Clinical prognostic value of different NPM1 mutations in acute myeloid leukemia patients.

BACKGROUND: Acute myeloid leukemia (AML) patients with various nucleophosmin 1 (NPM1) mutations are controversial in the prognosis. This study aimed to investigate the prognosis of patients according to types of NPM1 mutations (NPM1mut). METHODS: Bone marrow samples of 528 patients newly diagnosed with AML, were collected for morphology, immunology, cytogenetics, and molecular biology examinations. Gene mutations were detected by next-generation sequencing (NGS) technology. RESULTS: About 25.2% of cases exhibited NPM1mut. 83.5% of cases were type A, while type B and D were respectively account for 2.3% and 3.0%. Furthermore, 15 cases of rare types were identified, of which 2 cases have not been reported. Clinical characteristics were similar between patients with A-type NPM1 mutations (NPM1A - type mut) and non-A-type NPM1 mutations (NPM1non - A-type mut). Event-free survival (EFS) was significantly different between patients with low NPM1non - A-type mut variant allele frequency (VAF) and low NPM1A - type mut VAF (median EFS = 3.9 vs. 8.5 months, P = 0.020). The median overall survival (OS) of the NPM1non - A-type mutFLT3-ITDmut group, the NPM1A - type mutFLT3-ITDmut group, the NPM1non - A-type mutFLT3-ITDwt group, and the NPM1A - type mutFLT3-ITDwt group were 3.9, 10.7, 17.3 and 18.8 months, while the median EFS of the corresponding groups was 1.4, 5.0, 7.6 and 9.2 months (P < 0.0001 and P = 0.004, respectively). CONCLUSIONS: No significant difference was observed in OS and EFS between patients with NPM1A - type mut and NPM1non - A-type mut. However, types of NPM1 mutations and the status of FLT3-ITD mutations may jointly have an impact on the prognosis of AML patients.

Dynamic Single-Cell RNA-Seq reveals mechanism of Selinexor-Resistance in Chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a type of hematologic malignancies caused by BCR-ABL chimeric oncogene. Resistance to tyrosine kinase inhibitors (TKIs) leads to the progression of CML into advanced stages. Selinexor is a small molecule inhibitor that targets a nuclear transporter called Exportin 1. Combined with imatinib, selinexor has been shown to disrupt nuclear-cytoplasmic transport signal of leukemia stem cells, resulting in cell death. The objective of this study was to investigate the mechanism of drug resistance to selinexor in CML. We established K562 cell line resistant to selinexor and conducted single cell dynamic transcriptome sequencing to analyze the heterogeneity within the parental and selinexor resistant cell populations. We identified specific gene expression changes associated with resistance to selinexor. Our results revealed differential expression patterns in genes such as MT2A, TFPI, MTND3, and HMGCS1 in the total RNA, as well as MT-TW, DNAJB1, and HSPB1 in the newly synthesized RNA, between the parental and drug-resistant groups. By applying pseudo-time analysis, we discovered that a specific cluster of cells exhibited characteristics of tumor stem cells. Furthermore, we observed a gradual decrease in the expression of ferroptosis-related molecules as drug resistance developed. In vitro experiments confirmed that the combination of a ferroptosis inducer called RSL3 effectively overcame drug resistance. In conclusion, this study revealed the resistance mechanism of selinexor in CML. In conclusion, we identified a subgroup of CML cells with tumor stem cell properties and demonstrated that ferroptosis inducer improved the efficacy of selinexor in overcoming drug resistance.

Voxel-Wise Fusion of 3T and 7T Diffusion MRI Data to Extract more Accurate Fiber Orientations.

