(+)-Borneol, the main component of "Natural Borneol" in the Chinese Pharmacopoeia, is a high-end spice and precious medicine. Plant extraction cannot meet the increasing demand for (+)-borneol, while microbial biosynthesis offers a sustainable supply route. However, its production was extremely low compared with other monoterpenes, even with extensively optimizing the mevalonate pathway. We found that the key challenge is the complex and unusual dephosphorylation reaction of bornyl diphosphate (BPP), which suffers the side-reaction and the competition from the cellular dephosphorylation process, especially lipid metabolism, thus limiting (+)-borneol synthesis. Here, we systematically optimized the dephosphorylation process by identifying, characterizing phosphatases, and balancing cellular dephosphorylation metabolism. For the first time, we identified two endogenous phosphatases and seven heterologous phosphatases, which significantly increased (+)-borneol production by up to 152%. By engineering BPP dephosphorylation and optimizing the MVA pathway, the production of (+)-borneol was increased by 33.8-fold, which enabled the production of 753 mg/L under fed-batch fermentation in shake flasks, so far the highest reported in the literature. This study showed that rewiring dephosphorylation metabolism was essential for high-level production of (+)-borneol in Saccharomyces cerevisiae, and balancing cellular dephosphorylation is also helpful for efficient biosynthesis of other terpenoids since all whose biosynthesis involves the dephosphorylation procedure.

The phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB/Akt)signaling pathway plays an important role in various biological processes,including cell growth,proliferation,differentiation,and apoptosis.The PI3K/Akt-related signaling pathways have been extensively studied,and they regulate neural cells to exert different or simi-lar functions.This study reviews the research progress on PI3K/Akt-related signaling pathways in apoptosis,autophagy,oxidative stress,neuroinflammation,and other pathophysiological mechanisms in neural cells.

Objective To explore the effect of physical exercise on semen quality in order to provide basic data and theoretical basis for the improvement of male reproductive health.Methods A cross-sectional study was conducted on 1 059 males who visited the Reproductive Medicine Center of Shandong Maternal and Child Health Hospital for medical treatment and physical examination during July 2022 and April 2023.Their demographic data and physical exercise data were surveyed with questionnaires.Total sperm count,sperm concentration,total sperm motility,forward movement and normal sperm morphology were analyzed with computer aided analysis.Logistic regression model and multiple linear regression model were applied to analyze the effects of physical exercise on semen quality.Results After adjustment for confounding factors such as age,body mass index,alcohol consumption and smoking,logistic regression analysis showed that the risk of abnormal semen quality was increased in patients with moderate and heavy exercise intensity(OR=2.103,OR=2.229).Compared with the participants with physical exercise ≤10 min per session,those with＞20 min per session had a lower risk of abnormal semen quality(OR=0.357,0.256,0.289 for exercise time for＞20～30,＞30～60,＞60 min,respectively).There was no statistical significance between physical exercise frequency and semen quality(P＞0.05).The participants having exercise well were at a lower risk for abnormal semen quality(OR=0.711).Multiple linear regression analysis revealed that the frequency of physical exercise was an influencing factor of sperm concentration(β=7.474,95％CI:4.800～10.149,P＜0.05);the time of physical exercise per session was an influencing factor for total sperm count(β=20.632,95％CI:7.634～33.629);the intensity of physical exercise(β=-1.461,95％CI:-2.392～-0.530)and time of physical exercise per session(β=2.608,95％CI:1.404～3.812,P＜0.05)were influencing factors for percentage of forward motility sperm(P＜0.05);and physical exercise intensity(β=-1.934,95％CI:-3.238～-0.630),time of physical exercise per session(β=4.211,95％CI:2.525～5.897)and frequency of physical exercise(β=-2.008,95％CI:-3.480～-0.536)were influencing factors of total sperm motility(P＜0.05).Conclusion Physical exercise may affect semen quality,greater intensity of physical exercise may be a risk factor for abnormal semen quality,and longer physical exercise time may be related to improving semen quality.Therefore,proper physical exercise can help improve semen quality.

