Mendelian randomization to evaluate the effect of folic acid supplement on the risk of Alzheimer disease.

We conducted a study to evaluate the impact of folic acid supplementation on the risk of Alzheimer disease (AD). A Mendelian randomization (MR) analysis model assessed the causal effects of folic acid supplementation on AD, utilizing data from recent genome-wide association studies. Effect estimates were scrutinized using various methods: inverse-variance weighted (IVW), simple mode, weighted mode, simple median, weighted median, penalized weighted median, and the MR-Egger method. The sensitivity analysis assessed heterogeneity and pleiotropy of individual single nucleotide polymorphisms (SNPs) using the IVW method with Cochran Q statistics and MR Egger intercept, respectively. Additionally, a leave-one-out sensitivity analysis determined potential SNP-driven associations. Both fixed-effect and random-effect IVW models in the MR analysis revealed a reduced risk of AD associated with folic acid supplementation (odds ratio, 0.930; 95% CI, 0.903-0.958, P < .001; odds ratio, 0.930; 95% CI, 0.910-0.950, P < .001) based on 7 SNPs as instrumental variables. The reverse MR analysis indicated no causal association between AD and folic acid supplementation. This study, utilizing genetic data, suggests that folic acid supplementation may potentially reduce the risk of AD and provides novel insights into its etiology and preventive measures.

Bio-Inspired 4D Printing of Dynamic Spider Silks.

Spider silks exhibit excellent mechanical properties and have promising application prospects in engineering fields. Because natural spider silk fibers cannot be manufactured on a large scale, researchers have attempted to fabricate bio-inspired spider silks. However, the fabrication of bio-inspired spider silks with dynamically tunable mechanical properties and stimulation-response characteristics remains a challenge. Herein, the 4D printing of shape memory polyurethane is employed to produce dynamic bio-inspired spider silks. The bio-inspired spider silks have two types of energy-absorbing units that can be adjusted, one by means of 4D printing with predefined nodes, and the other through different stimulation methods to make the bio-inspired spider silks contract and undergo spiral deformation. The shape morphing behaviors of bio-inspired spider silks are programmed via pre-stress assemblies enabled by 4D printing. The energy-absorbing units of bio-inspired spider silks can be dynamically adjusted owing to stress release generated with the stimuli of temperature or humidity. Therefore, the mechanical properties of bio-inspired spider silks can be controlled to change dynamically. This can further help in developing applications of bio-inspired spider silks in engineering fields with dynamic changes of environment.

TRIM24 promotes colorectal cancer cell progression via the Wnt/ß-catenin signaling pathway activation.

Overexpression of TRIM24 is observed in several human cancers and is correlated with an increase in the progression and metastasis of tumors. In this study, we investigated the changes in activity and biochemical events that occur after overexpression of TRIM24 in a colorectal cancer (CRC) mouse model. We observed upregulated TRIM24 expression in CRC tissues compared to that in nonneoplastic adjacent tissues. Enhanced expression of TRIM24 was significantly associated with the status of lymph nodes and poor recurrence-free survival of patients with CRC. The role of TRIM24 in CRC tumor growth was investigated using an orthotopic model of MC38 mouse colon cancer cells overexpressing TRIM24, and CRC tumor growth was found to increase dramatically by TRIM24 overexpression. Moreover, angiogenesis was stimulated by TRIM24 overexpression via the upregulation of vascular endothelial growth factor (VEGF) expression. Overexpression of TRIM24 in MC38 cells led to an increase in the protein levels of ALDH1 and other stem cell markers. In addition, we observed that Wnt/ß-catenin signaling is required for the function of TRIM24 in CRC cells. Tumor-associated macrophages (TAMs) were found to be recruited by tumor cells overexpressing TRIM24 via the increased expression of CCL2/5, CSF-1, and VEGF, further enhancing CRC tumor growth. In conclusion, overexpression of TRIM24 facilitates the growth of CRC and the remodeling of the tumor stroma via angiogenesis stimulation and TAM recruitment. The Wnt/ß-catenin pathway is a possible crucial link in the TRIM24-associated progression of tumors, which may provide opportunities for pharmacological intervention.

