Acetylation of yeast AMPK controls intrinsic aging independently of caloric restriction.

Acetylation of histone and nonhistone proteins is an important posttranslational modification affecting many cellular processes. Here, we report that NuA4 acetylation of Sip2, a regulatory ß subunit of the Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), and ultimately leading to slower growth but extended replicative life span. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a protein acetylation-phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging, and extends replicative life span in yeast.

Poly(U)-specific endoribonuclease ENDOU promotes translation of human CHOP mRNA by releasing uORF element-mediated inhibition.

Upstream open reading frames (uORFs) are known to negatively affect translation of the downstream ORF. The regulatory proteins involved in relieving this inhibition are however poorly characterized. In response to cellular stress, eIF2α phosphorylation leads to an inhibition of global protein synthesis, while translation of specific factors such as CHOP is induced. We analyzed a 105-nt inhibitory uORF in the transcript of human CHOP (huORFchop ) and found that overexpression of the zebrafish or human ENDOU poly(U)-endoribonuclease (Endouc or ENDOU-1, respectively) increases CHOP mRNA translation also in the absence of stress. We also found that Endouc/ENDOU-1 binds and cleaves the huORFchop transcript at position 80G-81U, which induces CHOP translation independently of phosphorylated eIF2α. However, both ENDOU and phospho-eIF2α are nonetheless required for maximal translation of CHOP mRNA. Increased levels of ENDOU shift a huORFchop reporter as well as endogenous CHOP transcripts from the monosome to polysome fraction, indicating an increase in translation. Furthermore, we found that the uncapped truncated huORFchop -69-105-nt transcript contains an internal ribosome entry site (IRES), facilitating translation of the cleaved transcript. Therefore, we propose a model where ENDOU-mediated transcript cleavage positively regulates CHOP translation resulting in increased CHOP protein levels upon stress. Specifically, CHOP transcript cleavage changes the configuration of huORFchop thereby releasing its inhibition and allowing the stalled ribosomes to resume translation of the downstream ORF.

Establishment of an in vitro model of monocyte-like THP-1 cells for trained immunity induced by bacillus Calmette-Guérin.

BACKGROUND: Mycobacteria bloodstream infections are common in immunocompromised people and usually have disastrous consequences. As the primary phagocytes in the bloodstream, monocytes and neutrophils play critical roles in the fight against bloodstream mycobacteria infections. In contrast to macrophages, the responses of monocytes infected with the mycobacteria have been less investigated. RESULTS: In this study, we first established a protocol for infection of non-adherent monocyte-like THP-1 cells (i.e. without the differentiation induced by phorbol 12-myristate 13-acetate (PMA) by bacillus Calmette-Guérin (BCG). Via the protocol, we were then capable of exploring the global transcriptomic profiles of non-adherent THP-1 cells infected with BCG, and found that NF-κB, MAPK and PI3K-Akt signaling pathways were enhanced, as well as some inflammatory chemokine/cytokine genes (e.g. CCL4, CXCL10, TNF and IL-1ß) were up-regulated. Surprisingly, the Akt-HIF-mTOR signaling pathway was also activated, which induces trained immunity. In this in vitro infection model, increased cytokine responses to lipopolysaccharides (LPS) restimulation, higher cell viability, and decreased Candida albicans loads were observed. CONCLUSIONS: We have first characterized the transcriptomic profiles of BCG-infected non-adherent THP-1 cells, and first developed a trained immunity in vitro model of the cells.

Long-term trend and interannual variation in evapotranspiration of a young temperate Douglas-fir stand over 2002-2022 reveals the impacts of climate change.

The shortage of decades-long continuous measurements of ecosystem processes limits our understanding of how changing climate impacts forest ecosystems. We used continuous eddy-covariance and hydrometeorological data over 2002-2022 from a young Douglas-fir stand on Vancouver Island, Canada to assess the long-term trend and interannual variability in evapotranspiration (ET) and transpiration (T). Collectively, annual T displayed a decreasing trend over the 21 years with a rate of 1% yr-1, which is attributed to the stomatal downregulation induced by rising atmospheric CO2 concentration. Similarly, annual ET also showed a decreasing trend since evaporation stayed relatively constant. Variability in detrended annual ET was mostly controlled by the average soil water storage during the growing season (May-October). Though the duration and intensity of the drought did not increase, the drought-induced decreases in T and ET showed an increasing trend. This pattern may reflect the changes in forest structure, related to the decline in the deciduous understory cover during the stand development. These results suggest that the water-saving effect of stomatal regulation and water-related factors mostly determined the trend and variability in ET, respectively. This may also imply an increase in the limitation of water availability on ET in young forests, associated with the structural and compositional changes related to forest growth.

