The E3 ubiquitin ligase (E3)-mediated ubiquitination and deubiquitinase (DUB)-mediated deubiquitination processes are closely associated with the occurrence and development of colonic inflammation. ...Ovarian tumor deubiquitinase 1 (OTUD1) is involved in immunoregulatory functions linked to infectious diseases. However, the effect of OTUD1 on intestinal immune responses during colonic inflammatory disorders such as inflammatory bowel disease (IBD) remains unclear. Here, we show that loss of OTUD1 in mice contributes to the pathogenesis of dextran sulfate sodium (DSS)-induced colitis via excessive release of proinflammatory cytokines. In addition, bone marrow transplantation experiments revealed that OTUD1 in hematopoietic cells plays a dominant role in protection against colitis. Mechanistically, OTUD1 physically interacts with receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and selectively cleaves K63-linked polyubiquitin chains from RIPK1 to inhibit the recruitment of NF-κB essential modulator (NEMO). Moreover, the expression of OTUD1 in mucosa samples from ulcerative colitis (UC) patients was lower than that in mucosa samples from healthy controls. Furthermore, we demonstrate that the UC-associated OTUD1 G430V mutation abolishes the ability of OTUD1 to inhibit RIPK1-mediated NF-κB activation and intestinal inflammation. Taken together, our study unveils a previously unexplored role of OTUD1 in moderating intestinal inflammation by inhibiting RIPK1-mediated NF-κB activation, suggesting that the OTUD1-RIPK1 axis could be a potential target for the treatment of IBD.
The polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is dysregulated in various cancers, and its upregulation strongly correlates with an invasive phenotype and poor ...prognosis in patients with nasopharyngeal carcinomas. However, the underlying mechanism of Bmi-1-mediated invasiveness remains unknown. In the current study, we found that upregulation of Bmi-1 induced epithelial-mesenchymal transition (EMT) and enhanced the motility and invasiveness of human nasopharyngeal epithelial cells, whereas silencing endogenous Bmi-1 expression reversed EMT and reduced motility. Furthermore, upregulation of Bmi-1 led to the stabilization of Snail, a transcriptional repressor associated with EMT, via modulation of PI3K/Akt/GSK-3beta signaling. Chromatin immunoprecipitation assays revealed that Bmi-1 transcriptionally downregulated expression of the tumor suppressor PTEN in tumor cells through direct association with the PTEN locus. This in vitro analysis was consistent with the statistical inverse correlation detected between Bmi-1 and PTEN expression in a cohort of human nasopharyngeal carcinoma biopsies. Moreover, ablation of PTEN expression partially rescued the migratory/invasive phenotype of Bmi-1-silenced cells, indicating that PTEN might be a major mediator of Bmi-1-induced EMT. Our results provide functional and mechanistic links between the oncoprotein Bmi-1 and the tumor suppressor PTEN in the development and progression of cancer.
•Different dosages of HEV p179 vaccine were safe and well tolerated in this study.•No vaccine related serious adverse effects (SAEs) occurred during the study.•The HEV vaccine was expressed in ...naturally-soluble form and self-assembled into VLPs.
This study aimed to evaluate the safety and tolerability for variable dosages of a novel hepatitis E vaccine p179.
The randomized open-label parallel control phase 1 clinical trial enrolled 120 eligible participants aged 16–65years in Jiangsu Province, China. The experimental groups were randomized to receive different dosages of 20μg, 30μg, and 40μg Hepatitis E Virus (HEV) p179 vaccines, with the 30μgHEV vaccine p239 Hecolin as control, and vaccinated at 0, 1 and 6month intervals. Participants were observed for solicited local and systemic adverse reactions (ARs) occurring within 7days after each vaccination, and any serious adverse events (SAEs) occurring within 6months post-vaccination. Blood samples were collected from participants 3days before and after each injection, to determine the blood routine and serum biochemical indexes.
The solicited local ARs incidence in experimental groups were significantly lower than that of the control group (P=0.027). The difference between solicited total and systemic ARs incidence of experimental groups and the control group were not significant (P>0.05). Similar patterns were observed when the analyses were performed on the group having ARs of varying grades and symptoms. All changes in blood biochemical indexes and routine blood tests before and after different vaccinations were mild (grade 1) or moderate (grade 2), and the difference in experimental groups and the control group were not statistically significant. No vaccine related SAEs occurred in any of the subjects during the study.
