A positive feedback inhibition of isocitrate dehydrogenase 3ß on paired-box gene 6 promotes Alzheimer-like pathology.

Impaired brain glucose metabolism is an early indicator of Alzheimer's disease (AD); however, the fundamental mechanism is unknown. In this study, we found a substantial decline in isocitrate dehydrogenase 3ß (IDH3ß) levels, a critical tricarboxylic acid cycle enzyme, in AD patients and AD-transgenic mice's brains. Further investigations demonstrated that the knockdown of IDH3ß induced oxidation-phosphorylation uncoupling, leading to reduced energy metabolism and lactate accumulation. The resulting increased lactate, a source of lactyl, was found to promote histone lactylation, thereby enhancing the expression of paired-box gene 6 (PAX6). As an inhibitory transcription factor of IDH3ß, the elevated PAX6 in turn inhibited the expression of IDH3ß, leading to tau hyperphosphorylation, synapse impairment, and learning and memory deficits resembling those seen in AD. In AD-transgenic mice, upregulating IDH3ß and downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies. Collectively, our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3ß-lactate-PAX6-IDH3ß. Breaking this loop by upregulating IDH3ß or downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.

Effect of high-fat diet on the fatty acid profiles of brain in offspring mice exposed to maternal gestational diabetes mellitus.

OBJECTIVE: Fatty acids play a critical role in the proper functioning of the brain. This study investigated the effects of a high-fat (HF) diet on brain fatty acid profiles of offspring exposed to maternal gestational diabetes mellitus (GDM). METHODS: Insulin receptor antagonist (S961) and HF diet were used to establish the GDM animal model. Brain fatty acid profiles of the offspring mice were measured by gas chromatography at weaning and adulthood. Protein expressions of the fatty acid transport pathway Wnt3/ß-catenin and the target protein major facilitator superfamily domain-containing 2a (MFSD2a) were measured in the offspring brain by Western blot. RESULTS: Maternal GDM increased the body weight of male offspring (P < 0.05). In weaning offspring, factorial analysis showed that maternal GDM increased the monounsaturated fatty acid (MUFA) percentage of the weaning offspring's brain (P < 0.05). Maternal GDM decreased offspring brain arachidonic acid (AA), but HF diet increased brain linoleic acid (LA) (P < 0.05). Maternal GDM and HF diet reduced offspring brain docosahexaenoic acid (DHA), and the male offspring had higher DHA than the female offspring (P < 0.05). In adult offspring, factorial analysis showed that HF diet increased brain MUFA in offspring, and male offspring had higher brain MUFA than female offspring (P < 0.05). The HF diet increased brain LA in the offspring. Male offspring had higher level of AA than female offspring (P < 0.05). HF diet reduced DHA in the brains of female offspring. The brain protein expression of ß-catenin and MFSD2a in both weaning and adult female offspring was lower in the HF + GDM group than in the CON group (P < 0.05). CONCLUSIONS: Maternal GDM increased the susceptibility of male offspring to HF diet-induced obesity. HF diet-induced adverse brain fatty acid profiles in both male and female offspring exposed to GDM.

Survival Benefit of Primary Tumor Resection Combined With Chemotherapy in Patients With Unresectable Colorectal Mucinous Adenocarcinoma With Liver Metastasis.

