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IntroductionMultiple myeloma (MM) is an incurable hematological malignancy with high chromosome instability and heavy dependence on the immunosuppressive bone marrow microenvironment. P53 mutations are adverse prognostic factors in MM; however, clinically, some patients without P53 mutations also exhibit aggressive disease progression. DNp73, an inhibitor of TP53 tumor suppressor family members, drives drug resistance and cancer progression in several solid malignancies. Nevertheless, the biological functions of DNp73 and the molecular mechanisms in myelomagenesis remain unclear.MethodsThe effects of DNp73 on proliferation and drug sensitivity were assessed using flow cytometry and xenograft models. To investigate the mechanisms of drug resistance, RNA-seq and ChIP-seq analyses were performed in MM cell lines, with validation by Western blot and RT-qPCR. Immunofluorescence and transwell assays were used to assess DNA damage and cell invasion in MM cells. Additionally, in vitro phagocytosis assays were conducted to confirm the role of DNp73 in immune evasion.ResultsOur study found that activation of NF-κB-p65 in multiple myeloma cells with different p53 mutation statuses upregulates DNp73 expression at the transcriptional level. Forced expression of DNp73 promoted aggressive proliferation and multidrug resistance in MM cells. Bulk RNA-seq analysis was conducted to assess the levels of MYCN, MYC, and CDK7. A ChIP-qPCR assay was used to reveal that DNp73 acts as a transcription factor regulating MYCN gene expression. Bulk RNA-seq analysis demonstrated increased levels of MYCN, MYC, and CDK7 with forced DNp73 expression in MM cells. A ChIP-qPCR assay revealed that DNp73 upregulates MYCN gene expression as a transcription factor. Additionally, DNp73 promoted immune evasion of MM cells by upregulating MYC target genes CD47 and PD-L1. Blockade of the CD47/SIRPα and PD-1/PD-L1 signaling pathways by the SIRPα-Fc fusion protein IMM01 and monoclonal antibody atezolizumab significantly restored the anti-MM activity of macrophages and T cells in the microenvironment, respectively.DiscussionIn summary, our study demonstrated for the first time that the p53 family member DNp73 remarkably induces proliferation, drug resistance, and immune escape of myeloma cells by directly targeting MYCN and regulating the MYC pathway. The oncogenic function of DNp73 is independent of p53 status in MM cells. These data contribute to a better understanding of the function of TP53 and its family members in tumorigenesis. Moreover, our study clarified that DNp73 overexpression not only promotes aggressive growth of tumor cells but, more importantly, promotes immune escape of MM cells through upregulation of immune checkpoints. DNp73 could serve as a biomarker for immunotherapy targeting PD-L1 and CD47 blockade in MM patients.

Nitrite is one of the most common toxic pollutants in intensive aquaculture and is harmful to aquatic animals. Recovery mechanisms post exposure to nitrite in shrimp have rarely been investigated. This study focuses on the effect of nitrite exposure and post-exposure recovery on the histological and physiological aspects of Litopenaeus vannamei and utilizes transcriptome sequencing to analyze the molecular mechanisms of adaptation to nitrite exposure. The results showed that histopathological damage to the hepatopancreas and gills caused by short-term nitrite exposure resolved with recovery. The total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and catalase (CAT) of shrimp were significantly reduced during nitrite exposure and returned to the control level after recovery, malondialdehyde (MDA) levels were opposite to them. Restoration of the antioxidant system after exposure mitigated oxidative damage. Nitrite exposure results in reduced activity of the immuno-enzymes acid phosphatase (ACP) and alkaline phosphatase (AKP), which can be recovered to the control level. L. vannamei can adapt to nitrite exposure by regulating Na+/K+-ATPase (NKA) activity. Transcriptome analysis revealed that activation of glutathione metabolism and peroxisomal pathways facilitated the mitigation of oxidative damage in L. vannamei during the recovery period. Excessive oxidative damage activates the apoptosis and p53 pathways. Additionally, Sestrin2 and STEAP4 may have a positive effect on recovery in shrimp. These results provide evidence for the damage caused by nitrite exposure and the recovery ability of L. vannamei. This study can complement the knowledge of the mechanisms of adaptation and recovery of shrimp under nitrite exposure.

Multiple myeloma (MM) remains an incurable hematological malignancy. Despite tremendous advances in the treatment, about 10% of patients still have very poor outcomes with median overall survival less than 24 months. Our study aimed to underscore the critical mechanisms pertaining to the rapid disease progression and provide novel therapeutic selection for these ultra-high-risk patients. We utilized single-cell transcriptomic sequencing to dissect the characteristic bone marrow niche of patients with survival of less than two years (EM24). Notably, an enrichment of LILRB4high pre-matured plasma-cell cluster was observed in the patients in EM24 compared to patients with durable remission. This cluster exhibited aggressive proliferation and drug-resistance phenotype. High-level LILRB4 promoted MM clonogenicity and progression. Clinically, high expression of LILRB4 was correlated with poor prognosis in both newly diagnosed MM patients and relapsed/refractory MM patients. The ATAC-seq analysis identified that high chromosomal accessibility caused the elevation of LILRB4 on MM cells. CRISPR-Cas9 deletion of LILRB4 alleviated the growth of MM cells, inhibited the immunosuppressive function of MDSCs, and further rescued T cell dysfunction in MM microenvironment. The more infiltration of myeloid-derived suppressive cells (MDSCs) was observed in EM24 patients as well. Therefore, we innovatively generated a TCR-based chimeric antigen receptor (CAR) T cell, LILRB4-STAR-T. Cytotoxicity experiment demonstrated that LILRB4-STAR-T cells efficaciously eliminated tumor cells and impeded MDSCs function. In conclusion, our study elucidates that LILRB4 is an ideal biomarker and promising immunotherapy target for high-risk MM. LILRB4-STAR-T cell immunotherapy is promising against tumor cells and immunosuppressive tumor microenvironment in MM.

