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Background Patients with lymphoma and hepatitis B virus infection need to be treated with both chemotherapy and nucleotide analogues (NAs) therapy. However, the dynamic change of HBV DNA with the increase of chemotherapy cycles is lacking. It is unknown that whether HBV replication markers: quantitative hepatitis B core antibody (qAnti-HBc), HBV RNA, and hepatitis B virus core-related antigen (HBcrAg) are also sensitive to predict HBV reactivation (HBVr). Methods From 29th June 2010 to 6th December 2021, clinical data and serial serum samples were collected from patients with diffuse large B lymphoma and HBV infection. Serum HBV DNA load (real time fluorescent quantitative PCR), qAnti-HBc (developed chemiluminescent particle immunoassay), HBV RNA (simultaneous amplification testing method based on real-time fluorescence detection), and HBcrAg (Lumipulse G HBcrAg assay) were tested and actors related to HBV DNA reactivation were analyzed. Results Under the NAs, load of HBV DNA in 69 HBsAg + lymphoma patients declined from 3.15 (2.13–4.73) lg IU/ml at baseline to 1.00 (1.00-1.75) lg IU/ml at the end of chemotherapy, and further declined to 1.00 (1.00-1.04) lg IU/ml at the end of 24-month follow-up. Serum qAnti-HBc level decreased gradually during chemotherapy in HBsAg + lymphoma patients (F = 7.090, p = 0.009). Serum HBV RNA and HBcrAg levels stayed stabled. Multivariate analysis revealed that a higher level of qAnti-HBc (1.97 ± 1.20 vs. 1.12 ± 0.84 lg IU/ml, OR = 8.367, [95% CI:1.439–48.645], p = 0.018) and a higher level of HBV RNA (1.00 ± 1.13 vs. 0.37 ± 0.80 lg copies/ml, OR = 3.654, [95% CI:1.208–11.048], p = 0.022) were related to HBVr in HBsAg-/anti-HBc + lymphoma patients. Conclusions The HBV DNA load declined by NAs under chemotherapy in lymphoma patients. In HBsAg-/anti-HBc + lymphoma patients, higher level of baseline serum qAnti-HBc and HBV RNA predict the HBVr during chemotherapy.

Glucagon-like peptide-1 (GLP-1) receptor stimulation ameliorates parkinsonian motor and non-motor deficits in both experimental animals and patients; however, the disease-modifying mechanisms of GLP-1 receptor activation have remained unknown. The present study investigated whether exendin-4 (a GLP-1 analogue) can rescue motor deficits and exert disease-modifying effects in a parkinsonian rat model of α-synucleinopathy. This model was established by unilaterally injecting AAV-9-A53T-α-synuclein into the right substantia nigra pars compacta, followed by 4 or 8 weeks of twice-daily intraperitoneal injections of exendin-4 (5 μg/kg/day) starting at 2 weeks after AAV-9-A53T-α-synuclein injections. Positron emission tomography/computed tomography (PET/CT) scanning and immunostaining established that treatment with exendin-4 attenuated tyrosine-hydroxylase-positive neuronal loss and terminal denervation and mitigated the decrease in expression of vesicular monoamine transporter 2 within the nigrostriatal dopaminergic systems of rats injected with AAV-9-A53T-α-synuclein. It also mitigated the parkinsonian motor deficits assessed in behavioral tests. Furthermore, through both in vivo and in vitro models of Parkinson’s disease, we showed that exendin-4 promoted autophagy and mediated degradation of pathological α-synuclein, the effects of which were counteracted by 3-methyladenine or chloroquine, the autophagic inhibitors. Additionally, exendin-4 attenuated dysregulation of the PI3K/Akt/mTOR pathway in rats injected with AAV-9-A53T-α-synuclein. Taken together, our results demonstrate that exendin-4 treatment relieved behavioral deficits, dopaminergic degeneration, and pathological α-synuclein aggregation in a parkinsonian rat model of α-synucleinopathy and that these effects were mediated by enhanced autophagy via inhibiting the PI3K/Akt/mTOR pathway. In light of the safety and tolerance of exendin-4 administration, our results suggest that exendin-4 may represent a promising disease-modifying treatment for Parkinson’s disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01018-5.

