Measurable residual disease testing by next generation sequencing is more accurate compared with multiparameter flow cytometry in adults with B-cell acute lymphoblastic leukemia.

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34-8.5; P = 0.01) and worse survival (HR = 4.87 [1.53-15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTROPC-14005546]).

A causal counterfactual graph neural network for arising-from-chair abnormality detection in parkinsonians.

The arising-from-chair task assessment is a key aspect of the evaluation of movement disorders in Parkinson's disease (PD). However, common scale-based clinical assessment methods are highly subjective and dependent on the neurologist's expertise. Alternate automated methods for arising-from-chair assessment can be established based on quantitative susceptibility mapping (QSM) images with multiple-instance learning. However, performance stability for such methods can be typically undermined by the presence of irrelevant or spuriously-relevant features that mask the intrinsic causal features. Therefore, we propose a QSM-based arising-from-chair assessment method using a causal graph-neural-network framework, where counterfactual and debiasing strategies are developed and integrated into this framework for capturing causal features. Specifically, the counterfactual strategy is proposed to suppress irrelevant features caused by background noise, by producing incorrect predictions when dropping causal parts. The debiasing strategy is proposed to suppress spuriously relevant features caused by the sampling bias and it comprises a resampling guidance scheme for selecting stable instances and a causal invariance constraint for improving stability under various interferences. The results of extensive experiments demonstrated the superiority of the proposed method in detecting arising-from-chair abnormalities. Its clinical feasibility was further confirmed by the coincidence between the selected causal features and those reported in earlier medical studies. Additionally, the proposed method was extensible for another motion task of leg agility. Overall, this study provides a potential tool for automated arising-from-chair assessment in PD patients, and also introduces causal counterfactual thinking in medical image analysis. Our source code is publicly available at https://github.com/SJTUBME-QianLab/CFGNN-PDarising.

ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer's disease mouse model.

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aß and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aß, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aß: ß-amyloid, GABA: gamma-aminobutyric acid.

Rapid and Amplification-free Nucleic Acid Detection with DNA Substrate-Mediated Autocatalysis of CRISPR/Cas12a.

To enable rapid and accurate point-of-care DNA detection, we have developed a single-step, amplification-free nucleic acid detection platform, a DNA substrate-mediated autocatalysis of CRISPR/Cas12a (DSAC). DSAC makes use of the trans-cleavage activity of Cas12a and target template-activated DNA substrate for dual signal amplifications. DSAC employs two distinct DNA substrate types: one that enhances signal amplification and the other that negatively modulates fluorescent signals. The positive inducer utilizes nicked- or loop-based DNA substrates to activate CRISPR/Cas12a, initiating trans-cleavage activity in a positive feedback loop, ultimately amplifying the fluorescent signals. The negative modulator, which involves competitor-based DNA substrates, competes with the probes for trans-cleaving, resulting in a signal decline in the presence of target DNA. These DNA substrate-based DSAC systems were adapted to fluorescence-based and paper-based lateral flow strip detection platforms. Our DSAC system accurately detected African swine fever virus (ASFV) in swine's blood samples at femtomolar sensitivity within 20 min. In contrast to the existing amplification-free CRISPR/Dx platforms, DSAC offers a cost-effective and straightforward detection method, requiring only the addition of a rationally designed DNA oligonucleotide. Notably, a common ASFV sequence-encoded DNA substrate can be directly applied to detect human nucleic acids through a dual crRNA targeting system. Consequently, our single-step DSAC system presents an alternative point-of-care diagnostic tool for the sensitive, accurate, and timely diagnosis of viral infections with potential applicability to human disease detection.

A novel OsGST gene encoding 9glutathione reductase negatively regulates cadmium accumulation in rice.

