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Purpose : The association between visual impairment (VI) and the risk of dementia has been poorly understood. We sought to investigate the VI-dementia relationship in the UK Biobank Study. Design : Prospective cohort study Methods : A total of 117,187 volunteers (aged 40-69 years) deemed free of dementia at baseline were included. Habitual distance visual acuity worse than 0.3 logMAR units in the better-seeing eye was used to define VI. The incident dementia was based on electronically linked hospital inpatient and death records. Results : During a median follow up of 5.96 years, the presence of VI was significantly associated with incident dementia (HR=1.78, 95% CI: 1.18-2.68, P=0.006). There was a clear trend between the severity of VI and the risk of dementia (P for trend=0.002). Conclusions : We found VI was associated with increased risk of dementia, with a progressively greater risk among those with worse visual acuity. Our findings suggested that visual impairment might be a modifiable risk factor for dementia and highlighted the potential value of VI elimination to delay the manifestation of dementia.

This article studies the therapeutic effect and nursing experience of octreotide in treating hypoglycemia in acute pancreatitis. Method: Sixty patients with acute pancreatitis treated in our hospital from January 2019 to February 2020 were selected as the study subjects, and the patients who met the criteria were randomly divided into intervention group (n=30) and control group (n=30).Both groups of patients were treated with octreotide, while the intervention group was given personalized whole-course intervention on the basis of it, to compare the treatment effect of the two groups and the occurrence of hypoglycemia. Results: The total effective rate was 73.33% in the control group and 96.67% in the intervention group. There was a significant difference in data between the intervention group and the control group (P < 0.05). The incidence of hypoglycemia was 26.67% in the control group and 3.33% in the intervention group. The difference between the control group and the intervention group was statistically significant (P < 0.05). The incidence of adverse reactions was 36.67% in the control group and 6.67% in the intervention group. The difference between the control group and the intervention group was statistically significant (P < 0.05). The nursing satisfaction of the patients in the control group was 79.00%, and that of the intervention group was 96.67%. The difference between the intervention group and the control group was statistically significant (P < 0.05). Conclusion: Octreotide has a good effect in the treatment of patients with acute pancreatitis. If personalized whole-course intervention can be given to patients with acute pancreatitis who receive 24-hour octreotide pump drip, the treatment effect, nursing satisfaction, adverse reactions and hypoglycemia can be further improved, and the patient’s condition can be effectively maintained stable and the patient can recover as soon as possible.

AimsTo examine independent and interactive associations of ophthalmic and systemic conditions with incident dementia.MethodsOur analysis included 12 364 adults aged 55–73 years from the UK Biobank cohort. Participants were assessed between 2006 and 2010 at baseline and were followed up until the early of 2021. Incident dementia was ascertained using hospital inpatient, death records and self-reported data.ResultsOver 1 263 513 person-years of follow-up, 2304 cases of incident dementia were documented. The multivariable-adjusted HRs (95% CI) for dementia associated with age-related macular degeneration (AMD), cataract, diabetes-related eye disease (DRED) and glaucoma at baseline were 1.26 (1.05 to 1.52), 1.11 (1.00 to 1.24), 1.61 (1.30 to 2.00) and (1.07 (0.92 to 1.25), respectively. Diabetes, heart disease, stroke and depression at baseline were all associated with an increased risk of dementia. Of the combination of AMD and a systemic condition, AMD-diabetes was associated with the highest risk for incident dementia (HR (95% CI): 2.73 (1.79 to 4.17)). Individuals with cataract and a systemic condition were 1.19–2.29 times more likely to develop dementia compared with those without cataract and systemic conditions. The corresponding number for DRED and a systemic condition was 1.50–3.24. Diabetes, hypertension, heart disease, depression and stroke newly identified during follow-up mediated the association between cataract and incident dementia as well as the association between DRED and incident dementia.ConclusionsAMD, cataract and DRED but not glaucoma are associated with an increased risk of dementia. Individuals with both ophthalmic and systemic conditions are at higher risk of dementia compared with those with an ophthalmic or systemic condition only.

Background Colorectal cancer (CRC) is a common aggressive tumor that poses a heavy burden to human health. An increasing number of studies have reported that circular RNA (circRNA) is involved in the progression of CRC. In this study, the special profiles of circASXL1 (circ_0001136) in CRC progression were revealed. Methods The expression of circASXL1, microRNA-1205 (miR-1205), and glutamate ionotropic receptor kainate type subunit 3 (GRIK3) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression was determined by Western blot or immunohistochemistry. Cell colony-forming ability was investigated by colony formation assay. Cell cycle and apoptosis were demonstrated using cell-cycle and cell-apoptosis analysis assays, respectively. Cell migration and invasion were detected by wound-healing and transwell migration and invasion assays, respectively. The binding sites between miR-1205 and circASXL1 or GRIK3 were predicted by circBank or miRDB online database, and identified by dual-luciferase reporter assay. The impact of circASXL1 on tumor formation in vivo was investigated by in vivo tumor formation assay. Results CircASXL1 and GRIK3 expression were apparently upregulated, and miR-1205 expression was downregulated in CRC tissues and cells relative to control groups. CircASXL1 knockdown inhibited cell colony-forming ability, migration and invasion, whereas induced cell arrest at G0/G1 phase and cell apoptosis in CRC cells; however, these effects were attenuated by miR-1205 inhibitor. Additionally, circASXL1 acted as a sponge for miR-1205, and miR-1205 was associated with GRIK3. Furthermore, circASXL1 silencing hindered tumor formation by upregulating miR-1205 and downregulating GRIK3 expression. Conclusion CircASXL1 acted an oncogenic role in CRC malignant progression via inducing GRIK3 through sponging miR-1205. Our findings provide a theoretical basis for studying circASXL1-directed therapy for CRC.