The Pacific white shrimp (Litopenaeus vannamei) is affected by the accumulation of ammonia and nitrite, in an intensive culture model. However, the mechanisms of combined stress toxicity remain unclear. We analyzed histopathology, antioxidant defense, immune competence, and hepatopancreatic transcriptional responses under ammonia and nitrite stress. The results indicated that combined stress caused more extensive histopathological damage compared to single stresses. Deeper histopathological damage was observed in hepatopancreas and gills than in muscles. Combined stress induces more severe oxidative stress and influences competence. The malondialdehyde (MDA) levels in the combined stress group were higher than those in the single stress group and the control group. The activities of superoxide dismutase (SOD) and acid phosphatase (ACP) activities in the hepatopancreas of the combined stress group were significantly lower than those of the single stress group and the control group. Transcriptome analysis showed that 418, 427, and 1158 differentially expressed genes (DEGs) were identified in the ammonia and nitrite single and combined stress groups, respectively, compared to the control. Lysosomes, drug metabolism - other enzymes, and glycine, serine, and threonine metabolic pathways were found to be significantly enriched by Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis in both single and combined stress groups. The genes CES and BHMT, which are related to detoxifying metabolic and immune, were up-regulated under both single and combined stresses. The response of these upregulated genes provides a better understanding of shrimp resistance to multiple environmental stressors stress. Retinol metabolism, sphingolipid metabolism, apoptosis, and FoxO signaling pathway were enriched only in the combined stress group, suggesting that combined stress had a more significant effect on shrimp xenobiotic metabolism, apoptosis, and oxidative stress than single stress. This study deepens our understanding of the response mechanisms of L.vannamei under ammonia and nitrite combined stresses.

The environmental pollution and climate change caused by rapid industrialization and economic growth have become worldwide concerns. In order to alleviate environmental pressures and seek sustainable development pathways, green consumption has become a focal point of attention. However, the practice of green consumption often constrained by individuals' levels of environmental literacy. Therefore, this study focuses on Shandong Province, comprehensively assessing residents' environmental literacy through four dimensions: environmental values, environmental responsibility, environmental problem perception, and environmental behavioral skills. Similarly, residents' green consumption is evaluated through four dimensions: green products, material recycling, biodiversity conservation, and efficient use of energy. The study investigates the connection between these two aspects to provide robust support for regional sustainable development. Data from 210 valid surveys collected through online questionnaires in Shandong Province revealed a generally high level of environmental literacy and green consumption, but relatively lower performance in dimensions like environmental behavioral skills, green products and material recycling. Further analysis demonstrates significant positive correlations between the four dimensions of environmental literacy and green consumption. Notably, environmental behavior skills and environmental responsibility played pivotal roles in influencing green consumption.

Abstract Exploiting the fundamental features of quantum mechanics, an entanglement-based quantum network offers a promising platform for many dramatic applications such as multi-user cryptography. Nevertheless, the implementation of a large-scale quantum network in real-world scenarios remains challenging owing to the multiple scattering events in complex environment, particularly those frequency-sensitive scatterings that disturb quantum correlation both spatially and temporally. Here, we demonstrate the frequency-insensitive spatiotemporal control of entangled photons in a fully connected network by leveraging a Fourier-transform setup and the genetic algorithm. Such an approach can effectively improve the entanglement distribution process through a multimode fiber while the quantum characteristic of the network can be maintained well after the spatiotemporal shaping. Our scheme can serve as a bridging technology to establish entanglement between remote nodes of spectrally interconnected quantum systems and has great potential applications in future real-world quantum networks.

An experimental study of the chronic and acute effects of insulin on angiotensin II (ANG II)-induced synthesis of aldosterone in cultured adenomatous and normal human adrenal glomerulosa cells reveals that short-term treatment of insulin blocks ANG II-induced synthesis of aldosterone while chronic insulin treatment promotes ANG II activity. An arachidonate metabolic pathway involving 12-lipoxygenase mediates ANG II-induced aldosterone synthesis and suppression of this pathway contributes to the harmful effects of insulin. Thus, chronic and acute levels of insulin have different effects on ANG II activity.

MicroRNAs (MiRNAs) carried by exosomes play pivotal roles in the crosstalk between cell components in the tumor microenvironment. Our study aimed at identifying the expression profile of exosomal miRNAs (exo-miRNAs) in the serum of multiple myeloma (MM) patients and investigating the regulation networks and their potential functions by integrated bioinformatics analysis. Exosomes in serum from 19 newly diagnosed MM patients and 9 healthy donors were isolated and the miRNA profile was investigated by small RNA sequencing. Differential expression of exo-miRNAs was calculated and target genes of miRNAs were predicted. CytoHubba was applied to identify the hub miRNAs and core target genes. The LASSO Cox regression model was used to develop the prognostic model, and the ESTIMATE immune score was calculated to investigate the correlation between the model and immune status in MM patients. The top six hub differentially expressed serum exo-miRNAs were identified. 513 target genes of the six hub exo-miRNAs were confirmed to be differentially expressed in MM cells in the Zhan Myeloma microarray dataset. Functional enrichment analysis indicated that these target genes were mainly involved in mRNA splicing, cellular response to stress, and deubiquitination. 13 core exo-miRNA target genes were applied to create a novel prognostic signature to provide risk stratification for MM patients, which is associated with the immune microenvironment of MM patients. Our study comprehensively investigated the exo-miRNA profiles in MM patients. A novel prognostic signature was constructed to facilitate the risk stratification of MM patients with distinct outcomes.