While 7T diffusion magnetic resonance imaging (dMRI) has high spatial resolution, its diffusion imaging quality is usually affected by signal loss due to B1 inhomogeneity, T2 decay, susceptibility, and chemical shift. In contrast, 3T dMRI has relative higher diffusion angular resolution, but lower spatial resolution. Combination of 3T and 7T dMRI, thus, may provide more detailed and accurate information about the voxel-wise fiber orientations to better understand the structural brain connectivity. However, this topic has not yet been thoroughly explored until now. In this study, we explored the feasibility of fusing 3T and 7T dMRI data to extract voxel-wise quantitative parameters at higher spatial resolution. After 3T and 7T dMRI data was preprocessed, respectively, 3T dMRI volumes were coregistered into 7T dMRI space. Then, 7T dMRI data was harmonized to the coregistered 3T dMRI B0 (b = 0) images. Last, harmonized 7T dMRI data was fused with 3T dMRI data according to four fusion rules proposed in this study. We employed high-quality 3T and 7T dMRI datasets (N = 24) from the Human Connectome Project to test our algorithms. The diffusion tensors (DTs) and orientation distribution functions (ODFs) estimated from the 3T-7T fused dMRI volumes were statistically analyzed. More voxels containing multiple fiber populations were found from the fused dMRI data than from 7T dMRI data set. Moreover, extra fiber directions were extracted in temporal brain regions from the fused dMRI data at Otsu's thresholds of quantitative anisotropy, but could not be extracted from 7T dMRI dataset. This study provides novel algorithms to fuse intra-subject 3T and 7T dMRI data for extracting more detailed information of voxel-wise quantitative parameters, and a new perspective to build more accurate structural brain networks.

Endoscopic-ultrasound-guided biliary drainage with placement of electrocautery-enhanced lumen-apposing metal stent for palliation of malignant biliary obstruction: Updated meta-analysis.

BACKGROUND: Endoscopic ultrasound-guided biliary drainage using electrocautery-enhanced (ECE) delivery of lumen-apposing metal stent (LAMS) is gradually being recognized as a viable palliative technique for malignant biliary obstruction after endoscopic retrograde cholangiopancreatography (ERCP) failure. However, most of the studies that have assessed its efficacy and safety were small and heterogeneous. Prior meta-analyses of six or fewer studies that were published 2 years ago were therefore underpowered to yield convincing evidence. AIM: To update the efficacy and safety of ECE-LAMS for treatment of biliary obstruction after ERCP failure. METHODS: We searched PubMed, EMBASE, and Scopus databases from the inception of the ECE technique to May 13, 2022. Primary outcome measure was pooled technical success rate, and secondary outcomes were pooled rates of clinical success, reintervention, and adverse events. Meta-analysis was performed using a random-effects model following Freeman-Tukey double-arcsine transformation in R software (version 4.1.3). RESULTS: Fourteen eligible studies involving 620 participants were ultimately included. The pooled rate of technical success was 96.7%, and clinical success was 91.0%. Adverse events were reported in 17.5% of patients. Overall reintervention rate was 7.3%. Subgroup analyses showed results were generally consistent. CONCLUSION: ECE-LAMS has favorable success with acceptable adverse events in relieving biliary obstruction when ERCP is impossible. The consistency of results across most subgroups suggested that this is a generalizable approach.

[Pollution Characteristics and Source Analysis of Soil Heavy Metal in Coal Mine Area near the Yellow River in Shandong].

To explore the pollution characteristics and source of soil heavy metal in a coal mine area near the Yellow River in Shandong, the geo-accumulation index method and improved Nemerow pollution index method were used to evaluate the pollution characteristics of soil heavy metal. The absolute principal component-multiple linear regression model (APCS-MLR) was used to quantitatively analyze the source of soil heavy metal, and the spatial distribution of Hg and Cd were analyzed using the Kriging spatial difference method in ArcGIS. The result accuracy of the APCS-MLR model was further verified. The results showed that:The measured contents of soil heavy metal Cu, Zn, Pb, Cr, Cd, Ni, As, and Hg all exceeded the normal site, among which, Hg and Cd exceeded the background values of soil elements in Shandong. The coefficient of variation (CV) of Hg was higher than 0.500, indicating significant spatial heterogeneity. Moreover, the correlation between Hg and other heavy metals was generally low, and the possibility of the same pollution source was small. The results of the geo-accumulation index and improved Nemerow pollution index showed that the overall soil heavy metal pollution was at a moderate level, among which the Hg pollution level was the highest, and its maximum value was at a slanted-heavy pollution level; Cu, Cd, and As in soil caused local pollution, which were at a slanted-light pollution level. Soil heavy metal pollution was closely related to mining activities, rehabilitation, and engineering construction in the coal mine area. The two major pollution sources of soil heavy metal in the research area were the compound source of the parent material and industrial and mining transportation sources (known source 1) and the compound source of atmospheric sedimentation and coal production (known source 2), the contribution rates of which were 76.705% and 16.171%, respectively. The results of the APCS-MLR model were shown to be reliable by analyzing the content distribution of Hg and Cd using the Kriging space difference mode. This research can provide scientific basis for the precise control and improvement of soil heavy metal pollution, ensuring the safety of food and agricultural products and improving the quality of the ecological environment in the coal mine area in the Shandong section of the Yellow River Basin.

