Changes to circulating tumor cells in the central vein during laparoscopic versus transanal endoscopic surgeries for rectal cancer: can surgical approach make a difference?

Background: The oncological safety of transanal total mesorectal excision (taTME) remains uncertain, and its special surgical approach may contribute to tumor cell dissemination. Thus, we conducted a study to investigate the impact of surgical approach on circulating tumor cell (CTC) counts and phenotypes in rectal cancer. Methods: This is a prospective randomized controlled study (ClinicalTrials: NCT05109130). The patients were randomized to either the taTME (n = 49) or laparoscopic TME (laTME) (n = 48) groups. Blood samples were collected from the central vein to measure CTC counts and phenotypes at three time points: preoperative (t1), immediately post-tumor removal (t2), and one week post-surgery (t3). The effect of surgical procedure on CTCs at each time point was analyzed, with the primary endpoint being the change in CTC counts from t1 to t3 for each surgical approach. This study adheres to Consolidated Standards of Reporting Trials Guidelines. Results: The baseline clinicopathologic characteristics of the laTME and taTME groups were balanced. The change in CTC count from t1 to t3 was 1.81 ± 5.66 in the laTME group and 2.18 ± 5.53 in the taTME group. The taTME surgery was non-inferior to laTME in terms of changing CTC counts (mean difference [MD]: -0.371; 95% confidence interval [CI]: -2.626 to 1.883, upper-sided 95% CI of 1.883 < 2, non-inferiority boundary value). Compared with that at t1, the CTC count at t2 did not change significantly. However, higher CTC counts were detected at t3 than at t2 in the taTME (P = 0.032) and laTME (P = 0.003) groups. From t1 to t3, CTC counts significantly increased in both the taTME (P = 0.008) and laTME (P = 0.031) groups. There were no significant differences in CTC phenotype changes between the two groups from t1 to t3. Conclusions: Compared with laTME, taTME did not affect CTC counts and phenotypes. Our findings indicate that taTME is not inferior to laTME in terms of CTC changes from an oncological perspective.

Tumor derived exosomal ENTPD2 impair CD8+ T cell function in colon cancer through ATP-adenosine metabolism reprogramming.

BACKGROUND: Extracellular ATP-AMP-adenosine metabolism plays a pivotal role in modulating tumor immune responses. Previous studies have shown that the conversion of ATP to AMP is primarily catalysed by Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), a widely studied ATPase, which is expressed in tumor-associated immune cells. However, the function of ATPases derived from tumor cells themselves remains poorly understood. The purpose of this study was to investigate the role of colon cancer cell-derived ATPases in the development and progression of colon cancer. METHODS: Bioinformatic and tissue microarray analyses were performed to investigate the expression of ATPase family members in colon cancer. An ATP hydrolysis assay, high-performance liquid chromatography (HPLC), and CCK8 and colony formation assays were used to determine the effects of ENTPD2 on the biological functions of colon cancer cells. Flow cytometric and RNA-seq analyses were used to explore the function of CD8+ T cells. Immunoelectron microscopy and western blotting were used to evaluate the expression of ENTPD2 in exosomes. Double-labelling immunofluorescence and western blotting were used to examine the expression of ENTPD2 in serum exosomes and colon cancer tissues. RESULTS: We found that ENTPD2, rather than the well-known ATPase CD39, is highly expressed in cancer cells and is significantly positively associated with poor patient prognosis in patients with colon cancer. The overexpression of ENTPD2 in cancer cells augmented tumor progression in immunocompetent mice by inhibiting the function of CD8+ T cells. Moreover, ENTPD2 is localized primarily within exosomes. On the one hand, exosomal ENTPD2 reduces extracellular ATP levels, thereby inhibiting P2X7R-mediated NFATc1 nuclear transcription; on the other hand, it facilitates the increased conversion of ATP to adenosine, hence promoting adenosine-A2AR pathway activity. In patients with colon cancer, the serum level of exosomal ENTPD2 is positively associated with advanced TNM stage and high tumor invasion depth. Moreover, the level of ENTPD2 in the serum exosomes of colon cancer patients is positively correlated with the ENTPD2 expression level in paired colon cancer tissues, and the ENTPD2 level in both serum exosomes and tissues is significantly negatively correlated with the ENTPD2 expression level in tumor-infiltrating CD8+ T cells. CONCLUSION: Our study suggests that exosomal ENTPD2, originated from colon cancer cells, contributes to the immunosuppressive microenvironment by promoting ATP-adenosine metabolism. These findings highlight the importance of exosome-derived hydrolytic enzymes as independent entities in shaping the tumor immune microenvironment.

