A review: targeting UBR5 domains to mediate emerging roles and mechanisms: chance or necessity?

Ubiquitinases are known to catalyze ubiquitin chains on target proteins to regulate various physiological functions like cell proliferation, autophagy, apoptosis, and cell cycle progression. As a member of E3 ligase, ubiquitin protein ligase E3 component n-recognin 5 (UBR5) belongs to the HECT E3 ligase and has been reported to be correlated with various pathophysiological processes. In this review, we give a comprehensive insight into the structure and function of UBR5. We discuss the specific domains of UBR5 and explore their biological functions separately. Furthermore, we describe the involvement of UBR5 in different pathophysiological conditions, including immune response, virus infection, DNA damage response and protein quality control. Moreover, we provide a thorough summary of the important roles and regulatory mechanisms of UBR5 in cancers and other diseases. On the whole, investigating the domains and functions of UBR5, elucidating the underlying mechanisms of UBR5 with various substrates in detail may provide new theoretical basis for the treatment of diseases, including cancers, which could improve future studies to construct novel UBR5-targeted therapy strategies.

Alterations of the cerebral microstructure in patients with noise-induced hearing loss: A diffusion tensor imaging study.

OBJECTIVE: To explore the changes in the cerebral microstructure of patients with noise-induced hearing loss (NIHL) using diffusion tensor imaging (DTI). METHOD: Overall, 122 patients with NIHL (mild [MP, n = 79], relatively severe patients [including moderate and severe; RSP, n = 32], and undetermined [lost to follow-up, n = 11]) and 84 healthy controls (HCs) were enrolled. All clinical data, including age, education level, hearing threshold, occupation type, noise exposure time, and some scale scores (including the Mini-Mental State Examination [MMSE], tinnitus handicap inventory [THI], and Hamilton Anxiety Scale [HAMA]), were collected and analyzed. All participants underwent T1WI3DFSPGR and DTI, and tract-based spatial statistics and region of interest (ROI) analysis were used for assessment. RESULTS: The final sample included 71 MP, 28 RSP, and 75 HCs. The HAMA scores of the three groups were significantly different (p < .05). The noise exposure times, hearing thresholds, and HAMA scores of the MP and RSP were significantly different (p < .05). The noise exposure time was positively correlated with the hearing threshold and negatively correlated with the HAMA scores (p < .05), whereas the THI scores were positively correlated with the hearing threshold (p < .05). DTI analysis showed that all DTI parameters (fractional anisotropy [FA], axial diffusivity [AD], mean diffusivity [MD], and radial diffusivity [RD]) were significantly different in the left inferior longitudinal fasciculus (ILF) and left inferior fronto-occipital fasciculus (IFOF) for the three groups (p < .05). In addition, the FA values were significantly lower in the bilateral corticospinal tract (CST), right fronto-pontine tract (FPT), right forceps major, left superior longitudinal fasciculus (temporal part) (SLF), and left cingulum (hippocampus) (C-H) of the MP and RSP than in those of the HCs (p < .05); the AD values showed diverse changes in the bilateral CST, left IFOF, right anterior thalamic radiation, right external capsule (EC), right SLF, and right superior cerebellar peduncle (SCP) of the MP and RSP relative to those of the HC (p < .05). However, there were no significant differences among the bilateral auditory cortex ROIs of the three groups (p > .05). There was a significant negative correlation between the FA and HAMA scores for the left IFOF/ILF, right FPT, left SLF, and left C-H for the three groups (p < .05). There was a significant positive correlation between the AD and HAMA scores for the left IFOF/ILF and right EC of the three groups (p < .05). There were significantly positive correlations between the RD/MD and HAMA scores in the left IFOF/ILF of the three groups (p < .05). There was a significant negative correlation between the AD in the right SCP and noise exposure time of the MP and RSP groups (p < .05). The AD, MD, and RD in the left ROI were significantly positively correlated with hearing threshold in the MP and RSP groups (p < .05), whereas FA in the right ROI was significantly positively correlated with the HAMA scores for the three groups (p < .05). CONCLUSION: The changes in the white matter (WM) microstructure may be related to hearing loss caused by noise exposure, and the WM structural abnormalities in patients with NIHL were mainly located in the syndesmotic fibers of the temporooccipital region, which affected the auditory and language pathways. This confirmed that the auditory pathways have abnormal structural connectivity in patients with NIHL.

An integrated investigation of sulfotransferases (SULTs) in hepatocellular carcinoma and identification of the role of SULT2A1 on stemness.

