A Flexible Magnetic Field Sensor Based on PZT/CFO Bilayer via van der Waals Oxide Heteroepitaxy.

Magnetoelectric (ME) magnetic field sensors utilize ME effects in ferroelectric ferromagnetic layered heterostructures to convert magnetic signals into electrical signals. However, the substrate clamping effect greatly limits the design and fabrication of ME composites with high ME coefficients. To reduce the clamping effect and improve the ME response, a flexible ME sensor based on PbZr0.2Ti0.8O3 (PZT)/CoFe2O4 (CFO) ME bilayered heterostructure was deposited on mica substrates via van der Waals oxide heteroepitaxy. A saturated magnetization of 114.5 emu/cm3 was observed in the bilayers. The flexible sensor exhibited a strong ME coefficient of 6.12 V/cm·Oe. The local ME coupling has been confirmed by the evolution of the ferroelectric domain under applied magnetic fields. The flexible ME sensor possessed a stable response with high sensitivity to both AC and DC weak magnetic fields. A high linearity of 0.9988 and sensitivity of 72.65 mV/Oe of the ME sensor were obtained under flat states. The ME output and limit-of-detection under different bending states showed an inferior trend as the bending radius increased. A flexible proximity sensor has been demonstrated, indicating a promising avenue for wearable device applications and significantly broadening the potential application of the flexible ME magnetic field sensors.

PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.

Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive. Here, we report that PRMT1 senses methionine/SAM by utilizing SAM as a cofactor for an enzymatic activity-based regulation of mTORC1 signaling. Under methionine-sufficient conditions, elevated cytosolic SAM releases SAMTOR from GATOR1, which confers the association of PRMT1 with GATOR1. Subsequently, SAM-loaded PRMT1 methylates NPRL2, the catalytic subunit of GATOR1, thereby suppressing its GAP activity and leading to mTORC1 activation. Notably, genetic or pharmacological inhibition of PRMT1 impedes hepatic methionine sensing by mTORC1 and improves insulin sensitivity in aged mice, establishing the role of PRMT1-mediated methionine sensing at physiological levels. Thus, PRMT1 coordinates with SAMTOR to form the methionine-sensing apparatus of mTORC1 signaling.

Ring domains are essential for GATOR2-dependent mTORC1 activation.

The GATOR2-GATOR1 signaling axis is essential for amino-acid-dependent mTORC1 activation. However, the molecular function of the GATOR2 complex remains unknown. Here, we report that disruption of the Ring domains of Mios, WDR24, or WDR59 completely impedes amino-acid-mediated mTORC1 activation. Mechanistically, via interacting with Ring domains of WDR59 and WDR24, the Ring domain of Mios acts as a hub to maintain GATOR2 integrity, disruption of which leads to self-ubiquitination of WDR24. Physiologically, leucine stimulation dissociates Sestrin2 from the Ring domain of WDR24 and confers its availability to UBE2D3 and subsequent ubiquitination of NPRL2, contributing to GATOR2-mediated GATOR1 inactivation. As such, WDR24 ablation or Ring deletion prevents mTORC1 activation, leading to severe growth defects and embryonic lethality at E10.5 in mice. Hence, our findings demonstrate that Ring domains are essential for GATOR2 to transmit amino acid availability to mTORC1 and further reveal the essentiality of nutrient sensing during embryonic development.

A Novel Ig Domain-Containing C-Type Lectin Triggers the Intestine-Hemocyte Axis to Regulate Antibacterial Immunity in Crab.