To evaluate the utility of a contact-free device in screening for obstructive sleep apnea.Three hundred fifty-nine participants (mean age 46 ± 13 years, body mass index 26.1 ± 4.2 kg/m², 67.7% male) underwent overnight monitoring using a contact-free device, the OrbSense, and polysomnography (PSG) in the sleep laboratory simultaneously. The OrbSense recordings were analyzed automatically, and PSG was scored based on recommended guidelines.The respiratory event index from the OrbSense was lower than the apnea-hypopnea index (AHI) from PSG (25.5 ± 20.7 vs 27.0 ± 25.2 events/h; P = .007) and was significantly correlated with AHI (Pearson coefficient, 0.92; P.0001). Bland-Altman analysis showed a mean difference of 1.5 events/h, and the limit of agreement was -18.6 to 21.5 events/h. Use of the OrbSense resulted in larger underestimates of AHI and lower negative predictive values at higher AHI values (especially when AHI ≥ 30 events/h). When we used a PSG diagnostic criterion of AHI5 events/h, the optimal diagnostic cutoff value from the OrbSense was 8 events/h, with a sensitivity of 90.4%, a specificity of 77.6%, a 94.6% positive predictive value, and a 65% negative predictive value. For patients with moderate to severe obstructive sleep apnea whose AHI was15 events/h, the OrbSense cutoff was 16.6 events/h, with a sensitivity of 87.1% and a specificity of 89.7%. Among the 359 participants, 250 patients (69.6%) had the same obstructive sleep apnea severity division classified by both PSG and the OrbSense.The contact-free device OrbSense can detect respiratory events during sleep and has close agreement with in-laboratory PSG in screening for obstructive sleep apnea. Further studies are warranted to test its utility in community-based settings and at home.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and is known for its high resistance and low response to treatment. Tumor immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Karyopherin alpha 2 (KPNA2), a member of the nuclear transporter family, is elevated in multiple human cancers and accelerates carcinogenesis. However, the specific role of KPNA2 in PDAC remains unclear. In this study, we found that expression of KPNA2 was significantly upregulated in PDAC compared to adjacent nontumor tissue and its high expression was correlated with poor survival outcome by analyzing the GEO datasets. Similar KPNA2 expression pattern was also found in both human patient samples and KPC mouse models through IHC staining. Although KPNA2 knockdown failed to impair the vitality and migration ability of PDAC cells in vitro, the in vivo tumor growth was significantly impeded and the expression of immune checkpoint ligand PD-L1 was reduced by silencing KPNA2. Furthermore, we uncovered that KPNA2 modulated the expression of PD-L1 by mediating nuclear translocation of STAT3. Collectively, our data suggested that KPNA2 has the potential to serve as a promising biomarker for diagnosis in PDAC.

In recent years, the amount of water and sediment in the Yellow River Basin has dropped drastically. This paper selected 125 rainfall and flood data points from 1965 to 2015, combined hydrological methods and mathematical statistics to analyze the hydrological factors and runoff generation mechanism, and combined the underlying surface conditions of the Gushanchuan Basin. The characteristics of change revealed the temporal and spatial variation characteristics and related factors of the runoff generation mechanism in the basin. The results showed that the Gushanchuan Basin is still dominated by HOF runoff, but the runoff generation mechanism has also changed with changes in the underlying surface, which are reflected in increased runoff components, the reduced proportion of HOF runoff, and the increased proportion of saturation-excess overland flow (SOF) runoff and mixed runoff. We analyzed the variation law of underlying surface in the basin, which indicated that the increase in the forest grass area was the main factor affecting changes in the watershed runoff generation mechanism. This research will enable a deeper understanding of the runoff generation mechanism of the main soil erosion areas in the Loess Plateau, and reveal variations in the runoff generation mechanism in the Yellow River. HIGHLIGHTS The increase in the forest grass area was the main factor affecting changes in the watershed runoff generation mechanism in Gushanchuan Basin.; Gushanchuan Basin is still dominated by HOF runoff, and the increased proportion of SOF runoff and mixed runoff.

Background Doctors play an important role in smoking control. This study aimed to assess doctors’ smoking control knowledge, attitudes and practices to help doctors raise awareness of smoking control assistance. Methods This cross-sectional study recruited 1046 doctors from Shandong Province, China, by using multistage sampling. Participants’ information was collected by questionnaire. Pearson’s χ2 test and Fisher’s exact probability method were used to compare the distributions of categorical variables between/among groups. Results Among the participants, 14.7% were current smokers. Approximately 50.3% of participants had heard of smoking cessation drugs and 59.2% of participants thought that low-tar and low-nicotine cigarettes were as harmful to health as common cigarettes. Approximately 98.2 and 60.9% of participants agreed that smoking was related to lung cancer and male sexual dysfunction, respectively. Although 72.0% of participants believed that doctors should actively provide smoking cessation assistance, only 58.1% of participants considered that doctors should be responsible for providing smoking cessation assistance. Similarly, 85.2% of participants often asked about the smoking history of patients or their family members, while only 4.9% of participants had prescribed smoking cessation drugs for patients. Pediatricians had a higher proportion of “Agree” responses to the assessment items than doctors in other departments. Conclusions The results showed that doctors in Shandong Province did not have sufficient knowledge of smoking control. Slightly more than half of doctors thought that providing smoking cessation assistance was their responsibility. Only a few participants had prescribed smoking cessation drugs.