Summary: Background: Multiple myeloma (MM) is an incurable hematological malignancy of the plasma cells. The maintenance of protein homeostasis is critical for MM cell survival. Elevated levels of paraproteins in MM cells are cleared by proteasomes or lysosomes, which are independent but inter-connected with each other. Proteasome inhibitors (PIs) work as a backbone agent and successfully improved the outcome of patients; however, the increasing activity of autophagy suppresses the sensitivity to PIs treatment. Methods: The transcription levels of CRIP1 were explored in plasma cells obtained from healthy donors, patients with newly diagnosed multiple myeloma (NDMM), and relapsed/refractory multiple myeloma (RRMM) using Gene expression omnibus datasets. Doxycycline-inducible CRIP1-shRNA and CRIP1 overexpressed MM cell lines were constructed to explore the role of CRIP1 in MM pathogenesis. Proliferation, invasion, migration, proteasome activity and autophagy were examined in MM cells with different CRIP1 levels. Co-immunoprecipitation (Co-IP) with Tandem affinity purification/Mass spectrum (TAP/MS) was performed to identify the binding proteins of CRIP1. The mouse xenograft model was used to determine the role of CRIP1 in the proliferation and drug-resistance of MM cells. Findings: High CRIP1 expression was associated with unfavorable clinical outcomes in patients with MM and served as a biomarker for RRMM with shorter overall survival. In vitro and in vivo studies showed that CRIP1 plays a critical role in protein homeostasis via the dual regulation of the activities of proteasome and autophagy in MM cells. A combined analysis of RNA-seq, Co-IP and TAP/MS demonstrated that CRIP1 promotes proteasome inhibitors resistance in MM cells by simultaneously binding to de-ubiquitinase USP7 and proteasome coactivator PA200. CRIP1 promoted proteasome activity and autophagosome maturation by facilitating the dequbiquitination and stabilization of PA200. Interpretation: Our findings clarified the pivotal roles of the CRIP1/USP7/PA200 complex in ubiquitin-dependent proteasome degradation and autophagy maturation involved in the pathogenesis of MM. Funding: A full list of funding sources can be found in the acknowledgements section.

Abstract Background The elderly population in China is growing, with hypertension being the most prevalent chronic disease in older adults. Despite the rapid penetration and efficient management effect of mobile health on hypertension healthcare, elderly patients are often less adopted and continue to use mobile health services. Quality perception significantly affects an individual’s satisfaction and continued intention to use mobile health services. The evaluation of the significant factors affecting mobile health quality perception by elderly individuals remains largely unexplored. The aim of this study was to develop and validate an evaluation scale to measure the perceived quality of mobile health applications for hypertension and determine the underlying influencing factors. Methods A cross-sectional survey was conducted between November 2018 and October 2019. A quality evaluation scale with three factors and seven indicators was developed based on the Information Systems Success model. Data was analyzed using structural equations modelling (SEM) and one-way analysis of variance (ANOVA). All tests were two-sided and statistically significant at P 10 years. Elderly patients who regularly visited primary hospitals assessed the information quality 0.13 higher (95% CI -0.08 ~ 0.34; P

Usual methods for optical encryption suffer from a tradeoff between the level of security and the complexity of operation given by multiple optical measurements or digital postprocessing. Here, the authors show a multi-d.o.f. metasurface-based vector optical manipulation protocol enabling secure decryption in real time.

Heterostructured composites with the coexistence of hard and soft phases can achieve a superior strength-ductility synergy. However, the deformation and fracture mechanisms of these composites under impact loading has not been comprehensively understood. In this work, an in-situ TiB2/2024 Al composite was adopted to investigate the role of heterogeneous structures on the tensile mechanical responses at different strain rates and temperatures. Surprisingly, a simultaneously enhancement of strength and ductility was found in the composite under impact loading. To explore the underlying mechanisms responsible for the observed mechanical behavior, microstructural analyses were performed on the samples before and after deformation. Results reveal that the composite has obvious heterogeneous structure consist of particle-rich regions (regard as hard phase) and particle-lean regions (soft phase). The interaction between the two phases can affect the strain hardening behavior of the composites at different plastic deformation stages. Compared with the strain rate insensitive matrix, the particle-induced constraint makes the flow stress of the composite increases substantially with an increase in strain rate. Meanwhile, the tortuous crack propagation paths induced by the cooperation of hard and soft phases contribute to the improved ductility at high strain rates.

Abstract Background Waldenström macroglobulinemia (WM) is a rare and incurable indolent B-cell malignancy. The molecular pathogenesis and the role of immunosuppressive microenvironment in WM development are still incompletely understood. Methods The multicellular ecosystem in bone marrow (BM) of WM were delineated by single-cell RNA-sequencing (scRNA-seq) and investigated the underlying molecular characteristics. Results Our data uncovered the heterogeneity of malignant cells in WM, and investigated the kinetic co-evolution of WM and immune cells, which played pivotal roles in disease development and progression. Two novel subpopulations of malignant cells, CD19+CD3+ and CD138+CD3+, co-expressing T-cell marker genes were identified at single-cell resolution. Pseudotime-ordered analysis elucidated that CD19+CD3+ malignant cells presented at an early stage of WM-B cell differentiation. Colony formation assay further identified that CD19+CD3+ malignant cells acted as potential WM precursors. Based on the findings of T cell marker aberrant expressed on WM tumor cells, we speculate the long-time activation of tumor antigen-induced immunosuppressive microenvironment that is involved in the pathogenesis of WM. Therefore, our study further investigated the possible molecular mechanism of immune cell dysfunction. A precursor exhausted CD8-T cells and functional deletion of NK cells were identified in WM, and CD47 would be a potential therapeutic target to reverse the dysfunction of immune cells. Conclusions Our study facilitates further understanding of the biological heterogeneity of tumor cells and immunosuppressive microenvironment in WM. These data may have implications for the development of novel immunotherapies, such as targeting pre-exhausted CD8-T cells in WM.