Transcription-related metabolic regulation in grafted lemon seedlings under magnesium deficiency stress.

Magnesium is one of the essential nutrients for plant growth, and plays a pivotal role in plant development and metabolism. Soil magnesium deficiency is evident in citrus production, which ultimately leads to failure of normal plant growth and development, as well as decreased productivity. Citrus is mainly propagated by grafting, so it is necessary to fully understand the different regulatory mechanisms of rootstock and scion response to magnesium deficiency. Here, we characterized the differences in morphological alterations, physiological metabolism and differential gene expression between trifoliate orange rootstocks and lemon scions under normal and magnesium-deficient conditions, revealing the different responses of rootstocks and scions to magnesium deficiency. The transcriptomic data showed that differentially expressed genes were enriched in 14 and 4 metabolic pathways in leaves and roots, respectively, after magnesium deficiency treatment. And the magnesium transport-related genes MHX and MRS2 may respond to magnesium deficiency stress. In addition, magnesium deficiency may affect plant growth by affecting POD, SOD, and CAT enzyme activity, as well as altering the levels of hormones such as IAA, ABA, GA3, JA, and SA, and the expression of related responsive genes. In conclusion, our research suggests that the leaves of lemon grafted onto trifoliate orange were more significantly affected than the roots under magnesium-deficient conditions, further indicating that the metabolic imbalance of scion lemon leaves was more severe.

Effect of terahertz waves on the aggregation behavior of neurotransmitters.

Understanding the dynamics of neurotransmitters is crucial for unraveling synaptic transmission mechanisms in neuroscience. In this study, we investigated the impact of terahertz (THz) waves on the aggregation of four common neurotransmitters through all-atom molecular dynamics (MD) simulations. The simulations revealed enhanced nicotine (NCT) aggregation under 11.05 and 21.44 THz, with a minimal effect at 42.55 THz. Structural analysis further indicated strengthened intermolecular interactions and weakened hydration effects under specific THz stimulation. In addition, enhanced aggregation was observed at stronger field strengths, particularly at 21.44 THz. Furthermore, similar investigations on epinephrine (EPI), 5-hydroxytryptamine (5-HT), and γ-aminobutyric acid (GABA) corroborated these findings. Notably, EPI showed increased aggregation at 19.05 THz, emphasizing the influence of vibrational modes on aggregation. However, 5-HT and GABA, with charged or hydrophilic functional groups, exhibited minimal aggregation under THz stimulation. The present study sheds some light on neurotransmitter responses to THz waves, offering implications for neuroscience and interdisciplinary applications.

Folic acid-decorated astrocytes-derived exosomes enhanced the effect of temozolomide against glioma.

A direct strategy to achieve specific treatments and reduce side effects is through cell type-specific drug delivery. Exosomes (Exos) can be modified with folic acid (FA) to prepare drug delivery systems targeting tumor cells that highly express FA receptors. This study aimed to produce an exo drug delivery system with FA decoration and temozolomide (TMZ) loading to improve the sustained TMZ release and targeting. We used DSPE-PEG2000-FA to modify exos derived from astrocyte U-87 to prepare FA-modified exos (Astro-exo-FA). TMZ was encapsulated into Astro-exo-FA or Astro-exo through electroporation to produce TMZ@Astro-exo and TMZ@Astro-exo-FA. In vitro drug release was examined using the dialysis bag method. Through cell experiments in vitro and mouse glioma models in vivo, the effect of TMZ@Astro-exo-FA on U-87 cells was determined. Exo properties were not affected by FA modification and TMZ loading. The drug release rate of TMZ@Astro-exo-FA was slower. TMZ@Astro-exo-FA uptake by U-87 cells was higher compared to TMZ@Astro-exo, indicating that TMZ@Astro-exo-FA has a stronger targeting toward U-87 cells. TMZ@Astro-exo-FA remarkably reduced U-87 cell proliferation, migration, and invasion compared with TMZ@Astro-exo and free TMZ. Treatment with TMZ@Astro-exo-FA reduced the side effects of TMZ (minimal change in body weight), prolonged survival, and inhibited tumor growth in mouse glioma models, and its efficacy was stronger than that of TMZ@Astro-exo and free TMZ. TMZ@Astro-exo-FA could enhance the effect of TMZ against glioma, providing novel ideas for drug targeting delivery and exploring exos as drug carriers against glioma.