The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils., Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease characterized by an immunosuppressive microenvironment. Here the authors show that a subset of P2RX1-negative neutrophils with immunosuppressive properties accumulate in PDAC metastatic liver tissues and promote tumor growth.

Astaxanthin has great potential commercial value in the feed, cosmetics, and nutraceutical industries due to its strong antioxidant capacity. In this study, the Escherichia coli strain CAR026 with completely balanced metabolic flow was selected as the starting strain for the production of astaxanthin. The expression of β-carotene ketolase (CrtW) and β-carotene hydroxylase (CrtZ), which catalyze the conversion of β-carotene to astaxanthin, was coordinated, and a bottleneck was eliminated by increasing the copy number of crtY in CAR026. The resulting strain Ast007 produced 21.36 mg/L and 4.6 mg/g DCW of astaxanthin in shake flasks. In addition, the molecular chaperone genes groES-groEL were regulated to further improve the astaxanthin yield. The best strain Gro-46 produced 26 mg/L astaxanthin with a yield of 6.17 mg/g DCW in shake flasks and 1.18 g/L astaxanthin after 60 h of fermentation under fed-batch conditions. To the best of our knowledge, this is the highest astaxanthin obtained using engineered E. coli to date.

Revealing the aggregation and fibrillation process of variant amyloid proteins is critical for understanding the molecular mechanism of related amyloidosis diseases. Here we characterized the fibrillation morphology and kinetics of type 2 diabetes (T2D) related human islet amyloid polypeptide (hIAPP1-37) fibril formation process using negative staining transmission electron microscopy (NS-TEM), cryo-electron microscopy (cryo-EM) analysis, and 3D cryo-electron tomography (cryo-ET) reconstruction, together with circular dichroism (CD) and Thioflavin-T (ThT) assays. Our results showed that various amyloid fibrils can be observed at different time points of hIAPP1-37 fibrillization process, while the winding of protofibrils presents in different growth stages, which suggests a synchronous process of hIAPP1-37 amyloid fibrillization. This work provides insights into the understanding of hIAPP1-37 amyloid aggregation process and the pathogenesis of Type 2 diabetes disease.

Glycolate is an important α-hydroxy acid with a wide range of industrial applications. The current industrial production of glycolate mainly depends on chemical synthesis, but biochemical production from renewable resources using engineered microorganisms is increasingly viewed as an attractive alternative. Crude glycerol is an abundant byproduct of biodiesel production and a widely investigated potential sustainable feedstock. Here, we constructed a novel biosynthetic pathway for the production of glycolate from glycerol in Escherichia coli. The pathway starts from the oxidation of glycerol to d-glycerate by alditol oxidase, followed by sequential enzymatic dehydrogenation and decarboxylation as well as reduction reactions. We screened and characterized the catalytic activity of candidate enzymes, and a variant of alditol oxidase from Streptomyces coelicolor A3(2), 2-hydroxyglutarate-pyruvate transhydrogenase from Saccharomyces cerevisiae, α-ketoisovalerate decarboxylase from Lactococcus lactis, and aldehyde dehydrogenase from Escherichia coli were selected and assembled to create an artificial operon for the biosynthetic production of glycolate from glycerol. We also characterized the native strong constitutive promoter Plpp from E. coli and compared it with the PT7 promoter, which was employed to express the artificial operon on the plasmid pSC105-ADKA. To redirect glycerol flux toward glycolate synthesis, we deleted key genes of the native glycerol assimilation pathways and other branches of native E. coli metabolism, and we introduced a second plasmid expressing Dld3 to reduce the accumulation of the intermediate d-glycerate. Finally, the engineered strain TZ-108 harboring pSC105-ADKA and pACYC184-Plpp-Dld3 produced 0.64 g/L glycolate in shake flasks, which was increased to 4.74 g/L in fed-batch fermentation. This study provides an alternative pathway for glycolate synthesis and demonstrates the potential for producing other commodity chemicals by redesigning glycerol metabolism.