Cadmium (Cd) accumulates in rice and then moves up the food chain, causing serious health problems for humans. Glutathione S-transferase (GST) binds exogenous hazardous compounds to glutathione (GSH), which performs a variety of roles in plant responses to Cd stress. Here, Cd stimulated the transcripts of a novel OsGST gene, and the OsGST protein, which was localized in the nucleus and cytoplasm, was also induced by Cd. In OsGST deletion mutant lines generated by CRISPR/Cas9, more Cd was accumulated, and Cd hypersensitive phenotypes were observed, while transgenic lines overexpressing OsGST exhibited enhanced Cd tolerance and less Cd accumulation. Further analysis indicated that the osgst mutants exhibited considerably greater reactive oxygen species (ROS) and higher GSH level, and the antioxidant activity associated genes' expression were down-regulated, imply that OsGST controlled rice Cd accumulation and resistance through preserving the equilibrium of the GSH and redox in rice.

Influence of leaf inclination angle and tillering on population transpiration, soil evaporation, and yield in winter wheat near-isogenic lines.

Leaf inclination angle (LIA) and tillering impact the winter wheat (Triticum aestivum L.) population canopy structure. Understanding their effects on water use (WU) parameters and yield can guide water-saving strategies through population control. In this study, six near-isogenic lines (NILs) and their parents were selected as materials. These special materials were characterized by varying tillering at the current sowing density, a similar genetic background, and, particularly, a gradient in mean flag leaf LIA. The investigation focused on the jointing to early grain-filling stage, the peak water requirement period of wheat crops. Population-scale transpiration (PT) and evaporation from the soil surface (E) were partitioned from total evapotranspiration (ET) by the means of micro-lysimeters. The results showed decreased PT, E, and ET with increased population density (PD) within a narrow density range derived from varying tillering across genotypes. Significant correlations existed between PD and ET, E, and PT, especially in the wettest 2017-2018 growing season. Within such narrow PD range, all the correlations between WU parameters and PD were negative, although some correlations were not statistically significant, thereby suggesting the population structure's predominant impact. No significant correlation existed between LIA and both ET and PT within the LIA range of 35°-65°. However, significant correlations occurred between LIA and E in two growing seasons. Genotypes with similar LIA but different PD produced varied ET; while with similar PD, the four pairs of genotypes with different LIA each consumed similar ET, thus highlighting PD's more crucial role in regulating ET. The yield increased with higher LIA, and showed a significant correlation, emphasizing the LIA's significant effect on yield. However, no correlation was observed with PD, indicating the minor effect of tillering at the current sowing density. Therefore these results might offer valuable insights for breeding water-saving cultivars and optimizing population structures for effective field water conservation.

Genome-wide analysis of MYB transcription factor family and AsMYB1R subfamily contribution to ROS homeostasis regulation in Avena sativa under PEG-induced drought stress.

BACKGROUND: The myeloblastosis (MYB) transcription factor (TF) family is one of the largest and most important TF families in plants, playing an important role in a life cycle and abiotic stress. RESULTS: In this study, 268 Avena sativa MYB (AsMYB) TFs from Avena sativa were identified and named according to their order of location on the chromosomes, respectively. Phylogenetic analysis of the AsMYB and Arabidopsis MYB proteins were performed to determine their homology, the AsMYB1R proteins were classified into 5 subgroups, and the AsMYB2R proteins were classified into 34 subgroups. The conserved domains and gene structure were highly conserved among the subgroups. Eight differentially expressed AsMYB genes were screened in the transcriptome of transcriptional data and validated through RT-qPCR. Three genes in AsMYB2R subgroup, which are related to the shortened growth period, stomatal closure, and nutrient and water transport by PEG-induced drought stress, were investigated in more details. The AsMYB1R subgroup genes LHY and REV 1, together with GST, regulate ROS homeostasis to ensure ROS signal transduction and scavenge excess ROS to avoid oxidative damage. CONCLUSION: The results of this study confirmed that the AsMYB TFs family is involved in the homeostatic regulation of ROS under drought stress. This lays the foundation for further investigating the involvement of the AsMYB TFs family in regulating A. sativa drought response mechanisms.

Association between spot urinary sodium-to-potassium ratio and blood pressure among Chinese adults aged 18-69 years: the SMASH study.

