BTK kinase activity is dispensable for the survival of diffuse large B-cell lymphoma.

Inhibitors targeting Bruton's tyrosine kinase (BTK) have revolutionized the treatment for various B-cell malignancies but are limited by acquired resistance after prolonged treatment as a result of mutations in BTK. Here, by a combination of structural modeling, in vitro assays, and deep phospho-tyrosine proteomics, we demonstrated that four clinically observed BTK mutations-C481F, C481Y, C481R, and L528W-inactivated BTK kinase activity both in vitro and in diffused large B-cell lymphoma (DLBCL) cells. Paradoxically, we found that DLBCL cells harboring kinase-inactive BTK exhibited intact B cell receptor (BCR) signaling, unperturbed transcription, and optimal cellular growth. Moreover, we determined that DLBCL cells with kinase-inactive BTK remained addicted to BCR signaling and were thus sensitive to targeted BTK degradation by the proteolysis-targeting chimera. By performing parallel genome-wide CRISPR-Cas9 screening in DLBCL cells with WT or kinase-inactive BTK, we discovered that DLBCL cells with kinase-inactive BTK displayed increased dependence on Toll-like receptor 9 (TLR9) for their growth and/or survival. Our study demonstrates that the kinase activity of BTK is not essential for oncogenic BCR signaling and suggests that BTK's noncatalytic function is sufficient to sustain the survival of DLBCL.

Employment of the Phage Cocktail as a Species-Specific Recognition Agent for Wide-Spectrum Detection of Bacterial Strains.

Phages have already been employed to detect bacteria because of their specific recognition capability and strong infectious activity toward their host. However, the reported single-phage-based techniques are inevitably restricted by false negative results that arose from extremely high strain specificity of phages. In this study, a cocktail composed of three Klebsiella pneumoniae (K. pneumoniae) phages was prepared as a recognition agent to broaden the recognition spectrum for detecting this bacterial species. A total of 155 clinically isolated strains of K. pneumoniae collected from four hospitals were adopted to test its recognition spectrum. A superior recognition rate of 91.6% for the strains was achieved due to the complementarity of the recognition spectra of the three phages composed of the cocktail. However, the recognition rate is as low as 42.3-62.2% if a single phage is employed. Based on the wide-spectrum recognition capability of the phage cocktail, a fluorescence resonance energy transfer method was established for detecting K. pneumoniae strains by employing fluorescein isothiocyanate labeled to the phage cocktail and Au nanoparticles labeled to p-mercaptophenylboronic acid as energy donors and acceptors, respectively. The detection process can be completed within 35 min, with a wide dynamic range of 5.0 × 102-1.0 × 107 CFU/mL. The application potential was verified by applying it to quantitate K. pneumoniae in different sample matrixes. This pioneer work opens an avenue for achieving wide-spectrum detection of different strains belonging to the same bacterial species with the phage cocktail.

Mn Single-Atom Nanozymes with Superior Loading Capability and Superb Superoxide Dismutase-like Activity for Bioassay.

Single-atom nanozymes (SANs) with highly exposed active sites and remarkable catalytic activity have shown noteworthy practicability in heterogeneous catalysis-based bioassay. Nevertheless, most of them were reported with peroxidase-like activity and ordinary loading capability. It is still a challenge to prepare high-loading SANs with desirable superoxide dismutase (SOD)-like activity. In this work, Mn SAN was successfully confined in the frameworks of Prussian blue analogues formed on Ti3C2 MXene sheets with the assistance of massive surfactants, which show a superior loading efficiency of 13.5 wt % (typically <2.0 wt %). The prepared Mn SAN exhibits desirable superoxide radical anion elimination capability because of its SOD-like activity. Moreover, due to the wide-spectrum absorption behavior of the carriers, Mn SAN shows a synergistically quenching efficiency up to 98.89% on the emission of the reactive oxygen species-mediated chemiluminescent (CL) system. Inspired by these features, a CL quenching method was developed on a lateral flow test strip platform by utilizing Mn SAN as a signal quencher and acetamiprid as a model analyte. The method for detecting acetamiprid shows a detection range of 1.0-10,000 pg mL-1 and a limit of detection of 0.3 pg mL-1. Its accuracy has been validated by detecting acetamiprid in medicinal herbs with acceptable recoveries. This work opens an avenue for preparing SANs with a surfactant-assisted protocol and pioneers the study of SANs with SOD-like activity in bioassay.

