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Background iPSC reprogramming technology exhibits significant promise in the realms of clinical therapeutics, disease modeling, pharmaceutical drug discovery, and various other applications. However, the extensive utilization of this technology has encountered impediments in the form of inefficiency, prolonged procedures, and ambiguous biological processes. Consequently, in order to improve this technology, it is of great significance to delve into the underlying mechanisms involved in iPSC reprogramming. The BET protein BRD4 plays a crucial role in the late stage of reprogramming; however, its precise function in the early stage remains unclear. Results Our study aims to investigate BRD4’s role in the early stages of iPSC reprogramming. Our investigation reveals that early inhibition of BRD4 substantially enhances iPSC reprogramming, whereas its implementation during the middle-late stage impedes the process. During the reprogramming, ribosome DNA expression initially increases before decreasing and then gradually recovers. Early inhibition of BRD4 improved the decline and restoration of rDNA expression in the early and middle-late stages, respectively. Additionally, we uncovered the mechanism of BRD4’s regulation of rDNA transcription throughout reprogramming. Specifically, BRD4 interacts with UBF and co-localizes to both the rDNA promoter and enhancer regions. Ultimately, BRD4 facilitates rDNA transcription by promoting the enrichment of histone H3 lysine 27 acetylation in the surrounding chromatin. Moreover, we also discovered that early inhibition of BRD4 facilitates cells’ transition out of the somatic cell state and activate pluripotent genes. Conclusions In conclusion, our results demonstrate that early inhibition of BRD4 promotes sequential dynamic expression of rDNA, which improves iPSC reprogramming efficiency.

Cyclobutanone is a strained motif with broad applications, while direct assembly of the aromatic ring fused cyclobutanones beyond benzocyclobutenone (BCB) skeletons remains challenging. Herein, we report a Rh-catalyzed formal [3+2] annulation of diazo group tethered alkynes involving a 4-exo-dig carbocyclization process, providing a straightforward access to furan-fused cyclobutanones. DFT calculations disclose that, by comparison to the competitive 5- endo - dig process, 4- exo - dig carbocyclization is mainly due to lower angle strain of the key sp -hybridized vinyl cationic transition state in the cyclization step. Using less reactive catalysts Rh 2 (carboxylate) 4 is critical for high selectivity, which is explained as catalyst-substrate hydrogen bonding interaction. This method is proved successful to direct access previously inaccessible and unknown furan-fused cyclobutanone scaffolds, which can participate in a variety of post-functionalization reactions as versatile synthetic blocks. In addition, preliminary antitumor activity study of these products indicates that some molecules exhibite significant anticancer potency against different human cancer cell lines. Aromatic ring fused cyclobutanone is a strained motif with broad applications. Here, the authors report a catalytic 4- exo-dig process, which proved successful to access furan-fused cyclobutanones that can serve as versatile synthetic blocks.

The geometric error distributed on components’ contact surfaces is a critical factor affecting assembly accuracy and precision instrument stability. Effective error separation methods can improve model accuracy, thereby aiding in performance prediction and process optimization. Here, an error separation method for geometric distribution error modeling for precision machining surfaces based on the K-space spectrum is proposed. To determine the boundary of systematical error and random error, we used a cruciform boundary line method based on the K-space spectrum, achieving the optimal separation of the two with frequency difference. The effectiveness of the method was experimentally verified using two sets of machined surfaces. By comparing with current common random error filtering methods, the outstanding role of the proposed error separation method in separating random error and preserving processing features has been verified.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading global health threat, exacerbated by drug resistance and inadequate vaccine efficacy. The PE/PPE protein family, unique to mycobacteria, constitutes ~10% of the Mtb genome and plays critical roles in bacterial physiology, immune evasion, and host-pathogen interactions. This review synthesizes advances in understanding the evolutionary expansion, structural diversity, and functional versatility of PE/PPE proteins, emphasizing their co-evolution with type VII secretion systems (T7SS). We highlight their roles in nutrient acquisition, immune modulation, and pathogenesis, alongside their potential as diagnostic and vaccine targets. Clinical progress in PE/PPE-based vaccines, such as M72/AS01E and ID93/GLA-SE, underscores their promise in combating TB, while challenges in epitope variability and functional redundancy demand innovative strategies. By integrating evolutionary, structural, and immunological insights, this review provides a roadmap for leveraging PE/PPE biology to develop next-generation TB interventions.