Glomerular mesangial cell (MC) proliferation is one of the main pathological changes in diabetic nephropathy (DN), but its mechanism needs further elaboration. The Hippo and PI3K/Akt signalling pathways are involved in the regulation of MC proliferation, but their relationship in hyperglycaemia-induced MC proliferation has not been reported. We used db/db mice and high-glucose-cultured mesangial cells to generate a diabetic nephropathy model. An MST1-knockdown plasmid was used to identify whether the PI3K/Akt pathway is linked to the Hippo pathway through MST1. LY294002 and SC79 were used to verify the role of the PI3K/Akt signalling pathway in MC cells. RNA silencing and overexpression were performed by using YAP and PTEN-expression/knockdown plasmids to investigate the function of YAP and PTEN, respectively, in the Hippo and PI3K/Akt signalling pathways. By examining a potential feedback loop, we found decreased phosphorylation of MST1 and Lats1 and increased PI3K/Akt activation in db/db mice and high glucose-treated MCs, along with increased MC proliferation. The results of our gene silencing experiment proved PI3K/Akt-mediated intervention in the Hippo pathway and the regulatory effect of YAP on PI3K/Akt through PTEN. The Hippo pathway is inhibited under diabetic conditions, leading to YAP activation and promoting MC proliferation. The PI3K/Akt pathway is activated through the inhibitory effect of YAP on its repressor, PTEN. Finally, activation of the PI3K/Akt pathway inhibits the Hippo pathway, resulting in nuclear YAP accumulation and accelerating MC proliferation and DN formation.

Background & Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis even cancer, antiviral therapy can reverse liver fibrosis with limited effect, thus we aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with ETV.Methods: Treatment naïve patients with CHB from Oct 1st, 2013 to Dec 31st, 2020 were randomly treated with ETV alone or combined with ALHX (ETV+ALHX). Patients’ demographic, laboratory and liver histology data before and after 78 weeks of treatment were collected. Ishak fibrosis score (F) was used and fibrosis regression means F decreased ≥1 after treatment.Results: In total, 394 patients with a second liver biopsy after treatment were included in per-protocol population: 132 patients in ETV group and 262 patients in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group were significantly higher than ETV group in baseline F≥3 patients: 124/211 (58.8%) verse 45/98 (45.9%), p=0.035. The degradation rate of liver stiffness measurement (LSM) is also consistent with it: 154/262 (73.0%) in ETV+ALHX group and 60/132 (61.2%) in ETV group, p=0.037. Logistic regression analysis showed that combined with ALHX was related to fibrosis regression (OR=1.94, p=0.018), and family history of hepatocellular carcinoma was on the contrary (OR=0.41, p=0.031).Conclusions: ETV combined with ALHX can significantly increase liver fibrosis regression in CHB patients.

α-Synuclein (α-syn) fibrillar aggregates are the major component of Lewy bodies and Lewy neurites presenting as the pathology hallmark of Parkinson’s disease (PD). Studies have shown that α-syn is potential to form different conformational fibrils associated with different synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is to be explored. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of preclinical (pre-PD) and late-stage postmortem PD (post-PD) patients. Our results show that compared to the CSF of pre-PD, that of post-PD is markedly stronger in seeding in vitro α-syn aggregation, and the amplified fibrils are more potent in inducing endogenous α-syn aggregation in neurons. Cryo-electron microscopic structures further reveal that the difference between the pre-PD- and post-PD-derived fibrils lies on a minor polymorph which in the pre-PD fibrils is morphologically straight, while in the post-PD fibrils represents a single protofilament assembled by a distinctive conformation of α-syn. Our work demonstrates structural and pathological differences between pre-PD and post-PD α-syn aggregation and suggests potential alteration of α-syn fibrils during the progression of PD clinical phases.Significance StatementIncreasing evidence support different conformational α-syn fibrils in patients with different α-synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is unknown. Here, we show that α-syn fibrils amplified from the cerebrospinal fluid (CSF) of the late-stage postmortem PD (post-PD) patient are more potent in inducing endogenous α-syn aggregation in neurons than that amplified from the preclinical (pre-PD) patient. Cryo-EM structures further reveal that the post-PD fibrils contain a novel conformation that is distinct from either the pre-PD fibrils or those previously reported. Our work suggests conformational evolution of α-syn fibrils along with PD progression.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Early diagnosis is the key to treatment but is still a great challenge in the clinic now. The discovery of alpha-synuclein (α-syn) aggregates ligands has become an attractive strategy to meet the early diagnosis of PD. Herein, we designed and synthesized a series of styrylaniline derivatives as novel α-syn aggregates ligands. Several compounds displayed good potency to α-syn aggregates with Kd values less than 0.1 μM. The docking study revealed that the hydrogen bonds and cation-pi interaction between ligands and α-syn aggregates would be crucial for the activity. The representative compound 7–16 not only detected α-syn aggregates in both SH-SY5Y cells and brain tissues prepared from two kinds of α-syn preformed-fibrils-injected mice models but also showed good blood-brain barrier penetration characteristics in vivo with a brain/plasma ratio over 1.0, which demonstrates its potential as a lead compound for further development of in vivo imaging agents.