Cobalt Species-Loaded MOFs as Chemiluminescent Catalysts for Monitoring Carbendazim.

The application of active metal-based nanoscale catalysts as signal enhancers for chemiluminescent immunoassay (CLIA) is restricted by poor thermodynamic stability and ease of aggregation. For the present exploration, zirconium-based MOFs UiO-66-NH2 were adopted as supports to load cobalt species by an impregnation-reduction approach. Cobalt species were uniformly distributed in the framework architecture of the MOF materials. The prepared cobalt-loaded MOF hybrids, noted as UiO-66-NH2/Co, display superior chemiluminescence (CL) catalytic activity owing to the introduction of cobalt catalytic centers. The CL catalytic capability of UiO-66-NH2/Co hybrids is about 18 times of that of free cobalt ions at the same cobalt amount. The results of mechanism exploration manifest that the hybrids are capable of accelerating the decay of hydrogen peroxide and promoting the yield of reactive oxygen species. Based on their remarkable CL catalytic capability, a CLIA approach was proposed to monitor carbendazim by adopting the hybrids as signal probes, which showed the merits of high sensitivity and satisfactory selectivity. Carbendazim was quantitated within a concentration range of 0.05 to 60 ng mL-1, with a detection limit of 19.8 pg mL-1. The results for monitoring spiked samples verify the acceptable practicality of the proposed CLIA approach.

TRPM2 facilitates tumor progression of clear cell renal cell carcinoma by relieving Endoplasmic Reticulum Stress.

Clear cell renal cell carcinoma (ccRCC) has the highest incidence rate among all pathological types of kidney cancers. Although the role of transient receptor potential (TRP) ion channel TRPM2 has been studied in many cancers, its function in ccRCC is still unexplored. In this study, using the KIRC module of TCGA, we found that TRPM2 was upregulated in ccRCC tissues and was related to poor prognosis. Gene set enrichment analysis (GSEA) showed that TRPM2 was related to epithelial-to-mesenchymal transition (EMT), TCA cycle, fatty acid metabolism, and immune system-related functions. Functional experimental results indicated that TRPM2 could promote ccRCC progression. Furthermore, mechanism analysis showed that knocking out TRPM2 can reverse these phenotypes by increasing endoplasmic reticulum stress and decreasing EMT. We also investigated the potential role of TRPM2 in immune cell infiltration in the tumor microenvironment. Our study indicated that TRPM2 promotes ccRCC progression and may be a novel target for ccRCC therapy.

In-capillary screening and quantifying the antioxidants of Yangxinshi Tablet using field-enhanced sample injection-micellar electrokinetic chromatography.

An in-capillary 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) as oxyradicals combining field-enhanced sample injection with micellar electrokinetic chromatography was developed for screening and determination of the major antioxidants in Yangxinshi Tablet. To obtain simultaneous separation and detection of radicals and analytes, relevant factors were optimized separately. Under the optimum conditions, four compounds including salvianolic acid B, hyperoside, puerarin, and caffeic acid were identified as the major antioxidants. All validation results covering recovery, precision, and stability demonstrated good applicability of the method. On this basis, the total antioxidant activity was successfully evaluated in terms of the decreased peak area of radicals. There was a correlation coefficient of 0.8974 between the total contents of major antioxidants and the total antioxidative activity of the sample. Therefore, these four compounds were selected as combinatorial markers for the quality evaluation of Yangxinshi Tablet. It was concluded that the established method presented a powerful potential to screen and quantify active ingredients in the complex preparation of Chinese medicine.

KDELR2-KIF20A axis facilitates bladder cancer growth and metastasis by enhancing Golgi-mediated secretion.

