Fusobacterium nucleatum-induced imbalance in microbiome-derived butyric acid levels promotes the occurrence and development of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) ranks among the most prevalent malignant tumors globally. Recent reports suggest that Fusobacterium nucleatum (F. nucleatum) contributes to the initiation, progression, and prognosis of CRC. Butyrate, a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber, is known to inhibit various cancers. This study is designed to explore whether F. nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid. AIM: To investigate the mechanism by which F. nucleatum affects CRC occurrence and development. METHODS: Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F. nucleatum. Additionally, DLD-1 and HCT116 cell lines were exposed to sodium butyrate (NaB) and F. nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function. RESULTS: Our research indicates that the prevalence of F. nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts, while the prevalence of butyrate-producing bacteria is notably lower. In mice colonized with F. nucleatum, the population of butyrate-producing bacteria decreased, resulting in altered levels of butyric acid, a key intestinal metabolite of butyrate. Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells. Consequently, this leads to modulated production of adenosine triphosphate and reactive oxygen species, thereby inhibiting cancer cell proliferation. Additionally, NaB triggers the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, blocks the cell cycle in HCT116 and DLD-1 cells, and curtails the proliferation of CRC cells. The combined presence of F. nucleatum and NaB attenuated the effects of the latter. By employing small interfering RNA to suppress AMPK, it was demonstrated that AMPK is essential for NaB's inhibition of CRC cell proliferation. CONCLUSION: F. nucleatum can promote cancer progression through its inhibitory effect on butyric acid, via the AMPK signaling pathway.

Dual Integrating Oxygen and Sulphur on Surface of CoTe Nanorods Triggers Enhanced Oxygen Evolution Reaction.

The bottleneck of large-scale implementation of electrocatalytic water-splitting technology lies in lacking inexpensive, efficient, and durable catalysts to accelerate the sluggish oxygen evolution reaction kinetics. Owing to more metallic features, transition metal telluride (TMT) with good electronic conductivity holds promising potential as an ideal type of electrocatalysts for oxygen evolution reaction (OER), whereas most TMTs reported up to now still show unsatisfactory OER performance that is far below corresponding sulfide and selenide counterparts. Here, the activation and stabilization of cobalt telluride (CoTe) nanoarrays toward OER through dual integration of sulfur (S) doping and surface oxidization is reported. The as-synthesized CoO@S-CoTe catalyst exhibits a low overpotential of only 246 mV at 10 mA cm-2 and a long-term stability of more than 36 h, outperforming commercial RuO2 and other reported telluride-based OER catalysts. The combined experimental and theoretical results reveal that the enhanced OER performance stems from increased active sites exposure, improved charge transfer ability, and optimized electronic state. This work will provide a valuable guidance to release the catalytic potential of telluride-based OER catalysts via interface modulating engineering.

Carbothermal redox reaction in constructing defective carbon as superior oxygen reduction catalysts.

Defects can greatly promote the catalytic activity of a carbon-based electrocatalyst due to charge redistribution of its electroneutral π-conjugated structure. However, it is still a huge challenge to introduce enough defects into carbon-based materials to improve their catalytic activity. Herein, we report a new method for defect generation by the pyrolysis of the sulfur-nitrogen-containing coordination polymer [Zn(ptt)2]n (ptt = 1-phenyl-1H-tetrazole-5-thiol). A series of controlled experiments clearly demonstrates that the carbothermal reduction reaction of zinc sulfide with carbon at a high temperature plays an important role in creating defects and enhancing the catalytic activity for the oxygen reduction reaction (ORR) of the carbon-based materials. The ZnS/C-1100 with a high content of defects and a small number of ZnS nanoparticles exhibits excellent ORR electrocatalytic performances in alkaline media, in which the half-wave potential (0.894 V vs. RHE), stability, and methanol tolerance are all superior to that of a 20 wt% Pt/C catalyst. Moreover, the ZnS/C-1100 driven ZAB (zinc air battery) exhibits a stable discharge at 10 mA, a peak power density of 134 mW cm-2 and a cathode current density of 265 mA cm-2, which are significantly better than that catalyzed by 20 wt% Pt/C under the same conditions. This research not only develops a new highly active catalyst, but also provides a new method for the preparation of defect-rich carbon materials.

