Comprehensive analysis of the m6A demethylase FTO in endothelial dysfunction by MeRIP sequencing.

N6-methyladenosine (m6A) is the most general post-transcriptional modification of eukaryotic mRNAs and long-stranded non-coding RNAs. In this process, It has been shown that FTO associates with the m6A mRNA demethylase and plays a role in diabetic vascular endothelial dysfunction. In the present study, we detected FTO protein expression in HUVECs by Western blot and found that FTO was highly expressed in all disease groups relative to the control group. To explore the mechanism of FTO in T2DM vasculopathy, we performed an analysis by methylated RNA immunoprecipitation sequencing (MeRIP-seq) to elucidate the role of aberrant m6A modification and mRNA expression in endothelial dysfunction. The results showed 202 overlapping genes with varying m6A modifications and varied mRNA expression, and GO and KEGG enrichment analysis revealed that these genes were predominantly enriched in pathways associated with T2DM complications and endothelial dysfunction. By an integrated analysis of MeRIP-seq and RNA-seq results, the IGV plots showed elevated kurtosis of downstream candidate gene modifications, which may be downstream targets for FTO to exercise biological functions. HOXA9 and PLAU mRNA expression levels were significantly down after FTO inhibition. In the current work, we set up a typological profile of the m6A genes among HUVECs as well as uncovered a hidden relationship between RNA methylation modifications for T2DM vasculopathy-associated genes. Taken together, this study indicates that endothelial functional impairment is present in T2DM patients and may be related to aberrant expression of FTO.

Hydrophilic reentrant SLIPS enabled flow separation for rapid water harvesting.

Water harvesting from air is desired for decentralized water supply wherever water is needed. When water vapor is condensed as droplets on a surface the unremoved droplets act as thermal barriers. A surface that can provide continual droplet-free areas for nucleation is favorable for condensation water harvesting. Here, we report a flow-separation condensation mode on a hydrophilic reentrant slippery liquid-infused porous surface (SLIPS) that rapidly removes droplets with diameters above 50 µm. The slippery reentrant channels lock the liquid columns inside and transport them to the end of each channel. We demonstrate that the liquid columns can harvest the droplets on top of the hydrophilic reentrant SLIPS at a high droplet removal frequency of 130 Hz/mm2. The sustainable flow separation without flooding increases the water harvesting rate by 110% compared to the state-of-the-art hydrophilic flat SLIPS. Such a flow-separation condensation approach paves a way for water harvesting.

Ultrasensitive Paper-Based Photoelectrochemical Biosensor for Acetamiprid Detection Enabled by Spin-State Manipulation and Polarity-Switching.

Efficient carrier separation is vitally crucial to improving the detection sensitivity of photoelectrochemical (PEC) biosensors. Here, we developed a facile strategy to efficiently regulate the carrier separation efficiency of the photoactive matrix BiOI and In2S3 signal label functionalized paper chip by manipulation of electrons spin-state and rational design of electron transport pathways. The spin-dependent electronic structures of BiOI and In2S3 were regulated via enhanced electron-spin parallel alignment induced by an external magnetic field, markedly retarding carrier recombination and extending their lifetime. Simultaneously, with the progress of the target-induced catalytic hairpin assembly process, the transfer path of photogenerated carriers was changed, leading to a switch in photocurrent polarity from cathode to anode. This reversed electron transport pathway not only boosted the separation ability of photogenerated electrons but also eliminated false-positive and false-negative signals, thereby further improving the detection sensitivity. As a proof of concept, the well-designed magnetic field-stimulated paper-based PEC biosensor showed highly selectivity and sensitivity for acetamiprid assay with a wide linear range of 1 fM to 20 nM and an ultralow detection limit of 0.73 fM. This work develops a universal strategy for improving the sensitivity of biosensors and exhibits enormous potential in the fields of bioanalysis and clinical diagnosis.

Exploring the mechanism underlying the therapeutic effects of butein in colorectal cancer using network pharmacology and single-cell RNA sequencing data.