Cervical cancer (CC) remains highest in the mortality of female reproductive system cancers, while cisplatin (CDDP) resistance is the one of main reasons for the lethality. Preceding evidence has supported that karyopherins are associated with chemoresistance. In this study, we simultaneously compared CDDP-incomplete responders with CDDP-complete responders of CC patients and CDDP‐insensitive CC cell lines with CDDP‐sensitive group. We finally identified that DNA-PKcs (PRKDC) was related to CDDP sensitivity after overlapping in CC sample tissues and CC cell lines. Further functional assay revealed that targeting PRKDC by shRNA and NU7026 (specific PRKDC inhibitor) could enhance CDDP sensitivity in vitro and in vivo, which was mediated by impairing DNA damage repair pathway in CC. Mechanistically, we found that PRKDC was transcriptionally upregulated by CCAAT/enhancer-binding protein delta (CEBPD), while intriguingly, CDDP treatment strengthened the transcriptional activity of CEBPD to PRKDC. We further disclosed that Importin 4 (IPO4) augmented the nuclear translocation of CEBPD through nuclear localization signals (NLS) to activate PRKDC-mediated DNA damage repair in response to CDDP. Moreover, we demonstrated that IPO4 and CEBPD knockdown improved CDDP-induced cytotoxicity in vitro and in vivo. Together, we shed the novel insight into the role of IPO4 in chemosensitivity and provide a clinical translational potential to enhance CC chemosensitivity since the IPO4-CEBPD-PRKDC axis is actionable via NU7026 (PRKDC inhibitor) or targeting IPO4 in combination with CDDP.

Background: Little is known about the genetic alterations characteristic of ovarian clear cell carcinoma (OCCC). Our aim was to identify targetable genomic alterations in this type of cancer. Methods: Forty-two OCCC formalin-fixed, paraffin-embedded (FFPE) tissue samples were analyzed by whole-exome sequencing (WES), and 74 FFPE tissue samples underwent targeted sequencing (TS) to confirm the relevant driver mutations. Cell proliferation was assessed by cell counting kit-8 (CCK8) assays. Findings: In the 42 samples, ARID1A (64.3%) and PIK3CA (28.5%) were frequently mutated, as were PPP2R1A (11.9%), PTEN (7.1%) and KRAS (4.8%), which have been reported in previous OCCC studies. We also detected mutations in MUC4 (28.6%), MAGEE1 (19%), and ARID3A (16.7%); associations with these genes have not been previously reported. The functional protein-activated pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 83% of OCCCs and with chromatin remodeling in 71% of OCCCs. Patients with alterations in MAGEE1 (64% in the targeted sequencing cohort) had worse clinical outcomes (log-rank p < 0.05). A functional study revealed that two MAGEE1 mutants, one lacking two MAGE domains and the other containing two MAGE domains, significantly decreased the proliferative capacity of OCCC cells. Funding: We successfully identified novel genetic alterations in OCCC using whole-exome sequencing and targeted sequencing of OCCC patient samples and potential therapeutic targets for the treatment of this malignancy. Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: The use of samples and medical records was approved by the research ethics committees of Shanghai University of Medicine & Health Sciences Affiliated with Sixth People’s Hospital South Campus (approval number: 2017-KY-01), Fujian Provincial Maternity and Children's Hospital (approval number: 2017049), Nanjing Medical University Affiliated with Changzhou Maternal and Child Health Care Hospital (approval number: 2017005), Nanjing Medical University Affiliated with Changzhou No. 2 People’s Hospital (approval number: 2016-017-01), and Nanjing Medical University Affiliated with Suzhou Municipal Hospital (approval number: L2017003).

Circulating tumor cells (CTCs) enable noninvasive liquid biopsy and identification of cancer. Various approaches exist for the capture and release of CTCs, including microfluidic methods and those involving magnetic beads or nanostructured solid interfaces. However, the concomitant cell damage and fragmentation that often occur during capture make it difficult to extensively characterize and analyze living CTCs. Here, we describe an aptamer-trigger-clamped hybridization chain reaction (atcHCR) method for the capture of CTCs by porous 3D DNA hydrogels. The 3D environment of the DNA networks minimizes cell damage, and the CTCs can subsequently be released for live-cell analysis. In this protocol, initiator DNAs with aptamer-toehold biblocks specifically bind to the epithelial cell adhesion molecule (EpCAM) on the surface of CTCs, which triggers the atcHCR and the formation of a DNA hydrogel. The DNA hydrogel cloaks the CTCs, facilitating quantification with minimal cell damage. This method can be used to quantitively identify as few as 10 MCF-7 cells in a 2-µL blood sample. Decloaking of tumor cells via gentle chemical stimulus (ATP) is used to release living tumor cells for subsequent cell culture and live-cell analysis. We also describe how to use the protocol to encapsulate and release cells of cancer cell lines, which can be used in preliminary experiments to model CTCs. The whole protocol takes ~2.5 d to complete, including downstream cell culture and analysis.

Intestinal tumors mainly originate from transformed crypt stem cells supported by Wnt signaling, which functions through downstream critical factors enriched in the intestinal stem/progenitor compartment. Here, we show Uhrf2 is predominantly expressed in intestinal crypts and adenomas in mice and is transcriptionally regulated by Wnt signaling. Upregulated UHRF2 correlates with poor prognosis in colorectal cancer patients. Although loss of Uhrf2 did not affect intestinal homeostasis and regeneration, tumor initiation and progression were inhibited, leading to a markedly prolonged life span in Uhrf2 null mice on an ApcMin background. Uhrf2 deficiency also strongly reduced primary tumor organoid formation suggesting impairment of tumor stem cells. Moreover, ablation of Uhrf2 suppressed tumor cell proliferation through downregulation of the Wnt/β-catenin pathway. Mechanistically, Uhrf2 directly interacts with and sumoylates Tcf4, a critical intranuclear effector of the Wnt pathway. Uhrf2 mediated SUMOylation stabilized Tcf4 and further sustained hyperactive Wnt signaling. Together, we demonstrate that Wnt-induced Uhrf2 expression promotes tumorigenesis through modulation of the stability of Tcf4 for maintaining oncogenic Wnt/β-catenin signaling. This is a new reciprocal feedforward regulation between Uhrf2 and Wnt signaling in tumor initiation and progression.