BACKGROUND: Bladder cancer (BCa) is a fatal form of cancer worldwide associated with a poor prognosis. Identifying novel drivers of growth and metastasis hold therapeutic potential for the disease. Transport homeostasis between the endoplasmic reticulum and Golgi and the secretion of matrix metalloproteinases (MMPs) mediated by Golgi have been reported to be closely associated with tumor progression. However, to date, mechanistic studies remain limited. RESULTS: Here, we identified KDELR2 as a potential risk factor with prognostic value in patients with BCa, especially those harbouring the KDELR2 amplification. In addition, we found that KDELR2 is a regulator of BCa cell proliferation and tumorigenicity based on bioinformatic analysis with functional studies. Mechanistically, we revealed that KDELR2 could regulate the expression of KIF20A, thus stimulating the expression of MMP2, MMP9 and MKI67. Functionally, the overexpression of KDELR2 and KIF20A markedly promoted proliferation, migration, and invasion in vitro and enhanced tumor growth in vivo, while knockdown of KDELR2 and KIF20A exerted the opposite effects. And the overexpression of KDELR2 also enhanced lymph node metastasis in vivo. CONCLUSIONS: Collectively, our findings clarified a hitherto unexplored mechanism of KDELR2-KIF20A axis in increasing Golgi-mediated secretion of MMPs to drive tumor progression in BCa.

M2-polarization-related CNTNAP1 gene might be a novel immunotherapeutic target and biomarker for clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies, characterized by high mortality rate in urology. Unfortunately, reliable biomarkers for ccRCC diagnosis and prognosis remain lacking. Contactin-associated protein 1 (CNTNAP1) has yet to be thoroughly investigated in cancer, especially its relationship with immune infiltration or clinical outcomes of ccRCC. Here, we explored The Cancer Genome Atlas Kidney Clear Cell Carcinoma database (TCGA-KIRC) for prognostic significance, differential expression, and probable mechanism of CNTNAP1. The aberrant CNTNAP1 expression was also validated by the International Cancer Genome Consortium (ICGC) and ccRCC clinic samples. We used Database for Annotation, Visualization, and Integrated Discovery to perform the GO and KEGG enrichment. TIMER database was further utilized to assess its correlation with immune infiltration in ccRCC. The CellMiner database was used to analyze the relationship between CNTNAP1 expression and drug sensitivity. Results showed CNTNAP1 was upregulated in TCGA-KIRC, ICGC, and clinic samples. And CNTNAP1 expression was positively related to infiltration levels of cancer-associated fibroblast, regulatory T cells, and myeloid-derived suppressor cells, while negatively related to eosinophils. Furthermore, we observed CNTNAP1 was appreciably positively associated with alternatively activated macrophage (M2) in ccRCC. Finally, high CNTNAP1 expression was negatively correlated with nilotinib, crizotinib, eribulin mesylate, and vinorelbine. Collectively, these results strongly suggest that CNTNAP1 might act as an immunotherapeutic target and a promising novel biomarker for ccRCC.

Evaluation of mild cognitive impairment genetic susceptibility risks in a Chinese population.

BACKGROUND: Mild cognitive impairment (MCI) is a kind of non-functional cognitive decline between normal aging and dementia. With the increase of individual age, the quality of cognitive function has become a more and more important topic. The study of gene loci in patients with MCI is essential for the prevention of dementia. In this study, we evaluate the gene polymorphism in Chinese Han patients with MCI by propensity score matching (PSM) and comparing them to healthy control (HC) subjects. METHODS: Four hundred seventeen patients with mild cognitive impairment and 508 healthy people were included. The two groups were matched by applying one-to-one PSM, and the matching tolerance was set to 0.002. The matching covariates included gender,age,occupation,marital status,living mode. Then, a case-control associated analysis was conducted to analyze the genotype and allele frequencies of single nucleotide polymorphisms (SNPs) in the MCI group and the control group. RESULTS: Three hundred eleven cases were successfully matched in each group, and there was no statistical difference on all the matching variables, gender, age, occupation, marital status, living mode between two groups after the match (P > 0.05). The allele frequency of bridging integrator 1(BIN1) rs7561528 showed minimal association with MCI in the Han Chinese population (P = 0.01). Compared with the healthy control (HC) group, A allele frequency of MCI group patients was significantly decreased. The genotype frequency of BIN1 rs6733839 showed minimal association with MCI in the recessive model (P = 0.03). The genotype frequency of rs7561528 showed minimal association with MCI in the codominant, dominant, overdominant, and log-additive model (P < 0.05). The genotype frequencies of StAR-related lipid transfer domain 6 (STARD6) rs10164112 showed nominal association with MCI in the codominant, dominant, and log-additive model (P < 0.05). Unfortunately, the significant differences did not survive Benjamini-Hochberg false discovery rate correction (adjusted P > 0.05). The patients with SPI1 rs1057233 may be the protective factor of MCI (OR = 0.733, 95%CI 0.625-0.859, P < 0.001), and patients with APOE rs10164112 may be a risk factor for MCI (OR = 1.323, 95%CI 1.023-1.711, P = 0.033). CONCLUSIONS: The polymorphisms of rs7561528, rs6733839 loci in the BIN1 gene, and rs1057233 loci in the SPI1 gene may be associated with the MCI in Chinese Han population. APOE gene was the risk factor of MCI, but further verification in a large sample population is still needed.

