Search

Abstract Ubiquitination was considered to be a crucial factor in intrahepatic cholangiocarcinoma (iCCA) development. Herein, we identified Ubiquitin-specific peptidase 8 (USP8) as a key regulator for promoting the tumorigenesis of iCCA cell via stabilizing OGT. USP8 was overexpressed in human tumor tissues and correlated with worse survival. Moreover, the mass spectrometry and co-immunoprecipitation analysis indicated that USP8 interacted with OGT. USP8 worked as a bona fide deubiquitylase of OGT. It stabilized OGT in a deubiquitylation activity-dependent manner. Meanwhile, DUB-IN3, the USP8 inhibitor, could also restrain the malignancy of intrahepatic cholangiocarcinoma. In addition, USP8 depletion promoted the response of iCCA to pemigatinib. In conclusion, our findings pointed to a previously undocumented catalytic role for USP8 as a deubiquitinating enzyme of OGT. The USP8-OGT axis could be a potential target for iCCA therapy.

Abstract Neurologic Rosai–Dorfman disease (RDD) is a rare type of non-Langerhans cell histiocytosis that affects the central nervous system. Most neurologic RDDs grow like meningiomas, have clear boundaries, and can be completely resected. However, a few RDDs are invasive and aggressive, and no effective treatment options are available because the molecular mechanisms involved remain unknown. Here, we report a case of deadly and glucocorticoid-resistant neurologic RDD and explore its possible pathogenic mechanisms via single-cell RNA sequencing. First, we identified two distinct but evolutionarily related histiocyte subpopulations (the C1Q+ and SPP1+ histiocytes) that accumulated in the biopsy sample. The expression of genes in the KRAS signaling pathway was upregulated, indicating gain-of-function of KRAS mutations. The C1Q+ and SPP1+ histiocytes were highly differentiated and arrested in the G1 phase, excluding the idea that RDD is a lympho-histio-proliferative disorder. Second, although C1Q+ histiocytes were the primary RDD cell type, SPP1+ histiocytes highly expressed several severe inflammation-related and invasive factors, such as WNT5A, IL-6, and MMP12, suggesting that SPP1+ histiocytes plays a central role in driving the progression of this disease. Third, oligodendrocytes were found to be the prominent cell type that initiates RDD via MIF and may resist glucocorticoid treatment via the MDK and PTN signaling pathways. In summary, in this case, we report a rare presentation of neurologic RDD and provided new insight into the pathogenic mechanisms of progressive neurologic RDD. This study will also offer evidence for developing precision therapies targeting this complex disease.

ERI1 is a 3-to-5 exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3 end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

Epoxy dielectrics with high through-plane thermal conductivity (λ) hold great promise for applications in the thermal management of advanced power electronics. Intensive attempts have been made to improve the λ of epoxy by filling with boron nitride nanosheets (BNNSs). However, it remains a great challenge to achieve a satisfactory increased λ by a small amount of BNNS loading. Herein, we reported a new strategy to prepare epoxy dielectrics with internal three-dimensional phonon transport channels by vacuum freeze-drying and vacuum impregnation. Aramid nanofibers (ANFs) and BNNSs were used for the collaborative construction of a vertical interconnected thermal framework. The resultant ANF-BNNS/epoxy achieved a high through-plane λ of 0.87 W m−1 K−1 at only 1.43 vol. % BNNS, which is ∼17.1% higher than that of the BNNS/epoxy counterpart with even 18.34 vol. % randomly distributed BNNS. The increasing efficiency of λ of epoxy by ANF-BNNS is tenfold more than that of the conventional blending methods. In addition, the ANF-BNNS/epoxy composite also exhibits a low dielectric constant and low dielectric loss. The findings of this study offer an inspired venue to develop high-performance thermally conductive epoxy dielectrics with a minimal BNNS loading. [ABSTRACT FROM AUTHOR]