OBJECTIVE: To evaluate the survival benefit of combining primary tumor resection (PTR) and chemotherapy in patients with unresectable colorectal mucinous adenocarcinoma with liver metastasis (UCR-MAC-LM). METHODS: We obtained data from the surveillance, epidemiology, and end results database for patients with UCR-MAC-LM from 2010 to 2017. Clinicopathological characteristics were analyzed using the χ2 test. Propensity score matching was performed to balance baseline characteristics. Kaplan-Meier analysis and log-rank tests were used to estimate and compare survival outcomes. Univariate and multivariate Cox regression analyses were conducted to identify the prognostic factors. RESULTS: A total of 10,178 patients with unresectable colorectal adenocarcinoma with liver metastasis were included, of whom 6.01% (n=612) had UCR-MAC-LM. The UCR-MAC-LM group had a higher proportion of female patients, a greater number of elderly patients, an increased incidence of right colon localization, larger tumor size, and higher T and N staging than the unresectable colorectal non-mucinous adenocarcinoma with liver metastasis group (P<0.05). Multivariate analysis identified several independent prognostic factors (P<0.05). Patients with unresectable colorectal adenocarcinoma with liver metastasis who underwent PTR+C had superior survival rates compared with those who received PTR/C alone or no treatment (cancer-specific survival, P<0.05; overall survival, P<0.05). Subgroup analysis revealed that 17 of 22 groups of patients with UCR-MAC-LM who received PTR+C had significantly prolonged long-term survival compared with those who received PTR/C alone. CONCLUSIONS: This surveillance, epidemiology, and end results-based study indicates that PTR+C may offer a survival advantage for a specific subgroup of patients with UCR-MAC-LM compared with PTR/C alone. Nonetheless, additional clinical trials are necessary to validate these findings.

Gestational Diabetes Mellitus Remodels the Fetal Brain Fatty Acid Profile Through Placenta-Brain Lipid Axis in C57BL/6J Mice.

BACKGROUND: Polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), are critical for proper fetal brain growth and development. Gestational diabetes mellitus (GDM) could affect maternal-fetal fatty acid metabolism. OBJECTIVE: This study aimed to explore the effect of GDM and high-fat (HF) diet on the DHA transport signaling pathway in the placenta-brain axis and fatty acid concentrations in the fetal brain. METHODS: Insulin receptor antagonist (S961) and HF diet were used to establish an animal model of GDM. Eighty female C57BL/6J mice were randomly divided into control (CON), GDM, HF, and HF+GDM groups. The fatty acid profiles of the maternal liver and fetal brain were analyzed by gas chromatography. In addition, we analyzed the protein amounts of maternal liver fatty acid desaturase (FADS1/3), elongase (ELOVL2/5) and the regulatory factor sterol-regulatory element-binding protein (SREBP)-1c, and the DHA transport signaling pathway (Wnt3/ß-catenin/MFSD2a) of the placenta and fetal brain using western blotting. RESULTS: GDM promoted the decrease of maternal liver ELOVL2, ELOVL5, and SREBP-1c. Accordingly, we observed a significant decrease in the amount of maternal liver arachidonic acid (AA), DHA, and total n-3 PUFA and n-6 PUFA induced by GDM. GDM also significantly decreased the amount of DHA and n-3 PUFA in the fetal brain. GDM downregulated the Wnt3/ß-catenin/MFSD2a signaling pathway, which transfers n-3 PUFA in the placenta and fetal brain. The HF diet increased n-6 PUFA amounts in the maternal liver, correspondingly increasing linoleic acid, gamma-linolenic acid, AA, and total n-6 PUFA in the fetal brain, but decreased DHA amount in the fetal brain. However, HF diet only tended to decrease placental ß-catenin and MFSD2a amounts (P = 0.074 and P = 0.098, respectively). CONCLUSIONS: Maternal GDM could affect the fatty acid profile of the fetal brain both by downregulating the Wnt3/ß-catenin/MFSD2a pathway of the placental-fetal barrier and by affecting maternal fatty acid metabolism.

Effects of dietary PUFA patterns and FADS genotype on breast milk PUFAs in Chinese lactating mothers.

BACKGROUND: Breastfeeding affects the growth and development of infants, and polyunsaturated fatty acids (PUFAs) play a crucial role in this process. To explore the factors influencing the PUFA concentration in breast milk, we conducted research on two aspects: dietary fatty acid patterns and single nucleotide polymorphisms (SNPs) in maternal fatty acid desaturase genes. METHODS: Three hundred seventy Chinese Han lactating mothers were recruited. A dietary semi-quantitative food frequency questionnaire (FFQ) was used to investigate the dietary intake of lactating mothers from 22 to 25 days postpartum for 1 year. Meanwhile, breast milk samples were collected from the participants and tested for the concentrations of 8 PUFAs and 10 SNP genotypes. We sought to determine the effect of dietary PUFA patterns and SNPs on breast milk PUFAs. We used SPSS 24.0 statistical software for data analysis. Statistical tests were all bilateral tests, with P < 0.05 as statistically significant. RESULTS: Under the same dietary background, PUFA contents in breast milk expressed by most major allele homozygote mothers tended to be higher than that expressed by their counterparts who carried minor allele genes. Moreover, under the same gene background, PUFA contents in breast milk expressed by the mother's intake of essential PUFA pattern tended to be higher than that expressed by their counterparts who took the other two kinds of dietary. CONCLUSIONS: Our study suggests that different genotypes and dietary PUFA patterns affect PUFA levels in breast milk. We recommend that lactating mothers consume enough essential fatty acids to ensure that their infants ingest sufficient PUFAs.