BACKGROUND: Butein has shown substantial potential as a cancer treatment, but its precise mechanism of action in colorectal cancer (CRC) remains unclear. This study aimed to uncover the underlying mechanisms through which butein operates in CRC and to identify potential biomarkers through a comprehensive investigation. METHODS: Target genes associated with butein were sourced from SwissTargetPrediction, CTD, BindingDB and TargetNet. Gene expression data from the GSE38026 dataset and the single-cell dataset (GSE222300) were retrieved from the Gene Expression Omnibus database. The activation of disease-related pathways was assessed using Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and differential gene analysis. Disease-associated genes were identified through differential analysis and weighted gene co-expression network analysis (WGCNA). The protein-protein interaction network was utilized to pinpoint potential drug targets. Molecular complex detection (MCODE) analysis was employed to uncover relevant genes influenced by butein within key subgroup networks. Machine learning techniques were applied for the screening of potential biomarkers, with receiver operating characteristic curves used to evaluate their clinical significance. Single-cell analysis was conducted to assess the pharmacological targets of butein in CRC, with validation performed using the external dataset GSE40967. RESULTS: A total of 232 target genes for butein were identified. Functional enrichment analysis revealed significant enrichment of signaling pathways, including mitogen-activated protein kinase, JAK-STAT and NF-κB, among these genes. Differential analysis, in conjunction with WGCNA, yielded 520 disease-related genes. Subsequently, a disease-drug-gene network consisting of 727 targets was established, and a subnetwork containing 56 crucial genes was extracted. Important pathways such as the FoxO signaling pathway exhibited significant enrichment within these key genes. Machine learning applied to the 56 important genes led to the identification of a potential biomarker, UBE2C. Receiver operating characteristic analysis demonstrated the excellent clinical predictive utility of UBE2C. Single-cell analysis suggested that butein's therapeutic effects might be linked to its influence on epithelial and T cells, with UBE2C expression associated with these cell types. Validation using the external dataset GSE40967 further confirmed the exceptional clinical predictive capability of UBE2C. CONCLUSION: This study combines network pharmacology with single-cell analysis to unravel the mechanisms underlying butein's effects in CRC. Notably, UBE2C emerged as a promising biomarker with superior clinical efficacy. These research findings contribute significantly to our understanding of specific molecular mechanisms, potentially shaping future clinical practices.

First Insight into the Mobilization and Sequestration of Arsenic in a Karstic Soil during Redox Changes.

Karst terrains provide drinking water for about 25% of the people on our planet, particularly in the southwest of China. Pollutants such as arsenic (As) in the soil can infiltrate groundwater through sinkholes and bedrock fractures in karst terrains. Despite this, the underlying mechanisms responsible for As release from karst soils under redox changes remain largely unexplored. Here, we used multiple synchrotron-based spectroscopic analyses to explore As mobilization and sequestration in As-polluted karstic soil under biogeochemical conditions that mimic field-validated redox conditions. We observed that As in the soil exists primarily as As(V), which is mainly associated with Fe(oxyhydr)oxides. The concentration of the dissolved As was high (294 µM) and As(III) was dominant (∼95%) at low Eh (≤-100 mV), indicating the high risk of As leaching under reducing conditions. This As mobilization was attributed to the fact that the dissolution of ferrihydrite and calcite promoted the release and reduction of associated As(V). The concentration of the dissolved As was low (17.0 µM) and As(V) was dominant (∼68%) at high Eh (≥+100 mV), which might be due to the oxidation and/or sequestration of As(III) by the recrystallized ferric phase. Our results showed that the combined effects of the reductive release of As(V) from both ferric and nonferric phases, along with the recrystallization of the ferric phase, govern the redox-induced mobilization and potential leaching of As in soils within karst environments.

Synthetic routes and clinical application of Small-Molecule HER2 inhibitors for cancer therapy.