The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes, which are widely expressed in the liver and mainly mediate the sulfation of numerous xenobiotics and endogenous compounds. However, the role of various SULTs genes has not been reported in hepatocellular carcinoma (HCC). This study aims to analyze the expression and potential functional roles of SULTs genes in HCC and to identify the role of SULT2A1 in HCC stemness as well as the possible mechanism. We found that all of the 12 SULTs genes were differentially expressed in HCC. Moreover, clinicopathological features and survival rates were also investigated. Multivariate regression analysis showed that SULT2A1 and SULT1C2 could be used as independent prognostic factors in HCC. SULT1C4, SULT1E1, and SULT2A1 were significantly associated with immune infiltration. SULT2A1 deficiency in HCC promoted chemotherapy resistance and stemness maintenance. Mechanistically, silencing of SULT2A1 activated the AKT signaling pathway, on the one hand, promoted the expression of downstream stemness gene c-Myc, on the other hand, facilitated the NRF2 expression to reduce the accumulation of ROS, and jointly increased HCC stemness. Moreover, knockdown NR1I3 was involved in the transcriptional regulation of SULT2A1 in stemness maintenance. In addition, SULT2A1 knockdown HCC cells promoted the proliferation and activation of hepatic stellate cells (HSCs), thereby exerting a potential stroma remodeling effect. Our study revealed the expression and role of SULTs genes in HCC and identified the contribution of SULT2A1 to the initiation and progression of HCC.

Artificial intelligence-assisted smartphone-based sensing for bioanalytical applications: A review.

Artificial intelligence (AI) has received great attention since the concept was proposed, and it has developed rapidly in recent years with applications in many fields. Meanwhile, newer iterations of smartphone hardware technologies which have excellent data processing capabilities have leveraged on AI capabilities. Based on the desirability for portable detection, researchers have been investigating intelligent analysis by combining smartphones with AI algorithms. Various examples of the application of AI algorithm-based smartphone detection and analysis have been developed. In this review, we give an overview of this field, with a particular focus on bioanalytical detection applications. The applications are presented in terms of hardware design, software algorithms, and specific application areas. We also discuss the existing limitations of AI-based smartphone detection and analytical approaches, and their future prospects. The take-home message of our review is that the application of AI in the field of detection analysis is restricted by the limitations of the smartphone's hardware as well as the model building of AI for detection targets with insufficient data. Nevertheless, at this juncture, while bioanalytical diagnostics and health monitoring have set the pace for AI-based smartphone applicability, the future should see the technology making greater inroads into other fields. In relation to the latter, it is likely that the ordinary or average person will play a greater participatory role.

Wafer-scale and universal van der Waals metal semiconductor contact.

Van der Waals (vdW) metallic contacts have been demonstrated as a promising approach to reduce the contact resistance and minimize the Fermi level pinning at the interface of two-dimensional (2D) semiconductors. However, only a limited number of metals can be mechanically peeled and laminated to fabricate vdW contacts, and the required manual transfer process is not scalable. Here, we report a wafer-scale and universal vdW metal integration strategy readily applicable to a wide range of metals and semiconductors. By utilizing a thermally decomposable polymer as the buffer layer, different metals were directly deposited without damaging the underlying 2D semiconductor channels. The polymer buffer could be dry-removed through thermal annealing. With this technique, various metals could be vdW integrated as the contact of 2D transistors, including Ag, Al, Ti, Cr, Ni, Cu, Co, Au, Pd. Finally, we demonstrate that this vdW integration strategy can be extended to bulk semiconductors with reduced Fermi level pinning effect.

Identification of novel autophagy-related lncRNAs associated with a poor prognosis of colon adenocarcinoma through bioinformatics analysis.

LncRNAs play a pivotal role in tumorigenesis and development. However, the potential involvement of lncRNAs in colon adenocarcinoma (COAD) needs to be further explored. All the data used in this study were obtained from The Cancer Genome Atlas database, and all analyses were conducted using R software. Basing on the seven prognosis-related lncRNAs finally selected, we developed a prognosis-predicting model with powerful effectiveness (training cohort, 1 year: AUC = 0.70, 95% Cl = 0.57-0.78; 3 years: AUC = 0.71, 95% Cl = 0.6-0.8; 5 years: AUC = 0.76, 95% Cl = 0.66-0.87; validation cohort, 1 year: AUC = 0.70, 95% Cl = 0.58-0.8; 3 years: AUC = 0.73, 95% Cl = 0.63-0.82; 5 years: AUC = 0.68, 95% Cl = 0.5-0.85). The VEGF and Notch pathway were analyzed through GSEA analysis, and low immune and stromal scores were found in high-risk patients (immune score, cor = - 0.15, P < 0.001; stromal score, cor = - 0.18, P < 0.001) , which may partially explain the poor prognosis of patients in the high-risk group. We screened lncRNAs that are significantly associated with the survival of patients with COAD and possibly participate in autophagy regulation. This study may provide direction for future research.