Danggui Buxue decoction ameliorates mitochondrial biogenesis and cognitive deficits through upregulating histone H4 lysine 12 acetylation in APP/PS1 mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement 'blood' and 'qi' (vital energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear. AIM OF THE STUDY: This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD). MATERIALS AND METHODS: The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot, immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification. RESULTS: In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aß accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1. Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters. CONCLUSIONS: These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment.

Polymeric Nanohybrids Engineered by Chitosan Nanoparticles and Antimicrobial Peptides as Novel Antimicrobials in Food Biopreservatives: Risk Assessment and Anti-Foodborne Pathogen Escherichia coli O157:H7 Infection by Immune Regulation.

Polymeric nanomaterials (APs) are gaining attention as promising clinical antimicrobials with rapidly increasing antibiotic resistance. Infections by zoonotic enterohemorrhagic Escherichia coli are a severe global threat to public health. Chitosan nanoparticles-microcin J25 (CNM), a class of APs engineered by bioactive peptides and chitosan nanoparticles, can be used as a novel antimicrobial agent against bacterial infections. However, the risk assessment of CNM on animal health or its potential immune modulation to treat serotype E. coli O157:H7 infection impacts in vivo are not well understood. Herein, our findings in mouse models uncovered that oral administration of low levels of CNM significantly increased the body weight and made beneficial effects on the lifespan or clinical signs, accompanied by a significant improvement in gut health, including enhancing the intestinal barrier, immune modulation, and changes in gut microbiota compositions or metabolites. However, high concentrations of CNM induced serious adverse effects, negatively improving intestinal health targets. Anti-infective results proved that oral 0.1% CNM enhances host defense against E. coli O157:H7 infection by improving immune functions and modulating the Th1/Th2 balance. In summary, these findings uncover an instrumental link between the dosage and toxicity risk, suggesting that APs need to be comprehensively assessed for risk before application as safe and reliable food preservatives or therapeutic agents. In addition, CNM as a promising AP may markedly enhance host immunity and therapeutic effects by oral administration.

Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling.

BACKGROUND: Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer's disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy. METHODS: The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Student's two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H+-ATPase (v-ATPase) activity, respectively, which were analysed by One-way ANOVA with post hoc tests. The Western blotting, co-immunoprecipitation and immunofluorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations, as analysed by Student's two-tailed t-test or One-way ANOVA with post hoc tests. The autophagosome formation was detected by immunofluorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC). RESULTS: We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine, P = 0.0038; Glutamic acid, P = 0.0348; Alanine, P = 0.0037; Glycine, P = 0.0104), with concordant upregulation of mTORC1 activity [phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1), P < 0.0001; phosphorylated 70 kDa ribosomal protein S6 kinase 1 (p-p70S6K1), P = 0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1), P = 0.0015] and inhibition of autophagosome formation [microtubule-associated protein light chain 3 II (LC3 II), P = 0.0073; LC3 puncta, P < 0.0001]. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment. CONCLUSIONS: Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treatment and that of related tauopathies.

Association of Prepregnancy Obesity and Remodeled Maternal-Fetal Plasma Fatty Acid Profiles.