The C-type lectin family with the signature C-type lectin-like domain promotes antibacterial host defense within the animal kingdom. We examined the role of Chinese mitten crab, Eriocheir sinensis (H. Milne-Edwards) (Decapoda: Grapsidae) Ig domain-containing C-type lectin (EsIgLectin), a novel and poorly understood member of the C-type lectin family. EsIgLectin was expressed primarily by both hemocytes (E sinensis) and intestines, with significantly induced mRNA expression on intestinal or hemolymph bacterial infections. As a soluble protein, both its C-type lectin-like domain and the Ig domain were required for bacterial binding, bacterial agglutination, bacterial growth inhibition, and in vivo bacterial clearance. Polymeric EsIgLectin could be constructed via the disulfide bond in the Ig domain, significantly enhancing EsIgLectin antibacterial activity. EsIgLectin promoted bacterial phagocytosis in an Ig domain-dependent manner in hemocytes, while it controlled microbial homeostasis and protected against bacteria-induced inflammation in the intestine. Protein interaction studies revealed that the EsIgLectin Ig domain bound to the first Ig domain of the polymeric Ig receptor, which was essential for EsIgLectin-induced bacterial phagocytosis. The temporal sequence of cell interactions during intestinal inflammation is only beginning to be understood. In this article, we show that hemocyte-derived EsIgLectin entered the intestinal wall at the later phase of intestinal inflammation. Moreover, EsIgLectin protected the host against intestinal and hemolymph infections in a polymeric Ig receptor-dependent manner. Therefore, the EsIgLectin promoted bacterial clearance and protected against inflammatory disease through an independent or synergistic effect of hemocytes and intestines in invertebrates.

Paricalcitol in hemodialysis patients with secondary hyperparathyroidism and its potential benefits.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a common complication in patients with end-stage renal disease and it is also common in hemodialysis patients. SHPT can increase bone fragility and calcification of blood vessels and soft tissues, which greatly increases the risk of death. AIM: To discuss the outcome, safety and other potential benefits of paricalcitol injection in hemodialysis patients with SHPT. METHODS: We recruited 40 patients who received hemodialysis at our hospital for chronic renal failure with SHPT between March and December 2019. They received paricalcitol injection for 24 wk (starting dose, 0.06-0.08 µg/kg), three times per week. They were followed up at the baseline (week 0), week 4, week 12 and week 24. The primary outcome indicator was the percentage of patients with a > 30% decrease in intact parathyroid hormone (iPTH) levels at week 24 compared with the baseline. The secondary outcome indicators included percentage decrease in iPTH levels at week 24, standard-reaching rate of iPTH (percentage of patients with iPTH down to 130-585 pg/mL), changes in serum levels of calcium (Ca), phosphate (P), Ca × P product, alkaline phosphatase (ALP), creatinine (Cre), hemoglobin (Hb), and C-reactive protein (CRP), and incidence of adverse events (AEs). RESULTS: After 24 wk of treatment, iPTH levels decreased significantly (598.88 ± 381.29 pg/mL vs 888.84 ± 376.88 pg/mL, P < 0.05). More than 30% decrease of iPTH was found in 21 of 36 (58.33%) patients. The average decrease in iPTH levels was 32.16 ± 4.33%; the standard-reaching rate of iPTH levels was 66.67% (24/36); and ALP levels decreased significantly compared with the baseline (113.72 ± 41.73 IU/L vs 133.45 ± 56.86 IU/L) (t = 2.798, P < 0.05). There were no significant differences in the serum levels of calcium, Hb, Cre and CRP compared with the baseline (P > 0.05). After 24 wk of treatment, serum P levels decreased compared with the baseline (1.91 ± 0.40 mmol/L vs 2.16 ± 0.66 mmol/L) (t = 2.830, P < 0.05). Ca × P product decreased significantly compared with the baseline (56.38 ± 13.22 mg2/dL2 vs 63.97 ± 20.30 mg2/dL2) (t = 2.717, P < 0.05). No serious adverse events occurred. CONCLUSION: Paricalcitol was a safe and effective treatment for hemodialysis patients with SHPT. It decreased serum levels of iPTH, ALP and P and maintained stability of serum Ca levels.

Linalool monoterpene exerts potent antitumor effects in OECM 1 human oral cancer cells by inducing sub-G1 cell cycle arrest, loss of mitochondrial membrane potential and inhibition of PI3K/AKT biochemical pathway.