Background: Excessive sodium and low potassium intake are involved in the development of hypertension. Growing evidence showed that the sodium-to-potassium ratio (Na/K) was significantly associated with blood pressure (BP). However, studies on the dose-response relationship of spot urinary Na/K ratio with hypertension and BP in the general population are scarce, especially in the Chinese population. Materials and methods: Data from the post-intervention survey of the Shandong Ministry of Health Action on Salt and Hypertension (SMASH) project was analyzed. Associations between Na/K molar ratio and hypertension prevalence and between Na/K molar ratio and BP indices were analyzed using multivariable logistic and linear regression, respectively, followed by subgroup analysis and interaction analysis. The restricted cubic spline model was used to explore the dose-response relationship. Informed by existing literature, we adjusted for potential confounding factors, including temperature and renal function, to assess the association and dose-response relationship. Results: There was a non-linear positive association between Na/K and hypertension (OR:1.09, 95%CI: 1.08-1.11) and a linear positive association between Na/K and systolic BP, diastolic BP, and mean arterial pressure (ß 0.53, 95%CI: 0.45-0.60; ß 0.36, 95%CI: 0.31-0.41; and ß 0.42, 95%CI: 0.36-0.47, respectively). The association was stronger in individuals with hypertension, female patients, those in the 50-59-year age group, and those who were obese. Environmental temperatures had little impact on associations. Conclusion: Our findings provide further evidence that the spot urinary Na/K ratio is a simple, useful, and convenient indicator for monitoring salt reduction and potassium increase, which could be used in clinical and public health practices.

[Source Apportionment and Health Risk Assessment of Heavy Metals in Dust Around Bus Stops in Kaifeng City Based on APCS-MLR Model].

In order to reveal the influence of urban transportation systems on the quality of urban ecological environment, this study selected surface dust from bus stops, which is strongly disturbed by transportation, as the research object. The contents of eight heavy metals (V, Cr, Co, Ni, Cu, Zn, Cd, and Pb) in the dust were determined through inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectroscopy (ICP-ASE). The spatial distribution characteristics and pollution levels of the eight heavy metals in the dust were analyzed using the geo-accumulation index method. A combined qualitative (correlation analysis and principal component analysis) and quantitative (absolute principal component scores-multiple linear regression model (APCS-MLR)) method was used to explore the sources of heavy metals in surface dust near bus stops. The spatial distribution characteristics of heavy metals from different sources were elucidated using the Kriging interpolation method. The health risk assessment model proposed by the United States Environmental Protection Agency was used to evaluate the human health risks. The results showed that the average values of ω(V), ω(Cr), ω(Co), ω(Ni), ω(Cu), ω(Zn), ω(Cd), ω(Pb), and ω(As) in the bus stop surface dust were 68.36, 59.73, 5.81, 19.34, 40.10, 208.32, 1.01, and 49.46 mg·kg-1, respectively. The concentrations of heavy metals (Cd, Zn, Pb, Cu, and Cr) in the dust were all higher than the background values in the surrounding dust, exceeding them by 3.37, 2.70, 2.01, 1.95, and 1.28 times, respectively. The order of the geo-accumulation index for the eight heavy metals was Cd > Zn > Pb > Cu > Cr > V > Ni > Co, with Cd, Zn, Cu, and Pb in the dust indicating mild pollution levels and the others showing no pollution. The source analysis results showed that Cr, Co, and Ni were natural sources, whereas Cu, Zn, Pb, and Cd were traffic sources, and V was derived from a combination of industrial and natural sources. The APCS-MLR results indicated that the average contribution rates of the four sources were as follows:natural source (34.17 %), traffic source (29.84 %), industrial-natural mixed source (14.64 %), and unknown source (21.35 %). The spatial distribution map of the contribution rate of the traffic source was consistent with the trends of traffic volume and bus route density distribution. According to the health risk assessment, the cancer risk and non-cancer risk for children were both higher than those for adults. Cr was the main non-cancer factor, and Cd was the main cancer-causing factor. Natural and traffic sources contributed the most to non-cancer risk and cancer risk, respectively.