Podocyte injury following abnormal podocyte autophagy plays an indispensable role in diabetic nephropathy (DN), therefore, restoration of podocyte autophagy is considered as a feasible strategy for the treatment of DN. Here, we investigated the preventive effects of sarsasapogenin (Sar), the main active ingredient in Anemarrhena asphodeloides Bunge, on the podocyte injury in diabetic rats, and tried to illustrate the mechanisms underlying the effects in high glucose (HG, 40 mM)-treated podocytes (MPs). Diabetes model was established in rats with single streptozocin (60 mg· kg−1) intraperitoneal administration. The rats were then treated with Sar (20, 60 mg· kg−1· d−1, i.g.) or a positive control drug insulin (INS) (40 U· kg−1· d−1, i.h.) for 10 weeks. Our results showed that both Sar and insulin precluded the decreases of autophagy-related proteins (ATG5, Beclin1 and LC3B) and podocyte marker proteins (podocin, nephrin and synaptopodin) in the diabetic kidney. Furthermore, network pharmacology was utilized to assess GSK3β as the potential target involved in the action of Sar on DN and were substantiated by significant changes of GSK3β signaling in the diabetic kidney. The underlying protection mechanisms of Sar were explored in HG-treated MPs. Sar (20, 40 μM) or insulin (50 mU/L) significantly increased the expression of autophagy- related proteins and podocyte marker proteins in HG-treated MPs. Furthermore, Sar or insulin treatment efficiently regulated phosphorylation at activation and inhibition sites of GSK3β. To sum up, this study certifies that Sar meliorates experimental DN through targeting GSK3β signaling pathway and restoring podocyte autophagy.

The stability, surface micromorphology, and volatile organic compounds (VOCs) of silicone rubber baking molds (SRBMs) were tested while using the molds under severe conditions: baking at 175 °C, microwaving at 800 W, and freezing at −18 °C. Moreover, migration tests of SRBMs to food simulants (isooctane, 95% ethanol, and Tenax®) at 70 °C for 2 h (accelerated conditions) were performed. The initial total VOCs concentration was 2.53% higher than that recommended by BfR Recommendations on Food Contact Materials. Therefore, the SRBM samples were considered as badly tempered materials, and 18 different types of silicone oligomers were identified during the migration tests. The following percentage of silicone oligomers with a molecular weight lower than 1000 Da in isooctane, 95% ethanol, and Tenax® were detected: 70.7%, 91.8%, and 97.2%, respectively. It has been proven that previous baking treatments effectively reduced the content of silicone oligomers migrating from SRBMs.

To explore the clinical efficacy and safety of posterior intervertebral foraminal discectomy via Delta channel for cervical spondylotic radiculopathy in the early phase.From September 2017 to July 2018, 10 patients with cervical spondylotic radiculopathy underwent posterior intervertebral foraminal discectomy via Delta channel. There were 6 males and 4 females, aged from 30 to 62 years old with an average of (41.5±4.3) years old. All of them had unilateral symptoms caused by cervical nerve root compression, including 2 cases of CAll patients successfully completed the surgeries without any spinal cord, nerve root or major blood vessel injury. The operation time was 70 to 120 min with an average of 90 min. Intraoperative blood loss ranged from 30 to 90 ml with an average of 40 ml. All the 10 patients were followed up for 6 to 14 months with an average of 9 months. Postoperative nerve root pain got relievd and nerve function was improved in all patients. VAS score decreased from 7.15±2.01 before surgery to 1.59±0.83 at the latest follow-up;JOA score increased from 12.57±1.24 before surgery to 16.42±0.58 at the latest follow-up;NDI score increased from 41.82±4.71 before surgery to 9.59±3.52 at the latest follow-up. All the results above presented significant difference between latest follow-up and preoperative (Treatment of cervical spondylotic radiculopathy by posterior intervertebral foraminal discectomy via Delta channel can obtain a satisfactory clinical outcome without affecting the stability of cervical vertebra. The surgery is safe, reliable and worthy of clinical application.