Environmental concentrations of microplastic-induced gut microbiota and metabolite disruption in silkworm, Bombyx mori.

Microplastics (MPs) existing extensively in various ecosystems can be ingested by marine organisms and enter the food chain, resulting the health risks from the presence of MPs in aquatic and terrestrial ecosystems. In the present study, an ideal model for Lepidoptera, the silkworm, Bombyx mori, was exposed to environmental concentrations (0.125 µg, 0.25 µg or 0.5 µg/diet) of MPs for 5 days, and the global changes in gut microbes and metabolites were subsequently examined via 16S rDNA sequencing and GC‒MS-based metabolomics. The results showed that MPs exposure did not seriously threaten survival but may regulate signaling pathways involved in development and cocoon production. MPs exposure induced gut microbiota perturbation according to the indices of α-diversity and ß-diversity, and the functional prediction of the altered microbiome and associated metabolites demonstrated the potential roles of the altered microbiome following MPs exposure in the metabolic and physiological states of silkworm. The metabolites markedly altered following MPs exposure may play vital biological roles in energy metabolism, lipid metabolism, xenobiotic detoxification and the immune system by directly or indirectly affecting the physiological state of silkworms. These findings contribute to assessing the health risks of MPs exposure in model insects and provide novel insight into the toxicity mechanism of MPs.

Vonoprazan-amoxicillin dual therapy with different amoxicillin dosages for treatment-naive patients of Helicobacter pylori infection in China: a prospective, randomized controlled study.

BACKGROUND: The vonoprazan (VPZ)-amoxicillin (AMO) dual therapy (VA) demonstrates a satisfactory eradication rate for Helicobacter pylori (H. pylori ). However, the optimal dosage of AMO in this regimen remains uncertain. The objective of this study is to investigate the efficacy of different doses of AMO in the VA regimen for first-line treatment of H. pylori infection. METHODS: A total of 192 treatment-naive H. pylori -infected patients were randomly assigned to one of three groups: low-dose VA (LD-VA: VPZ 20 mg b.i.d + AMO 750 mg t.i.d), moderate-dose VA (MD-VA:VPZ 20 mg b.i.d + AMO 1000 mg t.i.d), and high-dose VA (HD-VA: VPZ 20 mg b.i.d + AMO 1250 mg t.i.d). All groups received 14 days of treatment. The study evaluated and compared the eradication rates, adverse events (AEs), and patient compliance among the three groups. RESULTS: Eradication rates for LD-VA, MD-VA, and HD-VA were 76.6% (49/64), 79.7% (51/64), and 84.4% (54/64), respectively, as determined by intention-to-treat analysis; 90.6% (48/53), 94.3% (50/53), and 98.1% (53/54) according to per-protocol analysis; 89.1% (49/55), 94.4% (51/54), and 96.4% (54/56) with modified intention-to-treat analysis (all P  > 0.05). Although not statistically significant, numerically higher eradication rates were observed with the higher dose AMO VA regimen. There were no statistically significant differences in the incidence of AEs and compliance among the three VA regimens. CONCLUSION: Fourteen-day VA regimens with AMO doses exceeding 2 g/day demonstrated satisfactory eradication rates. HD-VA therapy is potentially the most effective regimen. Large-sample clinical trials are required to further validate these findings.

Comparison of vonoprazan-based dual therapy with vonoprazan-based bismuth quadruple therapy for treatment-naive patients with Helicobacter pylori infection: A propensity score matching analysis.