Homozygous deleterious variants in the C-terminal of TDRD5 impair spermiogenesis, causing severe oligoasthenoteratozoospermia in humans.

BACKGROUND: PiRNA pathway factors, including evolutionarily conserved Tudor domain-containing proteins, play crucial roles in suppressing transposons and regulating post-meiotic gene expression. TDRD5 is essential for retrotransposon silencing and pachytene piRNA biogenesis; however, a causal link between TDRD5 variants and human infertility has not yet been established. OBJECTIVE: To identify the likely pathogenic variants of TDRD5 in infertile men, characterised by azoospermia or severe oligozoospermia. MATERIAL AND METHODS: Potential candidate variants were identified and confirmed using whole-exome and Sanger sequencing. Haematoxylin and eosin staining, immunofluorescence, and ultrastructural analyses were performed to investigate the structural and functional abnormalities of spermatozoa. The pathogenicity of the identified TDRD5 variants was verified using in vitro experiments. Functional effects of the C-terminal nonsense variant were assessed via histology, immunofluorescence staining, and small-RNA sequencing. Intracytoplasmic sperm injection (ICSI) was also performed to evaluate the efficacy of the clinical treatment. RESULTS: We identified a homozygous missense variant (c.3043G > A, p.A1015T) and a homozygous nonsense variant (c.2293G > T, p.E765*) of TDRD5 in two unrelated infertile men. Both patients exhibited severe oligoasthenoteratozoospermia, characterised by the presence of spermatozoa with multiple heads and/or flagella, as well as acrosomal hypoplasia. In vitro experiments revealed that the p.A1015T variant caused a diffuse distribution of TDRD5 granules, whereas the p.E765* variant led to the production of a C-terminal truncated protein with nuclear localisation, instead of the typical cytoplasmic localisation observed for the wild-type protein. Functional investigations also revealed that truncation of the C-terminal region of TDRD5 could potentially lead to a decline in the expression levels of intermitochondrial cement and chromatoid body components, such as MIWI (PIWIL1) and UPF1, and a slight decrease in the abundance of pachytene piRNA, ultimately resulting in compromised spermiogenesis. ICSI may be an effective treatment for these deficiencies. DISCUSSION AND CONCLUSION: This study implicates TDRD5 as a novel candidate gene in the pathogenesis of human male infertility, emphasising the contribution of piRNA pathway genes to male infertility. In addition, our data suggest that ICSI could be a promising treatment for infertile men harbouring TDRD5 variants.

Intervention effects of low-molecular-weight chondroitin sulfate from the nasal cartilage of yellow cattle on lipopolysaccharide-induced behavioral disorders: regulation of the microbiome-gut-brain axis.

Chondroitin sulfate (CS) is a sulfated linear polysaccharide with different functional activities, including antioxidant, anti-inflammatory, lipid-lowering, and immune regulation. As natural sulfated polysaccharides have high molecular weight, high apparent viscosity, low water solubility, complex structure, and high negative charge, they have difficulty binding to receptors within cells across tissue barriers, resulting in low bioavailability and unclear structure-activity relationships. In this study, an H2O2-Vc oxidative degradation system was employed to perform environmentally friendly and controllable degradation of CS extracted from the nasal cartilage of Shaanxi Yellow cattle. Two low-molecular-weight chondroitin sulfates (LMWCSs), CS-1 (14.8 kDa) and CS-2 (50.9 kDa), that exhibit strong in vitro free radical scavenging ability were obtained, and their structures were characterized. Mice intraperitoneally administered lipopolysaccharide (LPS) were used to explore the cognitive intervention effects of LMWCS. Supplementing CS-1 and CS-2 significantly downregulated the levels of the serum inflammatory factors, TNF-α and IL-1ß, promoted the expression of GSH in the brain, and inhibited the production of the lipid peroxidation product, malondialdehyde (MDA), ultimately inhibiting LPS-induced cognitive impairment in mice. Surprisingly, compared to the LPS model group, the abundances of Streptococcus, Eisenbergiella, Vampirovibrio, Coprococcus, Enterococcus and Lachnoanaerobaculum were significantly increased in the intestines of mice in the CS-1 and CS-2 group, whereas those of Parabacteroides and Mycoplasma were significantly decreased. Altogether, this study provides a theoretical basis for the comprehensive utilization of agricultural and animal resources and the application of brain nutrition, anti-inflammatory, and LMWCS health products.