Histone acetyltransferases (HATs) GCN5 and PCAF (GCN5/PCAF) and CBP and p300 (CBP/p300) are transcription co‐activators. However, how these two distinct families of HATs regulate gene activation remains unclear. Here, we show deletion of GCN5/PCAF in cells specifically and dramatically reduces acetylation on histone H3K9 (H3K9ac) while deletion of CBP/p300 specifically and dramatically reduces acetylations on H3K18 and H3K27 (H3K18/27ac). A ligand for nuclear receptor (NR) PPARδ induces sequential enrichment of H3K18/27ac, RNA polymerase II (Pol II) and H3K9ac on PPARδ target gene Angptl4 promoter, which correlates with a robust Angptl4 expression. Inhibiting transcription elongation blocks ligand‐induced H3K9ac, but not H3K18/27ac, on the Angptl4 promoter. Finally, we show GCN5/PCAF and GCN5/PCAF‐mediated H3K9ac correlate with, but are surprisingly dispensable for, NR target gene activation. In contrast, CBP/p300 and their HAT activities are essential for ligand‐induced Pol II recruitment on, and activation of, NR target genes. These results highlight the substrate and site specificities of HATs in cells, demonstrate the distinct roles of GCN5/PCAF‐ and CBP/p300‐mediated histone acetylations in gene activation, and suggest an important role of CBP/p300‐mediated H3K18/27ac in NR‐dependent transcription. In general, histone acetylation correlates with gene activation; however, it is not clear if it is a cause or consequence of increased transcription. Here, the related histone acetyltransferases CBP and p300, which acetylate H3K18 and H3K27, are shown to be required for the induction of PPARδ target genes, while GCN5/PCAF‐mediated H3K9 acetylation is dispensable.

Tooth profile errors are the internal excitations that cause gear meshing errors, which are critical error factors affecting gear transmission accuracy. In existing studies, it is usually regarded as a constant or random distribution function. However, the actual machined tooth profile error is not a constant, so this estimation is inconsistent with the actual situation, resulting in an inaccurate evaluation of transmission accuracy. This paper proposes a method for representing tooth profile errors using distribution errors (including systematic and random errors), and a mathematical model of distributed tooth profile errors is presented. The contact stresses of the complex transmission system were compared with those obtained by formulas, proving that tooth profile errors increase contact stress. A method for calculating gear meshing error is proposed to evaluate the actual output accuracy of the complex transmission system. Compared with the test, the output accuracy is reduced by 13.8% under the temperature environment and distributed tooth profile errors. The proposed methods can accurately predict the transmission accuracy of precision transmission systems at the design stage and provide theoretical support for reducing systematic and random errors at the gear machining stage.

Background Intensive care unit-acquired weakness (ICU-AW) is very common in ICU patients. It is important to understand the status quo of knowledge, attitude and behavior of ICU nurses about ICU-AW. This survey aimed to investigate the knowledge, attitude and behavior of ICU nurses about ICU-AW, to provide useful implications for clinical care. Methods ICU nurses from two tertiary hospitals in China from October 10 to November 15, 2023 were included. The ICU-AW knowledge, attitude and behavior questionnaire of ICU nurses with 31 items were used for survey. SPSS24.0 statistical software was used for data analysis. Results A total of 364 ICU nurses were included for survey. The ICU-AW knowledge of ICU nurses was 21.96 ± 5.72 (< 50% of the total knowledge score), the ICU-AW attitude of ICU nurses was 30.24 ± 5.05(< 75% of the total attitude score), the ICU-AW behavior of ICU nurses was 26.77 ± 5.81(< 75% of the total behavior score), the total score was 79.21 ± 12.69(< 75% of the total score). Nurses’ ICU-AW knowledge, attitude and behavior were all correlated (all P  < 0.05). Multiple linear regression analyses indicated that age, years of ICU work experience, professional ranks and titles, had received the training about the ICU-AW were the influencing factors of knowledge, attitude and behavior of ICU nurses about ICU-AW (all P  < 0.05). Conclusions The knowledge, attitude and behavior of ICU nurses’ ICU-AW needs to be improved, and there are many influencing factors. Hospital nursing administrators should strengthen the training of nurses’ ICU-AW knowledge and improve the cognitive and practical ability of ICU nurses on ICU-AW, so as to reduce the occurrence of ICU-AW.

