Receptor-interacting protein kinase-3 （RIP3 or RIPK3） is an essential part of the cellular machinery that executes ＂programmed＂ or ＂regulated＂ necrosis. Here we show that programmed necrosis is ...activated in response to many chemotherapeutic agents and contributes to chemotherapy-induced cell death. However, we show that RIP3 expres- sion is often silenced in cancer cells due to genomic methylation near its transcriptional start site, thus RIP3-depen- dent activation of MLKL and downstream programmed necrosis during chemotherapeutic death is largely repressed. Nevertheless, treatment with hypomethylating agents restores RIP3 expression, and thereby promotes sensitivity to chemotherapeutics in a RIP3-dependent manner. RIP3 expression is reduced in tumors compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is positively selected during tumor growth/develop- ment. Since hypomethylating agents are reasonably well-tolerated in patients, we propose that RIP3-deficient cancer patients may benefit from receiving hypomethylating agents to induce RIP3 expression prior to treatment with con- ventional chemotherapeutics.
Female subfertility is highly associated with endometriosis. Endometrial progesterone resistance is suggested as a crucial element in the development of endometrial diseases. We report that MIG-6 is ...downregulated in the endometrium of infertile women with endometriosis and in a non-human primate model of endometriosis. We find ERBB2 overexpression in the endometrium of uterine-specific Mig-6 knockout mice (Pgr
Mig-6
; Mig-6
). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6
mice (Mig-6
Erbb2
mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6
mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6
mice revert to their normal expression in Mig-6
Erbb2
mice. Together, our results demonstrate that ERBB2 overexpression in endometrium with MIG-6 deficiency causes endometrial progesterone resistance and a nonreceptive endometrium in endometriosis-related infertility, and ERBB2 targeting reverses these effects.
Background
Obesity increases the risk of colorectal adenoma and colorectal cancer. However, the obesity-related parameters that are best for assessing the risk of colorectal adenoma development ...remain unclear. We analyzed the parameters that may best describe the association between obesity and colorectal adenoma development.
Methods
In this retrospective cohort study, 3405 individuals underwent screening colonoscopy during routine health examinations. We measured body mass index; waist circumference; and metabolic parameters such as high-density lipoprotein-cholesterol, glucose, triglyceride, and systolic blood pressure. We analyzed the risk of developing colorectal adenoma, relative to obesity-related parameters, over a mean interval of 5.8 years from baseline colonoscopy.
Results
In a multivariate analysis, waist circumference was the only obesity-related marker associated with an increased risk of metachronous colorectal adenoma. Men with waist circumferences ≥85 cm and women with waist circumference ≥82 cm had a 31% increased risk of metachronous colorectal adenoma compared to those with smaller waist circumferences odds ratio (OR) 1.31; 95% confidence interval (CI, 1.09–1.57). Other factors associated with metachronous colorectal adenoma were age (OR, 1.03; 95% CI 1.02–1.04), male sex (OR 1.49; 95% CI 1.17–1.88), alcohol consumption ≥3/week (OR 1.33; 95% CI 1.10–1.62), the number of adenoma at baseline (OR 1.21; 95% CI 1.10–1.33), and the presence of advanced adenoma at baseline (OR 1.60; 95% CI 1.24–2.06).
Conclusions
Our findings suggest that central obesity, represented by waist circumference, is a significant predictor of metachronous colorectal adenoma, independent of body mass index and other metabolic variables.
Available targeted therapies for esophageal squamous cell carcinoma (ESCC) are limited; thus, further genetic and epigenetic studies are needed. Recently, many long noncoding RNAs (lncRNAs) have been ...reported to be involved in various cancers. Here, we investigated whether the lncRNA LUCAT1 was related to the carcinogenesis of ESCC based on previous studies in lung cancer. LUCAT1 was significantly upregulated in ESCC cell lines and cancer tissue compared with normal cells and adjacent normal tissues. LUCAT1 knockdown reduced cell proliferation, induced apoptosis, and upregulated tumor-suppressor genes by reducing DNA methylation in KYSE-30 cells. Moreover, LUCAT1 siRNA reduced DNA methyltransferase 1 (DNMT1) protein levels without affecting transcription. Patients with high LUCAT1 expression had significantly lower survival rates than patients with low LUCAT1 expression. Our results thus suggest that LUCAT1 regulates the stability of DNMT1 and inhibits the expression of tumor suppressors through DNA methylation, leading to the formation and metastasis of ESCC. We identified LUCAT1 as a potential target for drug development and as a biomarker for ESCC.
•We investigated whether the lncRNA LUCAT1 was related to the carcinogenesis of ESCC.•LUCAT1 was significantly upregulated in ESCC cell lines and tissues.•LUCAT1 modulated cell proliferation, apoptosis, and tumor-suppressor genes in ESCC.•LUCAT1 regulated the stability of DNMT1.•We identified LUCAT1 as a potential drug target and biomarker for ESCC.
The switching parameters and device performance of memristors are predominately determined by their mobile species and matrix materials. Devices with oxygen or oxygen vacancies as the mobile species ...usually exhibit a great retention but also need a relatively high switching current (e.g., >30 µA), while devices with Ag or Cu as cation mobile species do not require a high switching current but usually show a poor retention. Here, Ru is studied as a new type of mobile species for memristors to achieve low switching current, fast speed, good reliability, scalability, and analog switching property simultaneously. An electrochemical metallization‐like memristor with a stack of Pt/Ta2O5/Ru is developed. Migration of Ru ions is revealed by energy‐dispersive X‐ray spectroscopy mapping and in situ transmission electron microscopy within a sub‐10 nm active device area before and after switching. The results open up a new avenue to engineer memristors for desired properties.