Background: Fatty acids, especially polyunsaturated fatty acid (PUFA), are found abundantly in the brain and are fundamental for a fetus's growth. The fatty acid profiles of mothers and fetuses may be affected by maternal prepregnancy body mass index (pre-BMI), thus affecting fetal growth and development. Methods: A total of 103 mother-fetus pairs were divided into overweight/obese (OW, n = 26), normal weight (NW, n = 60), and underweight (UW, n = 17) groups according to pre-BMI. Fatty acid profiles in maternal and umbilical cord plasma were analyzed by gas chromatography. Results: The infant birth BMI z-score of the OW group was higher than that of the NW and UW groups (p < 0.05). The OW mothers had significantly higher plasma n-6 PUFA and n-6/n-3, but lower docosahexaenoic acid (DHA) and n-3 PUFA (p < 0.05). In cord plasma, the proportions of DHA and n-3 PUFA were lower in the OW group (p < 0.05), whereas the n-6/n-3 ratio was higher in the OW group (p < 0.05). The pre-BMI was negatively correlated with cord plasma DHA in all subjects (r = -0.303, p = 0.002), and the same negative correlation can be observed in the OW group (r = -0.561, p = 0.004), but not in the NW and UW groups (p > 0.05). The pre-BMI was positively correlated with cord plasma n-6/n-3 in all subjects (r = 0.325, p = 0.001), and the same positive correlation can be found in the OW group (r = 0.558, p = 0.004), but not in NW and UW groups (p > 0.05). Conclusions: Maternal pre-BMI was associated with the maternal-fetal plasma fatty acid profiles, whereas the adverse fatty acid profiles are more noticeable in the prepregnancy OW mothers.

Effects of Ru doping on the structural stability and electrochemical properties of Li2MoO3 cathode materials for Li-ion batteries.

The Li2MoO3 (LMO) material is one promising cathode material for lithium-ion batteries due to its high specific capacity and absence of oxygen release. However, its surface instability in air and poor conductivity have limited its application. To solve these problems, the Ru element has been successfully introduced into the LMO lattice with the aid of the molten salt method. XRD and TEM characterization showed that the introduction of Ru does not change the crystal structure but expands the crystal plane spacing of the {001} facets, which is further evidenced by density functional theory (DFT) calculations. XPS and EDS tests indicated that the introduction of Ru inhibits the oxidation of Mo species and leads to a more uniform distribution of the material. In addition, DFT calculations revealed that covalent interactions are formed between Mo4d/Ru4d and O2p orbitals, leading to a significant reduction of the band gap. Therefore, Ru-doped samples exhibit good electrochemical performances. The initial discharge capacity of an LMRO-2 sample reaches 299.1 mA h g-1 at a 1C rate, and the capacity remains at 125.2 mA h g-1 after 100 cycles. In comparison, the initial discharge capacity of pure phase sample LMO is only 250.5 mA h g-1 under the same conditions, and the capacity remains only at 76.5 mA h g-1 after 100 cycles. The present results confirmed that Ru doping is an effective strategy to improve the performance of the LMO cathode material.

Ectopic intrauterine device in the bladder causing cystolithiasis: A case report.

BACKGROUND: An intrauterine device (IUD) is a commonly used contraceptive among women in China. It is widely used because it is safe, effective, simple, economic, and reversible. Among the possible complications, an ectopic IUD in the bladder is rare. It occurs insidiously, has a long course, is associated with a high risk for injury, and is difficult to treat. CASE SUMMARY: A 44-year-old woman was admitted for repeated episodes of urinary frequency, urgency, and dysuria over three months. Laboratory tests revealed significantly elevated urine leukocytes and bacteria. Urine culture suggested colonization with Enterococcus faecalis. Abdominal computed tomography images suggested an abnormally positioned IUD that was protruding into the bladder. Cystoscopy revealed a metallic foreign body with multiple stones on its surface in the left posterior bladder wall. The foreign body measured approximately 1 cm. Hysteroscopy revealed the arm of a V-type metal IUD embedded in the middle and upper sections of the anterior wall of the cervical canal. The majority of the IUD was located in the uterine cavity. Cystoscopy was performed, and a holmium laser was utilized to break the stones attached to the portion of the IUD in the bladder. The IUD was then removed through hysteroscopy. CONCLUSION: Ectopic IUDs in the bladder can be diagnosed with thorough imaging and safely removed through cystoscopy or hysteroscopy.