Purpose Although postoperative gastrointestinal dysfunction (POGD) is common after abdominal surgery, most evidence comes from major procedures, leaving its risk factors after short laparoscopic surgery poorly understood. This study aimed to explore the risk factors for POGD in this surgical context primarily and to examine modifiable strategies for enhancing gastrointestinal recovery secondarily. Methods In this prospective exploratory cohort study, 176 adults undergoing short laparoscopic surgery were included. Multivariable logistic regression was used to identify factors independently associated with POGD. Cox proportional hazards models were employed to assess the relationships between perioperative variables and the time to first flatus. Results Prolonged operating time (aOR = 1.294 per 10 min, 95% CI: 1.089–1.537, p  = 0.003) and longer preoperative fasting for clear liquids (aOR = 1.192 per hour, 95% CI: 1.057–1.345, p  = 0.004) were factors independently associated with POGD. Secondarily, in those patients undergoing short laparoscopic surgery, a higher step count on postoperative day 1 (aHR = 1.032 per 100 steps, 95% CI: 1.014–1.051, p  = 0.001) and earlier postoperative feeding (aHR = 0.968 per hour, 95% CI: 0.939–0.999, p  = 0.043) were significantly correlated with earlier time to flatus. Conclusions In patients undergoing short laparoscopic surgery, prolonged operating time and extended preoperative fluid fasting are modifiable risk factors for POGD. Earlier postoperative feeding and ambulation were associated with faster gastrointestinal recovery. These findings identify actionable perioperative targets for reducing POGD and enhancing recovery in this setting. Trial registration ChiCTR2400094411 (Registration Date: 2024-12-23)

Backgroud Perioperative neurocognitive disorder (PND) is a prevalent and serious complication in elderly surgical patients, with limited effective therapeutic options available. While our prior research has demonstrated the neuroprotective potential of the adiponectin pathway in PND, the underlying mechanisms remain to be fully elucidated. Methods In a prospective cohort study, we collected serum, cerebrospinal fluid (CSF), and sociodemographic data from 41 elderly hip fracture patients (29 normal and 12 PND patients). Further, twelve-month-old male Sprague-Dawley rats were divided into sham, PND (splenectomy), and PND + Adiporon (APN, 50 mg/kg/day intragastrically) group. Lactate, pyruvate, TNF-α and IL-1β levels in CSF and hippocampus were measured. Additionally, a PND + APN + LY294002 (a PI3K inhibitor, 25 mg/kg/day intraperitoneally) group was established to explore the underlying mechanisms further. Cognitive function was assessed using the Morris Water Maze (MWM) test. Glucose transport (Glut) 1, glycolysis (HK2, PFKFB3 and PKM2), energy production (ATP and Na + /K + -ATPase), microglia-mediated neuroinflammation (Iba1, TNF-α, IL-1β) and synaptic protein (PSD95, SYP and SYN I) were assessed in hippocampus. Results PND elderly patients exhibited lower serum adiponectin levels, which correlated with higher lactate/pyruvate ratio (Pearson’s r correlation: -0.4513; p  = 0.0031) and higher TNF-α level (Pearson’s r correlation: -0.4311; p  = 0.0049) in CSF. In PND rats, APN reduced lactate, lactate/pyruvate ratio, TNF-α, and IL-1β in brain. Mechanistically, APN activated AdipoR1-dependent PI3K/Akt signaling, enhanced Glut1 membrane localization, HK2 activity, and Na + /K + -ATPase activity. APN also inhibited microglia overactivation and neuroinflammation. Activation of the adiponectin pathway improved cognitive performance in the MWM test. Conclusion The adiponectin pathway regulates cerebral metabolic dysfunction and neuroinflammation via the AdipoR1/PI3K/Akt axis, which serves as a potential therapeutic target for improving perioperative cognitive outcomes in elderly patients.