Multi-objective and multi-solution source mask optimization using NSGA-II for more direct process window enhancement.

Source and mask optimization (SMO) technology is increasingly relied upon for resolution enhancement of photolithography as critical dimension (CD) shrinks. In advanced CD technology nodes, little process variation can impose a huge impact on the fidelity of lithography. However, traditional source and mask optimization (SMO) methods only evaluate the imaging quality in the focal plane, neglecting the process window (PW) that reflects the robustness of the lithography process. PW includes depth of focus (DOF) and exposure latitude (EL), which are computationally intensive and unfriendly to gradient-based SMO algorithms. In this study, we propose what we believe to be a novel process window enhancement SMO method based on the Nondominated Sorting Genetic Algorithm II (NSGA-II), which is a multi-objective optimization algorithm that can provide multiple solutions. By employing the variational lithography model (VLIM), a fast focus-variation aerial image model, our method, NSGA-SMO, can directly optimize the PW performance and improve the robustness of SMO results while maintaining the in-focus image quality. Referring to the simulations of two typical patterns, NSGA-SMO showcases an improvement of more than 20% in terms of DOF and EL compared to conventional multi-objective SMO, and even four times superior to single-objective SMO for complicated patterns.

Long-term outcomes with HLX01 (HanliKang®), a rituximab biosimilar, in previously untreated patients with diffuse large B-cell lymphoma: 5-year follow-up results of the phase 3 HLX01-NHL03 study.

HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2-76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9-87.5%) and 75.4% (95% CI: 68.9-82.6%)( HR: 0.75, 95% CI 0.47-1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4-84.6%) and 73.0% (95% CI: 66.3-80.3%) (HR: 0.84, 95% CI 0.54-1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.

Characterization of Bacillus amyloliquefaciens PM415 as a potential bio-preserving probiotic.

Animal feed is vulnerable to fungal infections, and the use of bio-preserving probiotics has received increasing attention. In contrast to Lactobacillus and Bifidobacteria spp., fewer Bacillus spp. have been recognized as antifungal probiotics. Therefore, our objective was to screen antifungal strains and provide more Bacillus candidates to bridge this gap. Here, we screened 56 bacterial strains for cyclic lipopeptide genes and conducted an antifungal assay with Aspergillus niger as a representative fungus. We found that a Bacillus strain Bacillus amyloliquefaciens PM415, isolated from pigeon manure, exhibited the highest fungal inhibition activity as demonstrated by the confrontation assay and morphological observation under scanning electron microscope (SEM). Preliminary safety assessment and probiotic characterization revealed its non-pathogenic feature and stress tolerance capability. Whole genome sequencing of Bacillus amyloliquefaciens PM415 revealed a genome size of 4.16 Mbp and 84 housekeeping genes thereof were used for phylogenetic analysis showing that it is most closely related to Bacillus amyloliquefaciens LFB112. The in silico analysis further supported its non-pathogenic feature at the genomic level and revealed potential biosynthetic gene clusters responsible for its antifungal property. RNA-seq analysis revealed genome-wide changes in transportation, amino acid metabolism, non-ribosomal peptides (NRPs) biosynthesis and glycan degradation during fungal antagonism. Our results suggest that Bacillus amyloliquefaciens PM415 is a safe and effective probiotic strain that can prevent fungal growth in animal feeds.

Internal validation of the GA118-24B Genetic Analyzer, a stable capillary electrophoresis system for forensic DNA identification.

The GA118-24B Genetic Analyzer (hereafter, "GA118-24B") is an independently developed capillary electrophoresis instrument. In the present research, we designed a series of validation experiments to test its performance at detecting DNA fragments compared to the Applied Biosystems 3500 Genetic Analyzer (hereafter, "3500"). Three commercially available autosomal short tandem repeat multiplex kits were used in this validation. The results showed that GA118-24B had acceptable spectral calibration for three kits. The results of accuracy and concordance studies were also satisfactory. GA118-24B showed excellent precision, with a standard deviation of less than 0.1 bp. Sensitivity and mixture studies indicated that GA118-24B could detect low-template DNA and complex mixtures as well as the results generated by 3500 in parallel experiments. Based on the experimental results, we set specific analytical and stochastic thresholds. Besides, GA118-24B showed superiority than 3500 within certain size ranges in the resolution study. Instead of conventional commercial multiplex kits, GA118-24B performed stably on a self-developed eight-dye multiplex system, which were not performed on 3500 Genetic Analyzer. We compared our validation results with those of previous research and found our results to be convincing. Overall, we conclude that GA118-24B is a stable and reliable genetic analyzer for forensic DNA identification.