A case of a death caused by an atrial-oesophageal-thoracic fistula after radiofrequency ablation of atrial fibrillation.

The report is about a 49-year-old man with rheumatic heart disease and atrial fibrillation. He underwent mitral valve replacement, tricuspid valvuloplasty, and atrial fibrillation radiofrequency ablation in the hospital. He vomited blood on the 2nd postoperative day, and the bleeding gradually worsened thereafter. He had to have repeated drainage of large amounts of blood from his right thoracic cavity and digestive tract. He died suddenly after undergoing an oesophageal endoscopy on the 24th postoperative day. The autopsy revealed an atrial-oesophageal-thoracic fistula. By excluding the possibility of the fistula being caused by complications from nasoenteric feeding, tracheal intubation, and a foreign body ingestion, we determined that the atrial-oesophageal-thoracic fistula was a complication after radiofrequency ablation according to the finding of coagulation necrosis of the myocardial cells at the left atrium fistula. In addition, we also performed an elemental analysis on the radiofrequency ablation area and other cardiac tissues by scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) and found five metal elements, Cr, Cu, Zn, Mn, and Ti, which specifically existed in the radiofrequency ablation area. This finding has the potential to serve as new evidence for radiofrequency ablation and is a worthy direction of research.

Facile synthesis of porous Co3O4 nanoflakes as an interlayer for high performance lithium-sulfur batteries.

The "shuttle effect" of long-chain polysulfides and the low conductivity of elemental sulfur lead to the inferior cycling stability of lithium-sulfur batteries and imped their practical applications. Herein, Co3O4 nanoflakes with uniform macro pores distribution were synthesized via facile oil bath and calcination methods. Coupled with super P and coated on common polypropylene separators, they were expected to hinder the migration of lithium polysulfides (LiPSs) and accelerate the redox kinetics of polysulfides. Coin cells assembled with the Co3O4-super P interlayer exhibited a capacity of 760 mA h g-1 at 1 C, maintained 598 mA h g-1 after 350 cycles, and the decay rate of discharge capacity was only about 0.062% per cycle. Such high performance can be attributed to the synergistic effects between polar Co3O4 and conductive super P. The facile fabrication method and high performance make the Co3O4-super P interlayer a feasible material to apply in lithium-sulfur batteries.

c(RGDyk)-modified nanoparticles encapsulating quantum dots as a stable fluorescence probe for imaging-guided surgical resection of glioma under the auxiliary UTMD.

Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of -10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery.

The Effect of Next-Generation TKI in Non-Small Cell Lung Cancer after Failure of First-Line Treatment: a Meta-Analysis.

Resistance develops against first-generation tyrosine kinase inhibitors (TKIs), which target the epidermal growth factor receptor (EGFR), after a while for non-small-cell lung cancer (NSCLC). Recently, researchers have developed specific inhibitors against them. Among those inhibitors, next-generation EGFR-TKIs have gained prominence due to the greater efficacy and more favorable tolerability. Today, the efficacy of next-generation EGFR-TKIs in patients with advanced NSCLC after failure on first-generation EGFR-TKIs still remains under investigation. The aim of this meta-analysis was to systematically assess the efficacy and safety profiles of next-generation EGFR-TKIs in advanced NSCLC after failure on first-generation EGFR-TKIs. We performed a comprehensive search of the several electronic databases to September, 2018 to identify clinical trials. The primary endpoint was overall survival (OS), progression-free survival (PFS), disease controlled rate (DCR), objective response rate (ORR), and adverse events (AEs). Severe adverse events (AEs) (grade ≥ 3) based on the EGFR-TKIs were analysed. Odds Ratio (OR) along with 95% confidence interval (95% CI) were utilized for the main outcome analysis. In total, we had 3 randomized controlled trials in this analysis. The group of next-generation EGFR-TKIs was significantly improved PFS (OR = 0.34,95%CI = 0.29-0.40, P < 0.00001), as well with the ORR (OR = 10.48,95%CI = 3.87-28.34, P < 0.00001) and DCR (OR = 6.03,95%CI = 4.41-8.25, P < 0.00001), respectively. However, there is no significant difference in overall survival with next-generation EGFR-TKIs (OR = 1.05,95%CI = 0.85-1.31, P = 0.66). While, the OR for the treatment-related AEs of grade 3 or 4 (diarrhoea, rash/acne, nausea, vomiting, anemia) between the patients who received next-generation EGFR-TKIs and chemotherapy did not show safety benefit (P>0.05). Next-generation EGFR-TKIs was shown to be the better agent to achieve higher response rate and the longer PFS in NSCLC patients as the later-line therapy for previously treated patients with first-generation EGFR-TKIs. While, the benefit of the OS and safety compared with the chemotherapy did not achieved. Further research is needed to develop a database of all EGFR mutations and their individual impact on the differing treatments.