This comprehensive review undertakes a meticulous scrutiny of the synthesis and clinical applications pertaining to small-molecule tyrosine kinase inhibitors (TKIs) directed towards the human epidermal growth factor receptor 2 (HER2), a pivotal protagonist in the pathogenesis of cancer. Focused on compounds like lapatinib, neratinib, and tucatinib, the review delves into the intricate synthesis strategies, emphasizing the challenges associated with their structural complexity. The clinical utilization of HER2 TKIs underscores noteworthy strides in the therapeutic landscape for HER2-positive breast and gastric malignancies. Lapatinib, a dual HER2/ epidermal growth factor receptor (EGFR) inhibitor, has demonstrated efficacy in combination therapies, addressing the need for overcoming resistance mechanisms. Neratinib, an irreversible HER2 inhibitor, presents a promising avenue for patients with refractory tumors. Tucatinib, strategically engineered to traverse the blood-brain barrier, epitomizes a groundbreaking advancement in the management of metastatic HER2-positive breast cancer manifesting cerebral involvement. Despite their success, challenges such as resistance mechanisms and off-target effects persist, urging continuous research for the development of next-generation HER2 TKIs. This comprehensive review serves as a valuable resource for pharmaceutical scientists, offering insights into the synthetic intricacies and clinical impact of small-molecule TKIs targeting HER2.

LSM14B controls oocyte mRNA storage and stability to ensure female fertility.

Controlled mRNA storage and stability is essential for oocyte meiosis and early embryonic development. However, how to regulate mRNA storage and stability in mammalian oogenesis remains elusive. Here we showed that LSM14B, a component of membraneless compartments including P-body-like granules and mitochondria-associated ribonucleoprotein domain (MARDO) in germ cell, is indispensable for female fertility. To reveal loss of LSM14B disrupted primordial follicle assembly and caused mRNA reduction in non-growing oocytes, which was concomitant with the impaired assembly of P-body-like granules. 10× Genomics single-cell RNA-sequencing and immunostaining were performed. Meanwhile, we conducted RNA-seq analysis of GV-stage oocytes and found that Lsm14b deficiency not only impaired the maternal mRNA accumulation but also disrupted the translation in fully grown oocytes, which was closely associated with dissolution of MARDO components. Moreover, Lsm14b-deficient oocytes reassembled a pronucleus containing decondensed chromatin after extrusion of the first polar body, through compromising the activation of maturation promoting factor, while the defects were restored via WEE1/2 inhibitor. Together, our findings reveal that Lsm14b plays a pivotal role in mammalian oogenesis by specifically controlling of oocyte mRNA storage and stability.

Safety and efficacy of stoma site selection in CT-guided percutaneous gastrostomy: a retrospective analysis.

PURPOSE: To compare the safety and efficacy of CPG in the rectus abdominis and intercostal regions. MATERIALS AND METHODS: This retrospective study included 226 patients who underwent CPG at a single center, with the stoma placed in the rectus abdominis or intercostal region. Surgical outcomes and complications, such as pain and infection within 6 months postoperatively, were recorded. RESULTS: The surgical success rate was 100%, and the all-cause mortality rate within 1 month was 0%. An intercostal stoma was placed in 56 patients; a rectus abdominis stoma was placed in 170 patients. The duration of surgery was longer for intercostal stoma placement (37.66 ± 14.63 min) than for rectus abdominis stoma placement (30.26 ± 12.40 min) (P = 0.000). At 1 month postsurgery, the rate of stoma infection was greater in the intercostal group (32.1%) than in the rectus abdominis group (20.6%), but the difference was not significant (P = 0.077). No significant difference was observed in the infection rate between the two groups at 3 or 6 months postsurgery (P > 0.05). Intercostal stoma patients reported higher pain scores during the perioperative period and at 1 month postsurgery (P = 0.000), but pain scores were similar between the two groups at 3 and 6 months postsurgery. The perioperative complication rates for intercostal and rectus abdominis surgery were 1.8% and 5.3%, respectively (P = 0.464), with no significant difference in the incidence of tube dislodgement (P = 0.514). Patient weight improved significantly at 3 and 6 months postoperatively compared to preoperatively (P < 0.05). CONCLUSION: Rectus abdominis and intercostal stomas have similar safety and efficacy. However, intercostal stomas may result in greater short-term patient discomfort.