Efficacy and safety of geptanolimab (GB226) for relapsed/refractory primary mediastinal large B-cell lymphoma: an open-label phase II study (Gxplore-003).

BACKGROUND: This study aimed to assess the efficacy and safety of geptanolimab (GB226), a fully humanized, recombinant anti-programmed cell death-1 monoclonal antibody, in Chinese patients with refractory or relapsed (r/r) primary mediastinal large B-cell lymphoma (PMBCL). METHODS: This was a multicenter, open-label, single-arm phase II study (Gxplore-003), conducted at 43 hospitals in China (NCT03639181). Patients received geptanolimab intravenously at a dose of 3 mg/kg every 2 weeks until documented confirmed disease progression, intolerable toxicity, or any other cessation criteria was met. The primary endpoint was objective response rate (ORR) in the full analysis set assessed by the independent review committee (IRC) according to the Lugano Classification 2014. RESULTS: This study was prematurely terminated due to the slow rate of patient accrual. Between Oct 15th, 2018 and Oct 7th, 2020, 25 patients were enrolled and treated. By the data cutoff date on Dec 23rd, 2020, the IRC-assessed ORR was 68.0% (17/25; 95% confidence interval [CI] 46.5-85.1%), with the complete response rate of 24%. The disease control rate was 88% (22/25; 95%CI 68.8-97.5%). Median duration of response was not reached (NR) (95%CI, 5.62 months to NR), with 79.5% of patients having response durations of more than 12 months. Median progression-free survival was NR (95%CI, 6.83 months to NR). Treatment-related adverse events (TRAEs) were reported in 20 of 25 (80.0%) patients, and grade 3 or higher TRAEs occurred in 11 of 25 (44%) patients. No treatment-related deaths occurred. The immune-related adverse events (irAEs) of any grade were observed in 6 (24.0%) patients, and no grade 4 or grade 5 irAEs were reported. CONCLUSION: Geptanolimab (GB226) demonstrated promising efficacy and a manageable safety profile in Chinese patients with r/r PMBCL.

High power, broad tuning quantum cascade laser at λ ∼ 8.9 µm.

Many molecules have broad fingerprint absorption spectra in mid-wave infrared range which requires broadly tunable lasers to cover the interested spectrum in one scan. We report a strain-balanced, InAlAs/InGaAs/InP quantum cascade laser structure based on diagonal transition active region with high output power and and wide tuning range at λ ∼ 8.9 µm. The maximum pulsed optical power and the wall-plug efficiency at room temperature are 4 W and 11.7%, respectively. Maximum continuous wave double-facet power is 1.2 W at 25 °C for a 4 mm by 9 µm laser mounted epi-side down on a diamond/copper composite submount. The maximum pulsed and continuous wave external-cavity tuning range are from 7.71 µm to 9.15 µm and from 8 µm to 8.9 µm, respectively. The continuous wave power of the external cavity mode exceeds 200 mW across the entire spectrum.

Phase-type diffractive micro-optics elements in sulfur-based polymeric glass by femtosecond laser direct writing.

Sulfur-based polymeric glasses are promising alternative low-cost IR materials due to their profoundly high IR transparency. In this Letter, femtosecond-laser-induced refractive index change (RIC) was investigated in one typical sulfur-based polymeric glass material, poly(S-r-DIB), for the first time, to the best of our knowledge. The RIC in the laser-engineered region was quantitively characterized, which laid a foundation for phase-type optical element design. By the integration of RIC traces, embedded phase-type micro-optics elements, including Fresnel zone plates, and a Dammann grating were fabricated in bulk poly(S-r-DIB) polymeric glass substrate via the femtosecond laser direct writing technique. The imaging and beam shaping performance were demoed in the near-infrared (NIR) region.

In situ vaccination followed by intramuscular poly-ICLC injections for the treatment of hepatocellular carcinoma in mouse models.