PURPOSE: Oral cancer is one of the prevalent types of cancer and has been reported to responsible for significant mortality and morbidity. Since treatment options for oral cancer are limited, there is need to explore novel molecules for treatment of oral cancer. In the current study we evaluated the anticancer activity of a plant derived monoterpene, Linalool against oral cancer cell line, OECM-1. METHODS: Cell viability was determined by MTT assay. Apoptosis was detected by DAPI and annexin V/PI staining. Cell cycle analysis was carried out by flow cytometry. Cell migration was assessed by wound healing assay and the expression of the proteins was determined by western blotting. RESULTS: The results showed that Linalool inhibited the viability of oral cancer OECM-1 cells in a concentration-dependent manner. The IC50 of Linalool against OECM-1 oral cancer cells was 10 µM as compared to its IC50 of 65 µM against non-cancer FR-2 cells. The anticancer effects were due to the induction of the apoptosis and sub-G1 cell cycle arrest. The results of annexin V/PI further revealed that the apoptotic cell populations increased from 2.6% in the control to 61.3% at 20 µM concentrations. It was observed that Linalool decreased the expression of p-PI3K and p-AKT in a concentration-dependent manner. However, the expression of PI3K and AKT remained almost unaltered. CONCLUSIONS: Taken together it was shown that Linalool monoterpene exerted significant anticancer effects in OECM-1 human oral cancer cells via inducing cell cycle arrest, loss of mitochondrial membrane potential (MMP) and suppressing PI3K/AKT signalling pathway.

AMPK Promotes SPOP-Mediated NANOG Degradation to Regulate Prostate Cancer Cell Stemness.

NANOG is an essential transcriptional factor for the maintenance of embryonic stem cells (ESCs) and cancer stem cells (CSCs) in prostate cancer (PCa). However, the regulation mechanism of NANOG protein stability in cancer progression is still elusive. Here, we report that NANOG is degraded by SPOP, a frequently mutated tumor suppressor of PCa. Cancer-associated mutations of SPOP or the mutation of NANOG at S68Y abrogates the SPOP-mediated NANOG degradation, leading to elevated PCa cancer stemness and poor prognosis. In addition, SPOP-mediated NANOG degradation is controlled by the AMPK-BRAF signal axis through the phosphorylation of NANOG at Ser68, which blocked the interaction between SPOP and NANOG. Thus, our study provides a regulation mechanism of PCa stemness controlled by phosphorylation-mediated NANOG stability, which helps to identify novel drug targets and improve therapeutic strategy for PCa.

Ubiquitination of Rheb governs growth factor-induced mTORC1 activation.

Mechanistic target of rapamycin mTOR complex 1 (mTORC1) plays a key role in the integration of various environmental signals to regulate cell growth and metabolism. mTORC1 is recruited to the lysosome where it is activated by its interaction with GTP-bound Rheb GTPase. However, the regulatory mechanism of Rheb activity remains largely unknown. Here, we show that ubiquitination governs the nucleotide-bound status of Rheb. Lysosome-anchored E3 ligase RNF152 catalyzes Rheb ubiquitination and promotes its binding to the TSC complex. EGF enhances the deubiquitination of Rheb through AKT-dependent USP4 phosphorylation, leading to the release of Rheb from the TSC complex. Functionally, ubiquitination of Rheb is linked to mTORC1-mediated signaling and  consequently regulates tumor growth. Thus, we propose a mechanistic model whereby Rheb-mediated mTORC1 activation is dictated by a dynamic opposing act between Rheb ubiquitination and deubiquitination that are catalyzed by RNF152 and USP4 respectively.

OTUB1 protein suppresses mTOR complex 1 (mTORC1) activity by deubiquitinating the mTORC1 inhibitor DEPTOR.

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates various environmental signals to regulate cell growth and metabolism. DEPTOR, also termed DEPDC6, is an endogenous inhibitor of mTORC1 and mTORC2 activities. The abundance of DEPTOR centrally orchestrates the mTOR signaling network. However, the mechanisms by which DEPTOR stability is regulated are still elusive. Here, we report that OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) specifically deubiquitinates DEPTOR in a deubiquitination assay. We found that OTUB1 directly interacted with DEPTOR via its N-terminal domain, deubiquitinated DEPTOR, and thereby stabilized DEPTOR in a Cys-91-independent but Asp-88-dependent manner, suggesting that OTUB1 targets DEPTOR for deubiquitination via a deubiquitinase activity-independent non-canonical mechanism. The interaction between OTUB1 and DEPTOR was enhanced when the cells were treated with amino acids. Moreover, OTUB1 suppressed amino acid-induced activation of mTORC1 in a DEPTOR-dependent manner and thereby ultimately controlled cellular autophagy, cell proliferation, and size. Our findings reveal a mechanism that stabilizes the mTORC1 inhibitor DEPTOR via OTUB1's deubiquitinase activity. Our insights may inform research into various mTOR activity-related diseases, such as cancer, and may contribute to the identification of new diagnostic markers and therapeutic strategies for cancer treatments.

