FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress.

Fanconi anemia (FA) signaling, a key genomic maintenance pathway, is activated in response to replication stress. Here, we report that phosphorylation of the pivotal pathway protein FANCD2 by CHK1 triggers its FBXL12-dependent proteasomal degradation, facilitating FANCD2 clearance at stalled replication forks. This promotes efficient DNA replication under conditions of CYCLIN E- and drug-induced replication stress. Reconstituting FANCD2-deficient fibroblasts with phosphodegron mutants failed to re-establish fork progression. In the absence of FBXL12, FANCD2 becomes trapped on chromatin, leading to replication stress and excessive DNA damage. In human cancers, FBXL12, CYCLIN E, and FA signaling are positively correlated, and FBXL12 upregulation is linked to reduced survival in patients with high CYCLIN E-expressing breast tumors. Finally, depletion of FBXL12 exacerbated oncogene-induced replication stress and sensitized cancer cells to drug-induced replication stress by WEE1 inhibition. Collectively, our results indicate that FBXL12 constitutes a vulnerability and a potential therapeutic target in CYCLIN E-overexpressing cancers.

Biophysical characterization of histone H3.3 K27M point mutation.

Lysine 27 to methionine (K27 M) mutation of the histone variant H3.3 drives the formation of an aggressive glioblastoma multiforme tumor in infants. Here we analyzed how the methionine substitution alters the stability of H3.3 nucleosomes in vitro and modifies its kinetic properties in live cells. We also determined whether the presence of mutant nucleosomes perturbed the mobility of the PRC2 subunit Ezh2 (enhancer-of-zeste homolog 2). We found that K27 M nucleosomes maintained the wild-type molecular architecture both at the level of bulk histones and single nucleosomes and followed similar diffusion kinetics to wild-type histones in live cells. Nevertheless, we observed a remarkable differential recovery of Ezh2 in response to transcriptional stress that was accompanied by a faster diffusion rate of the mobile fraction of Ezh2 and a significantly increased immobile fraction, suggesting tighter chromatin binding of Ezh2 upon transcription inhibition. The differential recovery of Ezh2 was dependent on transcription, however, it was independent from K27 M mutation status. These biophysical characteristics shed more light on the mechanism of histone H3.3 K27M in glioma genesis in relation to the kinetic properties of Ezh2.

The impact of smart manufacturing demonstration projects on green innovation of Chinese firms: Based on random forest methods.

Employing the data of Chinese A-share listed firms from 2010 to 2020 and random forest approaches, this paper investigates whether and how smart manufacturing demonstration projects influence green innovation of firms. The main results are as follows. First, smart manufacturing demonstration projects contribute to promoting firms' green innovation. Additionally, information processing capability improvement, innovation efficiency enhancement, public attention increasement, and signal effect are the main channels that improve firms' green innovation. Finally, the positive effect of smart manufacturing demonstration projects on firms' green innovation is pronounced for capital-intensive firms, and firms in western and eastern regions.

Coordinated Cut and Bypass: Replication of Interstrand Crosslink-Containing DNA.

DNA interstrand crosslinks (ICLs) are covalently bound DNA lesions, which are commonly induced by chemotherapeutic drugs, such as cisplatin and mitomycin C or endogenous byproducts of metabolic processes. This type of DNA lesion can block ongoing RNA transcription and DNA replication and thus cause genome instability and cancer. Several cellular defense mechanism, such as the Fanconi anemia pathway have developed to ensure accurate repair and DNA replication when ICLs are present. Various structure-specific nucleases and translesion synthesis (TLS) polymerases have come into focus in relation to ICL bypass. Current models propose that a structure-specific nuclease incision is needed to unhook the ICL from the replication fork, followed by the activity of a low-fidelity TLS polymerase enabling replication through the unhooked ICL adduct. This review focuses on how, in parallel with the Fanconi anemia pathway, PCNA interactions and ICL-induced PCNA ubiquitylation regulate the recruitment, substrate specificity, activity, and coordinated action of certain nucleases and TLS polymerases in the execution of stalled replication fork rescue via ICL bypass.