Solute carrier family 16 member 5 downregulation and its methylation might serve as a prognostic indicator of prostate cancer.

Prostate cancer (PCa), characterized by high invasion, metastasis, and recurrence, is the most prevalent malignant tumor in men worldwide. A clear understanding of the underlying molecular mechanisms and their role during PCa tumorigenesis can help develop prognostic and targeted therapies. We analyzed datasets from public databases, including the Cancer Genome Atlas (TCGA) and Oncomine and Gene Expression Profiling Interactive Analysis for differential expression of solute carrier family 16 member 5 (SLC16A5). We further investigated its relationship with clinical stage, pathological grade, and prognosis of PCa. The promoter methylation level of SLC16A5 in PCa was also investigated by UALCAN. We also utilized datasets from UCSC Xena to explore the prognostic role of SLC16A5 methylation levels and CpG site. Correlations between SLC16A5 and immune infiltration were discovered through TIMER. We observed significantly lower levels of SLC16A5 mRNA in PCa relative to normal tissues across six datasets from Oncomine database (p < .001) and 498 cases from TCGA database (p < .0001). SLC16A5 is strongly negatively regulated by its DNA methylation, with a Spearman of -0.81 and Pearson of -0.80 (p < .001). The aberrant SLC16A5 expression resulted in a significant relationship with clinical stage, pathological grade, and lower SLC16A5 mRNA expression, and its hypermethylation was related to a poorer PCa prognosis. SLC16A5 acted as an important factor for PCa diagnosis, with an AUC of 0.9038 (95% CI: 0.8597-0.9479; p < .0001). Besides, the aberrant SLC16A5 expression revealed close correlations with multiple immune cells. Overall, these results indicate that decreased SLC16A5 expression might be a potential biomarker for determining prognosis and immune infiltration in PCa. The positive SLC16A5 modulation might be a promising therapeutic target for PCa.

Interaction between piperine and genes associated with sciatica and its mechanism based on molecular docking technology and network pharmacology.

Piperine is the main active component of Piper longum L., which is also the main component of anti-sciatica Mongolian medicine Naru Sanwei pill. It has many pharmacological activities such as anti-inflammatory and immune regulation. This paper aims to preliminarily explore the potential mechanism of piperine in the treatment of sciatica through network pharmacology and molecular docking. TCMSP, ETCM database and literature mining were used to collect the active compounds of Piper longum L. Swiss TargetPrediction and SuperPred server were used to find the targets of compounds. At the same time, CTD database was used to collect the targets of sciatica. Then the above targets were compared and analyzed to select the targets of anti-sciatica in Piper longum L. The Go (gene ontology) annotation and KEGG pathway of the targets were enriched and analyzed by Metascape database platform. The molecular docking between the effective components and the targets was verified by Autodock. After that, the sciatica model of rats was established and treated with piperine. The expression level of inflammatory factors and proteins in the serum and tissues of rat sciatic nerve were detected by ELISA and Western blot. HE staining and immunohistochemistry were carried out on the sciatica tissues of rats. The results showed that Piper longum L. can regulate the development of sciatica and affect the expressions of PPARG and NF-kB1 through its active ingredient piperine, and there is endogenous interaction between PPARG and NF-kB1.

Study on the effect of Mongolian medicine Qiwei Qinggan Powder on hepatic fibrosis through JAK2/STAT3 pathway.