Abstract Primary central nervous system lymphoma (PCNSL) is a type of central nervous system restricted non-Hodgkin lymphoma, whose histopathological diagnosis is majorly large B cell lymphoma. To provide specific, evidence-based recommendations for medical professionals and to promote more standardized, effective and safe treatment for patients with PCNSL, a panel of experts from the Chinese Neurosurgical Society of the Chinese Medical Association and the Society of Hematological Malignancies of the Chinese Anti-Cancer Association jointly developed an evidence-based consensus. After comprehensively searching literature and conducting systematic reviews, two rounds of Delphi were conducted to reach consensus on the recommendations as follows: The histopathological specimens of PCNSL patients should be obtained as safely and comprehensively as possible by multimodal tomography-guided biopsy or minimally invasive surgery. Corticosteroids should be withdrawn from, or not be administered to, patients with suspected PCNSL before biopsy if the patient’s status permits. MRI (enhanced and DWI) should be performed for diagnosing and evaluating PCNSL patients where whole-body PET-CT be used at necessary time points. Mini-mental status examination can be used to assess cognitive function in the clinical management. Newly diagnosed PCNSL patients should be treated with combined high-dose methotrexate-based regimen and can be treated with a rituximab-inclusive regimen at induction therapy. Autologous stem cell transplantation can be used as a consolidation therapy. Refractory or relapsed PCNSL patients can be treated with ibrutinib with or without high-dose chemotherapy as re-induction therapy. Stereotactic radiosurgery can be used for PCNSL patients with a limited recurrent lesion who were refractory to chemotherapy and have previously received whole-brain radiotherapy. Patients with suspected primary vitreoretinal lymphoma (PVRL) should be diagnosed by vitreous biopsy. PVRL or PCNSL patients with concurrent VRL can be treated with combined systemic and local therapy.

Ammonia nitrogen is one of the main toxic substances in aquatic cultivation environments. Chronic exposure to excessive amounts of ammonia-N creates toxic consequences, retarding the growth of aquatic organisms. This study investigated the growth performance, morphological and physiological alterations, and transcriptome changes in the hepatopancreas and gills of white shrimp Litopenaeus vannamei. The results showed that there was no significant difference in the survival rate (p > 0.05), whereas growth performance was reduced significantly in the treated groups compared to the control groups (p < 0.05). Significant structural damage and vacuolation occurred in hepatopancreas and gill tissues in the treated groups. Superoxide dismutase (SOD) activity and Na+/K+-ATPase content were significantly increased by chronic ammonia-N exposure in the two tissue groups. In addition, catalase (CAT) activity and malondialdehyde (MDA) levels were significantly altered in the hepatopancreas groups (p < 0.05), whereas no differences were observed in the gill groups (p > 0.05). There were 890 and 1572 differentially expressed genes identified in the hepatopancreas (treated versus control groups) and gills (treated versus control groups), respectively, of L. vannamei under chronic ammonia-N exposure. Functional enrichment analysis revealed associations with oxidative stress, protein synthesis, lipid metabolism, and different serine proteases. The gills maintained cellular homeostasis mainly through high expression of cytoskeleton and transcription genes, whereas the hepatopancreas down-regulated related genes in the ribosome, proteasome, and spliceosome pathways. These genes and pathways are important in the biosynthesis and transformation of living organisms. In addition, both tissues maintained organismal growth primarily through lipid metabolism, which may serve as an effective strategy for ammonia-N resistance in L. vannamei. These results provided a new perspective in understanding the mechanisms of ammonia-N resistance in crustaceans.

Metallic nanolaminated materials possess excellent mechanical properties due to their unique modulation structures and interfacial properties. However, how microdefects affect their mechanical properties is still uncertain. To evaluate the influences of void location (in the crystalline layer and the Ti/Ni interface), void diameter (d) and thickness of the intermediate layer (h) on overall tensile behaviors, various types of defective Ti/Ni nanolaminates with pre-existing void are established by the molecular dynamics method in this work. The results indicate that the strength and plastic deformation mechanisms are strongly dependent on those determinants. Yield stresses of Ti/Ni nanolaminates decrease distinctly with increasing void diameter, while peak stresses with a void in the crystalline layer decrease with increasing d/h. Different void locations lead eventually to disparate initial plastic deformation carriers around the void, and various evolutions in the microstructure of the defective Ti/Ni nanolaminates. The Ti/Ni interface plays a significant role in the tensile process. The semi-coherent interface impedes new grains and lattice dislocations from passing across the interface, while the incoherent interface facilitates dislocations generating and sliding along the interface, and absorbs the dislocations moving to the interface. The results also indicate that the strain rate significantly affects the evolution of the microstructure and the tensile properties of defective Ti/Ni nanolaminates.

Abstract Exosomes are extracellular vesicles that actively secreted by most live cells via endosome pathway. They distribute ubiquitously in body fluids and play important roles in physiological and pathological processes. Recent studies have revealed that exosomes carry cell‐specific cargoes, such as proteins and nucleic acids, which have been recognized as emerging noninvasive biomarkers in liquid biopsy. Therefore, the molecular profiling of tumor‐derived exosomes is crucial in facilitating the discovery of cancer‐related biomarkers. Recently, various techniques have been proposed for sensitive, accurate, and rapid molecular characterization of these small vesicles. To meet the growing demands for multiplexed detection, microfluidics has been integrated with diverse traditional analytical methods as powerful components for exosomes analysis. Taking advantages of their inherent merits of great sensitivity, high analysis performance and system integration, short analysis time, low cost, small volume of sample, improved potential for control, automation, and disposability, microfluidic systems have significantly improved the molecular profiling of exosomes. In this review, we summarized the most recent progresses in microfluidic technologies for molecular profiling of tumor‐derived exosomes, including proteins, nucleic acids, metabolites, lipids. Furthermore, we discussed the major challenges and offered a perspective of the microfluidic strategy‐based exosomal biomarkers discovery. We expected that the in‐depth summary of microfluidic devices–assisted analysis of exosomes will greatly facilitate the discovery of biomarkers, thereby realizing highly efficient and accurate diagnosis, and prediction of cancers. Moreover, in view of the significance of this interesting approach in exosomes‐based liquid biopsy, this review will contribute to the translation of microfluidic technology into clinical applications.

