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A novel gate-voltage-modulated strategy based on FET biosensors is developed to comprehensively improve the detection performance of telomerase.

Harmful algal blooms lead to cyanobacteria toxins increase in natural water. A novel nanochannel-based sensing system utilizing metal–organic frameworks and DNA aptamers was developed for highly sensitive detecting microcystin-LR in real water.

Peptide–nanoparticle conjugates show hydrolase-like activity, which is tuned by amino acid sequences.

Assessment of fetal maturity is essential for timely termination of pregnancy, especially in pregnant women with pregnancy complications. However, there is a lack of methods to assess the maturity of fetal intestinal function. Here, we constructed erythrocyte membrane-camouflaged aggregation-induced emission (AIE) nanoparticles. Nanocore is formed using a hollow mesoporous silicon nanobox (HMSN) of different particle sizes loaded with AIE luminogens -PyTPA (P), which are then co-extruded with erythrocyte membranes (M) to construct M@HMSN@P. The 100 nm M@HMSN@P has a more effective cellular uptake efficiency in vitro and in vivo. Swallowing and intestinal function in fetal mice mature with the increase in gestational age. After intrauterine injection of M@HMSN@P, they were swallowed and absorbed by fetal mice, and their swallowed and absorbed amount was positively correlated with the gestational age with a correlation coefficient of 0.9625. Using the M@HMSN@P (fluorescence intensity) in fetal mice, the gestational age can be imputed, and the difference between this imputed gestational age and the actual gestational age is less than 1 day. Importantly, M@HMSN@P has no side effect on the health status of pregnant and fetal mice, showing good biocompatibility. In conclusion, we constructed M@HMSN@P nanoparticles with different particle sizes and confirmed that the smaller size M@HMSN@P has more efficient absorption efficiency and it can assess fetal intestinal maturity by the intensity of the fluorescence signal.

Solid-state nanopores, inspired by biological nanopores, have the advantages of good mechanical properties, stability, and easy modification. They have attracted wide attention in the fields of sequencing, sensing, molecular sieving, nanofluidic devices, nanoelectrochemistry, and energy conversion. Because of the ion/molecule transport characteristic of the pore, the research on solid-state nanopores mainly focuses on the functional modification of its inner wall. In recent years, the outer surface of nanopores has also attracted the attention of researchers, and the functional elements on the outer surface have the functions of anti-interference and ionic signal enhancement. In this perspective, we review research progress of inner wall and outer surface distinguished solid-state nanopores, highlight their processing and advantages, summarize their functions and applications in sensing, and give insight into further research.

Cyclosporin A is a calcineurin inhibitor which has a narrow therapeutic window and high interindividual variability. Various population pharmacokinetic models have been reported; however, professional software and technical personnel were needed and the variables of the models were limited. Therefore, the aim of this study was to establish a model based on machine learning to predict CsA trough concentrations in Chinese allo-HSCT patients. A total of 7874 cases of CsA therapeutic drug monitoring data from 2069 allo-HSCT patients were retrospectively included. Sequential forward selection was used to select variable subsets, and eight different algorithms were applied to establish the prediction model. XGBoost exhibited the highest prediction ability. Except for the variables that were identified by previous studies, some rarely reported variables were found, such as norethindrone, WBC, PAB, and hCRP. The prediction accuracy within ±30% of the actual trough concentration was above 0.80, and the predictive ability of the models was demonstrated to be effective in external validation. In this study, models based on machine learning technology were established to predict CsA levels 3–4 days in advance during the early inpatient phase after HSCT. A new perspective for CsA clinical application is provided.

The rigidity of polymeric micelles plays an important role in their biological behaviors. However, how drug loading affects the rigidity of polymeric micelles remains elusive. Herein, the indomethacin (IMC)-loaded Pluronic F127 micelle is used as a model system to illustrate the impact of drug loading on the rigidity and biological behaviors of polymeric micelles. Against expectations, micelles with moderate drug loading show higher cellular uptake and more severe cytotoxicity as compared to both high and low drug loading counterparts. Extensive one- and two-dimensional nuclear magnetic resonance (NMR) measurements are employed to reveal that the higher drug loading induces stronger interaction between IMC and hydrophilic block to boost the micellar rigidity; consequently, the moderate drug loading imparts micelles with appropriate rigidity for satisfactory cellular uptake and cytotoxicity. In summary, NMR spectroscopy is an important tool to gain insight into drug loading regulated micellar rigidity, which is helpful to understand their biological behaviors.