Global burdens of nasopharyngeal carcinoma in children and young adults and predictions to 2040.

OBJECTIVES: To investigate the epidemiological trend for nasopharyngeal carcinoma among children and young adults and the disease burden they caused. MATERIALS AND METHODS: Data were collected from the Global Burden of Disease (GBD) study 2019. A comprehensive analysis was performed, with age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), disability-adjusted life-years (DALYs) and estimated annual percentage changes (EAPC). And decomposition and frontier analyses were done. Future trends were predicted using Bayesian age-period-cohort model. RESULTS: Globally, there were decreases in the ASIR (EAPC -0.175, 95 % confidence interval [CI]: -0.352 to 0.002), ASMR (EAPC -2.681, 95 % CI: -2.937 to -2.424), and age-standardized DALYs rates (EAPC -2.643, 95 % CI: -2.895 to -2.391). However, the ASIR for males in global (EAPC 0.454, 95 % CI: 0.302 to 0.606), Asia (EAPC 0.782, 95 % CI: 0.610 to 0.954) and America (EAPC 0.448, 95 % CI: 0.379 to 0.517), as well as females in European (EAPC 0.595, 95 % CI: 0.479 to 0.712) and American (EAPC 0.369, 95 % CI: 0.324 to 0.415), showed an increasing trend. The future ASIR per 100,000 will likely show a slight upward trend in 2020 to 2040 (increased from 0.254 to 0.284), particularly among females (increased from 0.177 to 0.206), and a continued decline in ASMR for both sexes (decreased from 0.070 to 0.061). CONCLUSIONS: Globally, NPC in children and young adults remains a major public health issue, with the global distribution and magnitude of the burden varies markedly, highlighting the need to formulate regional and population-based policies for primary prevention.

Preparation and efficacy of antibacterial methacrylate monomer-based polymethyl methacrylate bone cement containing N-halamine compounds.

Introduction: Our objective in this study was to prepare a novel type of polymethyl methacrylate (PMMA) bone cement, analyze its material properties, and evaluate its safety and antibacterial efficacy. Methods: A halamine compound methacrylate antibacterial PMMA bone cement containing an N-Cl bond structure was formulated, and its material characterization was determined with Fourier transform infrared spectroscopy (FT-IR) and 1H-NMR. The antibacterial properties of the material were studied using contact bacteriostasis and releasing-type bacteriostasis experiments. Finally, in vitro and in vivo biocompatibility experiments were performed to analyze the toxic effects of the material on mice and embryonic osteoblast precursor cells (MC3T3-E1). Results: Incorporation of the antibacterial methacrylate monomer with the N-halamine compound in the new antibacterial PMMA bone cement significantly increased its contact and releasing-type bacteriostatic performance against Staphylococcus aureus. Notably, at 20% and 25% additions of N-halamine compound, the contact and releasing-type bacteriostasis rates of bone cement samples reached 100% (p < 0.001). Furthermore, the new antibacterial bone cement containing 5%, 10%, and 15% N-halamine compounds showed good biocompatibility in vitro and in vivo. Conclusion: In this study, we found that the novel antibacterial PMMA bone cement with N-halamine compound methacrylate demonstrated good contact and releasing-type bacteriostatic properties against S. aureus. In particular, bone cement containing a 15% N-halamine monomer exhibited strong antibacterial properties and good in vitro and in vivo biocompatibility.