In situ synthesis and electrochemical performance of MoO3-x nanobelts as anode materials for lithium-ion batteries.

MoO3-x nanobelts with different concentrations of oxygen vacancies were synthesized by a one-step hydrothermal process. XPS test results show that oxygen vacancies are distributed from the exterior to the interior of the MoO3-x nanobelts. As an anode material for lithium-ion batteries, MoO3-x-10 releases excellent rate capacitance. It can maintain a high specific capacitance of about 500 mA h·g-1 at a high current density of 1000 mA·g-1. In the aspect of cycling stability, MoO3-x-10 can retain a high specific capacity of 641 mA h·g-1 after cycling for 50 times at 100 mA·g-1 and 420 mA h·g-1 after cycling for 100 times at 500 mA·g-1. The coexistence of oxygen vacancies and low-valence Mo ions is conducive to the intercalation/de-intercalation of Li ions and to promoting redox reactions. It has been proved to be a significantly effective way in which oxygen vacancies can improve the integrated performance of MoO3-x nanobelts as anode materials.

In situ aluminium ions regulation for quantum efficiency and light stability promotion in white light emitting material.

In this study, we have proposed an in situ ion regulation strategy to assemble a white-light-emitting material with high stability and efficiency. A fluorescence tunable hybrid material was first fabricated by a "ship around the bottle" method in which the fluorescent dyes, disodium 2-naphthol-3,6-disulfonate (R) and ZnO Quantum Dots (QDs), were embedded into metal-organic frameworks (MOFs) in proportion. Then, the competition coordination of aluminium ions over zinc ions to R were utilized to subtly adjust the intensity of blue fluorescence, leading to an ideal white light with Commission Internationale de l'Eclairage (CIE) coordinates of (0.30, 0.33) and a high Color-Rendering Index (CRI) value of 93%. Compared with the material fabricated by the ratio tuning of the R salt and ZnO QDs directly, the in situ ions regulation strategy enabled the final product to have a higher quantum efficiency and light stability. Moreover, this strategy also settled the non-tunable problem of fluorescence due to the competition coordination effects of aluminium ions and zinc ions in the same synthetic system. This synthetic strategy and our new findings can provide more ideas for designing new white-light-emitting materials.

Gas-solid aldol condensation reaction in confined space of metal organic framework for formaldehyde detection.

Herein, a gas-sensitive functional nanomaterial was constructed by confining Tb(acac)3(H2O)2 (acac = acetylacetone) in the space of the metal organic framework ZIF-8. This functional nanomaterial can realize a gas-solid state aldol condensation reaction, even at room temperature and without the use of a catalyst. In the reaction process, formaldehyde (FA) gas molecules can invalidate the antenna effect of the acac ligands, and it can therefore act as an ultrasensitive FA gas remover and detector (limit of detection value = 49 ppb).

Divalent metal ions modulated strong frustrated M(II)-Fe(III)3O (M = Fe, Mn, Mg) chains with metamagnetism only in a mixed valence iron complex.