Association of Headache Disorders and the Risk of Dementia: Meta-Analysis of Cohort Studies.

OBJECTIVES: The purpose of this meta-analysis is to assess whether there is an association between headache disorders and all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). METHODS: PubMed, Cochrane Library, Embase, and Web of Science were searched for cohort studies published from database inception to October 8, 2021, using medical subject headings (MeSH) and keywords. All statistical analyses were performed using Stata statistical software version 14.0. If P > 0.1 and I 2 ≤ 50%, a fixed-effects model was adopted. If I 2 > 50% (which indicated great heterogeneity), a random-effects model was adopted. The funnel plot and Egger's test were used to evaluate publication bias. RESULTS: This meta-analysis included 12 cohort studies covering 465,358 individuals, which were published between 2001 and 2020. The pooling analysis shows that a history of any headache disorder is associated with an increased risk of all-cause dementia (OR = 1.35; 95% CI: 1.21-1.50; I 2 = 81.6%, P < 0.001). The history of any headache was associated with an increased risk of AD (OR = 1.49; 95% CI: 1.08-2.05; I 2 = 70.0%, P = 0.003) and VaD (OR = 1.72; 95% CI: 1.32-2.25; I 2 = 0%, P < 0.001). In the subgroup analysis, females with a history of headache have a slightly higher risk of dementia than males (OR = 1.32; 95% CI: 1.16-1.51; I 2 = 88.3%, P < 0.001) and the risk of dementia in the retrospective cohort was slightly higher than in the prospective cohort (OR = 1.38; 95% CI: 1.22-1.56; I 2 = 83.4%, P < 0.001). CONCLUSIONS: Our meta-analysis shows that any headache disorder increases the risk of all-cause dementia, AD, or VaD. These findings provide evidence that headache should be recognized as an independent risk factor for dementia, AD, or VaD.

Novel dTDP-l-Rhamnose Synthetic Enzymes (RmlABCD) From Saccharothrix syringae CGMCC 4.1716 for One-Pot Four-Enzyme Synthesis of dTDP-l-Rhamnose.

Deoxythymidine diphospho-l-rhamnose (dTDP-l-rhamnose) is used by prokaryotic rhamnosyltransferases as the glycosyl donor for the synthesis of rhamnose-containing polysaccharides and compounds that have potential in pharmaceutical development, so its efficient synthesis has attracted much attention. In this study, we successfully cloned four putative dTDP-l-rhamnose synthesis genes Ss-rmlABCD from Saccharothrix syringae CGMCC 4.1716 and expressed them in Escherichia coli. The recombinant enzymes, Ss-RmlA (glucose-1-phosphate thymidylyltransferase), Ss-RmlB (dTDP-d-glucose 4,6-dehydratase), Ss-RmlC (dTDP-4-keto-6-deoxy-glucose 3,5-epimerase), and Ss-RmlD (dTDP-4-keto-rhamnose reductase), were confirmed to catalyze the sequential formation of dTDP-l-rhamnose from deoxythymidine triphosphate (dTTP) and glucose-1-phosphate (Glc-1-P). Ss-RmlA showed maximal enzyme activity at 37°C and pH 9.0 with 2.5mMMg2+, and the K m and k cat values for dTTP and Glc-1-P were 49.56µM and 5.39s-1, and 117.30µM and 3.46s-1, respectively. Ss-RmlA was promiscuous in the substrate choice and it could use three nucleoside triphosphates (dTTP, dUTP, and UTP) and three sugar-1-Ps (Glc-1-P, GlcNH2-1-P, and GlcN3-1-P) to form nine sugar nucleotides (dTDP-GlcNH2, dTDP-GlcN3, UDP-Glc, UDP-GlcNH2, UDP-GlcN3, dUDP-Glc, dUDP-GlcNH2, and dUDP-GlcN3). Ss-RmlB showed maximal enzyme activity at 50°C and pH 7.5 with 0.02mM NAD+, and the K m and k cat values for dTDP-glucose were 98.60µM and 11.2s-1, respectively. A one-pot four-enzyme reaction system was developed by simultaneously mixing all of the substrates, reagents, and four enzymes Ss-RmlABCD in one pot for the synthesis of dTDP-l-rhamnose and dUDP-l-rhamnose with the maximal yield of 65% and 46%, respectively, under the optimal conditions. dUDP-l-rhamnose was a novel nucleotide-activated rhamnose reported for the first time.