Interleukin-17 and ischaemic stroke.

Interleukin-17 (IL-17) is a cytokine family that includes 6 members, IL-17A through IL-17F, most of them are reported to have pro-inflammatory role. Through binding to their receptors (IL-17Rs), IL-17 activates the intracellular signalling pathways to play an important role in autoimmune diseases, including rheumatoid arthritis (RA) and multiple sclerosis (MS). Ischaemic stroke is a complex pathophysiological process mainly caused by regional cerebral ischaemia. Inflammatory factors contribute to the physiological process of stroke that leads to poor prognosis. IL-17 plays a crucial role in promoting inflammatory response and inducing secondary injury in post-stroke. Though immune cells and inflammatory factors have been reported to be involved in the damage of stroke, the functions of IL-17 in this process need to be elucidated. This review focuses on the pathological modulation and the mechanism of IL-17 family in ischaemic stroke and seeking to provide new insights for future therapies.

Upregulation of KIF20A promotes tumor proliferation and invasion in renal clear cell carcinoma and is associated with adverse clinical outcome.

Extensive research has revealed the pivotal role of kinesin family member 20A (KIF20A) in cancer. However, its latent involvement in renal clear cell carcinoma (ccRCC) still remains unclear. Thus, here we explored the role of KIF20A in ccRCC. For this, a series of software including R (v. 3.6.1), SPSS (v. 23), ImageJ and FlowJo were used for the analyses. Open-access data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) databases. Weighted Gene Co-expression Network Analysis (WGCNA) was used for module gene identification. In vitro results indicated that KIF20A expression is up-regulated in ccRCC tissue. KIF20A knockdown was able to inhibite cell proliferation and invasion of kidney A498 and Caki-1 cells. Meanwhile, KIF20A showed a strong association with immune infiltration. Particularly, KIF20A had a strong positive correlation with Th2 cells, Treg cells and Macrophages, but a negative correlation with Th17 cells, Mast cells and NK cells. These correlations may suggest the use of KIF20A as an underlying immunotherapy target in ccRCC. Our data indicated that KIF20A may promote cell invasion and proliferation in ccRCC, thus serving as an independent tumor marker and a putative therapeutic target.

Fas and GIT1 signalling in the prefrontal cortex mediate behavioural sensitization to methamphetamine in mice.

PURPOSE: Repeated methamphetamine (METH) administration in mice readily produces behavioural sensitization, but the underlying mechanisms remain elusive. The present research aimed to identify new targets affecting METH-induced behavioural sensitization. METHODS: We first established a mouse model of METH-induced behavioural sensitization. To characterize the animal model, we performed behavioural tests at different stages of behavioural sensitization and simultaneously detected changes in several neurotransmitters in the prefrontal cortex (PFC). Next, we perfromed RNA sequencing (RNA-seq) to screen new targets, which were subsequently and verified by RT-PCR and western blot. Finally, we confirmed the roles of the new targets in METH-induced behavioural sensitization by injection of overexpressed lentiviruses and further detected related protein levels by western blot and histological changes by haematoxylin and eosin (HE) staining. RESULTS: We successfully established a mouse model of METH-induced behavioural sensitization. The locomotor activities of the mice changed at different stages of sensitization, accompanied by changes in the levels of DA, 5-HT, GABA and glutamate. For RNA-seq analysis, we chose Fas as target, meanwhile, we chose GIT1 as target through literature. The detection of gene expression by RT-PCR indicated that METH-sensitized mice exhibited decreased levels of Fas, MEK1 and CREB and increased levels of Erk1/2 in the PFC. Western blot analysis revealed decreased Fas, GIT1, MEK1 and phosphorylated CREB levels and increased phosphorylated Erk1/2 levels in METH-sensitized mice. Injection of Fas and GIT1 injection showed that overexpression of Fas and GIT1 inhibited the induction of METH sensitization and reversed the changes in neurotransmitter levels and related protein levels, including MEK1, phosphorylated CREB and phosphorylated Erk1/2, in METH-sensitized mice. Overexpression of Fas and GIT1 also reduced histological lesions induced by METH. CONCLUSION: The findings indicated that the development of behavioural sensitization to METH may be mediated by Fas and GIT1 through the MEK1-Erk1/2-CREB pathway.