Ruthenium is proposed and experimentally demonstrated to be able to serve as a new type of mobile species memristive devices with some desirable properties. An example device with a Pt/Ta2O5/Ru stack structure exhibits low switching current and voltage, fast speed, good scalability, and analog switching property simultaneously.
Objective
We investigated whether (1) imported pre-cut tissue is feasible for Descemet membrane endothelial keratoplasty (DMEK) in eyes of Asian patients, (2) the clinical outcome is comparable ...between the endothelium‐in and endothelium‐out methods, and (3) the corneal edema-induced anterior curvature changes may have an effect on the refractive error.
Methods
The medical records of 32 DMEK patients who underwent either the endothelium-out or endothelium-in method using imported pre-cut grafts with a 3-day pre-cut-to-use time were retrospectively analyzed. Fuchs’ endothelial dystrophy (37.5%) and bullous keratopathy (62.5%) cases were included. The main clinical outcome measures were graft survival, best corrected visual acuity (BCVA), endothelial cell density (ECD), corneal thickness (CT), and complications. Correlation of the anterior curvature changes with refractive error was analyzed in the DMEK with cataract surgery group.
Results
The overall survival rate was 71.9%. Final graft failures were caused by rejection, glaucoma, and infection. Visual acuities improved by 89.3%. BCVA better than 20/40 and 20/20 was found in 75% and 28.6% of patients, respectively. The ECDs at 3 months and 1 year were 1400 and 1083 cells/mm
2
, respectively. The mean survival time, ECD, BCVA, CT, and complication rates were not different between the endothelium-in and endothelium-out methods. A hyperopic shift by +0.42 D was not related to the anterior curvature changes.
Conclusion
Imported pre-cut tissues with a ≤ 3-day pre-cut-to-use time are feasible for DMEK in the treatment of corneal endothelial edema in eyes of Asian patients, and both endothelium-in and endothelium-out methods appear to be comparatively effective. Edema-induced anterior curvature change may not affect the refractive shift.
The suitable materials, metal nitrides, are a promising class of electrocatalyst materials for a highly efficient oxygen evolution reaction (OER) because they exhibit superior intrinsic conductivity ...and have higher sustainability than oxide-based materials. To our knowledge, for the first time, we report a designable synthesis of three-dimensional (3D) and mesoporous Co
3
N@amorphous N-doped carbon (AN-C) nanocubes (NCs) with well-controlled open-framework structures via monodispersed Co
3
Co(CN)
6
2
Prussian blue analogue (PBA) NC precursors using
in situ
nitridation and calcination processes. Co
3
N@AN-C NCs (2 h) demonstrate better OER activity with a remarkably low Tafel plot (69.6 mV·dec
−1
), low overpotential of 280 mV at a current density of 10 mA·cm
−2
. Additionally, excellent cycling stability in alkaline electrolytes was exhibited without morphological changes and voltage elevations, superior to most reported hierarchical structures of transition-metal nitride particles. The presented strategy for synergy effects of metal-organic frameworks (MOFs)-derived transition-metal nitrides-carbon hybrid nanostructures provides prospects for developing high-performance and advanced electrocatalyst materials.
Endometriosis is a disease in which tissue that normally grows inside the uterus grows outside the uterus and causes chronic pelvic pain and infertility. However, the exact mechanisms of the ...pathogenesis of endometriosis-associated infertility are unknown. Epigenetic dysregulation has recently been implicated in infertility. Here, we report a reduction of histone deacetylase 3 (HDAC3) protein amounts in eutopic endometrium of infertile women with endometriosis compared to a control group. To investigate the effect of HDAC3 loss in the uterus, we generated mice with conditional ablation of
in progesterone receptor (PGR)-positive cells (
;
). Loss of
in the uterus of mice results in infertility due to implantation failure and decidualization defect. Expression microarray and ChIP-seq analyses identified
and
as direct targets of HDAC3 in both mice and humans. Reduction of
abrogated decidualization in a primary culture of human endometrial stromal cells (hESCs) similar to that observed in infertile patients with endometriosis. Whereas attenuation of
resulted in p300 recruitment to
and
genes in the uterus of mice as well as hESCs, inhibition of p300 permitted hESCs to undergo decidualization. Collectively, we found attenuation of HDAC3 and overexpression of collagen type I in the eutopic endometrium of infertile patients with endometriosis. HDAC3 loss caused a defect of decidualization through the aberrant transcriptional activation of
and
genes in mice and
and
genes in humans. Our results suggest that HDAC3 is critical for endometrial receptivity and decidualization.
A nociceptor is a critical and special receptor of a sensory neuron that is able to detect noxious stimulus and provide a rapid warning to the central nervous system to start the motor response in ...the human body and humanoid robotics. It differs from other common sensory receptors with its key features and functions, including the "no adaptation" and "sensitization" phenomena. In this study, we propose and experimentally demonstrate an artificial nociceptor based on a diffusive memristor with critical dynamics for the first time. Using this artificial nociceptor, we further built an artificial sensory alarm system to experimentally demonstrate the feasibility and simplicity of integrating such novel artificial nociceptor devices in artificial intelligence systems, such as humanoid robots.
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