Linking magnetically frustrated triangular FeO units by divalent metal ions (M(II) = Fe(II) for 1, Mn(II) for 2) gives isostructural 1D spin chains. Strong antiferromagnetic interactions were found in these complexes with significant frustrations but very interesting ferrimagnetic like transition and metamagnetism were found in mixed valence 1. By comparing the magnetic behaviours with isostructural complex 3 (with M(II) = Mg(II)), it is proposed that the spins of Fe(II) ions and Mn(II) ions have ferromagnetic and antiferromagnetic contributions respectively.

Discovery and characterization of human antibody inhibitors of pregnancy-associated plasma protein-A.

Pregnancy-associated plasma protein-A (PAPP-A) is a metalloprotease that cleaves insulin-like growth factor-binding proteins (IGFBPs) to release bioactive levels of free insulin-like growth factor. Specific and potent inhibitors of PAPP-A may further elucidate the biological functions of this protease and could prove to be of therapeutic value. Phage display was used to discover fully human antibody inhibitors of PAPP-A activity towards IGFBP4 cleavage. Estimates of the inhibition constants for these antibodies were subsequently determined using a novel continuous assay of PAPP-A protease activity that uses an internally quenched synthetic peptide substrate (DX-1655). DX-1655 was hydrolyzed by PAPP-A with a K(m) of 33 muM and a k(cat) of 0.3 s(-1) (k(cat)/K(m)=9.1x10(3) M(-1) s(-1)). PAPP-A activity towards DX-1655 displays a bell-shaped pH profile, with pK(a) values of 8.2 and 10.8 and a maximum rate at approximately pH 9.5. Using this continuous assay, we measured apparent K(i) values of 1.7+/-0.2 and 7.4+/-1.5 nM for the F2 and D9 antibodies, respectively.

High-throughput affinity ranking of antibodies using surface plasmon resonance microarrays.

A method was developed to rapidly identify high-affinity human antibodies from phage display library selection outputs. It combines high-throughput Fab fragment expression and purification with surface plasmon resonance (SPR) microarrays to determine kinetic constants (kon and koff) for 96 different Fab fragments in a single experiment. Fabs against human tissue kallikrein 1 (hK1, KLK1 gene product) were discovered by phage display, expressed in Escherichia coli in batches of 96, and purified using protein A PhyTip columns. Kinetic constants were obtained for 191 unique anti-hK1 Fabs using the Flexchip SPR microarray device. The highest affinity Fabs discovered had dissociation constants of less than 1 nM. The described SPR method was also used to categorize Fabs according to their ability to recognize an apparent active site epitope. The ability to rapidly determine the affinities of hundreds of antibodies significantly accelerates the discovery of high-affinity antibody leads.

[Canonical correlation and redundancy analysis on the indices of abdominal ultrasonography of schistosomiasis japonica].

OBJECTIVE: To explore the correlation of the ultrasound indices of liver and spleen in schistosomiasis japonica and with infection frequency, infection time and EPG. METHODS: The canonical correlation was applied to analyze the correlation of the hepatosplenic ultrasound indices in schistosomiasis japonica, and the correlation of the ultrasound indices with infection frequency, infection time and EPG. The proportions of variation related to each other in liver and spleen were analyzed by the redundancy analysis. RESULTS: The correlation coefficients of the first pair correlation canonical variable were 0.7842, 0.5483 and 0.5800, 0.4220, respectively, in males and females without infection, males and females with infection history (P<0.01). The correlation coefficients of the first pair correlation canonical variable were 0.6063, 0.5215 and 0.6595, 0.3849, respectively, in male negatives and female negatives, male positives and female positives (P<0.01). In groups of males and females without infection, the variations of liver ultrasound indices related with the variation of spleen ultrasound indices were 43.5% and 17.5% respectively, and in groups infection history, they were 22.1% and 11.4% respectively. In male and female negative groups, the variations of liver ultrasound indices related with the variation of spleen ultrasound indices were 26.8% and 16.8% respectively, and in positive groups, they were 27.6% and 10.7% respectively. The infection frequency, infection time and EPG in the stool-positive groups were not significantly related with the canonical variables of liver and spleen ultrasound indices (P>0.05). CONCLUSION: There is a significant canonical correlation between the liver and spleen ultrasound indices in schistosomiasis japonica, especially in males. In groups with infection history, the infection frequency, infection time and EPG of those stool-positives are not relevant to the canonical variables of liver and spleen ultrasound indices.

