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Abstract Molecular features are incorporated into the integrated diagnostic system for adult diffuse gliomas. Of these, copy number variation (CNV) markers, including both arm‐level (1p/19q codeletion, +7/−10 signature) and gene‐level (EGFR gene amplification, CDKN2A/B homozygous deletion) changes, have revolutionized the diagnostic paradigm by updating the subtyping and grading schemes. Shallow whole genome sequencing (sWGS) has been widely used for CNV detection due to its cost‐effectiveness and versatility. However, the parallel detection of glioma‐associated CNV markers using sWGS has not been optimized in a clinical setting. Herein, we established a model‐based approach to classify the CNV status of glioma‐associated diagnostic markers with a single test. To enhance its clinical utility, we carried out hypothesis testing model‐based analysis through the estimation of copy ratio fluctuation level, which was implemented individually and independently and, thus, avoided the necessity for normal controls. Besides, the customization of required minimal tumor fraction (TF) was evaluated and recommended for each glioma‐associated marker to ensure robust classification. As a result, with 1× sequencing depth and 0.05 TF, arm‐level CNVs could be reliably detected with at least 99.5% sensitivity and specificity. For EGFR gene amplification and CDKN2A/B homozygous deletion, the corresponding TF limits were 0.15 and 0.45 to ensure the evaluation metrics were both higher than 97%. Furthermore, we applied the algorithm to an independent glioma cohort and observed the expected sample distribution and prognostic stratification patterns. In conclusion, we provide a clinically applicable algorithm to classify the CNV status of glioma‐associated markers in parallel.

Endoribonuclease DICER is an RNase III enzyme that mainly processes microRNAs in the cytoplasm but also participates in nuclear functions such as chromatin remodelling, epigenetic modification and DNA damage repair. The expression of nuclear DICER is low in most human cancers, suggesting a tight regulation mechanism that is not well understood. Here, we found that ubiquitin carboxyl‐terminal hydrolase 7 (USP7), a deubiquitinase, bounded to DICER and reduced its nuclear protein level by promoting its ubiquitination and degradation through MDM2, a newly identified E3 ubiquitin‐protein ligase for DICER. This USP7‐MDM2‐DICER axis impaired histone γ‐H2AX signalling and the recruitment of DNA damage response (DDR) factors, possibly by influencing the processing of small DDR noncoding RNAs. We also showed that this negative regulation of DICER by USP7 via MDM2 was relevant to human tumours using cellular and clinical data. Our findings revealed a new way to understand the role of DICER in malignant tumour development and may offer new insights into the diagnosis, treatment and prognosis of cancers.

The rise in antibiotic-resistant bacteria highlights the need for novel antimicrobial agents. This study presents the design and synthesis of a series of rhein (RH)-derived compounds with improved antimicrobial properties. The lead compound, RH17, exhibited a potent antibacterial activity against Staphylococcus aureus (S. aureus) isolates, with minimum inhibitory concentrations (MICs) ranging from 8 to 16 μg/mL. RH17 disrupted bacterial membrane stability, hindered metabolic processes, and led to an increase in reactive oxygen species (ROS) production. These mechanisms were confirmed through bacterial growth inhibition assays, membrane function assessments, and ROS detection. Notably, RH17 outperformed the parent compound RH and demonstrated bactericidal effects in S. aureus. The findings suggest that RH17 is a promising candidate for further development as an antimicrobial agent against Gram-positive pathogens, addressing the urgent need for new therapies.

Due to the impact of scale variation of vehicle targets and changes in traffic environments in large-scale traffic monitoring systems, vehicle target detection methods often face challenges. To improve the adaptability of detection methods to these variations, we proposed an enhanced YOLOv7 for traffic systems (ETS-YOLOv7). To mitigate the effects of complex environments, we introduced the convolutional block attention module (CBAM) into the YOLOv7 framework, which filters important features in both channel and spatial dimensions, thereby enhancing the model’s capability to recognize traffic object features. To address the influence of aspect ratio variations in vehicle targets, we replaced the original complete intersection over union (CIoU) with wise intersection over union v3 (WIoUv3), eliminating the aspect ratio consistency loss and enhancing the model’s ability to generalize and its overall performance. Additionally, we employed the compact layer aggregation networks (CLAN) module to replace the efficient layer aggregation networks (ELAN) module, reducing redundant computations and improving computational efficiency without compromising model accuracy. The proposed method was validated on the large-scale traffic monitoring dataset UA-DETARC, achieving a mean average precision (mAP0.5–0.95) of 90.2%, which is a 3% improvement over the original YOLOv7. The frames per second (FPS) reached 149, demonstrating that the proposed model is highly competitive in terms of detection efficiency and vehicle detection accuracy compared to other advanced object detection methods.

