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Transcription-blocking lesions (TBLs) stall elongating RNA polymerase II (Pol II), which then initiates transcription-coupled repair (TCR) to remove TBLs and allow transcription recovery. In the absence of TCR, eviction of lesion-stalled Pol II is required for alternative pathways to address the damage, but the mechanism is unclear. Using Protein-Associated DNA Damage Sequencing (PADD-seq), this study reveals that the p97-proteasome pathway can evict lesion-stalled Pol II independently of repair. Both TCR and repair-independent eviction require CSA and ubiquitination. However, p97 is dispensable for TCR and Pol II eviction in TCR-proficient cells, highlighting repairs prioritization over repair-independent eviction. Moreover, ubiquitination of RPB1-K1268 is important for both pathways, with USP7s deubiquitinase activity promoting TCR without abolishing repair-independent Pol II release. In summary, this study elucidates the fate of lesion-stalled Pol II, and may shed light on the molecular basis of genetic diseases caused by the defects of TCR genes.

Niche-derived growth factors support self-renewal of mouse spermatogonial stem and progenitor cells through ERK MAPK signaling and other pathways. At the same time, dysregulated growth factor-dependent signaling has been associated with loss of stem cell activity and aberrant differentiation. We hypothesized that growth factor signaling through the ERK MAPK pathway in spermatogonial stem cells is tightly regulated within a narrow range through distinct intracellular negative feedback regulators. Evaluation of candidate extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK)-responsive genes known to dampen downstream signaling revealed robust induction of specific negative feedback regulators, including Spry4, in cultured mouse spermatogonial stem cells in response to glial cell line-derived neurotrophic factor or fibroblast growth factor 2. Undifferentiated spermatogonia in vivo exhibited high levels of Spry4 mRNA. Quantitative single-cell analysis of ERK MAPK signaling in spermatogonial stem cell cultures revealed both dynamic signaling patterns in response to growth factors and disruption of such effects when Spry4 was ablated, due to dysregulation of ERK MAPK downstream of RAS. Whereas negative feedback regulator expression decreased during differentiation, loss of Spry4 shifted cell fate toward early differentiation with concomitant loss of stem cell activity. Finally, a mouse Spry4 reporter line revealed that the adult spermatogonial stem cell population in vivo is demarcated by strong Spry4 promoter activity. Collectively, our data suggest that negative feedback-dependent regulation of ERK MAPK is critical for preservation of spermatogonial stem cell fate within the mammalian testis.

Light has profoundly impacted modern medicine and healthcare, with numerous luminescent agents and imaging techniques currently being used to assess health and treat diseases. As an emerging concept in luminescence, aggregation-induced emission (AIE) has shown great potential in biological applications due to its advantages in terms of brightness, biocompatibility, photostability, and positive correlation with concentration. This review provides a comprehensive summary of AIE luminogens applied in imaging of biological structure and dynamic physiological processes, disease diagnosis and treatment, and detection and monitoring of specific analytes, followed by representative works. Discussions on critical issues and perspectives on future directions are also included. This review aims to stimulate the interest of researchers from different fields, including chemistry, biology, materials science, medicine, etc., thus promoting the development of AIE in the fields of life and health.

Pancreatic cystic tumors (PCN) refer to cystic tumor lesions originating from the epithelium and/or interstitial tissue of the pancreatic duct. PCN can be roughly divided into mucinous tumors and non-mucinous tumors. The former mainly includes intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN), while the latter mainly includes serous cystic neoplasms (SCN) and solid-pseudopapillary neoplasms (SPN) and cystic neuroendocrine neoplasms (cNET). Different types of PCNs have differentiated biological behaviors, and some types of PCNs have a risk of developing a malignancy. Preoperative identification of PCN malignancy on CT and MRI imaging is of great significance. Malignant indications for MCN are surgical indications， such as a diameter greater than or equal to 4 cm. IPMN accounts for 22% of PCN, and the risk of malignancy in main pancreatic duct type and mixed type IPMN can reach up to 70.9% and 76.5%, while the risk of malignancy in branch pancreatic duct type IPMN is 2.8%-10.7%. High risk signs of malignancy for IPMN include enhanced parenchymal or diameter of parietal nodules ≥ 5 mm, main pancreatic duct dilation (≥ 10 mm), and obstructive jaundice, and surgical treatment is recommended for these patients. SCN is more common in middle-aged and elderly women, with a male to female ratio of 1:3. Serous cystadenocarcinoma is rare, accounting for only 0.1% of pancreatic SCN. The 2015 edition of the Diagnosis and Treatment Guidelines for Pancreatic Cystic Diseases recommends that all SPNs patients should undergo surgical treatment. When the tumor of SPN with incomplete capsule, the mass diameter larger than 6 cm, and the tumor located in the tail of the pancreas, may have a higher ability of invasiveness and distant metastasis. cNET accounts for approximately 7% of PCN. Imaging diagnosis should be combined with medical history and lesion components, etc. The diagnostic point for SPN on image is that MCN is a round, thick walled cystic tumor that almost exclusively occurs in females in the body and tail of the pancreas body, often presenting as an “intracystic cyst”. IPMN is more common in elderly men. The main pancreatic duct type of IPMN presents as diffuse or segmental dilation of the main pancreatic duct, excluding obstructive factors. Branch pancreatic duct type of IPMN usually presents as tubular cystic tumors that communicate with the pancreatic duct, while mixed type of IPMN combines both manifestations. SCN is a lobulated, thin-walled oligocystic or multicystic honeycomb tumor. SPN is a larger round cystic solid tumor that is more common in young women. cNET is a cystic solid tumor with significantly enhanced circular or crescent shaped edges. There is significant controversy in domestic and foreign guidelines regarding the selection of indications for PCN surgery, and pancreatic surgery is difficult with many postoperative complications, posing challenges to the standardized treatment of PCN. Identifying the imaging characteristics of PCN and clarifying imaging diagnosis has clinical significance.