Effect of a carbohydrate-rich beverage on rate of cesarean delivery in primigravidae with epidural labor analgesia: a multicenter randomized trial.

BACKGROUND: Labor represents a period of significant physical activity. Inefficient energy supply may delay labor process and even lead to cesarean delivery. Herein we investigated whether ingestion of a carbohydrate-rich beverage could reduce cesarean delivery in laboring women with epidural analgesia. METHODS: This multicenter randomized trial was conducted in obstetrician-led maternity units of nine tertiary hospitals in China. Primigravidae with single term cephalic pregnancy who were preparing for vaginal birth under epidural analgesia were randomized to intake a carbohydrate-rich beverage or commercially available low-carbohydrate beverages during labor. The primary outcome was the rate of cesarean delivery. Secondary outcomes included maternal feeling of hunger, assessed with an 11-point scale where 0 indicated no hunger and 10 the most severe hunger, and maternal and neonatal blood glucose after childbirth. RESULTS: Between 17 January 2018 and 20 July 2018, 2008 women were enrolled and randomized, 1953 were included in the intention-to-treat analysis. The rate of cesarean delivery did not differ between the two groups (11.3% [111/982] with carbohydrate-rich beverage vs. 10.9% [106/971] with low-carbohydrate beverages; relative risk 1.04, 95% CI 0.81 to 1.33; p = 0.79). Women in the carbohydrate-rich beverage group had lower subjective hunger score (median 3 [interquartile range 2 to 5] vs. 4 [2 to 6]; median difference - 1; 95% CI - 1 to 0; p < 0.01); their neonates had less hypoglycemia (1.0% [10/968] vs. 2.3% [22/956]; relative risk 0.45; 95% CI 0.21 to 0.94; p = 0.03) when compared with those in the low-carbohydrate beverage group. They also had higher rates of maternal hyperglycemia (6.9% [67/965] vs. 1.9% [18/953]; p < 0.01) and neonatal hyperglycemia (9.2% [89/968] vs. 5.8% [55/956]; p < 0.01), but none required special treatment. CONCLUSIONS: For laboring primigravidae with epidural analgesia, ingestion of a carbohydrate-rich beverage compared with low-carbohydrate beverages did not reduce cesarean delivery, but relieved maternal hunger and reduced neonatal hypoglycemia at the expense of increased hyperglycemia of both mothers and neonates. Optimal rate of carbohydrate supplementation remains to be determined. TRIAL REGISTRATION: www.chictr.org.cn ; identifier: ChiCTR-IOR-17011994 ; registered on 14 July 2017.

Effects of adatom species on the structure, stability, and work function of adatom-α-borophene nanocomposites.

Work function-tunable borophene-based electrode materials are of significant importance because they promote efficient carrier extraction/injection, thereby enabling electronic devices to achieve maximum energy conversion efficiency. Accordingly, determining the work function of adatom-borophene nanocomposites within a series wherein the adatom is systematically changed will facilitate the design of such materials. In this study, we theoretically determined that the M-B bond length, binding energy, electron transfer between adatoms and BBP, and work function (ϕ) are linearly dependent on the ionization potential (IP) and electronegativity for thermodynamically and kinetically stable adatom-α-borophene (M/BBP) systems involving a series of alkali (earth) metal/BBP (M = Li-Cs; Be-Ba) and halogen/BBP (M = F-I), respectively. However, the binding energies of Li/BBP and Be/BBP deviate from these dependencies owing to their super small adatoms and the resulting significantly enhanced effective M-B bonding areas. By interpreting the electron transfer picture among the different parts of M/BBP, we confirmed that metallic M/BBP possesses ionic sp-p and dsp-p M-B bonds in alkali (earth) metal/BBP but covalent-featured ionic p-p interactions in halogen/BBP. In particular, the direct proportionality between IP and ϕ for alkali (earth) metal/BBP originates from the synergistic effect of charge rearrangement and the increased induced dipole moment; however, the inverse proportionality between electronegativity and ϕ for halogen/BBP arises from the adsorption induced charge redistribution. Our results provide guidance for experimental efforts toward the realization of work function-tunable borophene-based electrodes as well as insight into the bonding rules between various adatoms and α-borophene.