Double-layer Ni-P coatings with low phosphorus content in the inner layer and high phosphorus content in the outer layer and Ni-Mo-P composite coatings are successfully prepared on the surface of AZ91D magnesium alloy by chemical plating process. The microstructures, friction and corrosion resistance of double-layer Ni-P and Ni-Mo-P coatings are studied in comparison. Meanwhile, the deposition and corrosion resistance mechanism for the coatings are investigated. Results convey that both Ni-P and Ni-Mo-P coatings showcase an amorphous structure. The coating possesses denser and more homogeneous structure with the co-doping of Mo. The micro-indentation hardness (859.7 HV) and friction coefficient (0.58) of Ni-Mo-P coatings show that the ternary alloy coating is firmly bonded to the magnesium alloy substrate. Besides, the Ni-Mo-P coatings demonstrate exceptional wear resistance attributed to Mo co-deposition, fostering grain refinement and facilitating the growth of passivation films.

Commensal enterococci with pathogenic potential often facilitate the growth of diverse pathogens, thereby exacerbating infections. However, there are few effective therapeutic strategies to prevent and intervene in enterococci-mediated polymicrobial infections. Here, we find that enterococci at high density drive the expansion and pathogenicity of enteric Salmonella enterica serotype Typhimurium (S. Tm). Subsequently, we show that the driving role of enterococci in such infections is counteracted by dietary coumarin glycosides in vivo. Enterococci, which are tolerant of iron-deficient environments, produce β-glucosidases to hydrolyze coumarin glycosides into bioactive aglycones, inhibiting S. Tm growth and ameliorating the severity of S. Tm-induced symptoms by inducing iron limitation. Overall, we demonstrate that coumarin glycosides as a common diet effectively reverse enterococci-facilitated enteric infections, providing an alternative intervention to combat polymicrobial infections.

Abstract Background Venous invasion (VI) is an adverse prognostic indicator in esophageal squamous cell carcinoma. However, grading criteria for venous invasion in thoracic esophageal squamous cell carcinoma (ESCC) have not been established. Methods We enrolled 598 thoracic ESCC patients from 2005 to 2017. We detected the presence of venous invasion using the hematoxylin and eosin (H&E)-staining method and evaluated the VI grade on the basis of the number and maximal size of the involved veins. The degree of VI was classified as either 0, V1, V2, or V3, according to the combination of V-number and V-size. Results The 1-year, 3-year and 5-year disease-free survival rates were 79.7%, 64.7% and 61.2%, respectively. Multivariate analysis demonstrated that lymphatic invasion (HR: 1.457, 95% CI: 1.058–2.006, p = 0.021), T category (HR: 1.457, 95% CI: 1.058–2.006, p = 0.022), N category (HR: 1.535, 95% CI: 1.276–2.846, p

Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50 = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50 > 5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

Aerial photoelectric imaging payloads have become an important means of reconnaissance and surveillance in recent years. However, aerial images are easily affected by external conditions and have unclear edges, which greatly reduces the accuracy of imaging target recognition. This paper proposes the M-YOLOv5 model, which uses a shallow feature layer. The RFBs module is introduced to improve the receptive field and detection effect of small targets. In the neck network part, the BiFPN structure is used to reuse the underlying features to integrate more features, and a CBAM attention mechanism is added to improve detection accuracy. The experimental results show that the detection effect of this method on the DroneVehicle dataset is better than that of the original network, with the precision rate increased by 2.8%, the recall rate increased by 16%, and the average precision increased by 2.3%. Considering the real-time problem of target detection, based on the improved model, the Clight-YOLOv5 model is proposed, by lightweighting the network structure and using the depth-separable convolution optimization module. After lightweighting, the number of model parameters is decreased by 71.3%, which provides a new idea for lightweight target detection and proves the model’s effectiveness in aviation scenarios.