This research aimed to evaluate the antihepatic fibrosis effect and explore the mechanism of Qiwei Qinggan Powder (QGS-7) in vivo and in vitro. Carbon tetrachloride (CCl4)-treated rats and hepatic stellate cells (HSCs) were used. QGS-7 treatment significantly improved the liver function of rats as indicated by decreased serum enzymatic activities of alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. Meanwhile, the hydroxyproline of liver was significantly decreased. Histopathological results indicated that QGS-7 alleviated liver damage and reduced the formation of fibrosis septa. Moreover, QGS-7 significantly attenuated expressions of Alpha smooth muscle actin, Collagen I, Janus kinase 2 (JAK2), phosphorylation-JAK2, signal transducer and activator of transcription 3 (STAT3), phosphorylation-STAT3 in the rat hepatic fibrosis model. QGS-7 inhibited HSC proliferation and promoted it apoptosis. QGS-7 may affect hepatic fibrosis through JAK2/STAT3 signaling pathway so as to play an antihepatic fibrosis role.

Suppression of Tafazzin promotes thyroid cancer apoptosis via activating the JNK signaling pathway and enhancing INF2-mediated mitochondrial fission.

Tafazzin has been found to be associated with tumor progression. Mitochondrial homeostasis regulates cancer cell viability and metastasis. However, the roles of Tafazzin and mitochondrial homeostasis in thyroid cancer have not been explored. The aim of our study is to investigate the influences of Tafazzin on thyroid cancer apoptosis with a focus on mitochondrial fission. Our results indicated that Tafazzin deletion induced death in thyroid cancer via apoptosis. Biological analysis demonstrated that mitochondrial stress, including mitochondrial bioenergetics disorder, mitochondrial oxidative stress, and mitochondrial apoptosis, was activated by Tafazzin deletion. Furthermore, we found that Tafazzin affected mitochondrial stress by triggering inverted formin 2 (INF2)-related mitochondrial fission. The loss of INF2 sustained mitochondrial function and promoted cancer cell survival. Molecular investigation illustrated that Tafazzin regulated INF2 expression via the JNK signaling pathway; moreover, the blockade of JNK prevented Tafazzin-mediated INF2 expression and improved cancer cell survival. Taken together, our results highlight the key role of Tafazzin as a master regulator of thyroid cancer viability via the modulation of INF2-related mitochondrial fission and the JNK signaling pathway. These findings defined Tafazzin deletion and INF2-related mitochondrial fission as tumor suppressors that act by promoting cancer apoptosis via the JNK signaling pathway, with potential implications for new approaches to thyroid cancer therapy.

An Experimental Study of the Effects of External Physiological Parameters on the Photoplethysmography Signals in the Context of Local Blood Pressure (Hydrostatic Pressure Changes).

A comprehensive study of the effect of a wide range of controlled human subject motion on Photoplethysmographic signals is reported. The investigation includes testing of two separate groups of 5 and 18 subjects who were asked to undertake set exercises whilst simultaneously monitoring a wide range of physiological parameters including Breathing Rate, Heart Rate and Localised Blood Pressure using commercial clinical sensing systems. The unique finger mounted PPG probe equipped with miniature three axis accelerometers for undertaking this investigation was a purpose built in-house version which is designed to facilitate reproducible application to a wide range of human subjects and the study of motion. The subjects were required to undertake several motion based exercises including standing, sitting and lying down and transitions between these states. They were also required to undertake set arm movements including arm-swinging and wrist rotation. A comprehensive set of experimental results corresponding to all motion inducing exercises have been recorded and analysed including the baseline (BL) value (DC component) and the amplitude of the oscillation of the PPG. All physiological parameters were also recorded as a simultaneous time varying waveform. The effects of the motion and specifically the localised Blood Pressure (BP) have been studied and related to possible influences of the Autonomic Nervous System (ANS) and hemodynamic pressure variations. It is envisaged that a comprehensive study of the effect of motion and the localised pressure fluctuations will provide valuable information for the future minimisation of motion artefact effect on the PPG signals of this probe and allow the accurate assessment of total haemoglobin concentration which is the primary function of the probe.

Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition.