Vonoprazan, a novel acid suppressant and the first potassium-competitive acid blocker, has the potential to enhance the eradication rate of Helicobacter pylori due to its robust acid-suppressing capacity. This study aimed to compare the efficacy of vonoprazan-based dual therapy (vonoprazan-amoxicillin, VA) with vonoprazan-based bismuth quadruple therapy (VBQT) as a first-line treatment for H pylori infection. This retrospective single-center non-inferiority study was conducted in China. Treatment-naive H pylori-positive patients aged 18 to 80 received one of the 2 treatment regimens at our center. The VA group received vonoprazan 20 mg twice daily and amoxicillin 1000 mg 3 times daily for 14 days, whereas the VBQT group received vonoprazan 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth potassium citrate 220 mg twice daily for 14 days. The eradication rate was evaluated 4 to 6 weeks after treatment using the carbon-13/14 urea breath test. Propensity score matching was used to analyze eradication rates, adverse events (AEs), and patient compliance between the 2 groups. Initially, 501 patients were included, and after propensity score analysis, 156 patients were selected for the study. Intention-to-treat analysis showed eradication rates of 87.2% (95% CI, 79.8-94.6%) for the VA group and 79.5% (95% CI, 70.5-88.4%) for the VBQT group (P = .195). Per-protocol analysis demonstrated rates of 94.4% (95% CI, 89.2-99.7%) for the VA group and 96.8% (95% CI, 92.4-100%) for the VBQT group (P = .507). Non-inferiority was confirmed between the 2 groups, with P values < .025. The VA group showed a lower rate of AEs (10.3% vs 17.9%, P = .250) compared to the VBQT group. There were no significant differences in patient compliance between the 2 groups. In treatment-naive patients with H pylori infection, both the 14-day VA and VBQT regimens demonstrated comparable efficacy, with excellent eradication rates. Moreover, due to reduced antibiotic usage, lower rate of AEs, and lower costs, VA dual therapy should be prioritized.

Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer.

The existing conventional treatments for breast cancer, including immune checkpoint blockade, exhibit limited effects in some cancers, particularly triple-negative breast cancer. Epigenetic alterations, specifically DNMT and HDAC alterations, are implicated in breast cancer pathogenesis. We demonstrated that DNMTs and HDACs are overexpressed and positively correlated in breast cancer. The combination of DNMT and HDAC inhibitors has shown synergistic antitumour effects, and our previously designed dual DNMT and HDAC inhibitor (termed DNMT/HDACi) 15a potently inhibits breast cancer cell proliferation, migration, and invasion and induces apoptosis in vitro and in vivo. Mechanistically, 15a induces a viral mimicry response by promoting the expression of endogenous retroviral elements in breast cancer cells, thus increasing the intracellular level of double-stranded RNA to activate the RIG-I-MAVS pathway. This in turn promotes the production of interferons and chemokines and augments the expression of interferon-stimulated genes and PD-L1. The combination of 15a and an anti-PD-L1 antibody had an additive effect in vivo. These findings indicate that this DNMT/HDACi has immunomodulatory functions and enhances the effectiveness of immune checkpoint blockade therapy. A novel dual DNMT and HDAC inhibitor induces viral mimicry, which induces the accumulation of dsRNA to activate tumoral IFN signalling and cytokine production to enhance the immune response in breast cancer.

Type I/II Immune Balance Contributes to the Protective Effect of AIF-1 on Hepatic Immunopathology Induced by Schistosoma japonicum in a Transgenic Mouse Model.

Schistosomiasis is the second most debilitating neglected tropical disease in the world. Liver egg granuloma and fibrosis are the main damage of schistosomiasis. In this study, the role of allograft inflammatory factor-1 (AIF-1) in liver pathology and its regulation in immune responses were investigated in a transgenic mouse infected with Schistosoma japonicum. We found that AIF-1 overexpression reduced worm burden and decreased egg granuloma sizes and serum alanine aminotransferase levels, along with inhibited hepatic collagen deposition and serum hydroxyproline levels during S. japonicum infection. Moreover, AIF-1 overexpression resulted in an increased ratio of Th1/Th2, increased levels of IFN-γ and T-bet, and lower levels of GATA-3 in the spleen, accompanied by increased M1 percentages, decreased M2 percentages, and thus a higher ratio of M1/M2 in the peritoneal cavity and liver. AIF-1 induced CD68 and iNOS mRNA expression and protein levels of cytoplasmic p-P38 and nuclear NF-κB, along with enhanced levels of TNF-α and TGF-ß in macrophages in vitro. Moreover, the hepatic pathology had a negative correlation with Th1/Th2 and M1/M2 ratios in the infected mice. The findings reveal that the beneficial role of AIF-1 in alleviating hepatic damage is related to restoring type I/II immune balance in S. japonicum infection.

Knowledge, attitude, and practice toward cochlear implants among deaf patients who received cochlear implants.