Summary: The study aimed to explore the clinical efficacy of the modified asymmetric Z-plasty with a central axis from the point near the edge of the skin fold of the medial canthus to the point of the innermost palpebral edge of medial canthus for epicanthus correction. A total of 130 followed-up patients who received modified asymmetric Z-plasty for epicanthus correction in Hunan Provincial People's Hospital from January 2019 to December 2019 were included. All patients were followed up with at 1, 3, and 6 months after surgery, and the scarring and surgical outcomes were assessed. The results showed the surgical wounds were healing well, and the sutures were removed at 7 days postoperatively in all patients. At 6 months postoperatively, epicanthus correction was successful in all patients, the lacrimal caruncle was moderately exposed, the incision was not red, and there were no obvious prominent scars. Slightly prominent and uneven scars below the edge of the lower eyelid were observed in 3 patients. Among these 3 patients, 1 patient received no further treatment, and the outcomes were considered acceptable; the outcomes were improved in the remaining 2 patients after a single session of fractional laser treatment, and none of these patients received further surgery. In conclusion, the modified asymmetric Z-plasty with a central axis from the point near the edge of the skin fold of the medial canthus to the point of the innermost palpebral edge of medial canthus is relatively simple and provides good surgical results for epicanthus correction.

Abstract Immune checkpoint therapies (ICT) have achieved unprecedented efficacy in multiple cancer treatments, but are still limited by low clinical response rates. Identification of immunogenic cell death (ICD)‐inducing drugs that can induce tumor cell immunogenicity and reprogram the tumor microenvironment is an attractive approach to enhance antitumor immunity. In the present study, Raddeanin A (RA), an oleanane class triterpenoid saponin isolated from Anemone raddeana Regel, is uncovered as a potent ICD inducer through an ICD reporter assay combined with a T cell activation assay. RA significantly increases high‐mobility group box 1 release in tumor cells and promotes dendritic cell (DC) maturation and CD8+ T cell activation for tumor control. Mechanistically, RA directly binds to transactive responsive DNA‐binding protein 43 (TDP‐43) and induces TDP‐43 localization to mitochondria and mtDNA leakage, leading to cyclic GMP‐AMP synthase/stimulator of interferon gene‐dependent upregulation of nuclear factor κB and type I interferon signaling, thereby potentiating the DC‐mediated antigen cross‐presentation and T cell activation. Moreover, combining RA with anti‐programmed death 1 antibody effectively enhances the efficacy of ICT in animals. These findings highlight the importance of TDP‐43 in ICD drug‐induced antitumor immunity and reveal a potential chemo‐immunotherapeutic role of RA in enhancing the efficacy of cancer immunotherapy.

Visual inspection of long-term electroencephalography (EEG) is a tedious task for physicians in neurology. Based on bidirectional gated recurrent unit (Bi-GRU) neural network, an automatic seizure detection method is proposed in this paper to facilitate the diagnosis and treatment of epilepsy. Firstly, wavelet transforms are applied to EEG recordings for filtering pre-processing. Then the relative energies of signals in several particular frequency bands are calculated and inputted into Bi-GRU network. Afterwards, the outputs of Bi-GRU network are further processed by moving average filtering, threshold comparison and seizure merging to generate the discriminant results that the tested EEG belong to seizure or not. Evaluated on CHB-MIT scalp EEG database, the proposed seizure detection method obtained an average sensitivity of 93.89% and an average specificity of 98.49%. 124 out of 128 seizures were correctly detected and the achieved average false detection rate was 0.31 per hour on 867.14 h testing data. The results show the superiority of Bi-GRU network in seizure detection and the proposed detection method has a promising potential in the monitoring of long-term EEG.

Background. Muscle dysfunction is an early complication of diabetic peripheral neuropathy (DPN). As a convenient and low-cost tool, muscle ultrasound has been used to assess muscle quality and muscle mass. However, the relationship between different muscle ultrasound parameters and DPN is unclear. Objectives. This study was designed to investigate the relationship between ultrasound parameters of different muscles and DPN among patients with type 2 diabetes mellitus, including the rectus femoris (RF), tibialis anterior (TA), and medial head of gastrocnemius (MG). Materials and Methods. The research enrolled 90 patients with type 2 diabetes mellitus (T2DM). All images were attained from both sides. Muscle measurements contained muscle thickness (MT), cross-sectional area (CSA), echo intensity (EI), and corrected EI. The binary logistic regression and multiple linear regression were used to investigate the association between muscle ultrasound parameters and DPN or vibration perception threshold (VPT). Results. EI, corrected EI, MT of MG, and EI of TA were associated with DPN separately after adjusting other clinical variates. Among these muscle parameters, the EI of MG had a better predictive value (OR: 1.114, 95% CI: 1.039, 1.196) of DPN. Combined with CSA of RF, peripheral artery disease (PAD), and sex, the corrected EI of MG was associated with the vibration perception threshold (VPT) (standard β=0.242, p

Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft via activating tumor-infiltrating T-cell immunity. Mechanistically, TBM-1 triggers PD-L1 lysosomal degradation in a TFEB-dependent, autophagy-independent pathway. TBM-1 selectively binds to the mammalian target of rapamycin (mTOR) kinase and suppresses the activation of mTORC1, leading to the nuclear translocation of TFEB and lysosome biogenesis. Moreover, the combination of TBM-1 and anti-CTLA-4 effectively enhances antitumor T-cell immunity and reduces immunosuppressive infiltration of myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells. Our findings reveal a previously unrecognized antitumor mechanism of TBM-1 and represent an alternative ICB therapeutic strategy to enhance the efficacy of cancer immunotherapy.