A Novel ß-Glucosidase From Chryseobacterium scophthalmum 1433 for Efficient Rubusoside Production From Stevioside.

As a natural sweetening and solubilizing agent, rubusoside has great potential in the application of healthy beverages and pharmaceuticals. However, the direct extraction and purification of rubusoside from raw materials is inefficient. In this work, a novel ß-glucosidase (CsBGL) was obtained from Chryseobacterium scophthalmum 1433 through screening of the environmental microorganisms. CsBGL markedly hydrolyzed sophorese (Glcß1-2Glc) and laminaribiose (Glcß1-3Glc), but for steviol glycosides, it only hydrolyzed the C-13/C-19-linked sophorese, instead of the C-13/C-19-linked Glcß1-2[Glcß1-3]Glc trisaccharide and Glcß1-monosaccharide. It efficiently hydrolyzed stevioside (240 g/L) to produce rubusoside (99% yield) at 47.5°C for 70 min. Even when using a crude steviol glycosides extract (500 g/L) containing ∼226 g/L stevioside as the substrate, CsBGL could also convert stevioside to rubusoside (99% yield) at 47.5°C for 2 h, in which the rubusoside concentration increased from the initial 42 g/L to the final 222 g/L. These results reveal that CsBGL would be a promising biocatalyst for the industry-scale production of rubusoside from stevioside or/and the crude steviol glycosides extract.

Copanlisib promotes growth inhibition and apoptosis by modulating the AKT/FoxO3a/PUMA axis in colorectal cancer.

Colorectal cancer (CRC) is the type of cancer with the third highest incidence and is associated with high mortality and low 5-year survival rates. We observed that copanlisib, an inhibitor of PI3K (pan-class I phosphoinositide 3-kinase) that preferentially inhibits PI3Kδ and PI3Kα, impedes the growth of CRC cells by inducing apoptosis via PUMA. There was a marked increase in the expression of PUMA independent of p53 after treatment with copanlisib. The response of CRC cells to copanlisib could be predicted by PUMA expression. Copanlisib was found to induce PUMA expression through FoxO3a by directly binding to the PUMA promoter after inhibiting AKT signaling. PUMA deficiency mitigated the apoptosis induced by copanlisib. Caspase activation and mitochondrial dysfunction led to copanlisib resistance, as observed through a clonogenic assay, whereas enhanced expression of PUMA increased the copanlisib-induced susceptibility to apoptosis. Moreover, the antitumor effects of copanlisib were suppressed by a deficiency of PUMA in a xenograft model, and caspase activation and reduced apoptosis were also observed in vivo. Copanlisib-mediated chemosensitization seemed to involve the concurrent induction of PUMA expression via mechanisms that were both dependent and independent of p53. These observations indicate that apoptosis mediated by PUMA is crucial for the anticancer effects of copanlisib and that manipulation of PUMA may aid in enhancing anticancer activities.

Designing Cr complexes for a neutral Fe-Cr redox flow battery.

We lay out the design principles of Cr complexes to address issues of slow kinetics and parasitic reactions in the Fe-Cr redox flow battery (ICRFB). We identify theoretically and experimentally dipicolinic acid as a promising ligand, and synthesize its derivative to improve the solubility of the Cr complex to 0.7 M. We couple it with ferrocyanide for a neutral ICRFB delivering 120 stable cycles.

Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT/GSK-3ß/NF-κB signaling pathway.