Objective To explore the role and mechanism of RNA demethylase fat mass and obesity-associated protein(FTO)in the ferroptosis in testicular interstitial cells induced by di(2-ethylhexyl)phthalate(DEHP).Methods Forty 3-week-old C57BL/6 male mice were randomly divided into a control group(corn oil)and 3 dosed DEHP treatment groups(5,250 and 500 mg/kg),and received an intragastric infusion of corresponding agents for 35 d,respectively.After mouse testicular interstitial TM3 cells was treated with 0,100,200 and 400 μmol/L mono-2-ethylhexyl phthalate(MEHP)for 24 h,corresponding plasmids were transfected to construct Fto overexpressing TM3 cells.Serum testosterone level was detected by ELISA,expression of testicular proteins was detected with immunohistochemical assay,and contents of Fe2+,malondialdehyde(MDA)and lipid peroxides in the testicle were detected by colorimetry.Methylated RNA immunoprecipitation,RT-PCR,and Western blotting were used to detect the level of N6-methyladenosine(m6A)modification.Results In the mice exposed to 250 and 500 mg/kg DEHP,the serum testosterone level was significantly reduced(P＜0.01),contents of Fe2+,MAD and lipid peroxides in testicular tissue were obviously increased(P＜0.01),and protein levels of RNA demethylase FTO,and ferroptosis related molecules ferritin heavy chain 1(FTH1)and glutathione peroxidase 4(GPX4)were significantly down-regulated(P＜0.05),while those of transferrin receptor(TFRC),ferroportin(FPN),cyclooxygenase-2(COX-2),and acyl-CoA synthetase long-chain family member 4(ACSL4)were notably up-regulated(P＜0.05).MEHP treatment for 24 h resulted in remarkably decreased cell viability in the TM3 cells,increased production of intracellular reactive oxygen species(ROS),reduced mitochondrial membrane potential(MMP)(P＜0.01),down-regulated mRNA and protein levels of Fto(P＜0.01),and the changes in other ferroptosis related proteins were consistent with the trend in testicular tissue,indicating ferroptosis in testicular interstitial cells.Intervention with ferroptosis inhibitor Fer-1 or overexpression of Fto significantly inhibited MEHP-induced toxicity and ferroptosis in TM3 cells(P＜0.05),and overexpression of Fto reduced the m6A modification of Gpx4 and Fth1 mRNA(P＜0.05).Conclusion Abnormal m6A modification of Gpx4 and Fth1 caused by inhibiting FTO expression may be the mechanism of ferroptosis in testicular interstitial cells induced by DEHP.

Objective:To explore the effects and mechanism of Salvianolic acid B(SalB)on Parkinson's disease(PD).Methods:Forty-eight C57BL/6 male mice were randomly separated into control group(control)withoutdrugs,model group(MPTP)with intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrah-ydropyridine(MPTP),SalB control group with intraperitoneal injection of SalB,and SalB treatment group(MPTP+SalB).Construction of PD mouse model by intraperitoneal injection of MPTP,and treatment with intraperitoneal injection of SalB.Pole climbing test was applied to assess behavior differences.The time of first black stool excretion and water content of feces were measured to evaluate intestinal dysfunctions.The number of tyrosine hydroxylase(TH)positive cells in substantia nigra and the level of Toll like receptor 4(TLR4)in colon were analyzed by immunohistochemistry.The pathological changes of colonic mucosa were observed by HE staining.The levels of calprotectin(CP)and tumor necrosis factor-α(TNF-α)in colon were determined by ELISA.Western blot was used to determine the level of TH in midbrain,the protein level of TH,tight junction protein(ZO-1),and protein level of TLR4/MyD88/NF-κB signaling pathways which express in colon.Results:Com-pared with the Control group,the climbing time,T-turn time and the first black stool excretion time in MPTP group increased while the fecal water content and the number of TH positive cells in substantia nigra were decreased.Accompanied by TLR4 positive cells in colon,pathological injury score of colonic mucosa,levels of CP and TNF-α in colon increased,expression of TH in midbrain and expression of ZO-1 in colon decreased.Expressions of TLR4,MyD88,Nuclear NF-κB p65 and p-NF-κB p65 in colon increased.Com-pared with MPTP group,SalB treatment shortened the climbing time,T-turn time and the first black stool excretion time in SalB treat-ment group,increased the fecal water content and the number of TH positive cells in substantia nigra,lowered TLR4 positive cells in colon,enhanced expression of TH in midbrain and colon,reduced the pathological injury score of colonic mucosa,significantly decreased levels of CP and TNF-α in colon,enhanced expression of ZO-1 in colon,inhibited expressions of TLR4,MyD88,Nuclear NF-κB p65 and p-NF-κB p65 in colon.Conclusion:SalB can protect the nerves and intestines and alleviate the intestinal inflamma-tion of PD mice,which may be related to the inhibition of TLR4/MyD88/NF-κB signal pathway.