The efficacy of treatment for advanced hepatocellular carcinoma (HCC) has remained limited. Polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) is a synthetic double-stranded RNA that serves as a viral mimic and induces an immune response. Intratumoral (IT) poly-ICLC injections can induce an autovaccination effect and prime the immune system, whereas intramuscular (IM) injection of poly-ICLC can attract and maintain tumor-specific cytotoxic T lymphocytes in tumors. We found that IT injection of poly-ICLC upregulated the expression of CD83 and CD86 on conventional type 1 dendritic cells in tumors. Combination therapy with IT followed by IM injections of poly-ICLC significantly inhibited tumor growth and increased the tumor-infiltrating CD8+ T cells in two syngeneic mouse models of HCC. Depletion of CD8+ T cells attenuated the antitumor effect. An IFN-γ enzyme-linked immunospot of purified tumoral CD8+ T cells revealed a significant proportion of tumor-specific T cells. Finally, the sequential poly-ICLC therapy induced abscopal effects in two dual-tumor models. This study provides evidence that the sequential poly-ICLC therapy significantly increased infiltration of tumor-specific CD8+ T cells in the tumors and induced CD8+ T cell-dependent inhibition of tumor growth, as well as abscopal effects.

Tf2O as a CF3 Source for the Synthesis of Trifluoromethoxylation Reagent nC4F9SO3CF3.

Described herein is the convenient synthesis of an efficient trifluoromethoxylation reagent, nC4F9SO3CF3, by using cheap and widely available reagents and without the need of any tedious column chromatography purification procedure.

Real-Time Fire Smoke Detection Method Combining a Self-Attention Mechanism and Radial Multi-Scale Feature Connection.

Fire remains a pressing issue that requires urgent attention. Due to its uncontrollable and unpredictable nature, it can easily trigger chain reactions and increase the difficulty of extinguishing, posing a significant threat to people's lives and property. The effectiveness of traditional photoelectric- or ionization-based detectors is inhibited when detecting fire smoke due to the variable shape, characteristics, and scale of the detected objects and the small size of the fire source in the early stages. Additionally, the uneven distribution of fire and smoke and the complexity and variety of the surroundings in which they occur contribute to inconspicuous pixel-level-based feature information, making identification difficult. We propose a real-time fire smoke detection algorithm based on multi-scale feature information and an attention mechanism. Firstly, the feature information layers extracted from the network are fused into a radial connection to enhance the semantic and location information of the features. Secondly, to address the challenge of recognizing harsh fire sources, we designed a permutation self-attention mechanism to concentrate on features in channel and spatial directions to gather contextual information as accurately as possible. Thirdly, we constructed a new feature extraction module to increase the detection efficiency of the network while retaining feature information. Finally, we propose a cross-grid sample matching approach and a weighted decay loss function to handle the issue of imbalanced samples. Our model achieves the best detection results compared to standard detection methods using a handcrafted fire smoke detection dataset, with APval reaching 62.5%, APSval reaching 58.5%, and FPS reaching 113.6.

Myd88 Signaling Is Involved in the Inflammatory Response in LPS-Induced Mouse Epididymitis and Bone-Marrow-Derived Dendritic Cells.

Epididymitis is an epididymal inflammation that may lead to male infertility. Dendritic cells (DCs) and myeloid differentiation primary response gene 88 (Myd88) were associated with epididymitis in rodents. However, the functions of Myd88 on epididymal DCs remain unclear. This study investigated the role of Myd88 in DCs for epididymitis. The Myd88 signaling pathway, phenotypes of DC subsets, and cytokines were investigated in lipopolysaccharide (LPS)-induced epididymitis in mice. CRISPR-Cas9 was used to knockout Myd88 in bone-marrow-derived dendritic cells (BMDCs) and immortalized mouse epididymal (DC2) cell line. In the vivo experiments, levels of the proinflammatory cytokines IL-1α, IL-6, IL-17A, TNF-α, IL-1ß, MCP-1, and GM-CSF, mRNA for MyD88 related genes, and the percentages of monocyte-derived DCs (Mo-DCs) were significantly elevated in mice with epididymitis. In the vitro experiments, LPS significantly promoted the apoptosis of BMDCs. In addition, the concentration of inflammatory cytokines in BMDCs and DC2s were increased in the LPS group, while decreasing after the knockout of Myd88. These findings indicate that Myd88 on DCs is involved in the inflammation of epididymitis in mice, which may be a potential target for better strategies regarding the treatment of immunological male infertility.

Analysis of genetic diversity and genetic structure of Qinchuan cattle conservation population using whole-genome resequencing.