Cabozantinib is a multi-kinase inhibitor targeting MET, AXL, and VEGFR2, and has been approved for use in multiple malignancies. The means by which Cabozantinib acts to target colorectal cancer (CRC) cells remains poorly understood, and we sought to investigate how this drug disrupts cell growth in CRC cells and how it interacts to enhance the efficacy of other chemotherapeutic agents. In this study, we found that Cabozantinib activated a p65-dependent signaling pathway in response to both inhibition of AKT and activation of glycogen synthase kinase 3ß (GSK3ß), leading to upregulation of PUMA in CRC cells regardless of p53 activity. PUMA upregulation facilitates CRC apoptosis in response to Cabozantinib, which also acts synergistically with the chemotherapeutic agents Cetuximab and 5-FU to induce robust apoptosis in a PUMA-dependent manner. Eliminating PUMA expression ablated this apoptosis induced by Cabozantinib in xenograft mouse model. Our findings revealed that Cabozantinib acts to drive CRC cells apoptosis via a PUMA-dependent mechanism, thus identifying PUMA expression as a potential predictor of Cabozantinib efficacy and a potential novel therapeutic target.

BET inhibitor I-BET151 sensitizes GBM cells to temozolomide via PUMA induction.

A significant roadblock in treatment of GBM multiforme (GBM) is resistance to temozolomide (TMZ). In this study, we investigated whether I-BET151, a specific BET inhibitor, could sensitize GBM cells to TMZ. Our findings showed that the action of I-BET151 could augment the effect of TMZ on cancer cells U251 and U87 cells. In U251 cells, administration of I-BET151 increased the TMZ-induced apoptosis GBM cells. I-BET151 remarkably enhanced the activities of caspase-3. In addition, I-BET151 promoted TMZ-induced migration and invasion in GBM cells. Moreover, I-BET151 increased the amount of reactive oxygen species as well as superoxide anions with a decrease of activity of SOD and the anti-oxidative properties of GBM cells. I-BET151 also induced increased PUMA expression, which is required for the functions of I-BET151 and regulates the synergistic cytotoxic effects of i-BET151 and TMZ in GBM cells. I-BET151 with TMZ also showed synergistic cytotoxic effects in vivo. These point out to an approach to tackle GBM using TMZ along with BET inhibitors.

Increased Serum Soluble Urokinase Plasminogen Activator Receptor Predicts Short-Term Outcome in Patients with Hepatitis B-Related Acute-on-Chronic Liver Failure.

AIMS: Soluble urokinase plasminogen activator receptor (suPAR) reflects the immune activation in circumstances of inflammation and infection. It has been considered as a risk biomarker associated with poor outcome in various low-grade inflammation and infectious diseases. The study is aimed at investigating whether suPAR has a predictive value with short-term survival in patients with hepatitis B-related acute-on-chronic liver failure (HB-ACLF). METHODS: Serum suPAR expression was compared among patients with different states of chronic hepatitis B virus infection. Sixty HB-ACLF patients were recruited as the training cohort and followed up for 90 days. Serum suPAR level and the clinical relevance with short-term outcome were investigated. The temporal dynamics of suPAR were evaluated in 50 HB-ACLF patients with available serum sequentially at baseline, week 2 and week 4. Another 167 HB-ACLF patients were enrolled to validate the predictive value of suPAR with respect to the prognosis. RESULTS: Serum suPAR level was significantly increased in HB-ACLF patients compared to non-ACLF patients. In the training set of HB-ACLF, we observed higher suPAR level, INR, MELD score, and more complications in nonsurvivors than survivors. Longitudinal analysis revealed an increased trend of suPAR level in nonsurvivors during week 0 to week 4 and the modest decline in survivors. It showed that the synchronous suPAR level was higher in nonsurvivors at all indicated time points. Elevated suPAR level at baseline was identified as a strong predictor of a 90-day mortality of HB-ACLF patients. It was confirmed suPAR > 16.26 ng/ml had a positive predictive value of 72.22% and a negative predictive value of 77.88% for poor outcome in the validation cohort. CONCLUSIONS: Serum suPAR level increases significantly in HB-ACLF patients and associated with a 90-day mortality. It suggests that suPAR might be a potential biomarker to predict the prognosis of HB-ACLF patients.