Aim: Circulating tumor DNA is promising for routine monitoring of breast cancer. Noninvasive testing allows regular probing using plasma and urine samples. Methods: Peripheral blood and simultaneous urine collection from patients were quantified. Concordance between methods were made. Serial time-point measurements were correlated to disease outcome. Results: Index measurements demonstrate over 90% concordance with biopsy. Receiver operating characteristics curves showed over 0.95 for both plasma and urine results comparing with controls. Patients with lower risk of relapse experienced greater declines in detected DNA levels. Maximal declines were registered at 4.0- and 6.8-fold for plasma and urine results, respectively. Conclusion: Measuring and monitoring DNA levels complement existing testing regimes and provides better risk profiling of patients for possible relapse.

Purpose of the article: To investigate the correlation between C7 slope and cervical lordosis in patients after expansive open-door laminoplasty (EOLP).Material and methods: We retrospectively analyzed 57 patients who underwent EOLP between June 2013 and January 2017 in the Department of Spinal Surgery of our hospital. The operation time, intraoperative blood loss and follow-up time were recorded. The C7 slope, C2-7 sagittal vertical axis, and C2-7 Cobb angle were measured anteroposterior radiograph of the cervical spine preoperatively and postoperatively. All patients were divided into two groups according to the preoperative C7 slope (C7 slope ≤20° group and C7 slope >20° group).Results: The amount of intraoperative bleeding was 220.2 ± 180.9ml, and the operation time was 143.4 ± 51.2min. The average follow-up time was 24.9 ± 10.3months (range12-48 months). The C2-7 Cobb angle was 13.49 ± 10.46°at the final follow-up, which was significantly lower than that preoperatively (p = .026). But, The C7 slope and C2-7 sagittal vertical axis showed no significant difference between preoperatively and postoperatively. Preoperative and postoperative C7 slope and C2-7 Cobb angle were positively correlated to age and significant difference was observed. In the group of C7 slope >20°, significant difference was observed in term of the change of the C2-7 Cobb angle and C2-7SVA postoperatively (p = .009 and p= .020). However, there was no statistically significant difference detected in these two parameters in the group of C7 slope ≤20°.Conclusion: This study indicated that C7 slope could be used as an indicator of the change in the curvature of the cervical spine after EOLP. The loss of cervical curvature after surgery was prone to occur when C7 slope was greater than 20°, which should be noted in clinical practice.

Purpose: Radiotherapy (RT) is a standard adjuvant therapy in progressive rectal cancer patients, but many patients are resistant to RT, leading to poor prognosis. Our study identified microRNA-652 (miR-652) value on RT response and outcome in rectal cancer patients.Methods: miR-652 expression was determined by RT-PCR in primary rectal cancer from 48 patients with and 53 patients without RT. The relationship of miR-652 with biological factors and prognosis were examined. The biological function of miR-652 was identified through TCGA and GEPIA database search. Two human colon cancer cell lines (HCT116 p53+/+ and p53-/-) were used for in vitro study. Results: miR-652 expression was augmented significantly in cancer than normal mucosa in non-RT patients (P=0.044). High miR-652 expression in non-RT patients was related to more apoptosis (P=0.036), ATM (P=0.010) and DNp73 expression (P=0.009). High miR-652 expression was related to worse disease-free survival of non-RT patients, independent of gender, age, tumor stage and differentiation (P=0.028; HR=7.398, 95% CI 0.217-3.786). The biological functional analysis further identified the prognostic value and potential relationship of miR-652 with the apoptosis in rectal cancer. In RT patients, miR-652 expression was notably decreased in cancers when compared to non-RT cases (P=0.047), and miR-652 expression in cancers was negatively related to WRAP53 expression (P=0.022). After miR-652 inhibition, the estimation of reactive oxygen species, caspase activity and apoptosis in HCT116 p53+/+ cells were significantly increased compared with HCT116 p53-/- cells after radiation.Conclusions Our findings suggest the potential value of miR-652 expression as a marker for the prediction of radiation response and clinical outcome in rectal cancer patients.

The G protein-coupled receptor-17 (GPR17) plays an important role in regulating the differentiation of oligodendrocytes and remyelination, which is a key negative regulator of oligodendrocyte differentiation. The present study aimed to investigate the function of GPR17 in the white matter of periventricular leukomalacia (PVL) neonatal rats. The PVL model was established in 2-day old neonatal rats by intracerebral injection of LPS (1 mg/kg). Compared to sham, GPR17 was significantly upregulated, while Olig1 was significantly downregulated in the PVL group at 1 d, 3 days, and 7 days post-modeling. Compared to the negative control (NC) group, the expression of GPR17 was suppressed, while that of Olig1 was elevated in the siRNA-GPR17 group as time progressed; the opposite results were observed in the GPR17-overexpressed group. Decreased formation of myelin sheaths as well as poor structure and loose arrangement were observed in the PVL group. Similar observations were found in the PVL + siRNA-GPR17 group at 1 d and 3 days post-modeling. However, on day 7 post-modeling, a dramatic increase in the formation of myelin sheath as well as thicker myelin sheaths were observed in the PVL + siRNA-GPR17 group. The migration ability of oligodendrocyte progenitor cells (OPCs) isolated from animals was found to be significantly suppressed in the GPR17-overexpressed group, accompanied by the downregulation of Olig1. Taken together, the regeneration and repair of myelin sheaths post-PVL white matter injury were induced by downregulating the GPR17 gene, which elevated the expression of Olig1.