Despite the growing use of cochlear implants in deaf patients, there is a lack of data on their knowledge, attitude, and practice (KAP) toward cochlear implants. This study aimed to investigate the KAP toward cochlear implants among deaf patients who received cochlear implants. A web-based cross-sectional study was conducted between August 2022 and December 2022 among deaf patients who had received cochlear implants. A self-administered questionnaire was used to collect demographic characteristics and KAP scores. A total of 526 participants were enrolled; 54.18% were female, 65.40% were above 60 years old, and 61.03% were surveyed at less than 3 years after implantation. The mean knowledge, attitude, and practice scores were 8.15 ± 2.18 (possible range: 0-10), 43.63 ± 6.98 (possible range: 12-60), and 41.11 ± 7.42 (possible range: 11-55), respectively, indicating good knowledge, moderate attitude and practice. Multivariable logistic regression analysis showed that attitude [odd ratio (OR) = 1.24, 95% confidence interval (CI) 1.18-1.29, P < 0.001] and unemployment (OR = 0.33, 95% CI 0.17-0.63, P = 0.001) were independently associated with practice. Path analysis showed that knowledge directly influenced attitude (ß = 0.93, 95% CI 0.61-1.19, P < 0.001), attitude directly influenced practice (ß = 0.53, 95% CI 0.46-0.61, P < 0.001), and knowledge directly (ß = 0.77, 95% CI 0.53-1.01, P < 0.001) and indirectly (ß = 0.50, 95% CI 0.34-0.66, P < 0.001) influenced practice. Deaf patients who received cochlear implants showed good knowledge, moderate attitude and practice toward cochlear implants. Knowledge should be strengthened to improve attitude and practice toward cochlear implants, which could translate into realistic expectations toward cochlear implants devices and proper care and maintenance.

3D simulation of conductive nanofilaments in multilayer h-BN memristors via a circuit breaker approach.

A 3D simulation of conductive nanofilaments (CNFs) in multilayer hexagonal-BN memristors is performed. To do so, a simulation tool based on circuit breakers is developed including for the first time a 3D resistive network. The circuit breakers employed can be modeled with two, three and four resistance states; in addition, a series resistance and a module to account for quantum effects, by means of the quantum point contact model, are also included. Finally, to describe real dielectric situations, regions with a high defect density are modeled with a great variety of geometrical shapes to consider their influence in the resistive switching (RS) process. The simulator has been tuned with measurements of h-BN memristive devices, fabricated with chemical-vapour-deposition grown h-BN layers, which were electrically and physically characterized. We show the formation of CNFs that produce filamentary charge conduction in our devices. Moreover, the simulation tool is employed to describe partial filament rupture in reset processes and show the low dependence of the set voltage on the device area, which is seen experimentally.

Over-expression of IL-33 enhances rabies virus early antigen presentations and cellular immune responses in mice.

Human inactivated rabies virus (RABV) vaccines have been widely used worldwide over 30 years. The mechanisms of humoral immunity elicited by previously reported rabies candidate vaccines have been fully investigated, but little is known about the cellular immunity profiles. Herein, the recombinant RABV rLBNSE-IL-33 overexpressing the mouse interleukin-33 (IL-33) proliferated well in Neuro-2a cells and had no effects with the parent virus on growth kinetic in vitro and viral pathogenicity in mice. The rLBNSE-IL-33 experienced more antigen presentations by MHC-II on DCs and activated more CD4+ T cells which helped recruit more CD19+CD40+ B cells in blood and promote rapid and robust IgG1 antibodies responses at initial infection stage compared with the parent rLBNSE strain. Simultaneously, the rLBNSE-IL-33 were also presented by MHC-I to CD8+ T cells which contributed to produce high levels of IgG2a. The rLBNSE-IL-33 elicited significantly high levels of RABV-specific IFN-γ secreting memory CD4+ T cells, more RABV-specific IL-4 and IFN-γ secreting memory CD8+ T cells in spleens at early infection stage in mice. Altogether, overexpression of IL-33 in rLBNSE-IL-33 enhanced early antigen presentation, markedly promote CD4+, memory CD4+ and CD8+ T cells-mediated responses and provided a 100 % protection from lethal RABV challenge in mice. These findings provided an alternative novel therapy and vaccine strategy in future.

Design, synthesis and biological evaluation of pyrimidine base hydroxamic acid derivatives as dual JMJD3 and HDAC inhibitors.