Author Correction: BET inhibitor I-BET151 sensitizes GBM cells to temozolomide via PUMA induction.

All animal experiments were approved by the Animal Care and Use Committee (ACUC), Louisiana State University Health Science Center and not The People's Hospital of Liaoning Province as indicated in the original version of the Article. The PDF and HTML versions of the Article have been modified accordingly.

Value of Real-Time Shear Wave Elastography Versus Acoustic Radiation Force Impulse Imaging in the Diagnosis of Female Bladder Neck Obstruction.

OBJECTIVE: To investigate the application value of shear wave elastography (SWE) and acoustic radiation force impulse imaging (ARFI) in the diagnosis of female bladder neck obstruction (FBNO), we compared the advantages of these 2 methods to provide a more accurate reference for clinical work. METHODS: From April 2016 to February 2018, 27 patients who were diagnosed with FBNO by cystoscopy and/or urine dynamics testing were selected for the study, together with 24 healthy adults in a case-control study at Liaoning Province People's Hospital. We collected general information from 27 patients with FBNO, and using transperineal 2-dimensional ultrasound detection, shear wave elastography (SWE) and ARFI were used, respectively, to detect the Young's modulus and shear wave velocity (SWV) of the bladder necks. Cystoscopy results were considered to be the gold standard, and receiver operating characteristic (ROC) curves were drawn for ARFI, SWE, and the combined diagnosis of the two. The efficacy of the diagnosis was determined by comparing the areas under the ROC curves and calculating the sensitivity, specificity, and accuracy. RESULTS: The areas under the ROC curve for the Q-box mean and max value detected by SWE for FBNO patients were 88.4% and 89.9%, respectively, and the sensitivity, specificity, and accuracy were 81.5%, 79.2%, and 80.4%, respectively. The area under the ROC curve detected by ARFI for FBNO patients was 93.7%, and the sensitivity, specificity, and accuracy were 88.9%, 79.2%, and 84.3%, respectively. The sensitivity, specificity, and accuracy of the combined detection of ARFI and SWE were 92.5%, 87.5%, and 90.2%, respectively. The best diagnostic cutoff point of the SWV or the Q-box mean and max value of SWE in FBNO obtained with the ROC curve was SWV = 2.38 m/s (sensitivity, 71.4%; specificity, 82.5%), Q-box mean = 20.2 kPa, Q-box max = 39.8 kPa (sensitivity, 67.5%; specificity, 76.2%). The average shear wave velocity of ARFI, Q-box mean, and Q-box max value of SWE in the control group were 1.89 ± 0.35 m/s, 15.3 ± 3.6 kPa, and 29.2 ± 8.7 kPa, respectively. In the FBNO group, these values were 2.81 ± 0.63) m/s, 27.2 ± 8.6 kPa, and 51.2 ± 12.3 kPa, respectively. The differences were statistically significant (P < .05). CONCLUSION: The value of the ARFI in the diagnosis of FBNO is a little greater than that of SWE in terms of sensitivity and accuracy, and the combined detection of ARFI and SWE performs better than ARFI or SWE employed separately.

NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction.

NVP-BKM120, a potent and highly selective PI3K inhibitor, is currently being investigated in phase I/II clinical trials. The mechanisms of action of NVP-BKM120 in colon cancer cells are unclear. In the present study, we investigated how NVP-BKM120 suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. We found that NVP-BKM120 treatment enhance PUMA induction irrespective of p53 status through the FoxO3a pathway following AKT inhibition. Furthermore, PUMA is required for NVP-BKM120-induced apoptosis in colon cancer cells. In addition, NVP-BKM120 also synergized with 5-Fluorouracil or regorafenib to induce marked apoptosis via PUMA induction. Deficiency of PUMA suppressed apoptosis and antitumor effect of NVP-BKM120 in xenograft model. These results demonstrate a key role of PUMA in mediating the anticancer effects of NVP-BKM120 and suggest that PUMA could be used as an indicator of NVP-BKM120 sensitivity, and also have important implications for it clinical applications.