Sarcopenia, characterized by loss of skeletal muscle mass, quality, and strength, has become a common hallmark of ageing and many chronic diseases. Diabetes mellitus patients have a higher prevalence of sarcopenia, which greatly aggravates the metabolic disturbance and compromises treatment response. Preclinical and clinical studies have shown differential impacts of anti‐diabetic drugs on skeletal muscle mass, strength, and performance, highlighting the importance of rational therapeutic regimen from the perspective of sarcopenia risk. In this review, we provide an update on the regulation of muscle mass and quality by major anti‐diabetic drugs, focusing primarily on emerging data from clinical studies. We also discuss the underlying mechanisms and clinical implications for optimal selection of anti‐diabetic drugs to reduce the risk of sarcopenia. In view of the lifelong use of anti‐diabetic drugs, we propose that a better understanding of the sarcopenia risk and interventional strategies is worthy of attention in future studies.

Objective: To assess the occupational injuries and psychological support received by nurses and to investigate the relationship between the two. Method: This was a nation-wide cross-sectional study of nurses working across 1858 hospitals in China. Data were collected using an online structured, self-administered questionnaire between 2016 and 2017. Results: Nearly half of respondents had experienced aggressive behavior from patients or their attendants; 13.4% respondents had experienced aggressive behavior on more than three occasions. 78.96% respondents had experienced needle-stick injuries and 51.22% had experienced psychological trauma. 20.5% respondents believed that hospitals do not pay any attention to occupational safety. 86.1% respondents expressed the need for little or moderate psychological support. Nurses who had experienced aggressive behavior expressed a greater need for psychological support. Nurses working at hospitals that adequately addressed the occupational safety issues expressed the lowest need for psychological support. Conclusion: We found a high prevalence of psychological stress and occupational injuries among nurses. Nursing managers need to address this issue and implement interventions to prevent and reduce injuries. RESUMO Objetivo: Avaliar os acidentes de trabalho e o apoio psicológico recebido pelos enfermeiros e investigar a relação entre os dois. Método: Este foi um estudo transversal nacional de enfermeiras que trabalham em 1858 hospitais na China. Os dados foram coletados por meio de um questionário online estruturado e autoaplicável entre 2016 e 2017. Resultados: Quase metade dos entrevistados experimentou comportamento agressivo por parte dos pacientes ou de seus acompanhantes; 13,4% dos entrevistados experimentaram comportamento agressivo em mais de três ocasiões. 78,96% dos entrevistados sofreram ferimentos com agulhas e 51,22% sofreram traumas psicológicos. 20,5% dos entrevistados acreditam que os hospitais não dão atenção à segurança do trabalho. 86,1% dos entrevistados expressaram a necessidade de pouco ou moderado apoio psicológico. Enfermeiros que vivenciaram comportamento agressivo expressaram maior necessidade de apoio psicológico. Os enfermeiros que trabalham em hospitais que abordam de forma adequada as questões de segurança do trabalho expressam a menor necessidade de apoio psicológico. Conclusão: Encontramos alta prevalência de estresse psicológico e lesões ocupacionais entre os enfermeiros. Os gerentes de enfermagem precisam abordar essa questão e implementar intervenções para prevenir e reduzir lesões. RESUMEN Objetivo: Evaluar las lesiones ocupacionales y el apoyo psicológico que reciben las enfermeras e investigar la relación entre ambos. Método: Este fue un estudio transversal a nivel nacional de enfermeras que trabajaban en 1858 hospitales en China. Los datos se recopilaron mediante un cuestionario autoadministrado estructurado en línea entre 2016 y 2017. Resultados: Casi la mitad de los encuestados había experimentado un comportamiento agresivo por parte de los pacientes o sus asistentes; El 13,4% de los encuestados había experimentado un comportamiento agresivo en más de tres ocasiones. El 78,96% de los encuestados había experimentado lesiones por pinchazos de aguja y el 51,22% había experimentado un trauma psicológico. El 20,5% de los encuestados cree que los hospitales no prestan atención a la seguridad laboral. El 86,1% de los encuestados expresó la necesidad de un apoyo psicológico escaso o moderado. Las enfermeras que habían experimentado un comportamiento agresivo expresaron una mayor necesidad de apoyo psicológico. Las enfermeras que trabajan en hospitales que abordaron adecuadamente los problemas de seguridad ocupacional expresaron la menor necesidad de apoyo psicológico. Conclusión: Encontramos una alta prevalencia de estrés psicológico y lesiones ocupacionales entre enfermeras. Los gerentes de enfermería deben abordar este problema e implementar intervenciones para prevenir y reducir las lesiones.