Aberrant expression of EGF receptors has been associated with hormone-refractory and metastatic prostate cancer (PCa). However, the molecular mechanism for EGF signaling in promoting PCa metastasis remains elusive. Using experimental models of PCa metastasis, we demonstrated that EGF could induce robust epithelial-mesenchymal transition (EMT) and increase invasiveness. Interestingly, EGF was found to be capable of promoting protein turnover of epithelial protein lost in neoplasm (EPLIN), a putative suppressor of EMT and tumor metastasis. Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. This study elucidated a novel molecular mechanism for EGF regulation of EMT and invasiveness in PCa cells, indicating that blockade of EGF signaling could be beneficial in preventing and retarding PCa metastasis at early stages.

Constructing N,S co-doped network biochar confined CoFe2O4 magnetic nanoparticles adsorbent: Insights into the synergistic and competitive adsorption of Pb2+ and ciprofloxacin.

To solve the problem of biochar lack of adsorption sites for heavy metal ions and the difficulty of recycling, CoFe2O4 magnetic nanoparticles confined in nitrogen, sulfur co-doped 3D network biochar matrix (C-CoFe2O4/N,S-BC) was designed and fabricated successfully. The obtained C-CoFe2O4/N,S-BC displays remarkable adsorption performance for both Pb2+ and ciprofloxacin (CIP) removal at the single or binary system due to the role of N,S as metal ion anchoring compared to the N,S-free sample (CoFe2O4/BC). N,S co-doped BC not only participates in adsorption reaction but also effectively inhibites the agglomeration of CoFe2O4 nanoparticles and increases the active sites as a carrier at the same time. In the single system, CoFe2O4/N,S-BC demonstrates a fast adsorption rate (equilibrium time: 30 min) and high adsorption capacity (224.77 mg g-1 for Pb2+, 400.11 mg g-1 for CIP) towards Pb2+ and CIP. The adsorption process is befitted pseudo-second-order model, and the equilibrium data are in great pertinence with Langmuir model. In the binary system, the maximum adsorption capacity of CoFe2O4/N,S-BC for Pb2+ and CIP is 244.80 mg g-1 (CIP: 10.00 mg L-1) and 418.42 mg g-1 (Pb2+: 10.00 mg L-1), respectively. The adsorption mechanism is discussed based on the experimental results. Moreover, C-CoFe2O4/N,S-BC shows good practical water treatment capacity, anti-interference ability and stable reusability (the removal efficiency＞80% after eight cycles). The rapid, multifunctional, reusable, and easily separable adsorption properties make C-CoFe2O4/N,S-BC promising for efficient environmental remediation. This study also offers a viable method for the construction of adsorption material for complex wastewater treatment.

Phages modified hydrogel pellet assembled in 3D printed both-in-one device for detecting Pseudomonas aeruginosa based on colorimetric and pressure readout modes.

Pseudomonas aeruginosa (P. aeruginosa) with noticeable drug-resistance profile is one of the most pernicious pathogens that attracts major public health concerns. Herein, a 3D printed device combined with hydrogel pellet modified with phages was designed for point-of-care testing (POCT) of this pathogen with both colorimetric and pressure readout modes. A P. aeruginosa phage belonging to the family of Podoviridae was isolated from river water and noted as vB_PaeP-JZ1 (JZ1). Due to its host specificity, phage JZ1 was used as a recognizing agent for modifying the hydrogel pellet, and the modified hydrogel pellet was assembled into the 3D printed device to act as the sensing interface. Polymyxin B (PMB) was tagged with Pd@Pt core-shell nanodendrites (Pd@PtNDs) showing excellent peroxidase-like activity to act as the colorimetric and pressure signal tracer. P. aeruginosa can be quantified within the concentration ranges of 2.6 × 103 cfu mL-1 - 2.6 × 108 cfu mL-1 and 2.6 × 102 cfu mL-1 - 2.6 × 107 cfu mL-1 with colorimetric and pressure readout modes, respectively. The both modes can achieve quantitation of P. aeruginosa within 25 min. Thus the "both-in-one" 3D printed device with dual-mode readout function offers a rapid, sensitive, and specific platform for POCT of pathogenic bacteria.

ß-arrestin2 is indispensable for the antidepressant effects of fluoxetine via inhibiting astrocytic pyroptosis in chronic mild stress mouse model for depression.