FBW7 targets KLF10 for ubiquitin-dependent degradation.

FBW7, a key component of SCFFBW7 E3 ubiquitin ligase, targets various proteins for degradation via the conserved Cdc4 phosphodegron (CPD) in substrates. In this study, we report that KLF10 is degraded by FBW7 via a conserved CPD. Through systematic analysis of the degradation of KLF transcription factors by FBW7, we identified KLF10 as a novel degradation target of FBW7. Ectopic expression of FBW7 markedly promoted the degradation of KLF10 while knockdown of endogenous FBW7 increased the protein levels of KLF10. In addition, simultaneous mutations of both threonine 82 (T82) and serine 86 (S86) significantly reduced the FBW7-mediated KLF10 degradation. Moreover, KLF10 containing a conserved putative CPD (TPPXSP) from amino acids 82 to 87, directly interacted with WD40 domain of FBW7 in a phosphorylation-dependent manner. Importantly, FBW7 could reverse the KLF10-mediated inhibition of Smad7 activity. Thus, our study uncovers a novel regulatory mechanism underlying which KLF10 stability and its biological function are mediated by FBW7.

p38 inhibition provides anti-DNA virus immunity by regulation of USP21 phosphorylation and STING activation.

Stimulator of IFN genes (STING) is a central adaptor protein that mediates the innate immune responses to DNA virus infection. Although ubiquitination is essential for STING function, how the ubiquitination/deubiquitination system is regulated by virus infection to control STING activity remains unknown. In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus-induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING. HSV-1 infection recruited USP21 to STING at late stage by p38-mediated phosphorylation of USP21 at Ser538. Inhibition of p38 MAPK enhanced the production of IFNs in response to virus infection and protected mice from lethal HSV-1 infection. Thus, our study reveals a critical role of p38-mediated USP21 phosphorylation in regulating STING-mediated antiviral functions and identifies p38-USP21 axis as an important pathway that DNA virus adopts to avoid innate immunity responses.

The deubiquitinase USP21 maintains the stemness of mouse embryonic stem cells via stabilization of Nanog.

Nanog is a master pluripotency factor of embryonic stem cells (ESCs). Stable expression of Nanog is essential to maintain the stemness of ESCs. However, Nanog is a short-lived protein and quickly degraded by the ubiquitin-dependent proteasome system. Here we report that the deubiquitinase USP21 interacts with, deubiquitinates and stabilizes Nanog, and therefore maintains the protein level of Nanog in mouse ESCs (mESCs). Loss of USP21 results in Nanog degradation, mESCs differentiation and reduces somatic cell reprogramming efficiency. USP21 is a transcriptional target of the LIF/STAT3 pathway and is downregulated upon differentiation. Moreover, differentiation cues promote ERK-mediated phosphorylation and dissociation of USP21 from Nanog, thus leading to Nanog degradation. In addition, USP21 is recruited to gene promoters by Nanog to deubiquitinate histone H2A at K119 and thus facilitates Nanog-mediated gene expression. Together, our findings provide a regulatory mechanism by which extrinsic signals regulate mESC fate via deubiquitinating Nanog.

The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation.

mTORC1 is essential for regulating cell growth and metabolism in response to various environmental stimuli. Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome. However, the mechanism by which amino acids regulate Rag activation remains not fully understood. Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases. RNF152 knockout results in the hyperactivation of mTORC1 and protects cells from amino-acid-starvation-induced autophagy. Thus, this study reveals a mechanism for regulation of mTORC1 signaling by RNF152-mediated K63-linked polyubiquitination of RagA.