The Jumonji domain-containing protein demethylase 3 (JMJD3) and histone deacetylase (HADC) are related to various cancers and regard as antitumor targets for drug discovery. In this study, based on rational drug design strategy, we designed and synthesized a series of pyrimidine derivatives with hydroxamic acid as novel dual JMJD3 and HDAC inhibitors for synergistic cancer treatment. Compound A5b exhibited inhibitory potency against JMJD3 and HDAC1/6 simultaneously and favorable cytotoxicity against human cancer cells such as A549 and U937. Furthermore, mechanistic studies showed that A5b treatment in A549 cells increased the hypermethylation of histone H3K27 and hyperacetylation of H3K9, suppressed clonogenicity, migration and invasion of cancer cells. Besides, A5b induced apoptosis via the cleavage of caspase-7 and PARP, and G1 cell cycle arrest via upregulated p21 expression. All these results suggested that A5b was the first dual inhibitor against JMJD3 and HDAC and can be a potential compound for cancer therapy.

The strong metal-support interactions induced electrocatalytic three-electron oxygen reduction to hydroxyl radicals for water treatment.

As a promising environmental remediation technology, the electro-Fenton (EF) process is mainly limited by the two rate-limiting steps, which are H2O2 generation and activation. The electrocatalytic three-electron oxygen reduction reaction (3e- ORR) can directly activate oxygen to hydroxyl radicals (•OH), which is expected to break through the rate-limiting steps of the EF process. However, limited success has been achieved in the design of 3e- ORR electrocatalysts. Herein, we propose Cu/CoSe2/C with the strong metal-support interactions to enhance the 3e- ORR process, exhibiting remarkable reactivity and stability for •OH generation. Both experiment and DFT calculation results reveal that CoSe2 is conducive to the generation of H2O2. Meanwhile, the metallic Cu can enhance the adsorption strength of *H2O2 intermediates and thus promotes the one-electron reduction to •OH. The Cu/CoSe2/C catalyst exhibits the electron-transfer number close to 3.0 during the ORR process, and exhibits the outstanding •OH generation performance, achieving a higher apparent rate constant (6.0 times faster) toward ciprofloxacin compared with its analogy without the SMSI effect. Our work represents that the SMSI effect endows Cu/CoSe2/C high activity and selectivity for •OH generation, providing a unique perspective for the design of a high-efficiency 3e- ORR catalyst.

Efficient Narrow-Bandgap Mixed Tin-Lead Perovskite Solar Cells via Natural Tin Oxide Doping.

Narrow-bandgap (NBG) mixed tin/lead-based (Sn-Pb) perovskite solar cells (PSCs) have attracted extensive attention for use in tandem solar cells. However, they are still plagued by serious carrier recombination due to inferior film properties resulting from the alloying of Sn with Pb elements, which leads to p-type self-doping behaviors. This work reports an effective tin oxide (SnOx ) doping strategy to produce high-quality Sn-Pb perovskite films for utilization in efficient single-junction and tandem PSCs. SnOx can be naturally oxidized from tin diiodide raw powders and successfully incorporated into Sn-Pb perovskite films. Consequently, Sn-Pb perovskite films doped with SnOx exhibit dramatically improved morphology, crystallization, absorption, and more interestingly, upward-shifted Fermi levels. The resulting narrow-bandgap Sn-Pb PSCs with natural SnOx doping have considerably reduced carrier recombination, therefore delivering a maximum power conversion efficiency (PCE) of 22.16% for single-junction cells and a remarkable PCE of 26.01% (with a steady-state efficiency of 25.33%) for two-terminal all-perovskite tandem cells. This work introduces a facile doping strategy for the manufacture of efficient single-junction narrow-bandgap PSCs and their tandem solar cells.

Comparisons of different lymph node staging systems for predicting overall survival of node-positive patients with renal cell carcinoma: a retrospective cohort study using the Surveillance, Epidemiology and End Results database.