Three different dosages of HEV p179 vaccine were deemed safe and well tolerated. No vaccine-associated SAEs were identified, and the 30μg dosage formulation was selected for further investigation for efficacy.
Clinical trials registration number: 2012L01657.
Lotus (Nelumbo nucifera Gaertn.) seeds are rich in proteins and are considered to be a beneficial source of plant proteins. In this study, lotus seed protein hydrolysate (LSPH) was prepared using ...Flavourzyme and antioxidant activities were evaluated. The LSPH possessed the highest DPPH-scavenging (EC50 2.9 mg/mL), H2O2-scavenging (EC50 16.1 mg/mL), and reducing power activity (8.0 mg/mL) at 180 min of hydrolysis. After gel filtration and reverse phase HPLC purification, the low molecular weight fraction was then analyzed by Nano-LC-MS/MS. Sixteen peptides with corresponding mass from 1 to 2 kDa were identified. Peptides with hydrophobic features and acidic amino acids, Asp and Glu, are considered to contribute to overall antioxidant activities. These results show Flavourzyme hydrolysis of lotus seed protein successfully generates low molecular fragments that make them a potential nutraceutical or health promoting supplement.
Display omitted
•Flavourzyme effectively hydrolyze lotus seed protein to reach 79.5% DH.•The degree of hydrolysis was negatively correlated with antioxidant activities.•The fraction with the smallest molecular weight has the best antioxidant activities.•Nano-LC-MS/MS was applied to characterize antioxidative peptide sequences.•Sixteen peptides with 8–17 residues were identified from an antioxidative fraction.
Our anatomical analysis revealed that a dry maize seed contains four to five embryonic leaves at different developmental stages. Rudimentary kranz structure (KS) is apparent in the first leaf with a ...substantial density, but its density decreases toward younger leaves. Upon imbibition, leaf expansion occurs rapidly with new KSs initiated from the palisade-like ground meristem cells in the middle of the leaf. In parallel to the anatomical analysis, we obtained the time course transcriptomes for the embryonic leaves in dry and imbibed seeds every 6 h up to hour 72. Over this time course, the embryonic leaves exhibit transcripts of 30,255 genes at a level that can be regarded as “expressed.” In dry seeds, ∼25,500 genes are expressed, showing functional enrichment in transcription, RNA processing, protein synthesis, primary metabolic pathways, and calcium transport. During the 72-h time course, ∼13,900 genes, including 590 transcription factor genes, are differentially expressed. Indeed, by 30 h postimbibition, ∼2,200 genes expressed in dry seeds are already down-regulated, and ∼2,000 are up-regulated. Moreover, the top 1% expressed genes at 54 h or later are very different from those before 30 h, reflecting important developmental and physiological transitions. Interestingly, clusters of genes involved in hormone metabolism, signaling, and responses are differentially expressed at various time points and TF gene expression is also modular and stage specific. Our dataset provides an opportunity for hypothesizing the timing of regulatory actions, particularly in the context of KS development.
The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and ...synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25, which demonstrated an 8-fold higher oral AUC (F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC-amplified cancers including SCLC.
This study examined the individual and combined predictive effects of two types of feedback (i.e., quantitative ratings and descriptive comments) in online peer-assessment learning systems on the ...quality of produced work. A total of 233 students participated in the study for six weeks. An online learning system that allows students to contribute to and benefit from the process of question-generation and peer-assessment was adopted. The regression results indicated that quantitative ratings and descriptive comments significantly predicted the quality of produced work (i.e., question-generation performance) both individually and collectively, and descriptive feedback explained more variance in quality of produced work than did quantitative ratings. The empirical significance of this study and suggestions for online learning system development, instructional implementation and future studies are discussed.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autophagy is essential for the maintenance of energy homeostasis and for survival during the neonatal starvation period. At birth, the trans-placental nutrient supply is suddenly interrupted, and ...neonates adapt to this adverse circumstance by activating autophagy. However, the mechanisms underlying the precise regulation of neonatal autophagy remain undefined. Here, we show that the destabilization of TP53 by the deubiquitylase ubiquitin-specific peptidase 10 (USP10) is essential for neonatal autophagy and survival. Usp10 deficiency results in decreased E3 ligase activity of MDM2 and accumulation of cytoplasmic TP53, which interferes with the conjugation of ATG12 and ATG5, the key autophagy-related genes, and ultimately inhibits autophagy in neonatal mice. Combined deletion of Tp53 and Usp10 recovers the nutrition supply and rescues the death phenotype of Usp10-deficient neonates. These findings reveal a role of the USP10-MDM2-TP53 axis in nutrient homeostasis and neonatal viability and provide insights into the long-perplexing mechanism by which cytoplasmic TP53 inhibits autophagy.