A Novel Machine Learning Model for Predicting Stroke-Associated Pneumonia After Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Pneumonia is one of the most common complications after spontaneous intracerebral hemorrhage (sICH), i.e., stroke-associated pneumonia (SAP). Timely identification of targeted patients is beneficial to reduce poor prognosis. So far, there is no consensus on SAP prediction, and application of existing predictors is limited. The aim of this study was to develop a machine learning model to predict SAP after sICH. METHODS: We retrospectively reviewed 748 patients diagnosed with sICH and collected data from 4 dimensions-demographic features, clinical features, medical history, and laboratory tests. Five machine learning algorithms-logistic regression, gradient boosting decision tree, random forest, extreme gradient boosting, and category boosting-were used to build and validate the predictive model. We also applied recursive feature elimination with cross-validation to obtain the best feature combination for each model. Predictive performance was evaluated by area under the receiver operating characteristic curve. RESULTS: SAP was diagnosed in 237 patients. The model developed by category boosting yielded the most satisfactory outcomes overall with area under the receiver operating characteristic curves in the training set and test set of 0.8307 and 0.8178, respectively. CONCLUSIONS: The incidence of SAP after sICH in our center was 31.68%. Machine learning could potentially provide assistance in the prediction of SAP after sICH.

Dual drug-loaded metal-phenolic networks for targeted magnetic resonance imaging and synergistic chemo-chemodynamic therapy of breast cancer.

The development of nanomedicines with simplified compositions and synergistic theranostic functionalities remains a great challenge. Herein, we develop a simple method to integrate both atovaquone (ATO, a mitochondrial inhibitor) and cisplatin within tannic acid (TA)-iron (Fe) networks coated with hyaluronic acid (HA) for targeted magnetic resonance (MR) imaging-guided chemo-chemodynamic synergistic therapy. The formed TFP@ATO-HA displayed good colloidal stability with a mean size of 95.5 nm, which could accumulate at tumor sites after circulation and be specifically taken up by metastatic 4T1 cells overexpressing CD44 receptors. In the tumor microenvironment, TFP@ATO-HA could release ATO/cisplatin and Fe3+ in a pH-responsive manner, deplete glutathione, and generate reactive oxygen species with endogenous H2O2 for chemodynamic therapy (CDT). Additionally, ATO could enhance chemotherapeutic efficacy by inhibiting mitochondrial respiration, relieving hypoxia, and amplifying the CDT effect by decreasing intracellular pH and elevating Fenton reaction efficiency. In vivo experiments demonstrated that TFP@ATO-HA could effectively inhibit tumor growth and suppress lung metastases without obvious systemic toxicity. Furthermore, TFP@ATO-HA exhibited a r1 relaxivity of 2.6 mM-1 s-1 and targeted MR imaging of 4T1 tumors. Dual drug-loaded metal-phenolic networks can be easily prepared and act as effective theranostic nanoplatforms for targeted MR imaging and synergistic chemo-chemodynamic therapy.

USP47 deficiency in mice modulates tumor infiltrating immune cells and enhances antitumor immune responses in prostate cancer.

This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.

Construction of a Full-Length Transcriptome of Western Honeybee Midgut Tissue and Improved Genome Annotation.

Honeybees are an indispensable pollinator in nature with pivotal ecological, economic, and scientific value. However, a full-length transcriptome for Apis mellifera, assembled with the advanced third-generation nanopore sequencing technology, has yet to be reported. Here, nanopore sequencing of the midgut tissues of uninoculated and Nosema ceranae-inoculated A. mellifera workers was conducted, and the full-length transcriptome was then constructed and annotated based on high-quality long reads. Next followed improvement of sequences and annotations of the current reference genome of A. mellifera. A total of 5,942,745 and 6,664,923 raw reads were produced from midguts of workers at 7 days post-inoculation (dpi) with N. ceranae and 10 dpi, while 7,100,161 and 6,506,665 raw reads were generated from the midguts of corresponding uninoculated workers. After strict quality control, 6,928,170, 6,353,066, 5,745,048, and 6,416,987 clean reads were obtained, with a length distribution ranging from 1 kb to 10 kb. Additionally, 16,824, 17,708, 15,744, and 18,246 full-length transcripts were respectively detected, including 28,019 nonredundant ones. Among these, 43,666, 30,945, 41,771, 26,442, and 24,532 full-length transcripts could be annotated to the Nr, KOG, eggNOG, GO, and KEGG databases, respectively. Additionally, 501 novel genes (20,326 novel transcripts) were identified for the first time, among which 401 (20,255), 193 (13,365), 414 (19,186), 228 (12,093), and 202 (11,703) were respectively annotated to each of the aforementioned five databases. The expression and sequences of three randomly selected novel transcripts were confirmed by RT-PCR and Sanger sequencing. The 5' UTR of 2082 genes, the 3' UTR of 2029 genes, and both the 5' and 3' UTRs of 730 genes were extended. Moreover, 17,345 SSRs, 14,789 complete ORFs, 1224 long non-coding RNAs (lncRNAs), and 650 transcription factors (TFs) from 37 families were detected. Findings from this work not only refine the annotation of the A. mellifera reference genome, but also provide a valuable resource and basis for relevant molecular and -omics studies.