ß-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of ß-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and ß-arrestin2-/- mice. Behavioral results demonstrated that CMS mice showed increased immobility time in the tail suspension test and forced swimming test, elevated concentrations of pro-inflammatory factors in peripheral blood, increased expression of pyroptosis-related proteins, and increased co-labeling of glial fibrillary acidic protein and Caspase1 p10 in the hippocampus compared to the CON group. Treatment with fluoxetine (FLX) ameliorated these conditions. However, compared with the ß-arrestin2-/- CMS group, these results of the ß-arrestin2-/- CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out ß-arrestin2. Mass spectrometry implying that FLX promoted the binding of ß-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to ß-arrestin2. We further found that the lack of ß-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, ß-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT2BR-ß-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine.

Hsa_circ_0086414/transducer of ERBB2 (TOB2) axis-driven lipid elimination and tumor suppression in clear cell renal cell cancer via perilipin 3.

BACKGROUND: Renal cell cancer (RCC) is characterized by abnormal lipid accumulation. However, the specific mechanism by which such lipid deposition is eliminated remains unclear. Circular RNAs (circRNAs) widely regulate various biological processes, but the effect of circRNAs on lipid metabolism in cancers, especially clear cell renal cell carcinoma (ccRCC), remains poorly understood. METHODS: The downregulated circRNA, hsa_circ_0086414, was identified from high-throughput RNA-sequencing data of human ccRCC and pair-matched normal tissues. The target relationship between circRNA_0086414 and miR-661, and the transducer of ERBB2 (TOB2) was predicted using publicly available software programs and verified by luciferase reporter assays. The clinical prognostic value of TOB2 was evaluated by bioinformatic analysis. The expression levels of circRNA_0086414, miR-661, TOB2, and perilipin 3 (PLIN3) were measured by quantitative reverse-transcription polymerase chain reaction or western blot analysis. Cell Counting Kit-8, transwell assays, and xenograft models were employed to assess the biological behaviors of the hsa_circ_0086414/TOB2 axis. Oil Red staining and triglyceride assay was conducted to assess lipid deposition. RESULTS: Herein, we identified a downregulated circRNA, hsa_circ_0086414. Functionally, the restored hsa_circ_0086414 inhibited ccRCC proliferation, metastasis, and lipid accumulation in vitro and in vivo. Furthermore, the downregulated TOB2 predicted adverse prognosis and promoted cancer progression and lipid deposition in ccRCC. Mechanically, the binding of hsa_circ_0086414 to miR-661, as a miRNA sponge, upregulates the expression of TOB2, wielding an anti-oncogene effect. Importantly, the restored hsa_circ_0086414/TOB2 axis significantly contributed to the elimination of lipid deposition by inhibiting the lipid metabolism regulator PLIN3 in ccRCC cells. CONCLUSIONS: Our data highlight the importance of the hsa_circ_0086414/TOB2/PLIN3 axis as a tumor suppressor and lipid eliminator in ccRCC. The positive modulation of the hsa_circ_0086414/TOB2 axis might lead to the development of novel treatment strategies for ccRCC.

Comprehensive study of algal blooms variation in Jiaozhou Bay based on google earth engine and deep learning.

The Jiaozhou Bay ecosystem, a crucial marine ecosystem in China, has been plagued by frequent harmful algal blooms as due to deteriorating water quality and eutrophication. This study analyzed the temporal and spatial changes of harmful algal blooms in Jiaozhou Bay from 2000 to 2022 using the Floating Algae Index (FAI) calculated from MODIS (2000-2022) and Sentinel-2 (2015-2022) satellite image datasets. The calculation results of the image datasets were compared. The frequency of planktonic algal outbreaks was low and constant until 2017, but has increased annually since then. Algae blooms are most common in the summer and primarily concentrated along the bay's coast, middle, and mouth, with obvious seasonal and spatial distribution characteristics. Several factors influencing algal outbreaks were identified, including sea surface temperature, wind speed, air pressure, dissolved oxygen, nitrogen and phosphorus ratios, chemical oxygen demand, and petroleum pollutants. Algal bloom outbreaks in Jiaozhou Bay are expected to remain high in 2023. The findings provide crucial information for water quality management and future algal outbreak prediction and prevention in Jiaozhou Bay.