PPID

Human epidermal growth factor receptor 2 (HER2) overexpression and activation are crucial for trastuzumab resistance in HER2-positive breast cancer; however, the potential regulatory mechanism of HER2 is still largely undetermined. In this study, a novel circular RNA derived from peptidylprolyl isomerase D (PPID) is identified as a negative regulator of trastuzumab resistance. Circ-PPID is highly stable and significantly downregulated in trastuzumab-resistant cells and tissues. Restoration of circ-PPID markedly enhances HER2-positive breast cell sensitivity to trastuzumab in vitro and in vivo. Circ-PPID directly binds to N-acetyltransferase 10 (NAT10) in the nucleus and blocks the interaction between NAT10 and HER2 mRNA, reducing N4-acetylcytidine (ac4C) modification on HER2 exon 25, leading to HER2 mRNA decay. Intriguingly, the subcellular localization of circ-PPID differs between trastuzumab-sensitive and -resistant cells. Circ-PPID in trastuzumab-resistant cells is located more in the cytoplasm, mainly due to the upregulation of Exportin 4 (XPO4), which results in the loss of spatial conditions for circ-PPID to bind to nuclear NAT10. Taken together, our data suggest that circ-PPID is a previously unappreciated ac4C-dependent HER2 epigenetic regulator, providing a promising therapeutic direction for overcoming trastuzumab resistance in clinical setting.

To improve the treatment performance of anaerobic ammonium oxidation (ANAMMOX) processes at low temperatures, the immobilized cold-acclimation ANAMMOX granules (R3) were prepared and their low-temperature nitrogen removal ability as well as the cold adaptation mechanism were analyzed. The results indicated that the total inorganic nitrogen (TIN) removal efficiency of R3 was significantly higher than that of R2 (cold-acclimation granules without immobilization) and R1 (common granules), especially at 11 ± 2 and 7 ± 2°C (68% and 54%). These were attributed to the remarkable biomass retention capacity of R3, high up to 4.3-4.9 mg/gVSS even at 5-18°C. Besides, higher protein (PN) content of tightly bound extracellular polymeric substances (TB-EPS) also facilitated microbial aggregation in R3. Meanwhile, R3 granules retained higher ANAMMOX activity and heme c content at 5-25°C. The original dominant ANAMMOX genus (Candidatus Kuenenia) in R3 kept higher abundance (49%-57%) at 23 ± 2 and 16 ± 2°C, whereas Candidatus Brocadia became the dominant ANAMMOX genus (25%-32%) in R3 at 11 ± 2 and 7 ± 2°C. Notably, different ANAMMOX genera in R3 may adapt to cold environment by regulating the expression of cold-stress proteins (CspA, CspB, PpiD, and UspA). PRACTITIONER POINTS: Immobilized cold-acclimation ANAMMOX granules showed higher nitrogen removal efficiency at 23°C → 5°C. Immobilization method effectively retained biomass (Candidatus Kuenenia and Candidatus Brocadia). Immobilization facilitated TB-EPS release and biological aggregation in cold-acclimation granules. Expression of cold-stress proteins in immobilized cold-acclimation granules was more active.

Given afferent functions, sensory nerves have recently been found to exert efferent effects and directly alter organ physiology. Additionally, several studies have highlighted the indirect but crucial role of sensory nerves in the regulation of the physiological function of osteoclasts. Nonetheless, evidence regarding the direct sensory nerve efferent influence on osteoclasts is lacking. In the current study, we found that high levels of efferent signals were transported directly from the sensory nerves into osteoclasts. Furthermore, sensory hypersensitivity significantly increased osteoclastic bone resorption, and sensory neurons (SNs) directly promoted osteoclastogenesis in an in vitro coculture system. Moreover, we screened a novel neuropeptide, Cyp40, using an isobaric tag for relative and absolute quantitation (iTRAQ). We observed that Cyp40 is the efferent signal from sensory nerves, and it plays a critical role in osteoclastogenesis via the aryl hydrocarbon receptor (AhR)-Ras/Raf-p-Erk-NFATc1 pathway. These findings revealed a novel mechanism regarding the influence of sensory nerves on bone regulation, i.e., a direct promoting effect on osteoclastogenesis by the secretion of Cyp40. Therefore, inhibiting Cyp40 could serve as a strategy to improve bone quality in osteoporosis and promote bone repair after bone injury.