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Abstract Determining the optimal timing for subsequent water flooding in Alkali-Surfactant-Polymer (ASP) flooding is essential to maximizing both the technical and economic outcomes of oilfield blocks. This study identified eight critical parameters that influence the benefits of ASP flooding and established parameter ranges based on data from completed blocks and actual field measurements. The optimal timing for subsequent water flooding was determined by evaluating cumulative net profit variations throughout the ASP flooding lifecycle. Given the complexity and high-dimensional nature of evaluating multiple parameters across diverse blocks, a machine learning-driven optimization model was developed. This model enhances work efficiency by automating complex analyses. However, predictive uncertainties and limitations remain due to the variability in oilfield development and the potential for unpredictable changes in reservoir conditions, external market factors and so on, which may affect the model’s results. The model was applied to six blocks in the Daqing oilfield currently in the chemical flooding phase, where injection schemes, such as extending the polymer slug, were adjusted according to the model’s optimized results. These adjustments yielded an increase in cumulative net profit of 224.9 million CNY compared to the original scheme, with a potential total increase of 752.1 million CNY by the end of the flooding process.

Abstract Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient’s sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level. Graphic Abstract

Abstract Intracranial aneurysm is the primary cause of nontraumatic subarachnoid hemorrhage. To assess aneurysm metabolism, we present a method of intra-operatively collecting blood samples from the aneurysm neck, as well as the proximal and distal responsible vessels, using microcatheters. Through these paired comparisons, we can eliminate the interpatient variation usually observed in plasma samples taken from the peripheral vein. We utilized 39 plasma samples from 13 intracranial patients to characterize the metabolite profiles using untargeted liquid chromatography-mass spectrometry. Our findings revealed that l-tyrosine is upregulated at relatively high levels at the aneurysm neck than the proximal and distal aneurysm, whereas phenylpyruvic acid, l-cystine, and l-ornithine are downregulated. Based on this, there was also a significant decrease in arginine within small aneurysm of the internal carotid artery. The 6-month follow-up indicated that patients who experienced good recovery had lower levels of biliverdin, bilirubin, and metabolites of coenzyme Q within the aneurysm. In conclusion, our investigation provides a comprehensive overview of plasma metabolites in patients with intracranial aneurysms, shedding light on potential pathogenetic mechanisms in unruptured intracranial aneurysms. Moreover, the study proposes innovative ideas for establishing postoperative follow-up timelines for flow diverter devices.

Abstract Chromatin remodeler ARID1A regulates gene transcription by modulating nucleosome positioning and chromatin accessibility. While ARID1A-mediated stage and lineage-restricted gene regulation during cell fate canalization remains unresolved. Using osteoclastogenesis as a model, we show that ARID1A transcriptionally safeguards the osteoclast (OC) fate canalization during proliferation-differentiation switching at single-cell resolution. Notably, ARID1A is indispensable for the transcriptional apparatus condensates formation with coactivator BRD4/lineage-specifying transcription factor (TF) PU.1 at Nfatc1 super-enhancer during safeguarding the OC fate canalization. Besides, the antagonist function between ARID1A-cBAF and BRD9-ncBAF complex during osteoclastogenesis has been validated with in vitro assay and compound mutant mouse model. Furthermore, the antagonistic function of ARID1A-“accelerator” and BRD9-“brake” both depend on coactivator BRD4-“clutch” during osteoclastogenesis. Overall, these results uncover sophisticated cooperation between chromatin remodeler ARID1A, coactivator, and lineage-specifying TF at super-enhancer of lineage master TF in a condensate manner, and antagonist between distinct BAF complexes in the proper and balanced cell fate canalization.

Maintaining cholesterol homeostasis is critical for preserving adipocyte function during the progression of obesity. Despite this, the regulatory role of cholesterol esterification in governing adipocyte expandability has been understudied. Acyl-coenzyme A (CoA):cholesterol acyltransferase/Sterol O-acyltransferase 1 (ACAT1/SOAT1) is the dominant enzyme to synthesize cholesteryl ester in most tissues. Our previous study demonstrated that knockdown of either ACAT1 or ACAT2 impaired adipogenesis. However, the underlying mechanism of how ACAT1 mediates adipogenesis remains unclear. Here, we reported that ACAT1 is the dominant isoform in white adipose tissue of both humans and mice, and knocking out ACAT1 reduced fat mass in mice. Furthermore, ACAT1-deficiency inhibited the early stage of adipogenesis via attenuating PPARγ pathway. Mechanistically, ACAT1 deficiency inhibited SREBP2-mediated cholesterol uptake and thus reduced intracellular and plasma membrane cholesterol levels during adipogenesis. Replenishing cholesterol could rescue adipogenic master gene–Pparγ′s—transcription in ACAT1-deficient cells during adipogenesis. Finally, overexpression of catalytically functional ACAT1, not the catalytic-dead ACAT1, rescued cholesterol levels and efficiently rescued the transcription of PPARγ as well as the adipogenesis in ACAT1-deficient preadipocytes. In summary, our study revealed the indispensable role of ACAT1 in adipogenesis via regulating intracellular cholesterol homeostasis.