Physiology and molecular basis of thallium toxicity and accumulation in Arabidopsis thaliana.

Thallium (Tl) is a non-essential metal mobilized through industrial processes which can lead to it entering the environment and exerting toxic effects. Plants are fundamental components of all ecosystems. Therefore, understanding the impact of Tl on plant growth and development is of great importance for assessing the potential environmental risks of Tl. Here, the responses of Arabidopsis thaliana to Tl were elucidated using physiological, genetic, and transcriptome analyses. Thallium can be absorbed by plant roots and translocated to the aerial parts, accumulating at comparable concentrations throughout plant parts. Genetic evidence supported the regulation of Tl uptake and movement by different molecular compartments within plants. Thallium primarily caused growth inhibition, oxidative stress, leaf chlorosis, and the impairment of K homeostasis. The disturbance of redox balance toward oxidative stress was supported by significant differences in the expression of genes involved in oxidative stress and antioxidant defense under Tl exposure. Reduced GSH levels in cad2-1 mutant rendered plants highly sensitive to Tl, suggesting that GSH has a prominent role in alleviating Tl-triggered oxidative responses. Thallium down-regulation of the expression of LCHII-related genes is believed to be responsible for leaf chlorosis. These findings illuminate some of the mechanisms underlying Tl toxicity at the physiological and molecular levels in plants with an eye toward the future environment management of this heavy metal.

Roles of centrioles in neural attraction of dental pulp stem cells.

BACKGROUND/PURPOSE: Human nerve development is vital, affecting trauma recovery and dental issues. Early embryonic clues link nerves to tooth development via factors like Wnt and Hedgehog pathways. Centrosomes play a role, and centriole issues can disrupt oral development, as in oral facial digital syndrome type 1. This study aimed to delve deeper into the role and influence of centrioles on the development of dental nerves. METHODS: Cell migration assessed by co-culturing mouse neural tissue and human dental pulp stem cells (DPSCs). Centrioles were fluorescently stained, and their positions observed with confocal microscopy. Centrinone was employed to inhibit centriole activity, evaluating its impact on cell mobility under activity inhibition. RESULTS: As the distance between nerve tissue and DPSCs decreased, more DPSCs had centrioles near nerve tissue. Co-culture with nerve tissue increased DPSCs migration toward it. In contrast, DPSCs cultured alone or with fibroblasts showed weaker migration, indicating neural tissue's attractive influence. The addition of 125 nM centrinone halted cell migration and centriole polymerization. After centrinone removal over two days, centrioles returned to normal, suggesting continued motility inhibition. CONCLUSION: Centrioles direct cell movement and polarization. There are two scenarios: centrioles at the cell center with the nucleus moving backward (as in NIH3T3 cells) and both cells and centrioles moving forward (as in DPSCs). DPSCs' attraction to neural tissue may shed light on nerve guidance by tooth germs, aiding embryonic cell differentiation into nerves. However, further in vivo and in vitro studies are needed to confirm the specific mechanism.

Tetrahedral DNA Nanostructure-Engineered Paper-Based Sensor with an Enhanced Antifouling Ability for Photoelectrochemical Sensing.

Herein, a newly designed two-in-one tetrahedral DNA (TDN) nanostructure with an antifouling surface and backbone-rigidified interfacial tracks was developed for highly sensitive and selective detection of miRNA-182-5p. The well-regulated TDN tracks were assembled onto the surface of the TiO2/MIL-125-NH2-functionalized paper electrode, which efficiently avoided the obstacle of DNA strand tangling and decreased the probability of suspension during the walking process, thus greatly promoting the moving efficiency of DNA walkers. More interestingly, the TDN-modified sensing interfaces demonstrated incomparable antifouling ability against protein samples and interfering miRNAs due to the strong hydrophilic capacity and special molecular conformations, which addressed the dilemma of low sensitivity from traditional antifouling coating strategies. As a proof of concept, the designed bifunctional tetrahedron-modified paper-based photoelectrochemical sensor was successfully used to quantify miRNA-182-5p with a low detection limit of 0.09 fM and high specificity and was validated for monitoring of miRNA-182-5p in real samples. This TDN-engineered biointerface could be used as a universal platform for tracking various targets by substituting the biorecognition events, providing great promise for bioanalysis and clinical diagnosis.