Modification of nitrilase based on computer screening and efficient biosynthesis of 4-cyanobenzoic acid.

4-cyanobenzoic acid serves as a crucial intermediate for the synthesis of various high-value organic compounds. The enzymatic hydrolysis of terephthalonitrile to produce 4-cyanobenzoic acid using nitrilase offers the advantages of a simple reaction pathway, environmental friendliness, and easy product separation. In order to efficiently develop nitrilases that meet industrial production requirements, the virtual screening method used in the study is established and mature. From a total of 371 amino acids in the nitrilase AfNIT, which exhibits activity in terephthalonitrile hydrolysis, three candidate sites (F168, S192, and T201) were identified, and a "small and accurate" mutant library was constructed. The triple mutant F168V/T201N/S192F was screened from this small mutant library with a specific activity of 227.3 U mg-1 , which was 3.8 times higher than that of the wild-type AfNIT. Using the whole-cell biocatalyst containing the mutant F168V/T201N/S192F, terephthalonitrile was successfully hydrolyzed at a concentration of 150 g L-1 to produce 4-cyanobenzoic acid with a final yield of 170.3 g L-1 and a conversion rate of 98.7%. The obtained nitrilase mutant F168V/T201N/S192F in this study can be effectively applied in the biomanufacturing of 4-cyanobenzoic acid using terephthalonitrile as a substrate. Furthermore, the results also demonstrate the significant improvement in predictive accuracy achieved through the latest AI-assisted computer simulation methods. This approach represents a promising and feasible new technological pathway for assisting enzyme engineering research, laying a theoretical foundation for other related studies.

A new scoring system for predicting the outcome of hepatocellular carcinoma patients without microvascular invasion-a large-scale multicentre study.

BACKGROUND: The prognosis of HCC patients without MVI (so called M0) is highly heterogeneous and the need for adjuvant therapy is still controversial. METHODS: Patients with HCC with M0 who underwent liver resection (LR) or liver transplantation (LT) as an initial therapy were included. The Eastern Hepatobiliary Surgery Hospital (EHBH)-M0 score was developed from a retrospective cohort to form the training cohort. The classification which was developed using multivariate cox regression analysis was externally validated. RESULTS: The score was developed using the following factors: α-fetoprotein level, tumour diameter, liver cirrhosis, total bilirubin, albumin and aspartate aminotransferase. The score differentiated two groups of M0 patients (≤3, >3 points) with distinct long-term prognoses outcomes (median overall survival (OS), 98.0 vs. 46.0 months; p < 0.001). The predictive accuracy of the score was greater than the other commonly used staging systems for HCC. And for M0 patients with a higher score underwent LR. Adjuvant transcatheter arterial chemoembolization (TACE) was effective to prolong OS. CONCLUSIONS: The EHBH M0 scoring system was more accurate in predicting the prognosis of HCC patients with M0 after LR or LT. Adjuvant therapy is recommended for HCC patients who have a higher score.

Covalent organic framework reinforced hollow fiber bar for extraction and detection of bisphenols from beverages.

Bisphenols (BPs) can migrate from packaging materials into foods, resulting in potentially harmful residues. For example, accumulation of BPs is associated with endocrine disorders. Owing to matrix effects, development of an effective and eco-friendly sample pretreatment would be helpful for BPs detection in beverages packed in plastic containers. In this work, an extraction bar, composed of hollow fiber (HF) functionalized with covalent organic frameworks (COF@Tp-NDA) and 1-ocanol, was prepared for extraction of five BPs simultaneously. The synergistic effect of COF@Tp-NDA and 1-octanol improved the extraction efficiency of BPs from milk-based beverage, juice, and tea beverage. Under optimal conditions, limits of detection ranged from 0.10 to 2.00 ng mL-1 (R2 ≥ 0.9974) and recoveries ranged from 70.1 % to 106.8 %. This method has the potential to enrich BPs, supporting their accurate determination in complex beverages.

Mechanochemical Synthesis of Cuprous Complexes for X-ray Scintillation and Imaging.