Met1-linked linear ubiquitination (M1-Ubi) is catalyzed by linear ubiquitin chain assembly complex (LUBAC). Here the authors show that Ago2 protein is M1-Ubi modified by LUBAC complex under hypoxia condition leading to less association of miRNA target mRNAs to Ago2 protein and de-repression of miRNA targets.

Abstract This study was conducted to explore the roles and related mechanisms of lncRNA-TCONS_00147848 (TCONS_00147848) in nasal mucosa cell apoptosis and allergic rhinitis (AR). AR mice were sensitized with ovalbumin (OVA), with the TCONS_00147848 interference lentiviral vector (TCONS_00147848 shRNA) and FOSL2 overexpressing lentiviral vectors (pCDH-FOSL2) constructed respectively. NC shRNA, TCONS_00147848 shRNA and TCONS_00147848 shRNA + pCDH-FOSL2 were transfected into AR mice and mice with TNF-α induced nasal mucosa cells. The allergic reaction symptoms were evaluated by scoring. And in this study, we used Hematoxylin–Eosin (HE) staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) to detect the histological changes of nasal mucosa and apoptosis of nasal mucosa epithelial cells in mice, cell counting kit-8 (CCK-8) assay, Transwell and annexin V/PI to detect proliferation, migration and apoptosis of nasal mucosa cells of mice, respectively, enzyme-linked immunosorbent assay (ELISA) to detect the expression of inflammatory factors, qRT-PCR to detect TCONS_00147848 expression, Western blot assay to detect the expressions of FOSL2, JAK-2, STAT3, p-STAT3, BAX and BCL-2, RNA-binding protein immunoprecipitation (RIP) assay, RNA pull down assay and Co-immunoprecipitation (CoIP) assay to identify TCONS_00147848 targeting FOSL2. All these findings above reveal that knocking down TCONS_00147848 can reduce the allergic reaction symptom score of AR mice and the inflammatory reaction. The expression of IgE, IL-4, IL-5, IL-10, IL-9, IFN-γ and TNF-α in serum decreased. The expression of FOSL2, JAK-2, p-STAT3 and BAX in nasal mucosa and nasal mucosa cells of mice decreased as well, but BCL-2 expression increased. In addition, koncking down TCONS_00147848 can also inhibit the apoptosis of TNF-α induced nasal mucosa cells in mice and promote cell proliferation and migration. However, FOSL2 overexpression neutralized the effect of TCONS_00147848 shRNA. In nasal mucosa cells of mice, TCONS_00147848 can target FOSL2, interacting with STAT3. Inhibition of TCONS_00147848 can regulate JAK/STAT3 signaling pathway and reduce inflammatory response in AR mice.

Abstract Exosomes are carriers of intercellular information that regulate the tumor microenvironment, and they have an essential role in drug resistance through various mechanisms such as transporting RNA molecules and proteins. Nevertheless, their effects on gemcitabine resistance in triple-negative breast cancer (TNBC) are unclear. In the present study, we examined the effects of exosomes on TNBC cell viability, colony formation, apoptosis, and annexin A6 (ANXA6)/EGFR expression. We addressed their roles in gemcitabine resistance and the underlying mechanism. Our results revealed that exosomes derived from resistant cancer cells improved cell viability and colony formation and inhibited apoptosis in sensitive cancer cells. The underlying mechanism included the transfer of exosomal ANXA6 from resistant cancer cells to sensitive cancer cells. Isobaric peptide labeling–liquid chromatography–tandem mass spectrometry and western blotting revealed that ANXA6 was upregulated in resistant cancer cells and their derived exosomes. Sensitive cancer cells exhibited resistance with increased viability and colony formation and decreased apoptosis when ANXA6 was stably overexpressed. On the contrary, knockdown ANXA6 restored the sensitivity of cells to gemcitabine. Co-immunoprecipitation expression and GST pulldown assay demonstrated that exosomal ANXA6 and EGFR could interact with each other and exosomal ANXA6 was associated with the suppression of EGFR ubiquitination and downregulation. While adding lapatinib reversed gemcitabine resistance induced by exosomal ANXA6. Moreover, ANXA6 and EGFR protein expression was correlated in TNBC tissues, and exosomal ANXA6 levels at baseline were lower in patients with highly sensitive TNBC than those with resistant TNBC when treated with first-line gemcitabine-based chemotherapy. In conclusion, resistant cancer cell-derived exosomes induced gemcitabine resistance via exosomal ANXA6, which was associated with the inhibition of EGFR ubiquitination and degradation. Exosomal ANXA6 levels in the serum of patients with TNBC might be predictive of the response to gemcitabine-based chemotherapy.