Sensitive and reliable analysis of endometrial cancer related microRNA using ternary hybridization hairpin probe.

MicroRNA (miRNA), as a kind of small non-coding ribonucleic acid (RNA) that plays a crucial role in regulating transcriptional activities, is a potential biomarker for EC diagnosis. However, reliable detection of miRNA remains a huge challenge, especially for these methods that require multiple probes for signal amplifications, due to the detective deviation caused by variation of probe concentrations. Herein, we present a novel approach for miRNA-205 identification and quantification by employing simply a ternary hairpin probe (TH probe). The ternary hybridization of three sequences results in the construction of the TH probe, which combines high-efficient signal amplification and specific target recognition. A significant number of G-rich sequences have been produced as a result of the enzymes assisted signal amplification process. The G-rich sequences can fold into G-quadruplexes, which can then be detected in a label-free manner by a common fluorescent dye (thioflavin T). Eventually, the approach exhibits a low limit of detection of 278 aM with a wide detection range of 7 orders of magnitude. In summary, the proposed approach possesses a great potential for both clinical diagnosis of EC and fundamental biomedical researches.

Single-cell RNA sequencing of the Mongolia sheep testis reveals a conserved and divergent transcriptome landscape of mammalian spermatogenesis.

Spermatogenesis is a highly coordinated and complex process, and is pivotal for transmitting genetic information between mammalian generations. In this study, we investigated the conservation, differences, and biological functions of homologous genes during spermatogenesis in Mongolia sheep, humans, cynomolgus monkey, and mice using single-cell RNA sequencing technology. We compared X chromosome meiotic inactivation events in Mongolia sheep, humans, cynomolgus monkey, and mice to uncover the concerted activity of X chromosome genes. Subsequently, we focused on the dynamics of gene expression, key biological functions, and signaling pathways at various stages of spermatogenesis in Mongolia sheep and humans. Additionally, the ligand-receptor networks of Mongolia sheep and humans in testicular somatic and germ cells at different developmental stages were mapped to reveal conserved germ cell-soma communication using single-cell resolution. These datasets provided novel information and insights to unravel the molecular regulatory mechanisms of Mongolia sheep spermatogenesis and highlight conservation in gene expression during spermatogenesis between Mongolia sheep and humans, providing a foundation for the establishment of a large mammalian disease model of male infertility.

The merging of dual umbilical port-incisions for contained morcellation in laparoscopic myomectomy.

Uncontained power morcellation during laparoscopic myomectomy may spread tissue fragments or malignant cells into the abdominal cavity. Recently, various approaches to contained morcellation, have been adopted to retrieve the specimen. However, each of these methods has its own drawbacks. Intraabdominal bag-contained power morcellation adopts a complex isolation system, which prolongs the operation and increases medical costs. Contained manual morcellation via colpotomy or mini-laparotomy increases the trauma and the risk of infection. Contained manual morcellation via umbilical incision during single-port laparoscopic myomectomy may be the most minimally invasive and cosmetic approach. But the popularization of single-port laparoscopy is challenging because of technical difficulties and high costs. We have therefore, developed a surgical technique using 2 umbilical port-incisions (5 mm and 10 mm), which are merged into 1 large umbilical incision (25-30mm) for contained manual morcellation during specimen retrieval, and one 5mm incision in the lower left abdomen for an ancillary instrument. As demonstrated in the video, this technique significantly facilitates surgical manipulation using conventional laparoscopic instruments while still keeping the incisions minimal. It is also economical because the use of an expensive single-port platform and special surgical instruments is avoided. In conclusion, the merging of dual umbilical port-incisions for contained morcellation adds a minimally invasive, cosmetic, and economical option to laparoscopic specimen retrieval that would enrich a gynecologist's skill set, which is particularly relevant in a low-resource settings.