Cuprous complex scintillators show promise for X-ray detection with abundant raw materials, diverse luminescent mechanisms, and adjustable structures. However, their synthesis typically requires a significant amount of organic solvents, which conflict with green chemistry principles. Herein, we present the synthesis of two high-performance cuprous complex scintillators using a simple mechanochemical method for the first time, namely [CuI(PPh3)2R] (R = 4-phenylpyridine hydroiodide (PH, Cu-1) and 4-(4-bromophenyl)pyridine hydroiodide (PH-Br, Cu-2). Both materials demonstrated remarkable scintillation performances, exhibiting radioluminescence (RL) intensities 1.52 times (Cu-1) and 2.52 times (Cu-2) greater than those of Bi4Ge3O12 (BGO), respectively. Compared to Cu-1, the enhanced RL performance of Cu-2 can be ascribed to its elevated quantum yield of 51.54%, significantly surpassing that of Cu-1 at 37.75%. This excellent luminescent performance is derived from the introduction of PH-Br, providing a more diverse array of intermolecular interactions that effectively constrain molecular vibration and rotation, further suppressing the nonradiative transition process. Furthermore, Cu-2 powder can be prepared into scintillator film with excellent X-ray imaging capabilities. This work establishes a pathway for the rapid, eco-friendly, and cost-effective synthesis of high-performance cuprous complex scintillators.

Unveiling the multicomponent phase separation through molecular dynamics simulation and graph theory.

Biomolecular condensates formed by multicomponent phase separation play crucial roles in diverse cellular processes. Accurate assessment of individual-molecule contributions to condensate formation and precise characterization of their spatial organization within condensates are crucial for understanding the underlying mechanism of phase separation. Using molecular dynamics simulations and graph theoretical analysis, we demonstrated quantitatively the significant roles of cation-π and π-π interactions mediated by aromatic residues and arginine in the formation of condensates in polypeptide systems. Our findings reveal temperature and chain length-dependent alterations in condensate network parameters, such as the number of condensate network layers, and changes in aggregation and connectivity. Notably, we observe a transition between assortativity and disassortativity in the condensate network. Moreover, polypeptides W, Y, F, and R consistently promote condensate formation, while the contributions of other charged and two polar polypeptides (Q and N) to condensate formation depend on temperature and chain length. Furthermore, polyadenosine and polyguanosine can establish stable connections with aromatic and R polypeptides, resulting in the reduced involvement of K, E, D, Q, and N in phase separation. Overall, this study provides a distinctive, precise, and quantitative approach to characterize the multicomponent phase separation.

Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

Uncovering the Importance of Ligand Mobility on Cellular Uptake of Nanoparticles: Insights from Experimental, Computational, and Theoretical Investigations.

The cellular uptake of nanoparticles (NPs) by biological cells is an important and fundamental process in drug delivery. Previous studies reveal that the physicochemical properties of nanoparticles as well as those of functionalized ligands can both critically affect the uptake behaviors. However, the effect of the conjugation strategy (i.e., the "bond" between the ligand and the NP) on the cellular uptake is overlooked and remains largely elusive. Here, by taking the broadly employed gold nanoparticle as an example, we comprehensively assessed the relationship between the conjugation strategy and uptake behaviors by introducing three ligands with the same functional terminal but different anchoring sites. As revealed by in vitro cell experiments and multiscale molecular simulations, the uptake efficiency of gold NPs was positively correlated with the strength of the "bond" and more specifically the ligand mobility on the NP surface. Moreover, we validated the results presented above by proposing a thermodynamic theory for the wrapping of NPs with mobile ligands. Further, we also showed that the endocytic pathway of NPs was highly dependent on ligand mobility. Overall, this study uncovered a vital role of conjugation strategy in the cellular uptake and may provide useful guidelines for tailoring the biobehaviors of nanoparticles.

PHGDH knockdown increases sensitivity to SR1, an aryl hydrocarbon receptor antagonist, in colorectal cancer by activating the autophagy pathway.

Colorectal cancer (CRC) has emerged as the third most prevalent and second deadliest cancer worldwide. Metabolic reprogramming is a key hallmark of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) is over-expressed in multiple cancers, including CRC. Although the role of PHGDH in metabolism has been extensively investigated, its effects on CRC development remains to be elucidated. In the present study, it was demonstrated that PHGDH expression was significantly up-regulated in colorectal cancer. PHGDH expression was positively correlated with that of the aryl hydrocarbon receptor (AhR) and its target genes, CYP1A1 and CYP1B1, in CRC cells. Knockdown of PHGDH reduced AhR levels and activity, as well as the ratio of reduced to oxidized glutathione. The selective AhR antagonist stemregenin 1 induced cell death through reactive oxygen species-dependent autophagy in CRC cells. PHGDH knockdown induced CRC cell sensitivity to stemregenin 1 via the autophagy pathway. Our findings suggest that PHGDH modulates AhR signaling and the redox-dependent autophagy pathway in CRC, and that the combination of inhibition of both PHGDH and AhR may be a novel therapeutic strategy for CRC.