In the conservation of livestock and poultry resources, population genetic diversity and genetic structure of the conservation population are important factors affecting the effectiveness of conservation. In this study, whole-genome resequencing technology was used to detect genomic variation in 100 Qinchuan cattle (30 bulls and 70 cows). By analyzing population genetic diversity, runs of homozygosity (ROH) distribution features, kinship relationships, and family structure, the conservation effectiveness of Qinchuan cattle was comprehensively evaluated. The results showed that a total of 20,968,017 high-quality SNPs were detected in 100 Qinchuan cattle, the average minimum allele frequency was 0.191±0.124, the average polymorphic information content was 0.279±0.131, and the average observed heterozygosity was 0.275±0.131, the average expected heterozygosity is 0.279±0.131, indicating that the genetic diversity of the Qinchuan cattle conservation population is relatively rich. The average identity by state (IBS) distance of the Qinchuan conservation population was 0.243±0.020, with a value of 0.242±0.021 for the bulls. The results of the kinship G-matrix were consistent with the results of the IBS distance matrix, both showing that some individuals in the conservation population had close kinship. A total of 8258 genomic ROH were detected in 100 Qinchuan cattle, with a total length of 9.64 GB. The average length of ROH fragments was 1.167±1.203 Mb, 69.35% of the ROH were short ROH with a length of 0.5~1 Mb, and the average total length of ROH per individual was 96.40 Mb. The average inbreeding coefficient based on ROH was 0.039±0.039, with a value of 0.044±0.035 for the bulls, indicating that some bulls had a certain degree of inbreeding accumulation. The results of the phylogenetic tree combined with kinship analysis showed that the individuals in the Qinchuan cattle conservation population could be divided into eight families, including seven families with bulls and one family without bulls. This study demonstrated that the genetic diversity of the Qinchuan conservation population is relatively rich, with no significant inbreeding accumulation, but there is a risk of inbreeding among some individuals. Therefore, it is necessary to strengthen selection and mating to ensure the sustainable development of Qinchuan cattle resources.

[Quality Evaluation of Temporomandibular Joint Images from 3 High-resolution Dynamic Sequences].

Objective To compare the image quality of three high-resolution dynamic MRI methods for evaluating the motion of temporomandibular joint disc and condyle. Methods Twenty-five patients with suspected temporomandibular joint disorders were examined by single-shot fast spin-echo (SSFSE),fast imaging employing steady-state acquisition (FIESTA),and spoiled gradient echo (SPGR) on the oblique sagittal position.Two radiologists performed subjective and objective evaluation on the images with double-blind method.The subjective evaluation included the signal intensity of mandibular condyle,articular disc,soft tissue around articular disc,and lateral pterygoid muscle,the contrast between articular disc and condyle,the contrast between articular disc and surrounding soft tissue,condylar motion,and disc movement.The objective evaluation indexes included image signal intensity,signal-to-noise ratio (SNR),and contrast-to-noise ratio (CNR).The subjective and objective indexes of the image quality were compared between the three sequences. Results The SSFSE sequence had lower signal intensity of articular disc and higher signal intensity of condyle and surrounding soft tissue than FIESTA and SPGR sequences (all P<0.001).The SPGR sequence showed higher signal intensity of lateral pterygoid muscle than the SSFSE and FIESTA sequences (P=0.017,P<0.001).Among the three sequences,SSFSE sequence showed the clearest articular disc structure (χ2=41.952,P<0.001),the strongest contrast between articular disc and condyle (χ2=35.379,P<0.001),the strongest contrast between articular disc and surrounding soft tissue (χ2=27.324,P<0.001),and the clearest movement of articular disc (χ2=44.655,P<0.001).SSFSE and FIESTA sequences showed higher proportion of disc displacement and reduction than SPGR sequence (all P<0.001).The CNR (χ2=21.400,P<0.001),SNR (χ2=34.880,P<0.001),and condyle signal intensity (F=337.151,P<0.001) demonstrated differences among SSFSE,FIESTA,and SPGR sequences.The CNR of SSFSE sequence was higher than that of FIESTA sequence (P<0.001),while it had no significant difference between SSFSE and SPGR sequences (P=0.472).In addition,the SSFSE sequence had higher SNR and signal intensity than FIESTA and SPGR sequences (all P<0.001). Conclusion The best image quality can be observed from SSFSE sequence where both the structure and movement of temporomandibular joint are well displayed.Therefore,SSFSE is preferred for the examination of temporomandibular joint movement.

[Analysis and evaluation on Paeoniae Radix Alba from different cultivars by UPLC-Q-TOF-MS and HPLC].