Compression molding is a manufacturing technique that is frequently and widely utilized in fabricating composites. However, bast fiber reinforced composites (BFRC) with good quality and high performance by compression molding are quite challenging because it is complicated to find suitable process parameters. Previous works on improving the mechanical performance of compression molded BFRCs normally considered the influence of a single process parameter and ignored the mutual effects of process parameters. To enhance the mechanical qualities of BFRCs and enlarge their applications, this paper studied the synergistic effects of two molding process parameters on the mechanical characteristics of jute reinforced polypropylene composites (jute/PP) from contour and surface plots through response surface methodology (RSM). The significance of each molding process factor on the mechanical behaviors of jute/PP was investigated by conducting the analysis of variance (ANOVA). Multi-parameter co-optimization achieved the optimal mechanical performance of molded jute/PP at 186.8°C, 5.6 MPa, and 10.1 min, which was consistent with experimental findings. This suggests that response surface equations obtained from RSM can accurately characterize the relationships between mechanical characteristics and molding parameters of jute/PP. The RSM provides a useful and reliable way to find the optimal process parameters for better mechanical behaviors.

Background A "Watch and Wait” (W&W) approach has become an alternative to surgery for locally advanced rectal cancer (LARC) after neoadjuvant chemoradiotherapy (nCRT). Precise prediction of pathological complete response (pCR) will improve patient selection for W&W. We investigated the utility of cell-free DNA (cfDNA) fragmentomics in predicting pCR. Methods We recruited 119 LARC patients and evaluated nCRT response by pCR status and pathological or MRI tumor regression grade (mrTRG). Plasma samples before, during, and after nCRT were applied to deep targeted-panel sequencing, with 103 patients having complete samples. cfDNA fragment and 5′-end motif profiles were used to construct elastic-net logistic regression models to predict non-pCR. Predictive performance was measured by area under the receiver operator characteristic curve (AUC), sensitivity, and specificity. Results In the training cohort, the model based on 5′-end motif profile plus mrTRG achieved the highest cross-validation AUC (0.92, 95% CI, 0.91–0.93). The AUC in a testing cohort was 0.96 (95% CI, 0.90–1.00). The models based on 5′-end motif profile alone or in combination with mrTRG both maintained good predictive ability for patients without detectable circulating tumor DNA (AUC 0.94, 95% CI, 0.93–0.95; AUC 0.95, 95% CI, 0.94–0.96). In an external validation cohort, the model trained with a local 5′-end motif profile obtained an AUC of 0.878 (95% CI, 0.801–0.956) in discriminating colorectal cancer from healthy subjects. Conclusions The combination of a 5′-end motif profile with mrTRG has the potential to predict the response to nCRT, and therefore may improve the patient selection for a W&W approach.

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first "tumor agnostic" drugs approved for pan-cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second-generation drugs designed to overcome first-generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and (DNA and/or RNA-based) next-generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first- and second-generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Background: GPC5 rs2352028 is associated with the risk of lung cancer, but its relationship with lung cancer prognosis is unclear. Materials & methods: The authors collected blood samples from 888 patients with lung cancer and used a Cox proportional hazards model to analyze the association between prognosis and GPC5 polymorphism rs2352028. Results: GPC5 rs2352028 C > T was associated with a better prognosis. Patients with CT genotype had longer overall survival than those with CC genotype. Additionally, older and early-stage patients with CT + TT genotype had a lower risk of death than those with CC genotype. Conclusion: GPC5 rs2352028 C > T may play a protective role in patients with lung cancer and GPC5 rs2352028 may be a potential genetic marker for lung cancer prognosis.

C30H36F2N6O9S, orthorhombic, P212121 (no. 19), a = 5.2364(8) Å, b = 10.0250(14) Å, c = 59.689(9) Å, V = 3133.4(8) Å3, Z = 4, Rgt (F) = 0.0384, wRref (F 2) = 0.0969, T = 170 K.

C20H24N2O8, monoclinic, P21/n (no. 14), a = 3.8981(3) Å, b = 16.0675(11) Å, c = 16.2908(10) Å, β = 94.537(3)°, V = 1017.14(12) Å3, Z = 2, R gt (F) = 0.0634, wR ref (F 2) = 0.1746, T = 170 K.

Refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) patients' failure of salvage chemotherapy had extremely worse prognoses. Herein, 14 R/R DLBCL patients failed to salvage chemotherapy were exposed to dual epigenetic agents (Chidamide 30 mg biw*2w and Decitabine 10 mg/m

To address the threat of bacterial infection in the following post-antibiotic era, developing effective antibacterial approaches is of utmost urgency. Theranostic medicine integrating diagnosis and therapy is a promising protocol to fight against pathogenic bacteria. But numerous reported antibacterial theranostic materials are disclosed to be trapped in the excessive invasiveness to living mammal cells, leading to false positives and possible biosafety risks. Herein, a series of cationic pyridinium-substituted phosphindole oxide derivatives featuring aggregation-induced emission are designed, and alkyl chain engineering is conducted to finely tune their hydrophobicity and investigate their bioaffinity preference for living mammal cells and pathogenic bacteria. Most importantly, an efficient theranostic agent (PyBu-PIO) is acquired that is free from living cell invasiveness with negligible cytotoxicity and yet holds a good affinity for Gram-positive bacteria, including drug-resistant strains, with a superior inactivating effect. Externally applying PyBu-PIO onto Gram-positive bacteria-infected skin wounds can achieve creditable imaging effects and successfully accelerate the healing processes with reliable biosafety. This work proposes living cell invasiveness as a criterion for antibacterial theranostic materials and provides important enlightenment for the design of antibacterial theranostic materials.

BACKGROUND: Local recurrence of colorectal cancer is associated with poor prognosis and quality of life. For patients not eligible for curative surgery, chemoradiation could be a promising therapeutic option, but there is no consensus yet for the concurrent chemotherapy regimen. This study evaluated the effects and safety of intensity-modulated radiation therapy (IMRT) when administered concurrently with raltitrexed and irinotecan to patients with unresectable recurrent colorectal cancer. METHODS: Eligible patients developed unresectable recurrent colorectal cancer, and were refractory to, or intolerant of, chemotherapy with fluoropyrimidine and oxaliplatin. IMRT was delivered (total dose: 50–60 Gy in 25–30 fractions) concurrently with irinotecan and raltitrexed (200 and 3 mg/m(2), respectively, on days 1 and 22). After treatment completion, patients underwent surgery or continued the same regimen of chemotherapy and were assessed by a multidisciplinary team. The primary endpoint was the objective response rate, defined as the proportion of patients with a confirmed complete response or partial response, assessed by radiologist and investigator after the completion of radiotherapy and reconfirmed a month later, in accordance with the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: All 30 patients enrolled in this study between January 2019 and July 2020 completed radiotherapy and received a median of five chemotherapy cycles (range, 2–10 cycles). Twelve patients (40.0%) experienced an objective response (two complete responses and ten partial responses) and 17 patients exhibited stable disease [disease control rate (DCR): 96.7%]. The median follow-up was 22 months (range, 4–35 months), by the end of follow-up, six (20.0%) patients had local failure in the irradiation field, four (13.3%) had regional progression outside the irradiation field, 13 (43.3%) had distant metastasis or metastatic progression and nine (30.0%) died. The median progression-free survival (PFS) and local PFS (LPFS) were 13.5 and 23 months, respectively. The incidence of grade 3 or 4 adverse events was 26.7%, the most common of which was neutropenia (13.3%). CONCLUSIONS: IMRT with concurrent raltitrexed and irinotecan is a feasible treatment for unresectable recurrent colorectal cancer, which allows good tumor response and local control with acceptable toxicity profile.

Deoxyribonucleic acid (DNA) provides a collection of intelligent tools for the development of information cryptography and biosensors. However, most conventional DNA regulation strategies rely solely on enthalpy regulation, which suffers from unpredictable stimuli-responsive performance and unsatisfactory accuracy due to relatively large energy fluctuations. Here, we report an enthalpy and entropy synergistic regulation–based pH-responsive A + /C DNA motif for programmable biosensing and information encryption. In the DNA motif, the variation in loop length alters entropic contribution, and the number of A + /C bases regulates enthalpy, which is verified through thermodynamic characterizations and analyses. On the basis of this straightforward strategy, the performances, such as p K a , of the DNA motif can be precisely and predictably tuned. The DNA motifs are finally successfully applied for glucose biosensing and crypto-steganography systems, highlighting their potential in the field of biosensing and information encryption.