L-alanine is extensively used in chemical, food, and medicine industries. Industrial production of L-alanine has been mainly based on the enzymatic process using petroleum-based L-aspartic acid as the substrate. L-alanine production from renewable biomass using microbial fermentation process is an alternative route. Many microorganisms can naturally produce L-alanine using aminotransferase or L-alanine dehydrogenase. However, production of L-alanine using the native strains has been limited due to their low yields and productivities. In this review, metabolic engineering of microorganisms for L-alanine production was summarized. Among them, the Escherichia coli strains developed by Dr. Lonnie Ingram's group which can produce L-alanine with anaerobic fermentation process had several advantages, especially having high L-alanine yield, and it was the first one that realized commercialization. L-alanine is also the first amino acid that could be industrially produced by anaerobic fermentation.

Background Bladder cancer (BC), a common cancer of the urinary system, has a low mortality but an extremely high recurrence rate. Patients who have undergone initial surgical treatment often undergo frequent prognostic examinations with a substantial burden of discomfort and costs. Urine samples can reflect early disease processes in the urinary system and may be an excellent source of biomarkers. Methods In the present study, we used the liquid chromatography with tandem mass spectrometry (LC-MS/MS) to perform proteomic analysis of pre- and postoperative urine samples from patients with stage III BC to identify biomarkers of cancer prognosis. Candidate biomarkers from proteomic analysis were simultaneously validated using western blotting in an independent cohort and immunohistochemical (IHC) staining, combined with gene expression data of BC samples in The Cancer Genome Atlas (TCGA). Results The comparison of pre- and postoperative urine samples from the same patients led to the discovery of several significantly differentially expressed proteins, whose functions could be closely related to the occurrence and development of BC. We confirmed a representative group of candidate biomarker molecules, such as cadherin-related family member 2 (CDHR2), heat shock protein beta-1 (HSP27), and heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1). Conclusions The candidate biomarker molecules can distinguish between pre- and postoperative urine samples, and alterations in their expression levels are significantly associated with recurrence rates in patients with BC. Therefore, these molecules may become useful biomarkers for the monitoring and prognosis of BC.

Background: Antenatal depression (AD) is a major public health issue worldwide and lacks objective laboratory-based tests to support its diagnosis. Recently, small metabolic molecules have been found to play a vital role in interpreting the pathogenesis of AD. Thus, non-target metabolomics was conducted in serum.Methods: Liquid chromatography—tandem mass spectrometry—based metabolomics platforms were used to conduct serum metabolic profiling of AD and non-antenatal depression (NAD). Orthogonal partial least squares discriminant analysis, the non-parametric Mann–Whitney U test, and Benjamini–Hochberg correction were used to identify the differential metabolites between AD and NAD groups; Spearman's correlation between the key differential metabolites and Edinburgh Postnatal Depression Scale (EPDS) and the stepwise logistic regression analysis was used to identify potential biomarkers.Results: In total, 79 significant differential metabolites between AD and NAD were identified. These metabolites mainly influence amino acid metabolism and glycerophospholipid metabolism. Then, PC (16:0/16:0) and betaine were significantly positively correlated with EPDS. The simplified biomarker panel consisting of these three metabolites [betaine, PC (16:0/16:0) and succinic acid] has excellent diagnostic performance (95% confidence interval = 0.911–1.000, specificity = 95%, sensitivity = 85%) in discriminating AD and NAD.Conclusion: The results suggested that betaine, PC (16:0/16:0), and succinic acid were potential biomarker panels, which significantly correlated with depression; and it could make for developing an objective method in future to diagnose AD.

D-glycerate is an attractive chemical for a wide variety of pharmaceutical, cosmetic, biodegradable polymers, and other applications. Now several studies have been reported about the synthesis of glycerate by different biotechnological and chemical routes from glycerol or other feedstock. Here, we present the construction of an Escherichia coli engineered strain to produce optically pure D-glycerate by oxidizing glycerol with an evolved variant of alditol oxidase (AldO) from Streptomyces coelicolor. This is achieved by starting from a previously reported variant mAldO and employing three rounds of directed evolution, as well as the combination of growth-coupled high throughput selection with colorimetric screening. The variant eAldO3-24 displays a higher substrate affinity toward glycerol with 5.23-fold than the wild-type AldO, and a 1.85-fold increase of catalytic efficiency (kcat/KM). Then we introduced an isopropyl-β-D-thiogalactopyranoside (IPTG)-inducible T7 expression system in E. coli to overexpress the variant eAldO3-24, and deleted glucosylglycerate phosphorylase encoding gene ycjM to block the consumption of D-glycerate. Finally, the resulting strain TZ-170 produced 30.1 g/l D-glycerate at 70 h with a yield of 0.376 mol/mol in 5-l fed-batch fermentation.

Wnt signaling is essential for the maintenance of adult stem cells and its aberrant activation is a stimulator of carcinogenesis. The transmembrane protein, Wntless, is an essential Wnt signaling component through regulating the secretion of Wnt ligands. Here, we generated a mouse model with specific Wntless knockout in intestinal epithelium to study its function in the intestinal epithelium. Wntless knockout exhibits no obvious defects in mice but significantly disrupted proliferation and differentiation of small intestinal organoids. We also discovered that these deficiencies could be partially rescued by Wnt3a supplement but not Wnt9b. To further investigate the role of Wntless in tumorigenesis, APC-deficient spontaneous intestinal tumors and chemical induced colorectal cancer mouse models were employed. To our surprise, intestinal epithelium-specific knockout of Wntless did not cause significant differences in tumor number and size. In summary, our data demonstrated that epithelial Wntless was required for the growth and differentiation of small intestinal organoids but not in live animals, suggesting the other tissues, such as mesenchymal tissue, play critical role for Wnt secretion in both intestinal homeostasis as well as tumorigenesis.