[Application of microdebritor in the treatment of the juvenile onset recurrent respiratory papillomatosis].

OBJECTIVE: To evaluate the treatment methods and improve the curative effects of the juvenile onset recurrent respiratory papillomatosis. METHOD: Fourteen patients with juvenile onset recurrent respiratory papillomatosis were treated from 2002 to 2003 by using microdebritor. RESULT: Among the 14 cases, eight cases had no recurrence after three to six operations within six month follow up and were decannulated,the other six cases had recurrence postoperatively. CONCLUSION: It is demonstrated that microdebritor surgery is an ideal therapy for the treatment of juvenile onset recurrent respiratory papillomatosis.

[Clinical study of uvulopalatopharyngoplasty treatment for middle degree of obstructive sleep apnea syndromes].

OBJECTIVE: In order to investigate the treatment of obstructive sleep apnea syndrome (OSAS) METHOD: The improved uvulopalatopharyngoplasty (UPPP) operations were performed on 64 cases. RESULT: The clinical results showed that 70. Thirty-one percent of the operated patients somewhat improved and 29. Seventy percent unimproved. CONCLUSION: UPPP is one of the effective methods to treat OSAS, especially for OSAS with stricture in pharyngeal cavity. It has less damage, less operative complications and so on.

[An etiological and clinicopathological study of early syphilis in oropharynx].

OBJECTIVE: To investigate the characteristics of the early stage treponema pallidum infected tissue in ear, nose, oropharynx and larynx and to raise relevance ratio of syphilis in nose and oropharynx and enhance doctor's self-protection awareness. METHODS: The histopathologic characteristics were studied by using HE staining, Warthin-Starry (W-S) staining was adopted to examine the treponema pallidum(TP) in lesion issue and its exudates smear for 12 cases biopsy tissues of suspicious syphilis. The diagnosis was confirmed by venereal disease research laboratory (VDRL), rapid plasma reagin circle test(RPR), treponema pallidum hemagglutination test(TPHA) and fluorescent treponemal antibody-absorption test (FTA-ABS). Treat with curing syphilis methods which published by nation. RESULTS: In the 12 cases mucous membrane specimen, the squamous epithelium proliferated, neutrophilic granulocyte infiltrated, within inherent membrane generous plasmacyte and lymphocyte infiltrated. W-S staining: plenty of treponema pallidum were found inside mucous membrane epithelium and exudate smear. Serology examination: 11 cases VDRL(++++), 7 cases RPR (+), 11 cases TPHA(+), 1 case FTA-ABS(+). After systemic treatment, 11 cases are clinically recovered. All patients serology become negative. CONCLUSION: W-S staining method can directly demonstrate histopathologic characteristics in early syphilis, in intrinsic membrane numerous plasmacyte infiltration. Combining with specific syphilis serology examination could increase diagnosis rate of syphilis in nose and oropharynx.

[Application of CO2 laser and T tube in the treatment of the laryngeal stenosis].

OBJECTIVE: To introduce a new method for treating laryngeal stenosis of both children and adults using silicon T tube and CO2 laser. METHODS: Twenty-two cases stenosis of adults and children were treated with silicon T tube and CO2 laser. The tracheotomy were enlarged upward, the laryngeal cavity scar was removed by using CO2 laser and the laryngeal cavity was exposed by distending laryngoscope under general anesthesia. The follow up time is between 1 to 3 years. RESULTS: The 22 cases were successfully decanulated postoperatively in 12 to 24 months. Silicon 4 cases's T tube were either too high or too low and had second operation. CONCLUSION: The method for treating laryngeal stenosis of both children and adults using silicon T tube and CO2 laser are effective, easy to operate, less invasive and have a short recovery interval.