IntroductionMultiple myeloma (MM) is still an incurable plasma cell malignancy. The efficacy of immunotherapy on MM remains unsatisfactory, and the underlying molecular mechanisms still are not fully understood.MethodsIn this study, we delineated the dynamic features of immune cell in MM bone marrow (BM) along with elevated tumor cell infiltration by single-cell RNA sequencing (scRNA-seq), and investigated the underlying mechanisms on dysfunction of immune cells associated with myelomagenesis.ResultsWe found that immune cells were activated in those patients with low infiltration of tumor cells, meanwhile suppressed with elevated infiltration of MM cells, which facilitated MM escaping from immune surveillance. Besides PD-1, abnormal expression of PIM kinases, KLRB1 and KLRC1 were involved in the defect of immune cells in MM patients. Importantly, we found aberrant metabolic processes were associated with the immunosuppressive microenvironment in MM patients. Disordered amino acid metabolism promoted the dysfunction of cytotoxicity CD8 T cells as well as lipid metabolism disorder was associated with the dysregulation of NK and DCs in MM. As metabolic checkpoints, PIM kinases would be potential effective strategies for MM immunotherapy.DiscussionIn summary, redressing the disordered metabolism should be the key points to get promising effects in immune-based therapies.

Mainstream deepfake detection algorithms generally fail to fully extract forgery traces and have low accuracy when detecting forged images with natural corruptions or human damage. On this basis, a new algorithm based on an adversarial dual-branch data augmentation framework and a modified attention mechanism is proposed in this paper to improve the robustness of detection models. First, this paper combines the traditional random sampling augmentation method with the adversarial sample idea to enhance and expand the forged images in data preprocessing. Then, we obtain training samples with diversity and hardness uniformity. Meanwhile, a new attention mechanism is modified and added to the ResNet50 model. The improved model serves as the backbone, effectively increasing the weight of forged traces in the multi-scale feature maps. The Jensen–Shannon divergence loss and cosine annealing algorithms are introduced into the training process to improve the model’s accuracy and convergence speed. The proposed algorithm is validated on standard and corrupted datasets. The experiments show that the algorithm proposed in this paper significantly improves effectiveness and robustness, with accuracies of 4.16%, 7.37%, and 3.87% better than the baseline model on DeepFakes, FaceSwap, and FaceShifer, respectively. Most importantly, its detection performance on the corrupted datasets DeepFakes-C, FaceSwap-C, and FaceShifer-C is much higher than that of mainstream methods.

In recent years, voice deepfake technology has developed rapidly, but current detection methods have the problems of insufficient detection generalization and insufficient feature extraction for unknown attacks. This paper presents a forged speech detection method (HuRawNet2_modified) based on a self-supervised pre-trained model (HuBERT) to improve detection (and address the above problems). A combination of impulsive signal-dependent additive noise and additive white Gaussian noise was adopted for data boosting and augmentation, and the HuBERT model was fine-tuned on different language databases. On this basis, the size of the extracted feature maps was modified independently by the α-feature map scaling (α-FMS) method, with a modified end-to-end method using the RawNet2 model as the backbone structure. The results showed that the HuBERT model could extract features more comprehensively and accurately. The best evaluation indicators were an equal error rate (EER) of 2.89% and a minimum tandem detection cost function (min t-DCF) of 0.2182 on the database of the ASVspoof2021 LA challenge, which verified the effectiveness of the detection method proposed in this paper. Compared with the baseline systems in databases of the ASVspoof 2021 LA challenge and the FMFCC-A, the values of EER and min t-DCF decreased. The results also showed that the self-supervised pre-trained model with fine-tuning can extract acoustic features across languages. And the detection can be slightly improved when the languages of the pre-trained database, and the fine-tuned and tested database are the same.

BackgroundGenetic factors play an important role in the pathogenesis of early-onset Parkinson’s disease (EOPD). To date, more than 20 pathogenic genes associated with Parkinson’s disease (PD) have been identified. This study aims to explore the mutation spectrum of EOPD and the clinical characteristics of mutation carriers in eastern China.MethodsWe recruited 155 unrelated EOPD patients, including 8 familial and 147 sporadic EOPD (age at onset ≤ 50 years). Overall, 24 known PD-associated genes were detected by whole exome sequencing and multiplex ligation-dependent probe amplification (MLPA) from patient samples. The genetic and clinical characteristics of pathogenic/likely pathogenic (P/LP) loci in this cohort were analyzed.ResultsOverall, 14 (9.03%) patients were detected with P/LP variants distributed in seven genes. The most frequent mutation occurred in PRKN (7/155, 4.52%), followed by LRRK2 (2/155, 1.29%), SNCA, CHCHD2, TMEM230, DNAJC13 and PLA2G6 (1/155, 0.64%, respectively). Exon rearrangement mutations accounted for 57.9% (11/19) of all mutations in PRKN. Four novel variants were detected: c.14T > C (p.M5T) in SNCA, c.297C > A (p.Y99X) in CHCHD2, c.2578C > T (p.R860C) in DNAJC13 and c.4C > T (p.Q2X) in TMEM230. We found the first case of LRRK2 c.6055G > A (p.G2019S) mutation in Chinese population. The median onset age of patients with P/LP mutations in autosomal recessive genes (PRKN and PLA2G6) was about 18.0 years earlier than patients without mutation. The proportion of patients with mutations were 63.64%, 27.03% and 9.68% when patients were stratified according to the age of onset at ≤ 30, ≤ 40 and ≤ 50 years, respectively.ConclusionEarly-onset Parkinson’s disease patients from eastern China present a regional specific mutation spectrum. Analysis of larger patient cohorts is required to support these findings, and mechanistic studies of the four novel missense/non-sense mutations will clarify their role in the pathogenicity of EOPD.