NIR-responsive CN-Pt-GEM hydrogel induces necroptosis and immunotherapeutic responses prevent postoperative recurrence and wound infection in lung carcinoma.

BACKGROUND: Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection is an important component of successful surgery. With the development of new nanotechnology, more treatment options have been provided for postoperative adjuvant therapy. This study presents an innovative hydrogel system that stimulates tumoricidal immunity after surgical resection of non-small cell lung cancer (NSCLC) and prevents cancer relapse. RESULTS: The hydrogel system is based on the excellent photothermal conversion performance of single-atom platinum (CN-Pt) along with the delivery and release of the chemotherapy drug, gemcitabine (GEM). The system is coated onto the wound surface after tumor removal with subsequent near-infrared (NIR) photothermal therapy, which efficiently induces necroptosis of residual cancer cells, amplifies the levels of damage-associated molecular patterns (DAMPs), and increases the number of M1 macrophages. The significantly higher levels of phagocytic macrophages enhance tumor immunogenicity and sensitize cancer cells to CD8 + T-cell immunity to control postoperative recurrence, which has been verified using an animal model of postoperative lung cancer recurrence. The CN-Pt-GEM-hydrogel with NIR can also inhibit postoperative wound infection. CONCLUSIONS: These findings introduce an alternative strategy for supplementing antitumor immunity in patients undergoing resection of NSCLC tumors. The CN-Pt-GEM-hydrogel with the NIR system also exhibits good biosafety and may be adaptable for clinical application in relation to tumor resection surgery, wound tissue filling, infection prevention, and recurrence prevention.

Causality-Enhanced Multiple Instance Learning With Graph Convolutional Networks for Parkinsonian Freezing-of-Gait Assessment.

Freezing of gait (FoG) is a common disabling symptom of Parkinson's disease (PD). It is clinically characterized by sudden and transient walking interruptions for specific human body parts, and it presents the localization in time and space. Due to the difficulty in extracting global fine-grained features from lengthy videos, developing an automated five-point FoG scoring system is quite challenging. Therefore, we propose a novel video-based automated five-classification FoG assessment method with a causality-enhanced multiple-instance-learning graph convolutional network (GCN). This method involves developing a temporal segmentation GCN to segment each video into three motion stages for stage-level feature modeling, followed by a multiple-instance-learning framework to divide each stage into short clips for instance-level feature extraction. Subsequently, an uncertainty-driven multiple-instance-learning GCN is developed to capture spatial and temporal fine-grained features through GCN scheme and uncertainty learning, respectively, for acquiring global representations. Finally, a causality-enhanced graph generation strategy is proposed to exploit causal inference for mining and enhancing human structures causally related to clinical assessment, thereby extracting spatial causal features. Extensive experimental results demonstrate the excellent performance of the proposed method on five-classification FoG assessment with an accuracy of 62.72% and an acceptable accuracy of 91.32%, which is confirmed by independent testing. Additionally, it enables temporal and spatial localization of FoG events to a certain extent, facilitating reasonable clinical interpretations. In conclusion, our method provides a valuable tool for automated FoG assessment in PD, and the proposed causality-related component exhibits promising potential for extension to other general and medical fine-grained action recognition tasks.