Advances in Isolation and Culture of Chicken Embryonic Stem Cells In Vitro.

Chicken embryonic stem cells (cESCs) isolated from the egg at the stage X hold great promise for cell therapy, tissue engineering, pharmaceutical, and biotechnological applications. They are considered to be pluripotent cells with the capacity to self-renewal and differentiate into specialized cells. However, long-term maintenance of cESCs cannot be realized now, which impedes the establishment of cESC line and limits their applications. Therefore, the separation locations, isolation methods, and culture conditions especially the supplements and action mechanisms of cytokines, including leukemia inhibitory factor, fibroblast growth factor, transforming growth factor beta, bone morphogenic protein, and activin for cESCs in vitro, have been reviewed here. These defined strategies will contribute to identify the key mechanism on the self-renewal of cESCs, facilitate to optimize system that supports the derivation and longtime maintenance of cESCs, establish the cESC line, and develop the biobank of genetic resources in chicken.

The protective effect of cordyceps sinensis extract on cerebral ischemic injury via modulating the mitochondrial respiratory chain and inhibiting the mitochondrial apoptotic pathway.

Cerebral ischemia is a common refractory brain disease, resulting from a reduction in the blood flow to the brain. Mitochondrial dysfunction leads to ischemic stroke and brain injury. Cordyceps sinensis (CS) is an important traditional Chinese medicine, which has been linked to neuroprotection in recent studies. In this study, we investigated the role of the mitochondrial respiratory chain and the mitochondrial apoptotic pathway on the protective effect of Cordyceps sinensis extract (CSE) against cerebral ischemia injury both in vivo and in vitro. In a murine middle cerebral artery occlusion (MCAO) model, administration of CSE relieved neuronal morphological damage and attenuated the neuronal apoptosis. CSE also reduced neurobehavioral scores and oxygen free radical (OFR), while improving the levels of ATP, cytochrome c oxidase (COX), and mitochondrial complexes I-IV. Furthermore, the mRNA expression of Bax, cytochrome c (Cyt c) and caspase-3 were down-regulated. In brain microvascular endothelial cells (BMECs) exposed to oxygen and glucose deprivation (OGD), CSE prevented OGD-induced cellular apoptosis, and recovered the reduction of mitochondrial membrane potential (MMP). Moreover, CSE treatment induced an increase of Bcl-2 protein expression and a decrease of Bax, Cyt c and caspase-3 protein expression. Meanwhile, the caspase-3, -8, and -9 activities were also inhibited. The results indicate that CSE can relieve cerebral ischemia injury and exhibit protective effects via modulating the mitochondrial respiratory chain and inhibiting the mitochondrial apoptotic pathway.

Potential Strategies for Cardiac Diseases: Lineage Reprogramming of Somatic Cells into Induced Cardiomyocytes.

Lineage reprogramming has become a potential strategy for therapy of cardiac diseases. Somatic cells can be directly converted into the induced cardiomyocytes (iCMs) without passing through an induced pluripotent stem cell stage; this strategy has some advantages such as directional differentiation and preferable security. However, there are still many challenges which need to be further studied, such as identification of safer induced factors, exploration of molecular mechanisms, improvement of the mature level of iCMs and so on. Therefore, the structures of key factors, including transcription factors, microRNAs (miRNAs), epigenetic regulators and small molecules and their functions in the cardiac development and lineage reprogramming, molecular mechanisms underlying lineage conversion, strategies for generating matured iCMs, and major challenges were reviewed to lay the foundation for further applications of iCMs.

Comparative outcomes of radio frequency ablation versus partial nephrectomy for T1 renal tumors: a systematic review.

BACKGROUND: The role of radio frequency ablation (RFA) in small renal tumors remains controversial. This systematic review was performed to compare clinical outcomes of RFA versus partial nephrectomy (PN) for the treatment of T1 renal tumors. METHODS: A total of 11 studies including 2,397 patients were analyzed in this systematic review after searching the databases of PubMed, EMBASE and Web of Science. P value and odds ratio (OR)/hazard ratio (HR) with 95% confidence interval (CI) were used to evaluate the strength of the association. RESULTS: A total of six studies (2,056 patients) provided either survival curves or HR and its 95% CI, demonstrating that the majority of the patients with RFA treatment tended to exhibit a similar long-term survival rate to those with PN treatment. In addition, according to four studies, no differences were found in the overall rate of complications between the two groups. Furthermore, there were significant differences in glomerular filtration rate (GFR) change between the two methods in four studies but no differences were observed in other two. CONCLUSIONS: Our systematic review indicated that RFA is an effective treatment option which could provide comparable oncologic outcomes to PN. Moreover, it may present obvious advantages in renal function preservation.