Molecular Modeling of the Fluorination Effect on the Penetration of Nanoparticles across Lipid Bilayers.

The fluorinated decorations have recently been widely used in many biomedical applications. However, the potential mechanism of the fluorination effect on the cellular delivery of nanoparticles (NPs) still remains elusive. In this work, we systemically explore the penetration of a perfluoro-octanethiol-coated gold NP (PF-Au NP) and, for comparison, an octanethiol-coated gold NP (OT-Au NP) across lipid bilayers. We also investigated the effect of these two types of NPs on the properties of lipid bilayers. Our findings indicate that the lipid type and the surface tension of the lipid bilayer significantly impact the penetration capabilities of the fluorinated gold NP. By examining the distribution of ligands on the surface of the two types of NPs in water and during the penetration process, we unveil their distinct penetration characteristics. Specifically, the PF-Au NP exhibits amphiphobic behavior (both hydrophobic and lipophobic), while the OT-Au NP exhibits solely hydrophobic characteristics. Finally, we observe that the penetration capabilities can be increased by adjusting the degree of fluorination of the ligands on the NP surface. Overall, this study provides useful physical insights into the unique properties of the fluorinated decorations in NP permeation.

Effect of low skeletal muscle mass on NK cells in patients with acute myeloid leukemia and its correlation with prognosis.

The objective of this study was to analyze the correlation between skeletal muscle mass and the distribution of peripheral blood lymphocytes and natural killer (NK) cells, as well as their impact on prognosis in patients with acute myeloid leukemia (AML). A retrospective analysis was conducted on 211 newly diagnosed AML patients, evaluating skeletal muscle index (SMI), NK cell proportion, and absolute value, along with relevant clinical data. Linear regression and Spearman's correlation coefficient were used to assess the relationship between various indicators and SMI, followed by multiple linear regression for further modeling. Univariate and multivariate Cox proportional hazards regression models were used to identify independent predictors for overall survival (OS). Among the 211 AML patients, 38 cases (18.0%) were diagnosed with sarcopenia. Multiple linear regression analysis included weight, fat mass, ECOG score, body mass index, and peripheral blood NK cell proportion, constructing a correlation model for SMI (R2 = 0.745). Univariate analysis identified higher NK cell count (> 9.53 × 106/L) as a poor predictor for OS. Multivariate Cox proportional hazards regression model indicated that age ≥ 60 years, PLT < 100 × 109/L, ELN high risk, sarcopenia, and B cell count > 94.6 × 106/L were independent adverse prognostic factors for AML patients. Low skeletal muscle mass may negatively impact the count and function of NK cells, thereby affecting the prognosis of AML. However, further basic and clinical research is needed to explore the specific mechanisms underlying the relationship between NK cells and SMI in AML.

Desloratadine alleviates ALS-like pathology in hSOD1G93A mice via targeting 5HTR2A on activated spinal astrocytes.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1G93A (hSOD1G93A) ALS model mice, and elucidated the underlying mechanisms. HSOD1G93A mice were administered DLT (20 mg·kg-1·d-1, i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1G93A mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1G93A mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease. DLT as a 5HTR2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice.

Effect of surface functionalization on DNA sequencing using MXene-based nanopores.

As one of the most promising types of label-free nanopores has great potential for DNA sequencing via fast detection of different DNA bases. As one of the most promising types of label-free nanopores, two-dimensional nanopore materials have been developed over the past two decades. However, how to detect different DNA bases efficiently and accurately is still a challenging problem. In the present work, the translocation of four homogeneous DNA strands (i.e., poly(A)20, poly(C)20, poly(G)20, and poly(T)20) through two-dimensional transition-metal carbide (MXene) membrane nanopores with different surface terminal groups is investigated via all-atom molecular dynamics simulations. Interestingly, it is found that the four types of bases can be distinguished by different ion currents and dwell times when they are transported through the Ti3C2(OH)2 nanopore. This is mainly attributed to the different orientation and position distributions of the bases, the hydrogen bonding inside the MXene nanopore, and the interaction of the ssDNA with the nanopore. The present study enhances the understanding of the interaction between DNA strands and MXene nanopores with different functional groups, which may provide useful guidelines for the design of MXene-based devices for DNA sequencing in the future.