Background and aim Skeletal muscle (SM) has been shown as a target of thyroid hormones (THs). However, the status and effectiveness of thyroid hormones transporters (THTs) and deiodinases in thyroid hormones signaling system (TH signaling) during aging are uncertain. This study aimed to explore the regulated relationships of TH signaling elements in SM of aging mice.Methods Twenty-four C57BL/6J male mice were divided into 6-, 15- and 24-month (6, 15 and 24M) groups according to different ages. The types and expression of THTs and deiodinases were analyzed by mRNA sequencing and proteomic sequencing. qRT-PCR, Western blotting and fluorescence immunoassay were used to compare the key factors of TH signaling in three groups. The ability of transported THs in THTs was analyzed by [125I] T3 and [125I] T4 uptake rate. The regulatory relationship of TH signaling was analyzed in C2C12 cells.Results We identified eight types of THTs in SM of mice, among which the expression of MCT8, MCT10, LAT2, LAT4 and OATP2B1 increased with age. MCT8, MCT10, LAT2 and OATP2B1 had the ability to take up [125I] T3, while MCT8, MCT10 and OATP2B1 possessed the ability to take up [125I] T4 in C2C12 cells. Expression levels of deiodinase type 2 (DIO2) and type 3 (DIO3) also augmented with aging, and the upregulation of DIO3 was regulated by MCT8 and MCT10. Neither deiodinases nor age-related THTs was regulated by TRα.Conclusions The expression of main types of THTs (MCT8, MCT10, LAT2, LAT4 and OATP2B1) and deiodinases (DIO2, DIO3) significantly increased in SM of aged mice, perhaps due to the compensation of age-related decrease of TRα. The expression of DIO3 was regulated by MCT8 and MCT10.

Background: Polymeric hollow particles with a single-hole structure have attracted broad interest due to their combined advantages of a hollow cavity and an opening hole in the shell. Aim: In the past decades, much progress has been made in the fabrication of such particles with various strategies. However, there is a lack of research on the easy fabrication of biodegradable polylactide (PLA) single hole particles (PLA SHHPs). Method: In this work, we reported a simple double emulsion method for the fabrication of PLA SHHPs. The W/O/W double emulsion was formed by homogenizing PLA chloroform and brilliant blue G (BBG) solution. Scanning electron microscopy and confocal laser scanning microscopy were used for the characterization. It was found that the concentrations of PLA chloroform and BBG solution both had a significant influ-ence on the emulsion structure. Result: PLA SHHPs with a percentage >85% were obtained from the emulsion composed of PLA chloroform (10.0w%) and BBG solution (4 mM). The particle formation mechanism was also pro-posed based on the result of the low interfacial tension between PLA chloroform/BBG solution. Conclusion: The results may inspire new development of PLA particles with unique structures, which are promising to be used in drug delivery, catalysis, microreaction and micromotors.

Background The preliminary result of the TORCH trial has showed promising complete response (CR) for managing locally advanced rectal cancer (LARC) with neoadjuvant short-couse radiotherapy (SCRT) combined with chemotherapy and PD-1 inhibitor. For locally advanced colon cancer (LACC) with bulky nodal disease and/or clinically T4, neoadjuvant chemotherapy followed by colectomy with en bloc removal of regional lymph nodes is the suggested treatment. However, the CR rate is less than 5%. TORCH-C will aim to investigate neoadjuvant short-couse radiotherapy combined with chemotherapy and PD-1 inhibitor in LACC.Methods TORCH-C is a randomized, prospective, multicentre, double-arm, open, phase Ⅱ trial of SCRT combined with chemotherapy and immunotherapy in LACC with microsatellite-stable (MSS) patients and cT4 or bulky nodes. Eligible patients will be identified by the multidisplinary team. 120 patients will be randomized 1:1 to the intervention or control arm. The patients in the control arm will receive 4 cycles of capecitabine plus oxaliplatin (CAPOX). The patients in the intervention arm will receive SCRT, followed by 4 cycles of CAPOX and PD-1 inhibitor (Serplulimab). Both arms will receive curative surgery, followed by 4 cycles of CAPOX. The primary endpoint is pathologic complete regression (pCR).Discussion TORCH-C trial aims to investigate whether the combination of immunotherapy and chemoradiotherapy improves the treatment effect in LACC with MSS. TORCH-C will establish the TORCH platform, a key part of our long-term strategy to develop neoadjuvant treatment for colorectal cancer (CRC).Trial registration: The trial has been registered in ClinicalTrials.gov on Feburary 16, 2023 (Registration No. NCT05732493).