Background: Vitamin D supplementation has been proven to be effective in the treatment of allergic rhinitis (AR). Objective: We conducted the present study to explore the role and efficacy of vitamin D adjuvant therapy for the treatment of inflammation in patients with AR. Methods: Out of 127 patients with potential eligible AR, 60 were randomly assigned into two groups and were finally included in our analysis (n=30 for each intervention). The patients with potential eligible AR were randomly allocated to intervention with desloratadine citrate disodium (DCD, 8.8 mg/day) without and with vitamin D3 nasal drops (1.5х106 IU, once/week) for four weeks. Thirty healthy control subjects were included in our study. We assessed the changes in the serum 25(OH)D, peripheral blood eosinophils, interleukin (IL)-4 levels, and nasal symptoms. Serum 25(OH)D, peripheral blood eosinophils, and IL-4 levels were detected respectively with liquid chromatography-tandem mass spectrometry (LC-MS/MS), a blood detector, and enzyme-linked immunosorbent assay. Results: Our patients who received vitamin D3 adjuvant therapy had a higher serum 25(OH)D level (47.57 ± 2.83 vs. 31.51 ± 2.95 ng/ml, p=0.000) and lower AR symptoms score (2.07 ± 1.89 vs. 3.37 ± 1.50, p=0.005), serum IL-4 (10.38 ± 3.41 vs. 12.79 ± 5.40 pg/ml, p=0.043), and peripheral blood eosinophils (0.34 ± 0.09 vs. 0.41 ± 0.10 109/l, p=0.003) compared with DCD single treatment. The efficacy rates of DCD with and without vitamin D3 in AR were 97% and 84%, respectively. Conclusion: Nasal vitamin D3 combined with DCD could improve the clinical symptoms of AR. Vitamin D3 adjunct therapy showed significant effects on inhibiting inflammation in patients with AR. We concluded that vitamin D3 supplementation could be an effective adjuvant therapy in AR patients.

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.

A DAC switching scheme that combines energy efficiency and resolution reconfigurability is proposed. Compared with the conventional switching scheme, the proposed scheme achieves 93.8%, 96.1%, and 97.3% switching energy saving in 8-bit, 9-bit, and 10-bit modes, respectively. Based on the proposed switching scheme, an 8–10-bit resolution-reconfigurable SAR ADC for biosensor applications is designed. The ADC consists of resolution-reconfigurable binary-weighted capacitive DAC, a two-stage full dynamic comparator, sampling switch, and the resolution-control SAR logic. Simulated in 180 nm CMOS process and 100 kS/s sampling rate, the ADC achieves the 46.80/53.89/60.14 dB signal-to-noise and distortion ratio (SNDR), the 55.22/62.51/73.09 dB spurious-free dynamic range (SFDR) and the 0.81/0.91/1.01 μW power consumption in 8/9/10-bit mode, respectively.

This paper presents a 10-bit successive approximation register analog-to-digital converter with energy-efficient low-complexity switching scheme, automatic ON/OFF comparator and automatic ON/OFF SAR logic for biomedical applications. The energy-efficient switching scheme achieves an average digital-to-analog converter switching energy of 63.56 CVref2, achieving a reduction of 95.34% compared with the conventional capacitor switching scheme for CDACs. With the switching scheme, the ADC can lower the dependency on the accuracy of Vcm and complexity of DAC control logic and DAC driver circuit. Moreover, dynamic circuits and automatic ON/OFF technology are used to reduce power consumption of comparator and SAR logic. The prototype is designed and fabricated in a 180 nm CMOS with a core size of 500 μm × 300 μm (0.15 mm2). It consumes 7.6 nW at 1 kS/s sampling rate and 1.8-V supply with an achieved signal-to-noise-and distortion ratio of 45.90 dB and a resulting figure of merit of 51.7 fJ/conv.-step.