The 14α-hydroxysteroids have specific anti-gonadotropic and carcinolytic biological activities and can be produced by microbial biotransformation. The steroid 11β-/14α-hydroxylase P-450lun from Cochliobolus lunatus is the only fungal cytochrome P450 enzyme identified to date with steroid C14 hydroxylation ability. Previous work has mainly revealed the 11β-hydroxylation activity of the P-450lun towards cortexolone (RSS) substrate; however, the potential steroid 14α-hydroxylation activity of this enzyme, especially for androstenedione (AD) substrate, has not yet conducted in-depth testing. In this work, we further tested the steroid 14α-hydroxylation activity of the P-450lun towards RSS and AD in the Saccharomyces cerevisiae system. We demonstrated that P-450lun functions as the specific 14α-hydroxylase towards the AD substrate (regiospecificity > 99%); however, it showed a poor C14-hydroxylation regiospecificity (around 40%) for the RSS substrate. In addition, through transcriptome analysis combined with gene functional characterizations, we also identified and cloned the gene for the P-450lun-associated redox partner CPRlun. Finally, through codon optimization, knockout of genes for the side reactions related enzymes GCY1 and YPR1, and increasing copies of the P-450lun and CPRlun, we developed a recombinant S. cerevisiae biocatalyst based on the C. lunatus steroid 14α-hydroxylation system to produce 14α-hydroxysteroids. Initial production of 14α-OH-AD (150 mg/L day productivity, 99% regioisomeric purity, and 60% w/w yield) and 14α-OH-RSS (64 mg/L day productivity, 40% regioisomeric purity, and 26% w/w yield) were separately achieved in shake flasks; these results represent the highest level of 14α-hydroxysteroid production in the current yeast system.

In this study, the FAD synthesis pathway was manipulated to increase its cellular concentration and thereby improve the electroactivity of E. coli. In a microbial electrosynthesis (MES) system with neutral red as electron carrier and fumarate as the sole electron acceptor, the engineered strains derived from three E. coli lines displayed increased electric current in the reaction system, indicating improved electroactivity. Furthermore, the production of succinate from fumarate increased by around 60% compared with that of the parent strains, confirming the improvement of E. coli electroactivity by manipulating the FAD synthesis pathway. An MES reaction was performed with engineered E. coli 8739, and an altered metabolic profile with more reductive fermentation products was obtained. When the electroactive succinate-producing strain E. coli T110 was used in the MES, a yield of 0.97 ± 0.02 mol/mol glucose was achieved, which corresponds to an approximately 1.4-fold increase compared with the fermentation with no electricity supply or non-electroactive T110. In addition, a carbon concentration mechanism (CCM) was employed to further improve succinate production and yield in the MES, which produced a succinate yield of 1.16 mol/mol glucose, a 1.7-fold increase compared with that of the parent strain T110, indicating that the electroactive E. coli could be used in MES to produce specific fermentation products with improved yield.

Multiple molecular events are involved in non-alcoholic steatohepatitis (NASH). There is no consensus on the role of inducible nitric oxide synthase (iNOS) in the progression of NASH. The present study therefore investigated the role of iNOS in NASH pathogenesis using bone marrow-transplanted iNOS chimeric mice under high-fat diet (HFD) conditions. The chimeric mice were fed a HFD for 16 wk, and primary hepatocytes were stimulated with oleic acid (OA). The molecular mechanisms underlying the role of iNOS in NASH were investigated. Marked hepatic steatosis and injury observed in the HFD mice and OA-stimulated hepatocytes were reduced by hepatocyte-derived iNOS. Mechanistically, iNOS upregulated heme oxygenase 1 (HO-1) by augmenting nuclear factor erythroid 2-related factor 2 (Nrf-2) binding to the HO-1 gene promoter. In conclusion, hepatocyte-derived iNOS may play a protective role against the progression of NASH by upregulating HO-1 through Nrf-2. Upregulation of hepatocellular iNOS may represent a potentially new therapeutic paradigm to combat NASH.

Although the role of inducible nitric oxide synthase (iNOS) in hepatic ischemia/reperfusion (I/R) injury remains controversial and confusing, with both harmful and beneficial effects in animal studies, the mechanism of these incongruous actions remains unclear. In the current study, we generated bone marrow chimeric mice with hepatocyte-restricted expression of iNOS. Chimeric mice and primary hepatocytes were subjected to I/R or anoxia/reoxygenation stimulation, respectively. The role of iNOS in liver I/R injury and the underlying molecular mechanisms were investigated. Hepatocyte-derived iNOS resulted in hepatoprotection from I/R injury, as well as in vitro experiments. Mechanistically, iNOS upregulates Heat shock protein (HSP) 70 by augmenting heat shock factor 1 (HSF1) binding to the HSP70 gene promoter. Importantly, inhibition of HSP70 partly reversed the iNOS overexpression-mediated hepatoprotection. The present findings demonstrate that hepatocellular iNOS protects from hepatic I/R injury through the HSF1-dependent activation of the HSP70. The upregulation of hepatocellular iNOS may offer a promising strategy for protecting against I/R injury.