AIM: To evaluate the clinical efficacy and systemic safety profile of conbercept in clinical practice on vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PLGF) levels after intravitreal injections for the neovascular age-related macular degeneration (AMD). METHODS: Thirty-five patients (35 eyes) with neovascular AMD received intravitreal injections of conbercept treatment with pro re nata protocol. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were detected before the intravitreal injection and at 1, 3, and 12mo after conbercept treatment. The levels of serum VEGF-A, VEGF-B, and PLGF were measured by enzyme-linked immunosorbent assay before the injection and 1 and 12mo after conbercept treatments. RESULTS: At baseline, the mean BCVA score was 39.89±14.64 letters. The mean BCVA scores were 51.03±15.78, 56.71±14.38, and 52.49±10.16 letters at 1, 3, and 12mo after conbercept treatment, and the BCVA improvements were all significant, respectively (P0.05). CONCLUSION: Conbercept intravitreal injection leads to BCVA and CRT improvement, however, it does not significantly affect systemic serum VEGF-A, VEGF-B, and PLGF levels at 1 and 12mo after intravitreal injection treating neovascular AMD.

AIM: To explore the feasibility of swept source optical coherence tomography angiography(SS-OCTA)in evaluating early retinal and choroidal microcirculation changes in patients with hypertension.METHODS:Prospective clinical study. A total of 27 patients with grade 2 or 3 essential hypertension(hypertension group)diagnosed in the Department of Cardiology of Xi'an First Hospital from July to November 2022 were included in the study. There were 14 males and 13 females. The mean age was(57.11±3.36)years. During the same period, 27 age- and sex-matched normal people without a history of hypertension were selected as the control group, including 12 males and 15 females. The average age was(55.74±2.95)years old. All patients underwent BCVA(LogMAR), intraocular pressure, axial length, slit lamp examination, fundus color photography and SS-OCTA examination. SS-OCTA was used to scan the macular area of the right eye in the range of 6×6 mm. The retina and choroid were divided into three concentric circles with diameters of 0-1 mm, 1-3 mm and 3-6 mm around the fovea according to ETDRS. Macular vessel density(VD), perfusion area(PA), retinal thickness(CMT), choroidal thickness(CT), choroidal vessel volume(CVV)and choroidal vasculr index(CVI)of the superficial capillary plexus(SCP)and the deep capillary plexus(DCP)in the macular area of 0-1 mm, 1-3 mm and 3-6 mm were analyzed and recorded. The changes in VD, PA, CMT, CT, CVV and CVI were compared between the two groups. Independent sample t-test was used to compare VD, PA, CMT and CVI between the two groups; CT, CVV and LogMAR visual acuity were analyzed by Wilcoxon signed rank test of independent samples.RESULTS:Compared with the control group, the hypertensive group had significantly lower VD in the macular area 0-3 mm(0-1 mm, t=-3.144; 1-3 mm, t=-3.611, P0.05). The CMT in the 0-1mm area of the macular area in the hypertension group was lower than that in the control group(t=-2.624, P0.05).CONCLUSION:The VD of DCP in the 0-3 mm area and the CMT in the 0-1 mm area are decreased in hypertensive patients. There were no significant differences in CT, CVV and CVI between the two groups. VD and CMT in macular DCP may be used as indicators to evaluate the early changes of retinal and choroidal microcirculation in hypertensive patients.

Abstract Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal human malignancies, and with quite limited treatment alternatives. The proteasome is responsible for most of the protein degradation in eukaryotic cells and required for the maintenance of intracellular homeostasis. However, its potential role in HCC is largely unknown. In the current study, we identified eukaryotic translation initiation factor 3 subunit H (EIF3H), belonging to the JAB1/MPN/MOV34 (JAMM) superfamily, as a bona fide deubiquitylase of O-GlcNAc transferase (OGT) in HCC. We explored that EIF3H was positively associated with OGT in HCC and was related to the unfavorable prognosis. EIF3H could interact with, deubiquitylate, and stabilize OGT in a deubiquitylase-dependent manner. Specifically, EIF3H was associated with the GT domain of ERα via its JAB/MP domain, thus inhibiting the K48-linked ubiquitin chain on OGT. Besides, we demonstrated that the knockdown of EIF3H significantly reduced OGT protein expression, cell proliferation and invasion, and caused G1/S arrest of HCC. We also found that the deletion of EIF3H prompted ferroptosis in HCC cells. Finally, the effects of EIF3H depletion could be reversed by further OGT overexpression, implying that the OGT status is indispensable for EIF3H function in HCC carcinogenesis. In summary, our study described the oncogenic function of EIF3H and revealed an interesting post-translational mechanism between EIF3H, OGT, and ferroptosis in HCC. Targeting the EIF3H may be a promising approach in HCC. Video Abstract