Involvement of Microplastics in the Conflict Between Host Immunity Defense and Viral Virulence: Promoting the Susceptibility of Shrimp to WSSV Infection.

As the concentration of microplastics/microspheres (MPs) in coastal and estuarine regions increases, the likelihood of disease outbreaks and epidemics also rises. Our study investigated the impact of polyvinyl chloride MPs (PVC-MPs) on white spot syndrome virus (WSSV) infection in shrimp. The results revealed that PVC-MPs obviously increased WSSV replication in vivo, leading to a high mortality rate among the larvae and facilitating the horizontal transmission of WSSV. Furthermore, the data of WSSV loads detected together with qPCR, agarose gel electrophoresis, and flow cytometry approaches indicated that PVC-MPs could interact with the virus to prolong survival and maintain the virulence of WSSV at different temperatures and pH values. In terms of host resistance, metabolomics and transcriptomics analysis demonstrated that exposure to PVC-MPs upregulated metabolic concentrations and gene expressions associated with phospholipid metabolism that were associated with innate immunity responses. Particularly, PVC-MPs stimulated the synthesis of phosphatidylcholine (PC) and induced lipid peroxidation. The inhibition of PC on Stimulator of Interferon Genes (STING) translocation from the endoplasmic reticulum to the Golgi apparatus reduces expression of the innate immunity genes (IFN-like genes Vago4 and Vago5) regulated by STING signaling pathways, resulting in a significant decrease in the shrimp's resistance to WSSV infection. Notably, a recovery operation in which the exposed larvae were transferred to a MPs-free aquatic environment led to decreased WSSV infectivity over time, indicating the restoration of antiviral properties in shrimp. Overall, these findings highlight that MPs promote shrimp susceptibility to WSSV in two aspects: host immune defense and viral virulence.

Health benefits of on-road transportation pollution control programs in China.

China started to implement comprehensive measures to mitigate traffic pollution at the end of 1990s, but the comprehensive effects, especially on ambient air quality and public health, have not yet been systematically evaluated. In this study, we analyze the effects of vehicle emission control measures on ambient air pollution and associated deaths attributable to long-term exposures of fine particulate matter (PM2.5) and O3 based on an integrated research framework that combines scenario analysis, air quality modeling, and population health risk assessment. We find that the total impact of these control measures was substantial. Vehicular emissions during 1998-2015 would have been 2-3 times as large as they actually were, had those measures not been implemented. The national population-weighted annual average concentrations of PM2.5 and O3 in 2015 would have been higher by 11.7 µg/m3 and 8.3 parts per billion, respectively, and the number of deaths attributable to 2015 air pollution would have been higher by 510 thousand (95% confidence interval: 360 thousand to 730 thousand) without these controls. Our analysis shows a concentration of mortality impacts in densely populated urban areas, motivating local policymakers to design stringent vehicle emission control policies. The results imply that vehicle emission control will require policy designs that are more multifaceted than traditional controls, primarily represented by the strict emission standards, with careful consideration of the challenges in coordinated mitigation of both PM2.5 and O3 in different regions, to sustain improvement in air quality and public health given continuing swift growth in China's vehicle population.

Comparison of periodontal health of primary teeth restored with zirconia and stainless steel crowns: A systemic review and meta-analysis.