Disruption prediction and mitigation is a crucial topic, especially for future large-scale tokamaks, due to disruption’s concomitant harmful effects on the devices. On this topic, disruption prediction algorithm takes the responsibility to give accurate trigger signal in advance of disruptions, therefore the disruption mitigation system can effectively alleviate the harmful effects. In the past 5 years, a deep learning-based algorithm is developed in HL-2A tokamak. It reaches a true positive rate of 92.2%, a false positive rate of 2.5% and a total accuracy of 96.1%. Further research is implemented on the basis of this algorithm to solve three key problems, i.e., the algorithm’s interpretability, real-time capability and transferability. For the interpretability, HL-2A’s algorithm gives saliency maps indicating the correlation between the algorithm’s input and output by perturbation analysis. The distribution of correlations shows good coherence with the disruption causes. For the transferability, a preliminary disruption predictor is successfully developed in HL-2M, a newly built tokamak in China. Although only 44 shots are used as the training set of this algorithm, it gives reasonable outputs with the help of data from HL-2A and J-TEXT. For the real-time capacity, the algorithm is accelerated to deal with an input slice within 0.3ms with the help of some adjustments on it and TFLite framework. It is also implemented into the plasma control system and gets an accuracy of 89.0% during online test. This paper gives a global perspective on these results and discusses the possible pathways to make HL-2A’s algorithm a more comprehensive solution for future tokamaks.

BackgroundAssociations between non-optimal temperatures and cardiovascular disease (CVD) mortality risk have been previously reported, yet the trends of CVD mortality attributable to non-optimal temperatures remain unclear in China. We analyzed trends in CVD mortality attributable to non-optimal temperatures and associations with age, period, and birth cohort.MethodsData were obtained from the Global Burden of Disease Study (GBD) 2019. Joinpoint regression analysis was used to calculate annual percent change (APC) and average annual percent change (AAPC) from 1990 to 2019. We used the age-period-cohort model to analyze age, period, and cohort effects in CVD mortality attributable to non-optimal temperatures between 1990 and 2019.ResultsThe age-standardized mortality rate (ASMR) of CVD attributable to non-optimal temperature generally declined in China from 1990 to 2019, whereas ischemic heart disease (IHD) increased slightly. Low temperatures have a greater death burden than high temperatures, but the death burden from high temperatures showed steady increases. Joinpoint regression analysis showed that CVD mortality decreased in all age groups except for IHD, and the decreases were greater in females than in males. The mortality of CVD attributable to non-optimal temperatures of males was higher than females. The mortality rate showed an upwards trend with age across all CVD categories. Period risks were generally found in unfavorable trends. The cohort effects showed a progressive downward trend during the entire period.ConclusionAlthough there have been reductions in CVD mortality attributable to non-optimum temperatures, the mortality of IHD has increased and the burden from non-optimal temperatures remains high in China. In the context of global climate change, our results call for more attention and strategies to address climate change that protect human health from non-optimal temperatures.

Immunotherapy as a rapidly developing therapeutic approach has revolutionized cancer treatment and revitalized the field of tumor immunology research. 3D in vitro models are emerging as powerful tools considering their feature to maintain tumor cells in a near-native state and have been widely applied in oncology research. The novel 3D culture methods including the co-culture of organoids and immune cells, ALI culture, 3D-microfluidic culture and 3D-bioprinting offer new approaches for tumor immunology study and can be applied in many fields such as personalized treatment, immunotherapy optimizing and adoptive cell therapy. In this review, we introduce commonly used 3D in vitro models and summarize their applications in different aspects of tumor immunology research. We also provide a preliminary analysis of the current shortcomings of these models and the outlook of future development.

Supplementary figures showing that the gut microbiome variations over the course of nCRT associated with therapeutic response.