low-grade glioma(LGG)is a slow-growing primary brain tumor originating from glial cells.The overall prognosis of LGG is good but incurable.The vast majority of LGG will have relapses,and some even progress to high-grade glioma(HGG).The treatment of LGG is still controversial.The current treatment includes surgical resection,radiation therapy(RT),chemical treatment(CT),targeting and immunotherapy,but its effectiveness and safety need further clinical exploration.This article describes the treatment of LGG,including surgery,radiotherapy,chemotherapy,targeting and immunotherapy,in order to develop an individualized treatment plan and provide theoretical strategies for maximizing the survival time of patients and improving the prognosis of patients.

Objective To investigate the correlation between baseline serum lipid levels and hematoma enlargement in patients with acute intracerebral hemorrhage (ICH). Methods From October 2013 to January 2018, patients with ICH admitted to the Department of Neurosurgery, Heze Municipal Hospital, were enrolled retrospectively. The first CT scan was completed within 6 h after onset, and the second one was completed at 48 h after onset. Hematoma enlargement was defined as an increase >33 % in the volume of hematoma on CT. The demographic and baseline clinical data in the hematoma enlargement group and the non -hematoma enlargement group were compared. Multivariate logistic regression analysis was used to identify the independent risk factors for hematoma enlargement. Results A total of 470 patients with acute ICH were enrolled, including 187 females (39.8%) and 283 males (60.2%), aged 47-81 years. Seventy-nine patients (16.8%) had hematoma enlargement. The proportion of patients with atrial fibrillation and who used warfarin before onset, as well as age, baseline National Institutes of Health Stroke Scale score, baseline hematoma volume, international normalized ratio, prothrombin time, activated partial thromboplastin time, and thrombin time of the hematoma enlargement group were significantly higher than those of the non -hematoma enlargement group ( all P< 0.05 ), while from the onset to the first CT scan time, total cholesterol, triglyceride, low-density lipoprotein cholesterol levels were significantly lower than those in the non- hematoma enlargement group (all P<0.05). Multivariate logistic regression analysis showed that baseline total cholesterol <3.20 mmol/L (odds ratio [ OR] 1.32, 95% confidence interval [ CI] 1.08-1.83; P=0.004), baseline hematoma volume≥30 ml (1.76,95% CI 1.30-2.15; P<0.001), and using anticoagulant before onset ( OR 2.37, 95% CI 1.81-3.02; P<0.001 ) had significantly independent correlation with hematoma enlargement. Conclusion Baseline total cholesterol <3.20 mmol/L, hematoma volume ≥30 ml, and using anticoagulant before onset were the independent risk factors for hematoma enlargement in patients with acute ICH.