OBJECTIVES: To compare the prognostic values of three lymph node staging systems in renal cell carcinoma (RCC), including the number of positive lymph nodes (NPLN), lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS). DESIGN: A retrospective cohort study using data from the Surveillance, Epidemiology and End Results (SEER) database. SETTING AND PARTICIPANTS: 1904 patients with pathological N1 RCC, diagnosed from 2004 to 2015 and underwent nephrectomy combined with lymph node dissection, were identified from the SEER database. PRIMARY OUTCOME MEASURE: The primary outcome of this study was overall survival (OS). Restricted cubic spline functions and multivariable Cox regression analyses were employed to characterise the associations of OS with NPLN, LNR and LODDS, respectively. RESULTS: Data of 1904 eligible RCC patients were extracted from the SEER database. The mortality risks of RCC patients increased with the increasing of NPLN, LNR and LODDS. NPLN (NPLN3 vs NPLN1, HR 1.22, 95% CI 1.05 to 1.43, p=0.001), LNR (LNR3 vs LNR1, HR 1.46, 95% CI 1.28 to 1.67, p<0.001; LNR2 vs LNR1, HR 1.28, 95% CI 1.09 to 1.50, p=0.002) and LODDS (LODDS3 vs LODDS1, HR 1.48, 95% CI 1.28 to 1.72, p<0.001; LODDS2 vs LODDS1, HR 1.34, 95% CI 1.17 to 1.53, p<0.001) were all independent prognostic factors of OS. The predictive abilities of LNR (Akaike information criterion, AIC: 19576.3, optimism-corrected C-index: 0.677) and LODDS (AIC: 19579.2, optimism-corrected C-index: 0.676) were comparable, superior to NPLN (AIC: 19603.7, optimism-corrected C-index: 0.673). In subgroup analyses, the LODDS classification could better stratify survival of RCC patients, in particular for those with the number of dissected lymph nodes <13 or NPLN≤2. CONCLUSIONS: NPLN, LNR and LODDS were all independent predictors of OS in RCC. When compared with NPLN and LNR, LODDS had a better performance in survival prediction and risk stratification. The three metrics all had the potential to be integrated into future versions of the American Joint Committee on Cancer staging manual.

[Retracted] MicroRNA­24 upregulation inhibits proliferation, metastasis and induces apoptosis in bladder cancer cells by targeting CARMA3.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the cell­cycle assay data shown in Fig. 2D, and certain of the flow cytometric data shown in Fig. 2E, on p. 1354 had already been submitted in different form in papers written by different authors at different research institutes. Moreover, a pair of data panels shown for the Transwell assay experiments in Fig. 4A were overlapping, such that data purportedly showing the results of differently performed experiments were likely to have been derived from the same original source.  Owing to the fact that the contentious data in the above article had already been submitted for publication prior to its submission to International Journal of Oncology, and due to an overall lack of confidence in the data, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 47: 1351­1360, 2015; DOI: 10.3892/ijo.2015.3117].

Investigation on the reaction kinetic mechanism of polydopamine-loaded copper as dual-functional catalyst in heterogeneous electro-Fenton process.

Heterogeneous electro-Fenton (HEF) process has been regarded as a promising method in environmental remediation. However, the reaction kinetic mechanism of the HEF catalyst for simultaneous production and activation of H2O2 remained confounded. Herein, the copper supported on polydopamine (Cu/C) was synthesized by a facile method and employed as a bifunctional HEFcatalyst, and the catalytic kinetic pathways were deeply investigated by using rotating ring-disk electrode (RRDE) voltammetry based on the Damjanovic model. Experimental results substantiated that a two-electron oxygen reduction reaction (2e- ORR) and a sequential Fenton oxidation reaction were proceeded on 1.0-Cu/C, where metallic copper played a crucial role in the fabrication of 2e- active sites as well as utmost H2O2 activation to produce highly reactive oxygen species (ROS), resulting in the high H2O2 productivity (52.2%) and the almost complete removal of contaminant ciprofloxacin (CIP) after 90 min. The work not only expanded the idea of reaction mechanism on Cu-based catalyst in HEF process but also provided a promising catalyst for pollutants degradation in wastewater treatment.

Hybrid 2D-CMOS microchips for memristive applications.

Exploiting the excellent electronic properties of two-dimensional (2D) materials to fabricate advanced electronic circuits is a major goal for the semiconductor industry1,2. However, most studies in this field have been limited to the fabrication and characterization of isolated large (more than 1 µm2) devices on unfunctional SiO2-Si substrates. Some studies have integrated monolayer graphene on silicon microchips as a large-area (more than 500 µm2) interconnection3 and as a channel of large transistors (roughly 16.5 µm2) (refs. 4,5), but in all cases the integration density was low, no computation was demonstrated and manipulating monolayer 2D materials was challenging because native pinholes and cracks during transfer increase variability and reduce yield. Here, we present the fabrication of high-integration-density 2D-CMOS hybrid microchips for memristive applications-CMOS stands for complementary metal-oxide-semiconductor. We transfer a sheet of multilayer hexagonal boron nitride onto the back-end-of-line interconnections of silicon microchips containing CMOS transistors of the 180 nm node, and finalize the circuits by patterning the top electrodes and interconnections. The CMOS transistors provide outstanding control over the currents across the hexagonal boron nitride memristors, which allows us to achieve endurances of roughly 5 million cycles in memristors as small as 0.053 µm2. We demonstrate in-memory computation by constructing logic gates, and measure spike-timing dependent plasticity signals that are suitable for the implementation of spiking neural networks. The high performance and the relatively-high technology readiness level achieved represent a notable advance towards the integration of 2D materials in microelectronic products and memristive applications.