BACKGROUND/PURPOSE: In children, the use of stainless steel crowns to treat caries has a high success rate. However, due to the unnatural color of stainless steel crowns, it still needs to modify crown types. The present meta-analysis study aims to explore the previous articles on the comparison of stainless steel crowns and zirconia crowns. METHODS: The systematic search of studies on the comparison of zirconia crowns and stainless steel crowns for primary teeth was mainly in PubMed and Cochrane database. The standardized mean differences (SMDs) of gingival health between zirconia crowns and stainless steel crowns comprised the primary outcome, and the SMDs of plaque index compared two crown treatments was treated as the secondary outcome. RESULTS: The meta-analysis extracted 187 papers from various databases and collected five randomized controlled trials, four comparisons on deciduous molars and one comparison on deciduous incisors. 160 children were included, ranging in age from 3-9 years old. The quantitative analysis showed a significantly lower gingival index of zirconia crowns in the primary molar group and the primary incisor group. The plaque index between two crown treatments groups was -4.51, indicating less accumulation of plaque on zirconia crown. However, the heterogeneity of included trials still need to be considered. CONCLUSION: Zirconia crowns for deciduous teeth had its advantages for gingival health. Although stainless steel crowns were more likely to have plaque deposition and gingival inflammation, zirconia crowns relatively caused the opposite tooth wearing and chipping. Therefore, the comprehensive consideration is important to choose deciduous tooth crown.

Berberine at sub-inhibitory concentration inhibits biofilm dispersal in Staphylococcus aureus.

Staphylococcus aureus is a major human pathogen, which has multiple drug resistance and can cause serious infections. Recent studies have shown that berberine has antibacterial activity and it can affect biofilm formation of S. aureus. However, the berberine effect on the biofilm of S. aureus is controversial. In this study, we investigate the effect of berberine on the biofilm development in S. aureus NCTC8325 and explore the possible mechanism. Susceptibility test shows that berberine inhibits growth of methicillin-sensitive S. aureus (MSSA), methicillin-resistant S. aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) at different concentrations. S. aureus NCTC8325 is chosen as a model strain to explore further the berberine effect. The MIC of berberine for S. aureus NCTC8325 is 256 µg ml-1. Berberine below 32 µg ml-1 inhibits the dispersal of biofilm and stimulates clumping of cells of NCTC8325 in a concentration-dependent manner, while not showing obvious inhibition on the bacterial growth. The transcription of the key negative regulator of biofilm dispersal AgrA is decreased and an agrA mutant forms biofilm reaching to a similar level of biomass to WT in the presence of berberine at 32 µg ml-1. Transcription of some genes involving synthesis of biofilm structure components, including polysaccharide intracellular adhesin (PIA), proteins and eDNA were also up-regulated, especially icaA for PIA synthesis. And consistently, PIA content was increased in cells exposed to berberine at 32 µg ml-1. This study reveals the dependence of berberine inhibition of biofilm dispersal on the Agr system, which is the first report exploring the molecule mechanism of the berberine effect on the biofilm of S. aureus.

Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study.

BACKGROUND: Central nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings. METHODS: In this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Sixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone. CONCLUSIONS: Our study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.

Remote-controlled cholangiography injection device: first clinical study in China.

BACKGROUND: X-ray cholangiography is of great value in the imaging of biliary tract diseases; however, occupational radiation exposure is unavoidable. Moreover, clinicians must manually inject the contrast dye, which may result in a relatively high incidence of adverse reactions due to unstable injection pressure. Thus, there is a need to develop a novel remote-controlled cholangiography injection device. METHODS: Patients with external biliary drainage requiring cholangiography were included. A remote-controlled injection device was developed with three major components: an injection pump, a pressure sensor, and a wireless remote-control panel. Image quality, adverse reactions, and radiation dose were evaluated. RESULTS: Different kinds of X-ray cholangiography were successfully and smoothly performed using this remote-controlled injection device in all patients. The incidence of adverse reactions in the device group was significantly lower than that in the manual group (4.17% vs. 13.9%, P = 0.001), and increasing the injection pressure increased the incidence of adverse reactions. In addition, the device helped operators avoid ionizing radiation completely. CONCLUSIONS: With good control of injection pressure (within 10 kPa), the remote-controlled cholangiography injection device could replace the need for the doctor to inject contrast agent with good security and effectivity. It is expected to be submitted for clinical application.