Objective To explore the cognition, emotion and will experience of nurses in rescue of major traffic accidents. Methods The study was carried out with the phenomenological approach within qualitative research. From January 2014 to June 2017, a total of 10 nurses of China-Japan Union Hospital of Jilin University taking part in traffic accident rescue were selected as interviewees. Colaizzi method was used to sort out and analyze data. Results According to data analysis, 7 themes were induced including management capacity, operation skills of first aid, shock and heartache, sense of responsibility and mission, fear, being conscious of negative emotions as well as finding ways to control negative emotions. Conclusions The controlling ways of psychological pressure problem for first aid nurses are put forward by analyzing psychological experience of nurses in rescue of traffic accident so as to provide a basis for managers to formulate training system.

OBJECTIVE:To investigate the omeprazole off-label use and provide reference for rational drug use in clinic. METHODS:In retrospective survey,1838 omeprazole prescriptions were selected from outpatient department during Jun. 2014 to May 2017 by random number table. According to the latest drug instruction,whether the off-label use or not was determined. Off-label use was determined by reviewing domestic and foreign guidelines,literatures and Micromedex database. RESULTS:Among 1838 pre-scriptions,there were 1750 prescriptions of off-label drug use (95.21％),involving 13 items and 3 types of off-label drug use. Main type of off-label drug use was over-indication medication,involving 1747 prescriptions (96.47％). There was no statistical significance in the incidence of off-label drug use between digestive department and non-digestive department or among physicians at different levels(P>0.05). Among 13 items of off-label drug use,7 items were supported by evidence-based medicine evidence of domestic and foreign guideline,expert consensus/suggestion or literature reports,etc.;among which 1 item of off-label drug use were included in Micromedex grading system and other 6 items had no evidence-based medicine evidence. CONCLUSIONS:The phenomenon of omeprazole off-label use is widespread in outpatient department of the hospital,and some off-label drug use are sup-ported by evidences. There are differences in the quality of those evidences. It is suggested to standardize the off-label drug use to avoid legal risks and guarantee the safety of drug use for patients.

Objective To better understand the clinical characteristics of Familial Idiopathic Basal Ganglia Calcifi?cation (FIBGC), including at the perspective of hereditary pattern, clinical test results, onset age, clinical heterogeneity and the volume of basal ganglia calcification (VBGC). Method 8 Eight FIBGC families were collected and draw family pedigrees were draw. Analysis of was conducted on the patient's clinical test results, head CT and MRI changes, onset ag?es, relationship of clinical manifestations with VBGC. Results No significant difference was found in serum calcium, alu?minum, arsenic, cobalt, magnesium, phosphorus, iron, parathyroid hormone and calcitonin concentration between the fam?ily members of patients and healthy controls (P>0.05). Family members from 8 FIBGC families including the two with consanguineous marriage manifested autosomal dominant heredity. The severity of , symptomatic s was correlated with VBGCpatients showed the same clinical manifestations in the dyskinesia family. The psychiatric symptoms was not asso? ciated with VBGC whereas patients with dyskinesia had a large VBGC. There was a significant difference in onset age be?tween patients with psychiatric symptoms and those with dyskinesia. P.atients with dyskinesia suffer larger VBGC, and is characterized by Patients with dyskinesia had relatively later onset age (43.95 ± 2.47 y) whereas those with. psychiatric symptoms hadsymptomatic patients with early onset age (31.32±10.16y). The comparison of the onset age (43.954±2.473 vs. 31.319±10.156 y, t=4.438, P=0.001) and VBGC (1.748±0.622 vs. 0.392±0.276 cm3, t=2.518, P=0.028) with symptom?atic patients between dyskinesia and psychogenic families was significant. Conclusions Eight FIBGC families manifested autosomal dominant heredity. Patients with dyskinesia suffer have a larger VBGC and are associated with a, and is char?acterized by relatively later onset age. In contrast, patients with psychiatric symptomspsychogeny is not related withhave a the small VBGC and showedand their age of onset is young. earlier onset age.