Vertically Oriented 2D Layered Perovskite Solar Cells with Enhanced Efficiency and Good Stability.

Vertically oriented highly crystalline 2D layered (BA)2 (MA)n-1 Pbn I3n+1 (BA = CH3 (CH2 )3 NH3 , MA = CH3 NH3 , n = 3, 4) perovskite thin-films are fabricated with the aid of ammonium thiocyanate (NH4 SCN) additive through one-step spin-coating process. The humidity-stability of the film is certified by the almost unchanged X-ray diffraction patterns after exposed to humid atmosphere (Hr = 55 ± 5%) for 40 d. The photovoltaic devices with the structure of indium tin oxide(ITO)/poly(3,4-ethylenedioxythiophene):poly(styrene-sulfonate)/(BA)2 (MA)n-1 Pbn I3n+1 (n = 3,4)/[6,6]-phenyl-C61 -butyric acid methyl ester/Bathocuproine/Ag are fabricated. The devices based on (BA)2 (MA)2 Pb3 I10 perovskite (n = 3) with the precursor composition of BAI:methylammonium iodide:PbI2 :NH4 SCN = 2:2:3:1 (by molar ratio) show an averaged power conversion efficiency (PCE) of 6.82%. In the case of (BA)2 (MA)3 Pb4 I13 (n = 4), a higher PCE of 8.79% is achieved. Both of the unsealed devices perform unique stability with almost unchanged PCE during the period of storage in purified N2 glove box. This work provides a simple and effective method to enhance the efficiency of the 2D perovskite solar cell.

Idelalisib induces PUMA-dependent apoptosis in colon cancer cells.

Idelalisib, a PI3K inhibitor, specifically targeting p110δ, has been approved for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. However, the mechanisms of action of idelalisib in colon cancer cells are not well understood. We investigated how idelalisib suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. In this study, we found that idelalisib treatment induces PUMA in colon cancer cells irrespective of p53 status through the p65 pathway following AKT inhibition and glycogen synthase kinase 3ß (GSK3ß) activation. PUMA is necessary for idelalisib-induced apoptosis in colon cancer cells. Idelalisib also synergized with 5-FU or regorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and antitumor effect of idelalisib in xenograft model. These results demonstrate a critical role of PUMA in mediating the anticancer effects of idelalisib in colon cancer cells and suggest that PUMA induction can be used as an indicator of idelalisib sensitivity, and also have important implications for it clinical applications.

Nonfullerene Tandem Organic Solar Cells with High Open-Circuit Voltage of 1.97 V.

Small-molecule nonfullerene-based tandem organic solar cells (OSCs) are fabricated for the first time by utilizing P3HT:SF(DPPB)4 and PTB7-Th:IEIC bulk heterojunctions as the front and back subcells, respectively. A power conversion efficiency of 8.48% is achieved with an ultrahigh open-circuit voltage of 1.97 V, which is the highest voltage value reported to date among efficient tandem OSCs.

Diversity and dynamics of the microbial community on decomposing wheat straw during mushroom compost production.

The development of communities of three important composting players including actinobacteria, fungi and clostridia was explored during the composting of wheat straw for mushroom production. The results revealed the presence of highly diversified actinobacteria and fungal communities during the composting process. The diversity of the fungal community, however, sharply decreased in the mature compost. Furthermore, an apparent succession of both actinobacteria and fungi with intensive changes in the composition of communities was demonstrated during composting. Notably, cellulolytic actinomycetal and fungal genera represented by Thermopolyspora, Microbispora and Humicola were highly enriched in the mature compost. Analysis of the key cellulolytic genes revealed their prevalence at different composting stages including several novel glycoside hydrolase family 48 exocellulase lineages. The community of cellulolytic microbiota also changed substantially over time. The prevalence of the diversified cellulolytic microorganisms holds the great potential of mining novel lignocellulose decomposing enzymes from this specific ecosystem.