AbstractBackground Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the β-oxidation of fatty acids. Yet, the functions of ANGPTL4 and ACACA in dyslipidemia of obstructive sleep apnea (OSA) remain unclear.Methods This study included 125 male OSA subjects from the Shanghai Sleep Health Study (SSHS) who were matched for age, body mass index (BMI), and lipid profile. Serum ANGPTL4 levels were measured via ELISA. The ANGPTL4 T266M variants of 4455 subjects along with their anthropometric, fasting biochemical, and standard polysomnographic parameters were collected. Linear regression was used to analyze the associations between quantitative traits and ANGPTL4 T266M. Molecular docking and molecular dynamic simulation were employed to compare the effects of the wild-type ANGPTL4 and its T266M mutation on ACACA.Results Serum ANGPTL4 levels significantly decreased with increasing OSA severity (non-OSA: 59.6 ± 17.4 ng/mL, mild OSA: 50.0 ± 17.5 ng/mL, moderate OSA: 46.3 ± 15.5 ng/mL, severe OSA: 19.9 ± 14.3 ng/mL, respectively, p = 6.02 × 10−16). No associations were found between T266M and clinical characteristics. Molecular docking indicated that mutant ANGTPL4 T266M had stronger binding affinity for the ACACA protein, compared with wild-type ANGPTL4. In terms of protein secondary structure, mutant ANGTPL4 T266M demonstrated greater stability than wild-type ANGPTL4.Conclusions Serum ANGTPL4 levels were significantly decreased in OSA patients, particularly among individuals with severe OSA. Although functional ANGTPL4 T266M variants were not associated with lipid levels in OSA, ANGTPL4 T266M could enhance binding affinity for the ACACA protein, potentially regulating lipid metabolism.

BackgroundThe prevalence of depression among university and college students in China is nearly one-quarter. This study aimed to investigate the knowledge, attitudes and practices (KAP) among medical students toward depression management. Depression, a significant public health issue, has a substantial impact on students, with a reported prevalence of 23.8% among university and college students in China.MethodsThis web-based cross-sectional study was conducted between January 2023 and October 2023 at three medical universities in China. A self-administered questionnaire collected demographic information and assessed medical students’ KAP on depression management.ResultsA total of 632 participants were enrolled in this study from three medical universities. Among them, 383 (60.60%) were female, and the participants were aged 20.17 years on average (SD ± 1.80). Most of their family members (521, 82.44%) were not in the medical profession. Using a validated 15-point knowledge scale, a 50-point attitude scale, and a 30-point practice scale, which covered areas such as symptom recognition, treatment approaches, and stigma related to depression, the mean knowledge, attitudes and practices scores were 10.55 ± 3.36 (possible range: 0–15), 41.72 ± 4.45 (possible range: 10–50) and 19.79 ± 5.44 (possible range: 6–30), respectively. Males had lower knowledge (p = 0.003). Only children had higher practice (p = 0.034). Urban residents had higher attitudes (p = 0.046). Higher income linked to better practice (p = 0.047). Freshmen scored higher across all KAP (p

Abstract Hair is an advantageous biological sample due to its recordable, collectable, and storable nature. Hair's primary components are keratin and keratin-associated proteins. Owing to its abundance of cystine, keratin possesses impressive mechanical strength and chemical stability, formed by creating disulfide bonds as crosslinks within the protein peptide chain. Furthermore, keratin is cross-linked with keratin-associated proteins to create a complex network structure that provides the hair with strength and rigidity. Protein extraction serves as the foundation for hair analysis research. Bleaching hair causes damage to the structure between keratin and keratin-associated proteins, resulting in texture issues and hair breakage. This article outlines various physical treatment methods and lysate analysis that enhance the efficiency of hair protein extraction. The PLEE method achieves a three-fold increase in hair protein extraction efficiency when using a lysis solution containing SDS and combining high temperatures with intense shaking, compared to previous methods found in literature. We utilized the PLEE method to extract hair from both normal and damaged groups. Normal samples identified 156–157 proteins, including 51 keratin and keratin-associated proteins. The damaged group consisted of 155–158 identified proteins, of which 48–50 were keratin and keratin-associated proteins. Bleaching did not cause any notable difference in the protein identification of hair. However, it did reduce coverage of keratin and keratin-associated proteins significantly. Our hair protein extraction method provides extensive coverage of the hair proteome. Our findings indicate that bleaching damage results in subpar hair quality due to reduced coverage of protein primary sequences in keratin and keratin-associated proteins.

Abstract The research of plant seeds has always been a focus of agricultural and forestry research, and seed identification is an indispensable part of it. With the continuous application of artificial intelligence technology in the field of agriculture, seed identification through computer vision can effectively promote the development of agricultural and forestry wisdom. Data is the foundation of computer vision, but there is a lack of suitable datasets in the agricultural field. In this paper, a seed dataset named LZUPSD is established. A device based on mobile phones and macro lenses was established to acquire images. The dataset contains 4496 images of 88 different seeds. This dataset can not only be used as data for training deep learning models in the computer field, but also provide important data support for agricultural and forestry research. As an important resource in this field, this dataset plays a positive role in modernizing agriculture and forestry.