Abstract The increasing emergence and dissemination of multidrug resistant (MDR) bacterial pathogens accelerate the desires for new antibiotics. Natural products dominate the preferred chemical scaffolds for the discovery of antibacterial agents. Here, the potential of natural flavonoids from plants against MDR bacteria, is demonstrated. Structure–activity relationship analysis shows the prenylation modulates the activity of flavonoids and obtains two compounds, α‐mangostin (AMG) and isobavachalcone (IBC). AMG and IBC not only display rapid bactericidal activity against Gram‐positive bacteria, but also restore the susceptibility of colistin against Gram‐negative pathogens. Mechanistic studies generally show such compounds bind to the phospholipids of bacterial membrane, and result in the dissipation of proton motive force and metabolic perturbations, through distinctive modes of action. The efficacy of AMG and IBC in four models associated with infection or contamination, is demonstrated. These results suggest that natural products of plants may be a promising and underappreciated reservoir to circumvent the existing antibiotic resistance.

Background: Programmed death-ligand 1 (PD-L1) is a T-cell inhibitory checkpoint molecule that suppresses antitumor immunity. Anti-PD-L1 antibodies have shown remarkable promise in treating tumors, but the patient response rate is low. Therefore, small-molecule checkpoint inhibitors blocking PD-L1 function are urgently needed. Methods: Changes of protein expression and phosphorylation levels were determined by immunoblotting. The level of Membrane PD-L1 was examined by flow cytometer. Cytotoxicity of T cells and NK cells toward tumor cells were detected using LDH and cell index assays. Lysosome function was investigated by NAG assay. Changes in lysosomal-related genes were measured by RT-PCR. In vivo anti-NSCLC cancer effects were assessed using C57BL/6 mice bearing Lewis tumor xenografts. Findings: We identified SA-49 as a new regulator of PD-L1 expression from a series of novel aloperine derivatives. SA-49 decreased the expression of PD-L1 in NSCLC cells and enhanced the cytotoxicity of co-cultured T and NK cells toward tumor cells. Importantly, lysosomal pathway contributed to SA-49-mediated down-regulation of PD-L1. SA-49 increased the biogenesis of lysosome and promoted translocation of PD-L1 to lysosome for proteolysis, which was associated with nuclear translocation of MITF. SA-49-induced MITF translocation acted through activation of PKCα and subsequently suppression of GSK3β activity. Furthermore, SA-49 suppressed Lewis tumor xenograft growth by activating immune microenvironment in C57BL/6 mice. Interpretation: Our data demonstrate that SA-49 can be used to regulate PD-L1 in cancer cells and trigger its degradation by activating lysosome function. Keywords: Aloperine, PD-L1, Lysosome, MITF, Checkpoint inhibitors

In this paper, the effects of different CO2 concentrations (400 and 800 μmol·mol−1) on photosynthetic gas exchange and chlorophyll fluorescence of mulberry (Morus alba L.) seedling leaves under drought stress were studied using an artificial climate chamber. The results showed that under non-drought conditions, the stomatal concentrations (Gs) and transpiratration rate (Tr) of mulberry seedling leaves decreased slightly with increased CO2 concentrations, but the net photosynthetic rate (Pn) increased significantly. Under mild drought stress (5 days of drought), higher CO2 concentrations significantly affected the photosynthetic gas exchange of mulberry seedling leaves, but had little effect on chlorophyll fluorescence. Under severe drought stress (10 das of drought), increased CO2 concentrations not only alleviated drought stress by increasing the WUE of mulberry seedling leaves, but also significantly increased its PSII photochemical activity, which promoted electron transfer on the PSII acceptor side. In conclusion, increased CO2 concentrations could raise the WUE of mulberry seedling leaves under normal water conditions and drought stress, and this effect was more significant under drought stress. Under severe drought stress, increased CO2 concentrations improved the drought resistance of mulberry seedlings by improving their PSII function.