Summary: Background: Multiple myeloma (MM) is still an incurable malignancy of plasma cells. Proteasome inhibitors (PIs) work as the backbone agent and have greatly improved the outcome in majority of newly diagnosed patients with myeloma. However, drug resistance remains the major obstacle causing treatment failure in clinical practice. Here, we investigated the effects of Indirubin-3’-monoxime (I3MO), one of the derivatives of Indirubin, in the treatment of MM. Methods: MM patient primary samples and human cell lines were examined. I3MO effects on myeloma treatment and the underling molecular mechanisms were investigated via in vivo and in vitro study. Findings: Our results demonstrated the anti-MM activity of I3MO in both drug- sensitive and -resistance MM cells. I3MO sensitizes MM cells to bortezomib-induced apoptosis. Mechanistically, I3MO acts as a multifaceted regulator of cell death, which induced DNA damage, cell cycle arrest, and abrogates NF-κB activation. I3MO efficiently down-regulated USP7 expression, promoted NEK2 degradation, and suppressed NF-κB signaling in MM. Our study reported that I3MO directly bound with and caused the down-regulation of PA28γ (PSME3), and PA200 (PSME4), the proteasome activators. Knockdown of PSME3 or PSME4 caused the inhibition of proteasome capacity and the overload of paraprotein, which sensitizes MM cells to bortezomib-mediated growth arrest. Clinical data demonstrated that PSME3 and PSME4 are over-expressed in relapsed/refractory MM (RRMM) and associated with inferior outcome. Interpretation: Altogether, our study indicates that I3MO is agent triggering proteasome inhibition and represents a promising therapeutic strategy to improve patient outcome in MM. Fundings: A full list of funding can be found in the acknowledgements.

BackgroundDepression, one of the most frequent non-motor symptoms in Parkinson’s disease (PD), was proposed to be related to neural network dysfunction in advanced PD patients. However, the underlying mechanisms in the early stage remain unclear. The study was aimed to explore the alterations of large-scale neural networks in de novo PD patients with depression.MethodsWe performed independent component analysis (ICA) on the data of resting-state functional magnetic resonance imaging from 21 de novo PD patients with depression (dPD), 34 de novo PD patients without depression (ndPD), and 43 healthy controls (HCs) to extract functional networks. Intranetwork and internetwork connectivity was calculated for comparison between groups, correlation analysis, and predicting the occurrence of depression in PD.ResultsWe observed an ordered decrease of connectivity among groups within the ventral attention network (VAN) (dPD < ndPD < HCs), mainly located in the left middle temporal cortex. Besides, dPD patients exhibited hypoconnectivity between the auditory network (AUD) and default mode network (DMN) or VAN compared to ndPD patients or healthy controls. Correlation analysis revealed that depression severity was negatively correlated with connectivity value within VAN and positively correlated with the connectivity value of AUD-VAN in dPD patients, respectively. Further analysis showed that the area under the curve (AUC) for dPD prediction was 0.863 when combining the intranetwork connectivity in VAN and internetwork connectivity in AUD-DMN and AUD-VAN.ConclusionOur results demonstrated that early dPD may be associated with abnormality of attention bias and especially auditory attention processing. Altered neural network connectivity is expected to be a potential neuroimaging biomarker to predict depression in PD.

Background: For anaphylaxis, a life-threatening allergic reaction, the incidence rate was presented to have increased from the beginning of the 21st century. Underdiagnosis and undertreatment of anaphylaxis are public health concerns.Objective: This guideline aimed to provide high-quality and evidence-based recommendations for the emergency management of anaphylaxis.Method: The panel of health professionals from fifteen medical areas selected twenty-five clinical questions and formulated the recommendations with the supervision of four methodologists. We collected evidence by conducting systematic literature retrieval and using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.Results: This guideline made twenty-five recommendations that covered the diagnosis, preparation, emergency treatment, and post-emergency management of anaphylaxis. We recommended the use of a set of adapted diagnostic criteria from the American National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network (NIAID/FAAN), and developed a severity grading system that classified anaphylaxis into four grades. We recommended epinephrine as the first-line treatment, with specific doses and routes of administration for different severity of anaphylaxis or different conditions. Proper dosage is critical in the administration of epinephrine, and the monitor is important in the IV administration. Though there was only very low or low-quality evidence supported the use of glucocorticoids and H1 antagonists, we still weakly recommended them as second-line medications. We could not make a well-directed recommendation regarding premedication for preventing anaphylaxis since it is difficult to weigh the concerns and potential effects.Conclusion: For the emergency management of anaphylaxis we conclude that:• NIAID/FAAN diagnostic criteria and the four-tier grading system should be used for the diagnosis• Prompt and proper administration of epinephrine is critical.

Abstract Anaemia is the most common complication of myeloma and is associated with worse clinical outcomes. Although marrow replacement with myeloma cells is widely considered a mechanistic rationale for anaemia, the exact process has not been fully understood. Our large cohort of 1363 myeloma patients had more than 50% of patients with moderate or severe anaemia at the time of diagnosis. Anaemia positively correlated with myeloma cell infiltration in the bone marrow (BM) and worse patient outcomes. The quantity and erythroid differentiation of HSPCs were affected by myeloma cell infiltration in the BM. The master regulators of erythropoiesis, GATA1 and KLF1, were obviously downregulated in myeloma HSPCs. However, the gene encoding the chemokine CCL3 showed significantly upregulated expression. Elevated CCL3 in the BM plasma of myeloma further inhibited the erythropoiesis of HSPCs via activation of CCL3/CCR1/p38 signalling and suppressed GATA1 expression. Treatment with a CCR1 antagonist effectively recovered GATA1 expression and rescued erythropoiesis in HSPCs. Myeloma cell infiltration causes elevated expression of CCL3 in BM, which suppresses the erythropoiesis of HSPCs and results in anaemia by downregulating the level of GATA1 in HSPCs. Thus, our study indicates that targeting CCL3 would be a potential strategy against anaemia and improve the survival of myeloma patients.

Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical indications are not fully understood. Here, we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA-Seq data from 48 samples. We classified MCL into 4 robust clusters (C1–C4). C1 featured mutated immunoglobulin heavy variable (IGHV), CCND1 mutation, amp(11q13), and active B cell receptor (BCR) signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-κB and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1, and NSD2, with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q), and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these 4 clusters had distinct outcomes (5-year overall survival [OS] rates for C1–C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival, while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes.

BackgroundDepression is one of the most prevalent and disturbing non-motor symptoms in Parkinson’s disease (PD), with few dynamic functional connectivity (dFC) features measured in previous studies. Our aim was to investigate the alterations of the dynamics in de novo patients with PD with depression (dPD).MethodsWe performed dFC analysis on the data of resting-state functional MRI from 21 de novo dPD, 34 de novo patients with PD without depression (ndPD), and 43 healthy controls (HCs). Group independent component analysis, a sliding window approach, followed by k-means clustering were conducted to assess functional connectivity states (which represented highly structured connectivity patterns reoccurring over time) and temporal properties for comparison between groups. We further performed dynamic graph-theoretical analysis to examine the variability of topological metrics.ResultsFour distinct functional connectivity states were clustered via dFC analysis. Compared to patients with ndPD and HCs, patients with dPD showed increased fractional time and mean dwell time in state 2, characterized by default mode network (DMN)-dominated and cognitive executive network (CEN)-disconnected patterns. Besides, compared to HCs, patients with dPD and patients with ndPD both showed weaker dynamic connectivity within the sensorimotor network (SMN) in state 4, a regionally densely connected state. We additionally observed that patients with dPD presented less variability in the local efficiency of the network.ConclusionsOur study demonstrated that altered network connection over time, mainly involving the DMN and CEN, with abnormal dynamic graph properties, may contribute to the presence of depression in patients with PD.

BackgroundThis study investigated different patterns of emotional labor among community nurses in China and analyzed the relationships between the sense of career success and emotional labor.MethodsA total of 385 community nurses from Beijing participated in this investigation. Latent class analysis was used to identify meaningful subgroups of participants, and analysis of variance was used to analyze relationships between emotional labor classes and the sense of career success.ResultsEmotional labor among community nursing staff in China was divided into three latent classes: active (n = 90, 25.6%), apathetic (n = 65, 18.5%), and moderate (n = 197, 55.9%). The active emotional labor classes had significantly higher career success (pConclusionOur findings suggested managers to implement a variety of measures to strengthen interventions for employees' emotional labor that are targeted to incentive mechanisms, which will improve nurses' sense of career success.

Ridge tillage is one of the essential tillage methods in China. It affects the soil structure by altering the soil-water environment. With the rapid development of agricultural mechanization, the mechanized ridge tillage technology that combines modern mechanized agriculture with conservation tillage has become a pertinent agricultural production technology in the hilly regions. However, to date, the effects of mechanized ridge tillage on soil structure have garnered little attention. In this study, a field plot experiment involving the following four treatments: conventional tillage with rice and winter fallow (CK1), conventional tillage with rice-rape rotation (CK2), wide ridge tillage with rice-rape rotation (BT), and narrow ridge tillage with rice-rape rotation (RT) was conducted to study the effects of mechanized ridge tillage with rice-rape rotation on soil aggregate stability and soil porosity. The results indicated that mechanized ridge tillage could reduce the porosity of pores > 30 μm in diameter and increase the porosity of pores < 0.5 μm. Furthermore, mechanized ridge tillage could increase soil aggregate stability; the order of average mass diameter and geometric average diameter was RT > BT > CK2 > CK1. The BT and RT treatments could increase the agglomeration degree of the soil particles, which followed the order of RT > BT > CK2 > CK1. Therefore, mechanized ridge tillage with rice-rape rotation is effective in enhancing soil structure.

Circulating microRNAs (miRNAs) have been proposed to be accessible biomarkers for Parkinson’s disease (PD). However, there is a lack of known miRNAs that can serve as biomarkers for prodromal PD (pPD). We previously identified that miR-31 and miR-214 were dysregulated in PD. The aim of this study was to explore the roles of miR-31 and miR-214 in pPD. We recruited 25 pPD patients, 20 patients with de novo PD (dnPD), 24 advanced PD (aPD) patients and 21 controls. Next, we investigated the expression of miR-31 and miR-214. Compared to controls, miR-214 was found to be significantly upregulated in pPD patients while miR-31 was significantly upregulated in aPD patients. In addition, the expression of miR-214 was lower in aPD patients compared to both dnPD or pPD patients, while the expression of miR-31 was higher in aPD patients compared to dnPD patients. In order to predict pPD via miRNA expression, the receiver operating characteristic curve was constructed and the area under curve (AUC) was calculated. For pPD prediction by miR-214, the AUC was 0.756. The optimal cut-off value of miR-214 was 0.1962, and the sensitivity and specificity were 72.0% and 76.2%, respectively. On the other hand, the AUC for aPD detection by miR-31 was 0.744. The optimal cut-off value for miR-31 was 0.0148, with a sensitivity of 87.5% and a specificity of 71.4%. In conclusion, miR-214 can distinguish pPD patients from controls and may be used as a potential biomarker for pPD diagnosis.