[Principal component analysis on ultrasound indexes of schistosomiasis and the assessment on prevalence rate].

OBJECTIVE: To explore the synthetical index for diagnosing schistosomiasis with ultrasound and to assess the prevalence rate with the index. METHODS: Ultrasound indexes of schistosomiasis Japonicum were analyzed by principal component analysis, and the synthetical indexes were assessed by ROC curve. RESULTS: Among the abnormal rates of the 6 indexes, the lowest was 1.6% comparing with the highest of 59.5%. Significant difference was noficed among the abnormal rates (chi(2) = 631.1, P < 0.01). The individual correlation of the six indexes to each other as will as with age distribution was significant (P < 0.05). The three principal components reflected the degree of pathological changes on liver and spleen. The first principal component was the factor reflecting the degree of liver pathological changes, and the second and third principal components reflected the degree of pathological changes on spleen. The synthetical index D(1) = 0.047X(1) + 0.428X(2) + 1.247X(3) + 0.095X(4) + 0.002X(5) + 0.213X(6) - 12.837 was found by adding the three weight principal components, and it's area under the ROC curve was 0.957. When -1.70 was taken as the critical value, the abnormal rate of population was 66.3%, close to the resident's actual prevalence rate 66.9%. CONCLUSION: Ultrasonography was considered as a method which could rapidly assessing the resident's prevalence rate in the endemic areas of schisitosomiasis Japonicum, and could also provide powerful information for development of strategy on chemotherapy.

Novel peptide inhibitors of angiotensin-converting enzyme 2.

Angiotensin-converting enzyme 2 (ACE2), a recently identified human homolog of ACE, is a novel metallocarboxypeptidase with specificity, tissue distribution, and function distinct from those of ACE. ACE2 may play a unique role in the renin-angiotensin system and mediate cardiovascular and renal function. Here we report the discovery of ACE2 peptide inhibitors through selection of constrained peptide libraries displayed on phage. Six constrained peptide libraries were constructed and selected against FLAG-tagged ACE2 target. ACE2 peptide binders were identified and classified into five groups, based on their effects on ACE2 activity. Peptides from the first three classes exhibited none, weak, or moderate inhibition on ACE2. Peptides from the fourth class exhibited strong inhibition, with equilibrium inhibition constants (K(i) values) from 0.38 to 1.7 microm. Peptides from the fifth class exhibited very strong inhibition, with K(i) values < 0.14 microm. The most potent inhibitor, DX600, had a K(i) of 2.8 nm. Steady-state enzyme kinetic analysis showed that these potent ACE2 inhibitors exhibited a mixed competitive and non-competitive type of inhibition. They were not hydrolyzed by ACE2. Furthermore, they did not inhibit ACE activity, and thus were specific to ACE2. Finally, they also inhibited ACE2 activity toward its natural substrate angiotensin I, suggesting that they would be functional in vivo. As novel ACE2-specific peptide inhibitors, they should be useful in elucidation of ACE2 in vivo function, thus contributing to our better understanding of the biology of cardiovascular regulation. Our results also demonstrate that library selection by phage display technology can be a rapid and efficient way to discover potent and specific protease inhibitors.

Development of mammalian serum albumin affinity purification media by peptide phage display.

Several phage isolates that bind specifically to human serum albumin (HSA) were isolated from disulfide-constrained cyclic peptide phage-display libraries. The majority of corresponding synthetic peptides bind with micromolar affinity to HSA in low salt at pH 6.2, as determined by fluorescence anisotropy. One of the highest affinity peptides, DX-236, also bound well to several mammalian serum albumins (SA). Immobilized DX-236 quantitatively captures HSA from human serum; mild conditions (100 mM Tris, pH 9.1) allow release of HSA. The DX-236 affinity column bound HSA from human serum with a greater specificity than does Cibacron Blue agarose beads. In addition to its likely utility in HSA and other mammalian SA purifications, this peptide media may be useful in the proteomics and medical research markets for selective removal of mammalian albumin from serum prior to mass spectrometric and other analyses.