Background/Aims: To investigate the mechanism that enables oxidative stress and cytoskeleton protein carbonylation to contribute to axonal dysfunction in traumatic brain injury (TBI). Methods: We created an in vitro model of neuronal oxidative damage by exposing a neuron-like cell line (PC-12) to different concentrations (100 μM, 200 μM, and 300 μM) of H2O2 for 24 h or 48 h. Carbonyl modification of cytoskeletal proteins (β-actin and β-tubulin) and its impact on β-actin/β-tubulin filament dynamics were determined by enzyme-linked immunosorbent assay, immunostaining, and western blotting. Depolymerization of β-actin/β-tubulin filaments was evaluated using the monomer/polymer ratio of each protein via western blotting. Phosphorylation of the neurofilament heavy chain (P-NFH) was used as an axonal injury marker and detected by immunostaining. Results: Our results showed that H2O2 treatment led to increased oxidative stress in PC-12 cells, as indicated by the increased generation of malondialdehyde and 8-hydroxydeoxyguanosine and decreased intracellular glutathione levels. H2O2 treatment also increased carbonyl modification of total proteins and cytoskeleton proteins β-actin/β-tubulin, which occurred concurrently with the suppression of proteasome activity. Moreover, H2O2 treatment increased the generation of the axonal injury marker P-NFH, and depolymerization of the β-actin/β-tubulin filaments was indicated by increased monomer/polymer ratios of each protein. Lastly, overexpression of the proteasome β5 subunit in PC-12 cells significantly reduced the H2O2-induced accumulation of carbonylated β-actin/ β-tubulin, P-NFH, and β-actin/β-tubulin depolymerization. Conclusions: We concluded that carbonylation of cytoskeleton proteins could lead to depolymerization of their filaments and axonal injury, and proteasome suppression contributes to the accumulation of carbonylated proteins under oxidative conditions.

Two fractions of non-starch polysaccharides termed TPS-1 and TPS-2 were sequentially purified from the corms of Colocasia esculenta. Structural characterizations of TPS-1 and TPS-2 were determined. The average molecular weight of TPS-1 and TPS-2 were estimated to be 10.502 and 10.191 kDa, respectively. TPS-1 consisted of Rha (8.5%), Xyl (0.73%), Glc (88.57%), and Gal (2.56%), while TPS-2 consisted of Rha (3.54%), Arf (1.6%), Glc (87.92%), and Gal (6.94%). The presence of glycosidic linkages in the two fractions of polysaccharides were identified and were significantly different. TPS-2 exhibited a higher immunomodulatory activity than TPS-1 through an immunostimulation assay promoting NO, TNF-α, and IL-6 production in RAW 264.7 cells. Furthermore, TPS-2 could significantly enhance the phagocytosis ability of macrophages. The membrane receptors of TPS-2 were identified to be TLR2, TLR4, GR, and SR. Taken together, TPS-1 and TPS-2 could be considered as novel potential immunostimulants of food and pharmaceutical supplements for hypoimmunity.

The overuse of antibiotics and the scarcity of new drugs have led to a serious antimicrobial resistance crisis, especially for multi-drug resistant (MDR) Gram-negative bacteria. In the present study, we investigated the antimicrobial activity of a marine antibiotic equisetin in combination with colistin against Gram-negative bacteria and explored the mechanisms of synergistic activity. We tested the synergistic effect of equisetin in combination with colistin on 23 clinical mcr-1 positive isolates and found that 4 µg/mL equisetin combined with 1 µg/mL colistin showed 100% inhibition. Consistently, equisetin restored the sensitivity of 10 species of mcr-1 positive Gram-negative bacteria to colistin. The combination of equisetin and colistin quickly killed 99.9% bacteria in one hour in time-kill assays. We found that colistin promoted intracellular accumulation of equisetin in colistin-resistant E. coli based on LC-MS/MS analysis. Interestingly, equisetin boosted ROS accumulation in E. coli in the presence of colistin. Moreover, we found that equisetin and colistin lost the synergistic effect in two LPS-deficient A. baumannii strains. These findings suggest that colistin destroys the hydrophobic barrier of Gram-negative bacteria, facilitating equisetin to enter the cell and exert its antibacterial effect. Lastly, equisetin restored the activity of colistin in a G. mellonella larvae infection model. Collectively, these results reveal that equisetin can potentiate colistin activity against MDR Gram-negative bacteria including colistin-resistant strains, providing an alternative approach to address Gram-negative pathogens associated with infections in clinics.

