequencing found two variants of ACACA with unknown significance. ACC1 mRNA expression level, protein expression level, and enzyme activity level were detected in patient-derived cells. Lipidomic analysis, and in vitro functional studies including cell proliferation, apoptosis, and the migratory ability of patient-derived cells were evaluated to investigate the possible pathogenic mechanism of ACC1 deficiency. RNAi-induced ACC1 deficiency fibroblasts were established to assess the causative role of ACC1 deficit in cell migratory disability in patient-derived cells. Palmitate supplementation assays were performed to assess the effect of palmitic acid on ACC1 deficiency-induced cell motility deficit.ResultsThe patient presented with global developmental delay, microcephaly, hypotonia, and dysmorphic facial features. A decreased level of ACC1 and ACC1 enzyme activity were detected in patient-derived lymphocytes. Lipidomic profiles revealed a disruption in the lipid homeostasis of the patient-derived cell lines. In vitro functional studies revealed a deficit of cell motility in patient-derived cells and the phenotype was further recapitulated in ACC1-knockdown (KD) fibroblasts. The cell motility deficit in both patient-derived cells and ACC1-KD were attenuated by palmitate.ConclusionWe report an individual with biallelic mutations in ACACA, presenting global development delay. In vitro studies revealed a disruption of lipid homeostasis in patient-derived lymphocytes, further inducing the deficit of cell motility capacity and that the deficiency could be partly attenuated by palmitate.

Summary: The assembly pathways of mitochondrial respirasome (supercomplex I+III2+IV) are not fully understood. Here, we show that an early sub-complex I assembly, rather than holo-complex I, is sufficient to initiate mitochondrial respirasome assembly. We find that a distal part of the membrane arm of complex I (PD-a module) is a scaffold for the incorporation of complexes III and IV to form a respirasome subcomplex. Depletion of PD-a, rather than other complex I modules, decreases the steady-state levels of complexes III and IV. Both HEK293T cells lacking TIMMDC1 and patient-derived cells with disease-causing mutations in TIMMDC1 showed accumulation of this respirasome subcomplex. This suggests that TIMMDC1, previously known as a complex-I assembly factor, may function as a respirasome assembly factor. Collectively, we provide a detailed, cooperative assembly model in which most complex-I subunits are added to the respirasome subcomplex in the lateral stages of respirasome assembly.

Background: Burnout is common among nurses and can lead to negative outcomes of medical care. This study aimed to explore the effectiveness of Balint groups to reduce burnout in head nurses in a Chinese hospital., Methods: This was a randomized controlled trial with a pre- and post-test. A total of 80 head nurses were randomly assigned to either a Balint group ( n = 40) or a control group ( n = 40). Participants participated in Balint group for a period of 3 months. Participants in both groups completed the Maslach Burnout Inventory-Human Services Survey and the General Self-Efficacy Scale at the beginning and end of the study. Balint group members also completed the Group Climate Questionnaire-Short Form., Results: In the Balint group, 33 participants attended all Balint groups, while the 40 participants in the control group had no intervention. Analysis of variance with repeated measures demonstrated a statistically significant difference on the Maslach Burnout Inventory subscale of sense of personal achievement ( F = 9.598, p = 0.003) between the Balint and control groups. However, there were no significant differences between the groups on the subscales of emotional exhaustion ( F = 0.110, p = 0.740) and depersonalization ( F = 0.75, p = 0.387), and the General Self-Efficacy Scale ( F = 0.709, p = 0.403)., Conclusions: Balint groups helped reduce burnout among head nurses in terms of personal achievement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shan, Leonhart, Zhijuan, Minjie, Xinxin, Xinzhu, Xiangyan and Fritzsche.)

Background: Atrial fibrillation (AF) often leads to an impaired Health-Related Quality of Life (HRQoL) in many patients. Moreover, psychological factors such as depression, anxiety, and illness perception have been found to significantly correlate with HRQoL. This study aims to evaluate the long-term effectiveness of Cognitive Behavioral Therapy (CBT) in enhancing HRQoL and mitigating psychological distress among AF patients., Methods: Employing a prospective, open design with pseudo-randomization, this study encompassed pre-tests, post-treatment evaluations, and a 6-month follow-up. A total of 102 consecutive patients diagnosed with paroxysmal AF were initially enrolled. Out of these, 90 were assigned to two groups; one to receive a 10-week CBT treatment specifically focusing on anxiety, and the other to receive standard care. Outcome measures were evaluated using tools such as the Item Short Form Health Survey (SF-12), General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), University of Toronto Atrial Fibrillation Severity Scale (AFSS), and Brief Illness Perception Questionnaire (BIPQ). These assessments were conducted at pre-treatment, post-treatment, and at the 6-month follow-up mark. We explored the effectiveness of CBT using Generalized Estimating Equations (GEE)., Results: Our analysis revealed a notable improvement in the CBT group relative to the control group. All metrics displayed consistent improvement across a 6-month duration. At the 6-month checkpoint, the CBT group exhibited a more favorable SF-12 Mental Component Score (MCS) (50.261 ± 0.758 vs. 45.208 ± 0.887, p < 0.001), reduced GAD-7 (4.150 ± 0.347 vs. 8.022 ± 0.423, p < 0.001), BIPQ (34.700 ± 0.432 vs. 38.026 ± 0.318, p < 0.001), and AFSS (9.890 ± 0.217 vs. 10.928 ± 0.218, p = 0.001) scores when compared to the TAU group. Conversely, the SF-12 PCS (44.212 ± 0.816 vs. 47.489 ± 0.960, p = 0.139) and PHQ-9 scores (8.419 ± 0.713 vs. 10.409 ± 0.741, p = 0.794) manifested no significant difference between the two groups., Conclusion: The findings suggest that CBT is effective in improving HRQoL and reducing psychological distress among patients with AF at 6 month follow-up. This highlights the potential benefits of integrating CBT into the therapeutic regimen for AF patients., Trial Registration: Retrospectively registered with ClinicalTrials.gov (NCT05716828). The date of registration : 5 June 2023., (© 2023. The Author(s).)