Type 2 diabetes mellitus and risk of oral cancer and precancerous lesions: a meta-analysis of observational studies.

OBJECTIVE: Associations between type 2 diabetes mellitus (type 2 DM) and risk of oral cancer and precancerous lesions have been reported with controversial findings. We performed a meta-analysis to explore these associations. METHODS: We identified studies by a literature search of MEDLINE and EMBASE through May 31, 2014, and by searching the reference lists of pertinent articles. Summary relative risk (SRR) with 95% confidence interval (CI) was calculated with a random-effects model. Between- study heterogeneity was assessed using the Cochran's Q and I(2) statistics. RESULTS: A total of 13 studies (4 case-control and 9 cohort studies) on the association between type 2 DM and oral cancer were included. Overall analysis found that compared with non-diabetic individuals, individuals with type 2 DM had a significantly elevated incidence of oral cancer (SRR=1.15, 95% CI: 1.02-1.29; Pheterogeneity=0.277, I(2)=15.4%; 10 studies). Subgroup analyses found that duration of follow-up (⩾11years) significantly altered this positive association. Type 2 DM was associated with increased oral cancer mortality (SRR=1.41, 95% CI: 1.16-1.72; 4 studies). Meta-analysis of the four case-control studies showed a positive association between type 2 DM and risk of oral precancerous lesions (SRR=1.85, 95%CI: 1.23-2.80; Pheterogeneity=0.038, I(2)=57.5%). No significant public bias was found across these studies. CONCLUSIONS: These findings of this meta-analysis indicate that compared with non-diabetic individuals, individuals with type 2 DM have an elevated risk of oral cancer and precancerous lesions development.

Prevalence of qnr, aac(6')-Ib-cr, qepA, and oqxAB in Escherichia coli isolates from humans, animals, and the environment.

qnr, aac(6')-Ib-cr, qepA, and oqxAB genes were detected in 5.7%, 4.9%, 2.6%, and 20.2% of 1,022 Escherichia coli isolates from humans, animals, and the environment, respectively, collected between 1993 and 2010 in China. The prevalence of oqxAB in porcine isolates (51.0%) was significantly higher than that in other isolates. This is the first report of oqxAB-positive isolates from ducks and geese and as early as 1994 from chickens.

Changes in antimicrobial resistance among Salmonella enterica subspecies enterica serovar Pullorum isolates in China from 1962 to 2007.

There are few data available for the trends of antimicrobial resistance of Salmonella enterica subspecies enterica serovar Pullorum (S. Pullorum) in China and other parts of the world. Thus, the objective of this study was to evaluate the changes in antimicrobial resistance of S. Pullorum isolated from diseased chickens in China from 1962 to 2007. A total of 450 S. Pullorum isolates were tested for their susceptibility to 17 antimicrobials in a disk diffusion method. 39-95% of the isolates displayed a high level of resistance, particularly against ampicillin, carbenicillin, streptomycin, tetracycline, trimethoprim and sulfafurazole. Isolates exhibited increased resistance to carbenicillin, spectinomycin, trimethoprim, trimethoprim/sulfamethoxazole and nalidixic acid during the study period. Moreover, 56.2% of the isolates exhibited multiple drug resistance (MDR; resistance> or =4 antimicrobials) and showed an increasing trend between 1970-1979 and 2000-2007. Therefore, the results suggest that certain measures, including continued surveillance of antimicrobial resistance and the rational use of antimicrobials, are necessary and important in order to control the rapid increase in antimicrobial resistance in S. Pullorum.

µ-α-Methyl-glutarato-bis-{aqua-[bis-(2-pyridylcarbon-yl)aminato]copper(II)} trihydrate.

In the title compound, [Cu(2)(C(12)H(8)N(3)O(2))(2)(C(6)H(8)O(4))(H(2)O)(2)]·3H(2)O, both crystallographically independent Cu atoms are in similar distorted square-pyramidal coordination environments. The dinuclear complex mol-ecules are assembled into one-dimensional supra-molecular chains extending in the [100] direction by hydrogen bonds. Inter-chain hydrogen bonds further link these chains into layers perpendicular to [001].