In this study, we investigated the mechanism of photosynthesis and physiological function of blueberry leaves under low temperature stress (4–6°C) by exogenous hydrogen sulfide (H2S) by spraying leaves with 0.5 mmol·L–1 NaHS (H2S donor) and 200 μmol·L–1 hypotaurine (Hypotaurine, H2S scavenger). The results showed that chlorophyll and carotenoid content in blueberry leaves decreased under low temperature stress, and the photochemical activities of photosystem II (PSII) and photosystem I (PSI) were also inhibited. Low temperature stress can reduce photosynthetic carbon assimilation capacity by inhibiting stomatal conductance (Gs) of blueberry leaves, and non-stomatal factors also play a limiting role at the 5th day of low temperature stress. Low temperature stress leads to the accumulation of Pro and H2O2 in blueberry leaves and increases membrane peroxidation. Spraying leaves with NaHS, a donor of exogenous H2S, could alleviate the degradation of chlorophyll and carotenoids in blueberry leaves caused by low temperature and reduce the photoinhibition of PSII and PSI. The main reason for the enhancement of photochemical activity of PSII was that exogenous H2S promoted the electron transfer from QA to QB on PSII acceptor side under low temperature stress. In addition, it promoted the accumulation of osmotic regulator proline under low temperature stress and significantly alleviated membrane peroxidation. H2S scavengers (Hypotaurine) aggravated photoinhibition and the degree of oxidative damage under low temperature stress. Improving photosynthetic capacity as well as alleviating photosynthetic inhibition and oxidative stress with exogenous H2S is possible in blueberry seedlings under low temperature stress.

Introduction Chronic neck pain is a challenging condition to treat in clinical practice and has a considerable impact on quality of life and disability. According to the theory of traditional Chinese medicine, acupoints and tender points may become sensitised when the body is in a diseased state. Stimulation of such sensitive points may lead to disease improvement and improved clinical efficacy. This study aims to evaluate the efficacy and safety of needling at sensitive acupoints in providing pain relief, improvement of cervical vertebral function and quality of life in patients with chronic neck pain.Methods and analysis This multicentre, randomised controlled, explanatory and parallel clinical trial will include 716 patients with chronic neck pain. Study participants will be randomly assigned in a 1:1:1:1 ratio to four treatment groups: the highly sensitive acupoints group, low/non-sensitive acupoints group, sham acupuncture group and waiting-list control group. The primary outcome will be the change in the visual analogue scale score for neck pain from baseline to 4 weeks. Secondary outcomes will be the Northwick Park Neck Pain Questionnaire and McGill pain questionnaire, 12-item Short-Form health survey, Neck Disability Index, changes in the pressure pain threshold, range of cervical motion, Self-Rating Anxiety Scale, Self-Rating Depression Scale and adverse events before treatment, post-treatment, and at 4, 8, 12, 16 and 20 weeks post-treatment. The intention-to-treat approach will be used in the statistical analysis. Group comparisons will be undertaken using χ2 tests for categorical characteristics, and analysis of variance for continuous variables to analyse whether acupuncture in the highly sensitive acupoints group achieves better treatment outcomes than in each of the other three groups.Ethics and dissemination Ethical approval of this study has been granted by the local Institutional Review Board (ID: 2017 KL-038). The outcomes of the trial will be disseminated through peer-reviewed publications.Trial registration number ChiCTR1800016371; Pre-results.

Inflammatory biomarkers are closely related to infectious diseases. However, traditional clinical tests of laboratory inspection are unable to achieve rapid and accurate detection of these biomarkers on-site due to shortcomings such as complex experimental operation, expensive equipment, and long test time. Herein, we proposed a lateral flow assay (LFA) strip based on surface-enhanced Raman scattering (SERS) nanotags (SERS-LFA strips) for the simultaneous and quantitative detection of dual infection biomarkers, serum amyloid A (SAA) and C-reactive protein (CRP), respectively. In practice, mesoporous silica (mSiO2)-coated Au nanoparticles (Au NPs) were used as the SERS substrate. Mercaptobenzoic acid (MBA) was embedded in the internal gap between Au NPs and the mSiO2 shell to prepare AuMBA@mSiO2 NPs, onto which SAA and CRP antibodies were modified to prepare two AuMBA@mSiO2 SERS nanotags. The Raman intensities of the test and control lines were simultaneously identified for the qualitative detection of SAA and CRP, with limits of detection (LODs) as low as 0.1 and 0.05 ng/mL for SAA and CRP, respectively. Finally, aiming at point-of-care testing (POCT) applications, we used a smartphone-based portable Raman spectrometer to quantitatively analyze the SERS-LFA strips. The Raman signal could still be accurately detected when the concentration of SAA and CRP was 10 ng/mL, which is lower than the LOD required in clinical practice for most diseases. Therefore, taking into account its simple operation and short analysis time, by using a portable Raman spectrometer which can be equipped with a 5G cloud-based healthcare management system, the current strategy based on SERS-LFA provides the potential for the quick and on-site diagnosis of infectious diseases such as sepsis, which is of great significance for medical guidance on the treatment of widely spread infection-related diseases in remote areas that lack well-developed medical resources.