[Bazi Granules improves sperm quality in rats with oligoasthenozoospermia induced by multi-glycosides of tripterygium wilfordii].

OBJECTIVE: To investigate the effect of Bazi Granules on sperm quality in male rats with oligoasthenozoospermia (OAS) induced by multi-glycosides of tripterygium wilfordii (GTW). METHODS: Thirty-six SD male rats were randomly divided into six groups of equal number: normal control, OAS model control, Wuziyanzong Pills (WYP), and low-, medium- and high-dose Bazi. The OAS model was established in the rats except those of the normal control group by intragastrical delivery of GTW at 30 mg/kg/d for 40 days. From the 41st day, the animals of the normal and OAS model control groups were fed with distilled water, those of the WYP group treated by gavage with WYP at 1.02 g/kg/d, and those of the low-, medium- and high-dose Bazi groups intragastically given Bazi Granules 3 (5.27 g/kg), 6 (10.54 g/kg) and 12 (21.08 g/kg) times, respectively, that of the human-equivalent dose. Semen parameters and the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) in the testis tissue were determined after 28 days of treatment. RESULTS: After treatment, the rats of the of the high-, medium- and low-dose Bazi groups, compared with the OAS model controls, showed significant increases in sperm concentration (ï¼»1 050.71 ± 203.71ï¼½, ï¼»1 370.06 ± 166.01ï¼½ and ï¼»1 302.53 ± 476.51ï¼½ vs ï¼»617.01 ± 237.08ï¼½ ×106/ml, P < 0.05), sperm motility (ï¼»0.56 ± 0.24ï¼½%, ï¼»0.73 ± 0.14ï¼½% and ï¼»0.70 ± 0.23ï¼½% vs ï¼»0.07 ± 0.05ï¼½%, P < 0.05), sperm average path velocity (ï¼»85.71 ± 30.35ï¼½, ï¼»83.83 ± 10.31ï¼½ and ï¼»75.06 ± 19.70ï¼½ vs ï¼»43.45 ± 38.74ï¼½ µm/s, P < 0.05), sperm curvilinear velocity (ï¼»101.76 ± 23.28ï¼½, ï¼»119.60 ± 21.22ï¼½ and ï¼»102.11 ± 32.89ï¼½ vs ï¼»53.63 ± 47.91ï¼½ µm/s, P < 0.05), sperm straight line velocity (ï¼»62.75 ± 7.63ï¼½, ï¼»67.80 ± 5.05ï¼½ and ï¼»64.11 ± 12.03ï¼½ vs ï¼»40.18 ± 36.86ï¼½ µm/s, P < 0.05), and the SOD level (ï¼»380.23 ± 75.07ï¼½, ï¼»349.53 ± 97.48ï¼½ and ï¼»415.07 ± 72.01ï¼½ vs ï¼»304.62 ± 27.17ï¼½ U/mg, P < 0.05), but a remarkable decrease in the MDA level (ï¼»0.33 ± 0.16ï¼½, ï¼»0.22 ± 0.05ï¼½ and ï¼»0.34 ± 0.22ï¼½ vs ï¼»0.73 ± 0.20ï¼½ nmol/mg, P < 0.05). CONCLUSIONS: Bazi Granules can significantly improve the sperm quality of OAS rats, which may be related to its abilities of repairing oxidative stress injury and enhancing oxidation resistance.

Selective Ring-Opening Polymerization of Non-Strained γ-Butyrolactone Catalyzed by A Cyclic Trimeric Phosphazene Base.

A new superbase, the cyclic trimeric phosphazene base (CTPB), was prepared with high yield and purity. In the presence of alcohol, the CTPB serves as a highly efficient organocatalyst for ring-opening polymerization of the "non-polymerizable" γ-butyrolactone to offer well-defined poly(γ-butyrolactone) with high conversions (up to 98 %) at -60 °C. The produced polymers have high molecular weights (up to 22.9 kg mol-1 ) and low polydispersity distributions (1.27-1.50). NMR analysis of initiation process and the structural analysis of resulting polymers by MALDI-TOF suggest a mechanism involving an activating initiator which leads only to linear polymers with BnO/H chain ends.