In this study, an established ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS) method was combined with multivariate statistical analysis to investigate the commonality and difference of main chemical components in the medicinal parts of Paeonia lactiflora from different cultivars; in addition, a high performance liquid chromatography(HPLC) method was established to simultaneously determine the content of eight active components in Paeoniae Radix Alba. Non-targeted analysis was carried out by UPLC-Q-TOF-MS on a Waters ACQUITY UPLC BEH C_(18)(2.1 mm×100 mm, 1.7 µm) column with a gradient elution of 0.1% aqueous formic acid(A)-acetonitrile(B) as the mobile phase at a flow rate of 0.2 mL·min~(-1). The column temperature was 30 ℃, and an electrospray ionization source was used to acquire mass spectrometry data in positive and negative ion modes. According to the accurate molecular weight and fragment ion information provided by multi-stage mass spectrometry and by comparison with reference substances and literature reports, thirty-six identical components were identified in Paeoniae Radix Alba from different cultivars with positive and negative ion modes. In the negative ion mode, two groups of samples were well separated; specifically, seventeen components with significant differences in content were screened and identified, and one component unique in "Bobaishao" was obtained. Quantitative analysis was conducted by high-performance liquid chromatography(HPLC) on an Agilent HC-C_(18)(4.6 mm×250 mm, 5 µm) column with a gradient elution of 0.1% aqueous phosphoric acid(A)-acetonitrile(B) as the mobile phase at a flow rate of 1.0 mL·min~(-1). The column temperature was 30 ℃ and the detection wavelength was at 230 nm. An HPLC method was developed for the simultaneous determination of eight active components(gallic acid, oxypaeoniflorin, catechin, albiflorin, paeoniflorin, galloylpaeoniflorin, 1,2,3,4,6-O-pentagalloylglucose, benzoyl-paeoniflorin) in Paeoniae Radix Albaa from different cultivars. Satisfactory linearity was achieved within the investigated linear ranges and with fine coefficients(r>0.999 0), and the methodological investigation showed that the method had good precision, repeatability and stability. The mean recoveries were 90.61% to 101.7% with RSD of 0.12% to 3.6%(n=6). UPLC-Q-OF-MS provided a rapid and efficient qualitative analytical method for the identification of the chemical components in Paeoniae Radix Alba, and the developed HPLC method was simple, rapid and accurate, which could provide a scientific basis for the evaluation of the germplasm resources and herbal quality of Paeoniae Radix Alba from different cultivars.

Serplulimab, a novel anti-PD-1 antibody, in patients with microsatellite instability-high solid tumours: an open-label, single-arm, multicentre, phase II trial.

BACKGROUND: Microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumours have a high response rate to immunotherapy. Antitumour activity and safety of serplulimab, a novel humanised anti-PD-1 monoclonal antibody, were evaluated in this phase II study. METHODS: In this ongoing, single-arm, open-label, phase II trial, patients with previously treated unresectable or metastatic MSI-H/dMMR solid tumours received intravenous serplulimab 3 mg/kg every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included additional efficacy measures, safety, and tolerability. RESULTS: As of 9 January 2021, 108 patients were enrolled, and 68 patients with confirmed MSI-H solid tumours were included in the main efficacy analysis population (MEAP). The median follow-up duration in the MEAP was 7.7 months, with an ORR of 38.2% (95% confidence interval, 26.7-50.8). Of the 108 patients, grade ≥3 treatment-emergent adverse events were reported in 53 (49.1%) patients; immune-related adverse events occurred in 52 (48.1%) patients. CONCLUSIONS: Serplulimab demonstrates a durable antitumour effect and a manageable safety profile in previously treated patients with MSI-H solid tumours. Serplulimab is a promising tissue-agnostic treatment for previously treated MSI-H solid tumours. TRIAL REGISTRATION: NCT03941574.

Global optimisation of source and mask in inverse lithography via tabu search combined with genetic algorithm.

Source mask optimisation (SMO) is a resolution enhancement technology that is utilised in the advanced process node of optical lithography to achieve acceptable imaging quality and fidelity. It is crucial in enhancing the convergence performance and optimisation capability of pixel-based SMO. In this study, an SMO approach that employs a genetic algorithm (GA), combined with the tabu search method (TS), is proposed. GA-TS, a hybrid-type global optimisation algorithm, has an outperforming capacity to avoid local optima owing to the excellent local searching function of TS. Furthermore, an edge-optimisation strategy was implemented to optimise the mask for a low-complexity mask layout. The simulation results confirm that the proposed approach exhibits exceptional optimisation capability and convergence performance.