Abstract In order to study the mechanism of selective catalytic reduction of activated coke to remove NO in low-temperature flue gas and provide some theoretical basis for the development of related technologies. The pore size distribution and BET specific surface area of AC were obtain by data analyzing of N2 adsorption/desorption isotherm at − 196 °C and carbon matrix and surface chemistry of virgin activated coke samples were characterized by acid–base titration and XPS. The process of selective catalytic reduction of activated coke (AC) samples with NH3 as reducing agent was studied in a fixed bed reactor at 150 °C. The result shows that pore size distribution or BET specific surface of activated cokes have not correlation with denitrification activity for SCR. The NO reduction activities of the activated cokes are apparent to increase with their surface oxygen element content and total amount of acidic sites. Obviously there is good linear relationship between the NH3 adsorption capacity and activity for SCR with linear correlation coefficient 0.943. It has been presented that adsorption of NH3 on acidic functional groups in the edge of large polycyclic aromatic ring of activated coke is key rate controlling step in the SCR heterogeneous catalytic reaction.

Mil-101 (Cr) material is considered to be one of the most potential thermochemical energy storage materials in recent years. It has the advantages of a typical S-type water adsorption isotherm. Has low working temperature and large water adsorption amount. However, the adsorption properties of the material need to be improved under low water pressure. To improve the performance, the acidified MWCNTs were added before the hydrothermal reaction of mil-101 (Cr) materials to optimize the micropore structure. After the preparation, the new composite thermochemical energy storage materials were prepared by impregnation with a certain concentration of calcium chloride aqueous solution. The effects of multi-walled carbon nanotubes and calcium chloride on the physical and chemical properties of the materials were discussed. Through X-ray diffraction experiment, scanning electron microscope, microstructure analysis, nitrogen adsorption capacity test, water adsorption capacity test, and other means, the micro characteristics, pore structure, crystal morphology, and chemical composition of the materials were characterized, and the water adsorption performance of the materials was synthesized. The experimental results show that the addition of carbon nanotubes can improve the pore properties of the materials so that the porous organic skeleton can accommodate more calcium chloride particles. The composite materials with calcium chloride can provide excellent hydrophilicity and high water adsorption capacity. Also, the water absorption rate and adsorption-desorption cycle capacity of the material have been significantly improved. The experimental results show that when the mass fraction of calcium chloride reaches 30% when 90 mg acidified MWCNTs are added into every four chromium nitrate crystals, the hydrophilicity and adsorption capacity of the composite can reach a high equilibrium state. At the same time, the experimental yield of the material is high, the product is easy to obtain, the environmental friendliness is also reflected, so it is expected to become the adsorption heat pump thermochemical energy storage material with research potential.

ObjectivePatients with Parkinson’s disease (PD) are commonly classified into subtypes based on motor symptoms. The aims of the present study were to determine the consistency between PD motor subtypes, to assess the stability of PD motor subtypes over time, and to explore the variables influencing PD motor subtype stability.MethodsThis study was part of a longitudinal study of de novo PD patients at a single center. Based on three different motor subtype classification systems proposed by Jankovic, Schiess, and Kang, patients were respectively categorized as tremor-dominant/indeterminate/postural instability and gait difficulty (TD/indeterminate/PIGD), TDS/mixedS/akinetic-rigidS (ARS), or TDK/mixedK/ARK at baseline evaluation and then re-assessed 1 month later. Demographic and clinical characteristics were recorded at each evaluation. The consistency between subtypes at baseline evaluation was assessed using Cohen’s kappa coefficient (κ). Additional variables were compared between PD subtype groups using the two-sample t-test, Mann–Whitney U-test or Chi-squared test.ResultsOf 283 newly diagnosed, untreated PD patients, 79 were followed up at 1 month. There was fair agreement between the Jankovic, Schiess, and Kang classification systems (κS = 0.383 ± 0.044, κK = 0.360 ± 0.042, κSK = 0.368 ± 0.038). Among the three classification systems, the Schiess classification was the most stable and the Jankovic classification was the most unstable. The non-motor symptoms questionnaire (NMSQuest) scores differed significantly between PD patients with stable and unstable subtypes based on the Jankovic classification (p = 0.008), and patients with a consistent subtype had more severe NMSQuest scores than patients with an inconsistent subtype.ConclusionFair consistency was observed between the Jankovic, Schiess, and Kang classification systems. For the first time, non-motor symptoms (NMSs) scores were found to influence the stability of the TD/indeterminate/PIGD classification. Our findings support combining NMSs with motor symptoms to increase the effectiveness of PD subtypes.

Levodopa (L-DOPA) is the most effective drug for Parkinson's disease (PD). However, the response to L-DOPA remains individually variable, which hampers the practical value of L-DOPA in the clinic. Genetic factors play a role in L-DOPA efficacy. This study explored the associations between polymorphisms and motor response to L-DOPA in Chinese patients with PD. A total of 51 Chinese PD patients were enrolled in this study. Patients underwent an acute L-DOPA challenge and were evaluated by the Unified Parkinson Disease Rating Scale (UPDRS) part III at baseline and after L-DOPA administration. Subjects were genotyped for polymorphisms: rs921451 and rs3837091 in the DDC loci, rs3836790 in the SLC6A3 locus, rs4680 in the COMT locus, and rs1799836 in the MAOB locus. We found that patients carrying the DDC CT or TT genotype exhibited a better motor response to L-DOPA than patients with the DDC CC genotype, and there was still a significant difference after adjustment for the L-DOPA dose in the acute challenge. Improvement in the UPDRS III subscores, including bradykinesia and axial symptoms, was significantly lower in patients with the DDC CC genotype than in patients with the CT or TT genotype. There were no significant associations between the motor response to L-DOPA and the rs3837091, rs3836790, rs4680, and rs1799836 variants. The DDC single nucleotide polymorphism rs921451 modulated the motor response to L-DOPA in Chinese PD patients. Our results suggested that DDC may be a modifier gene for the L-DOPA treatment response in PD.