Display omitted
•Usp10-deficient neonates exhibit postnatal death due to inadequate nutrition supply•Usp10 deletion leads to attenuated TP53 degradation and insufficient neonatal autophagy•Cytoplasmic TP53 interferes with the conjugation of ATG12 and ATG5•Combined deletion of Tp53 and Usp10 rescues postnatal death of Usp10-deficient mice
Li et al. show that the deubiquitylase USP10 removes the K27-linked ubiquitin chains on MDM2, which increases the ubiquitin ligase activity of MDM2 toward TP53 degradation. The USP10-MDM2 axis is essential for postnatal autophagy and survival of neonates during the neonatal starvation period.
Advanced artificial intelligence edge devices are expected to support floating-point (FP) multiply and accumulation operations while ensuring high energy efficiency and high inference accuracy. This ...work presents an FP compute-in-memory (CIM) macro that exploits the advantages of computing in the time, digital, and analog-voltage domain for high energy efficiency and accuracy. This work employs: 1) a hybrid-domain macrostructure to enable the computation of both the exponent and mantissa within the same CIM macro; 2) a time-domain computing scheme for energy-efficient exponent computation; 3) a product-exponent-based input-mantissa alignment scheme to enable the accumulation of the product mantissa in the same column; and 4) a place-value-dependent digital-analog-hybrid computing scheme to enable energy-efficient mantissa computations of sufficient accuracy. A 22-nm 832-kB FP-CIM macro fabricated using foundry-provided compact 6T-static random access memory (SRAM) cells achieved a high energy efficiency of 72.14 tera-floating-point operations per second (TFLOPS)/W while performing FP-multiply-and-accumulate (MAC) operations involving BF16-input, BF16-weight, FP32-output, and 128 accumulations.
Abstract
Background
Corticotropin-releasing factor (CRF) is the major neuromodulator orchestrating the stress response, and is secreted by neurons in various regions of the brain. Cerebellar CRF is ...released by afferents from inferior olivary neurons and other brainstem nuclei in response to stressful challenges, and contributes to modulation of synaptic plasticity and motor learning behavior via its receptors. We recently found that CRF modulates facial stimulation-evoked molecular layer interneuron-Purkinje cell (MLI-PC) synaptic transmission via CRF type 1 receptor (CRF-R1)
in vivo
in mice, suggesting that CRF modulates sensory stimulation-evoked MLI-PC synaptic plasticity. However, the mechanism of how CRF modulates MLI-PC synaptic plasticity is unclear. We investigated the effect of CRF on facial stimulation-evoked MLI-PC long-term depression (LTD) in urethane-anesthetized mice by cell-attached recording technique and pharmacological methods.
Results
Facial stimulation at 1 Hz induced LTD of MLI-PC synaptic transmission under control conditions, but not in the presence of CRF (100 nM). The CRF-abolished MLI-PC LTD was restored by application of a selective CRF-R1 antagonist, BMS-763,534 (200 nM), but it was not restored by application of a selective CRF-R2 antagonist, antisauvagine-30 (200 nM). Blocking cannabinoid type 1 (CB1) receptor abolished the facial stimulation-induced MLI-PC LTD, and revealed a CRF-triggered MLI-PC long-term potentiation (LTP) via CRF-R1. Notably, either inhibition of protein kinase C (PKC) with chelerythrine (5 µM) or depletion of intracellular Ca
2+
with cyclopiazonic acid (100 µM), completely prevented CRF-triggered MLI-PC LTP in mouse cerebellar cortex
in vivo
.
Conclusions
The present results indicated that CRF blocked sensory stimulation-induced opioid-dependent MLI-PC LTD by triggering MLI-PC LTP through CRF-R1/PKC and intracellular Ca
2+
signaling pathway in mouse cerebellar cortex. These results suggest that activation of CRF-R1 opposes opioid-mediated cerebellar MLI-PC plasticity
in vivo
in mice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