Expression of TMED3 is independently associated with colorectal cancer prognosis.

Colorectal cancer (CRC) is the third most common cancer type and one of the deadliest cancers worldwide. Transmembrane p24 trafficking protein 3 (TMED3) has previously been indicated to suppress CRC metastasis, but its clinical significance has remained undetermined. In the present study, the expression of TMED3 was indicated to be elevated at the mRNA and protein levels in CRC tumor samples relative to that in para-cancerous healthy tissue samples (P<0.05). Furthermore, Kaplan-Meier survival analysis revealed a significant negative association between elevated TMED3 protein levels and overall survival of patients with CRC (P<0.001, log-rank test). Multivariate Cox regression analysis additionally determined that elevated TMED3 expression in primary CRC tumors was an independent predictor of poor prognosis (P<0.05). These results revealed that elevated TMED3 expression in CRC was associated with patient survival outcomes, suggesting that TMED3 may be a potential prognostic biomarker for this cancer type.

Imparting α-Borophene with High Work Function by Fluorine Adsorption: A First-Principles Investigation.

Increasing the work function of borophene over a large range is crucial for the development of borophene-based anode materials for highly efficient electronic devices. In this study, the effect of fluorine adsorption on the structures and stabilities, particularly on the work function, of α-borophene (BBP), was systematically investigated via first-principles density functional theory. The calculations indicated that BBP was well-stabilized by fluorine adsorption and the work functions of metallic fluorine-adsorbed BBPs (Fn-BBPs) sharply increased with increasing fluorine content. Moreover, the work function of F-BBP was close to that of the frequently used anode material Au and even, for other Fn-BBPs, higher than that of Pt. Furthermore, we have comprehensively discussed the factors, including substrate deformation, charge transfer, induced dipole moment, and Fermi and vacuum energy levels, affecting the improvement of work function. Particularly, we have demonstrated that the charge redistribution of the substrate induced by the bonding interaction between fluorine and the matrix predominantly contributes to the observed increase in the work function. Additionally, the effect of fluorine adsorption on the increase in the work function of BBP was significantly stronger than that of silicene or graphene. Our results concretely support the fact that Fn-BBPs can be extremely attractive anode materials for electronic device applications.

[Clinical Features and Prognosis of Patients with Hematological Disease Complicated with Mucor Infection].

OBJECTIVE: To investigate the clinical features, treatment and prognosis of patients with hematological diseases complicated with mucor infection. METHODS: The risk factors, clinical features, treatment regimen and prognosis of 18 hematological disease patients with mucor infection diagnosed by histopathology in our center from April 2014 to June 2020 were retrospectively analyzed. RESULTS: Thirteen males and five females, with an average age of 30 (13－54) years old, were diagnosed as mucor infection by histopathological examination at the site of infection, including 16 cases of mucor infection alone and 2 cases of mucor + aspergillus mixed infection. There were 12 cases with malignant hematological disease and 6 cases with severe aplastic anemia, all of whom with long-term agranulocytosis, and their clinical manifestations and imaging findings were not specific. The common sites of infection were sinuses and lungs, and some patients showed multiple systemic manifestations. The remission status of hematological diseases and recovery of immune function showed an impact on the prognosis. All the patients were treated with amphotericin B liposome combined with posaconazole, and 15 patients were treated with surgery combined with antifungal drugs, 9 of whom were effective and 6 were ineffective, while intravenous administration in 3 cases was ineffective. CONCLUSION: It is difficult to diagnose hematological disease complicated with mucor infection. After early diagnosis, prognosis can be improved by amelioration of primary state and combination of drugs and surgery.

A positive feedback loop between Periostin and TGFß1 induces and maintains the stemness of hepatocellular carcinoma cells via AP-2α activation.