Silent information regulator 1 (Sirt1) is a deacetylase, which plays an important role in the occurrence and development of diabetic nephropathy (DN). Our previous study shows that Yin yang 1 (YY1), a widely expressed zinc finger DNA/RNA-binding transcription factor, is a novel regulator of renal fibrosis in diabetic nephropathy. Since the activity of YY1 is regulated via acetylation and deacetylation modification, this study aimed to explore whether Sirt1-induced deacetylation of YY1 mediated high glucose (HG)-induced renal tubular epithelial–mesenchymal transition (EMT) and renal fibrosis in vivo and in vitro. We first confirmed that Sirt1 expression level was significantly decreased in the kidney of db/db mice and in HG-treated HK-2 cells. Diabetes-induced Sirt1 reduction enhanced the level of YY1 acetylation and renal tubular EMT. Then, we manipulated Sirt1 expression in vivo and in vitro by injecting resveratrol (50 mg·kg −1 ·d −1 . ip) to db/db mice for 2 weeks or application of SRT1720 (2.5 μM) in HG-treated HK-2 cells, we found that activation of Sirt1 reversed the renal tubular EMT and YY1 acetylation induced by HG condition. On the contrary, Sirt1 was knocked down in db/m mice or EX527 (1 μM) was added in HK-2 cells, we found that inhibition of Sirt1 exacerbated renal fibrosis in diabetic mice and enhanced level of YY1 acetylation in HK-2 cells. Furthermore, knockdown of YY1 inhibited the ameliorating effect of resveratrol on renal tubular EMT and renal fibrosis in db/db mice. In conclusion, this study demonstrates that Sirt1 plays an important role in renal tubular EMT of DN through mediating deacetylation of YY1.

The migration behavior of silicone molecules including octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane (denoted as D4, D5, D6, respectively) for silicone rubber baking mold (SRBM) under two different baking methods into food simulants and to cakes were investigated. Meantime, different daily used oils including corn, peanut, sunflower and butter were used to investigate the effects of oil property on migration of D4, D5 and D6, respectively where cakes were baked using SRMB at 175 °C for 30 min. Results showed that for olive oil, the migration of D4, D5 and D6 reached maximum in 240 min at 175°C under electric baking condition and reached maximum in 20 min at 800 W under microwaving baking. Unlike olive oil, the migration rate of D4, D5 and D6 into Tanex® decreased significantly with used times under both electric baking and microwaving methods. Importantly, results also showed that the amounts of D4, D5 and D6 in cakes baked with peanut oil and corn oil were significantly higher (p

Entrepreneurical informatizational education pays attention to gain experience that is related to it, and is needed to the students who should be leaded to get perceptual cognition about entrepreneurial venture. This is the premise conditions to carry out education startup successfully. We can be consciously known to the students experience about related content, thus, to stimulate the students pioneering innovation consciousness.For the current college students, entrepreneurial education should be focused on changing its employment idea. According to the survey at present,many college students think: employment is his own thing to find work. These old ideas make many college students rather passive when finding a job. Entrepreneurial education is to converse the students the passive employment ideas and initiate to start a business. Students should be encouraged to regard entrepreneurial venture as a career choice,combined with their interests to create the value of life that are expected .

The stable linear switched systems will converge to the balance Point. If different switched laws be chosen, the convergence Process will not be the same, so there is an optimal switched law. The issues of optimal switched law based on norm, convergence radius, convergence distance and convergence direction are respectively studied, and the optimal switched law is confirmed by solution of matrix equation. All kinds of instance have been considered synthetically, the synthetic optimal switched law is given, by which an optimal status of system in convergence process is reflected roundly. By calculate and simulation of practice examples and the using process of stability criterion is realized distinctly.

Predictions of distortion and hardness after heat treatment by numerical simulation are very useful for determining the optimum condition and for controlling the distortion of machinery parts. In this article, the combination method of orthogonal experiment and numerical simulation is used to optimize the standard heat treatment condition by reducing the distortion after carburizing quenching. A helical gear made of carburizing steel 20MnCrS5 is simulated using three-dimensional coupled analysis that is based on thermo-mechanical theory. The good agreement between the experiment and simulation is verified by the comparison between the experimental data and the simulated data. Firstly, the influencing factors of distortion after carburizing quenching are investigated and discussed. Four influence factors of heat treatment are selected as follows: carburizing time, the cooling time before 860°C, the holding time at 860°C, and the gear orientation during quenching. Next, selection of the optimal case is then determined by comparing the distortions. Finally, a new optimization method of minimum distortion after carburizing quenching is provided.