TRAF3 activates STING-mediated suppression of EV-A71 and target of viral evasion.

Innate immunity represents one of the main host responses to viral infection.1-3 STING (Stimulator of interferon genes), a crucial immune adapter functioning in host cells, mediates cGAS (Cyclic GMP-AMP Synthase) sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown. In the present study, we discovered that human enterovirus A71 (EV-A71) infection triggered STING activation in a cGAS dependent manner. EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells. However, during EV-A71 infection, cGAS-STING activation was attenuated. EV-A71 proteins were screened and the viral protease 2Apro had the greatest capacity to inhibit cGAS-STING activation. We identified TRAF3 as an important factor during STING activation and as a target of 2Apro. Supplement of TRAF3 rescued cGAS-STING activation suppression by 2Apro. TRAF3 supported STING activation mediated TBK1 phosphorylation. Moreover, we found that 2Apro protease activity was essential for inhibiting STING activation. Furthermore, EV-D68 and CV-A16 infection also triggered STING activation. The viral protease 2Apro from EV-D68 and CV-A16 also had the ability to inhibit STING activation. As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication, blocking EV-A71-mediated STING suppression represents a new anti-viral target.

Hardware implementation of a true random number generator integrating a hexagonal boron nitride memristor with a commercial microcontroller.

The development of the internet-of-things requires cheap, light, small and reliable true random number generator (TRNG) circuits to encrypt the data-generated by objects or humans-before transmitting them. However, all current solutions consume too much power and require a relatively large battery, hindering the integration of TRNG circuits on most objects. Here we fabricated a TRNG circuit by exploiting stable random telegraph noise (RTN) current signals produced by memristors made of two-dimensional (2D) multi-layered hexagonal boron nitride (h-BN) grown by chemical vapor deposition and coupled with inkjet-printed Ag electrodes. When biased at small constant voltages (≤70 mV), the Ag/h-BN/Ag memristors exhibit RTN signals with very low power consumption (∼5.25 nW) and a relatively high current on/off ratio (∼2) for long periods (>1 hour). We constructed TRNG circuits connecting an h-BN memristor to a small, light and cheap commercial microcontroller, producing a highly-stochastic, high-throughput signal (up to 7.8 Mbit s-1) even if the RTN at the input gets interrupted for long times up to 20 s, and if the stochasticity of the RTN signal is reduced. Our study presents the first full hardware implementation of 2D-material-based TRNGs, enabled by the unique stability and figures of merit of the RTN signals in h-BN based memristors.

Quantitative Analysis for Chinese and US-listed Pharmaceutical Companies by the LightGBM Algorithm.

AIM: This article aims to quantitatively analyze the growth trend of listed pharmaceutical companies in the US and China by a machine learning algorithm. BACKGROUND: In the last two decades, the global pharmaceutical industry has faced the dilemma of low research & development (R&D) success rate. The US is the world's largest pharmaceutical market, while China is the largest emerging market. OBJECTIVE: To collect data from the database and apply machine learning to build the model. METHODS: LightGBM algorithm was used to build the model and identify the factor important to the performance of pharmaceutical companies. RESULTS: The prediction accuracy for US companies was 80.3%, while it was 64.9% for Chinese companies. The feature importance shows that the net profit growth rate and debt liability ratio are significant in financial indicators. The results indicated that the US may continue to dominate the global pharmaceutical industry, while several Chinese pharmaceutical companies rose sharply after 2015 with the narrowing gap between the Chinese and US pharmaceutical industries. CONCLUSION: In summary, our research quantitatively analyzed the growth trend of listed pharmaceutical companies in the US and China by a machine learning algorithm, which provide a novel perspective for the global pharmaceutical industry. According to the R&D capability and profitability, 141 US-listed and 129 China-listed pharmaceutical companies were divided into four levels to evaluate the growth trend of pharmaceutical firms.