BACKGROUND: Liver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research showed that the POSTN gene is closely related to the malignant progression and poor prognosis of HCC. This study aimed to elucidate the role of POSTN in generating LCSCs and maintaining their stemness as well as the underlying mechanisms. METHODS: Human HCC tissues and matched adjacent normal tissues were obtained from 110 patients. Immunohistochemistry, western blotting (WB), and RT-PCR were performed to detect the expression of POSTN and stemness factors. The roles of transforming growth factor (TGF)-ß1 and AP-2α in the POSTN-induced stemness transformation of HCC cells were explored in vitro and in vivo using LCSCs obtained by CD133+ cell sorting. RESULTS: The high expression of POSTN was correlated with the expression of various stemness factors, particularly CD133, in our HCC patient cohort and in TCGA and ICGC datasets. Knockdown of POSTN expression decreased the abilities of HCC cell lines to form tumours in xenograft mouse models. Knockdown of POSTN expression also suppressed cell viability and clone formation, invasion, and sphere formation abilities in vitro. Knockdown of AP-2α attenuated the generation of CD133+ LCSCs and their malignant behaviours, indicating that AP-2α was a critical factor that mediated the POSTN-induced stemness transformation and maintenance of HCC cells. The role of AP-2α was verified by using a specific αvß3 antagonist, cilengitide, in vitro and in vivo. Activation of POSTN could release TGFß1 from the extracellular matrix and initiated POSTN/TGFß1 positive feedback signalling. Furthermore, we found that the combined use of cilengitide and lenvatinib suppressed the growth of HCC cells with high POSTN expression more effectively than the use of lenvatinib alone in the patient-derived xenograft (PDX) mouse model. CONCLUSIONS: The POSTN/TGFß1 positive feedback pathway regulates the expression of stemness factors and the malignant progression of HCC cells by regulating the transcriptional activation of AP-2α. This pathway may serve as a new target for targeted gene therapy in HCC.

Severe hematuria due to vesical varices in a patient with portal hypertension: A case report.

BACKGROUND: Hematuria is one of the most common clinical symptoms for urologists and is typically observed in urinary system tumors, prostate hyperplasia, and urinary stone disease. Hematuria due to vesical varices is very rare, and only a few cases have been reported since 1989. We report the first case of vesical varices due to portal hypertension with aberrant development and functioning of the genitourinary system along with the complete diagnosis and treatment process. CASE SUMMARY: This patient was a 53-year-old man with a history of aberrant development of the genitourinary system and hepatitis B-associated cirrhosis. He was admitted to the emergency department with severe hematuria and bladder clot tamponade. Many abnormally dilated blood vessels were found surrounding the bladder in the pelvis by color Doppler ultrasound, contrast-enhanced computed tomography, and three-dimensional visualization technology. It was difficult to perform transurethral cystoscopy and hemostasis in this patient, so we performed open surgical bladder exploration for hemostasis and surgical devascularization around the bladder. CONCLUSION: Urologists should improve the understanding of the pathophysiology, clinical manifestations, diagnosis, and treatment of vesical varices. This case may be presented as a reference for the diagnosis and management of severe hematuria due to vesical varices.

Design and Synthesis of Novel c-di-GMP G-Quadruplex Inducers as Bacterial Biofilm Inhibitors.

The formation of biofilms by clinical pathogens typically leads to chronic and recurring antibiotic-resistant infections. High cellular levels of cyclic diguanylate (c-di-GMP), a ubiquitous secondary messenger of bacteria, have been proven to be associated with a sessile biofilm lifestyle of pathogens. A promising antibiofilm strategy involving the induction of c-di-GMP to form dysfunctional G-quadruplexes, thereby blocking the c-di-GMP-mediated biofilm regulatory pathway, was proposed in this study. In this new strategy, a series of novel c-di-GMP G-quadruplex inducers were designed and synthesized for development of therapeutic biofilm inhibitors. Compound 5h exhibited favorable c-di-GMP G-quadruplex-inducing activity and 62.18 ± 6.76% biofilm inhibitory activity at 1.25 µM without any DNA intercalation effect. Moreover, the favorable performance of 5h in interfering with c-di-GMP-related biological functions, including bacterial motility and bacterial extracellular polysaccharide secretion, combined with the reporter strain and transcriptome analysis results confirmed the c-di-GMP signaling-related action mechanism of 5h.