The liver toxicity of alkylphenols (APs) has been demonstrated in animal studies. However, relevant epidemiological evidence is still lacking in humans, especially during pregnancy. We obtained the levels of biochemical indicators of liver function in early (

Adjuvant therapy is essential in cancer treatment to enhance primary treatment effectiveness, reduce adverse effects, and prevent recurrence. Small molecule inhibitors as adjuvants in cancer immunotherapy aim to harness their immunomodulatory properties to optimize treatment outcomes. By modulating the tumor microenvironment, enhancing immune cell function, and increasing tumor sensitivity to immunotherapy, small molecule inhibitors have the potential to improve patient responses. This review discusses the evolving use of small molecule inhibitors as adjuvants in cancer treatment, highlighting their role in enhancing the efficacy of immunotherapy and the opportunities for advancing cancer therapies in the future.

Abstract Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy, and its fitness may be shaped by how its tumor cells evolve. However, ability to monitor tumor cell evolution is hampered by the presence of numerous passenger mutations that do not provide any biological consequences. Here we develop a strategy to determine the tumor clonality of three independent HCC cohorts of 524 patients with diverse etiologies and race/ethnicity by utilizing somatic mutations in cancer driver genes. We identify two main types of tumor evolution, i.e., linear, and non-linear models where non-linear type could be further divided into classes, which we call shallow branching and deep branching. We find that linear evolving HCC is less aggressive than other types. GTF2IRD2B mutations are enriched in HCC with linear evolution, while TP53 mutations are the most frequent genetic alterations in HCC with non-linear models. Furthermore, we observe significant B cell enrichment in linear trees compared to non-linear trees suggesting the need for further research to uncover potential variations in immune cell types within genomically determined phylogeny types. These results hint at the possibility that tumor cells and their microenvironment may collectively influence the tumor evolution process.

Abstract Drought-induced osmotic stress severely affects the growth and yield of maize. However, the mechanisms underlying the different responses of young and old maize leaves to osmotic stress remain unclear. To gain a systematic understanding of age-related stress responses, we compared osmotic-stress-induced changes in maize leaves of different ages using multi-omics approaches. After short-term osmotic stress, old leaves suffered more severe water deficits than young leaves. The adjustments of transcriptomes, proteomes, and hormones in response to osmotic stress were more dynamic in old leaves. Metabolic activities, stress signaling pathways, and hormones (especially abscisic acid) responded to osmotic stress in an age-dependent manner. We identified multiple functional clusters of genes and proteins with potential roles in stress adaptation. Old leaves significantly accumulated stress proteins such as dehydrin, aquaporin, and chaperones to cope with osmotic stress, accompanied by senescence-like cellular events, whereas young leaves exhibited an effective water conservation strategy mainly by hydrolyzing transitory starch and increasing proline production. The stress responses of individual leaves are primarily determined by their intracellular water status, resulting in differential transcriptomes, proteomes, and hormones. This study extends our understanding of the mechanisms underlying plant responses to osmotic stress.

Abstract Background Anterior cervical discectomy and fusion surgery (ACDF) is a common technique in treating degenerative cervical spondylosis. This study is to evaluate the changes of cervical muscles after ACDF and analyze the correlation between related muscle changes and clinical efficacy. Methods Sixty-five postoperative patients (single-level ACDF) with cervical spondylotic myelopathy from January 2013 to December 2022 were analyzed. The measured parameters include: the axial section of longus colli cross-sectional area (AxCSA), the volume of cervical longus, the ratio of long and short diameter line (RLS), the cervical extensor cross-sectional area (CESA), the vertebral body area (VBA), and the CESA/VBA. The visual analog scale (VAS), modified Japanese Orthopedic Association score (mJOA), and neck disability index (NDI) were evaluated. The changes in muscle morphology were analyzed, and the correlation analysis was conducted between morphological changes and function scores. Results The postoperative AxCSA of surgical segment (3rd month, 12th month, and the last follow-up) was decreased compared to preoperative (141.62 ± 19.78), and the differences were significant (P

Abstract Objective This study aims to compare the clinical effects and imaging data of patients who underwent endoscopic transforaminal lumbar interbody fusion (Endo-TLIF) with those who received unilateral biportal endoscopic lumbar interbody fusion (ULIF). Methods A retrospective analysis was conducted on the clinical data of 69 patients presenting with typical intermittent claudication and signs and symptoms indicative of unilateral lower extremity nerve root compression, meeting inclusion criteria between April 2022 and June 2022. Among the cohort, 35 patients underwent ULIF group, while 34 patients underwent Endo-TLIF group. We compared perioperative parameters, including intraoperative blood loss, duration of hospital stay, and operation time between the two groups. Pre-operative and post-operative changes in the height and cross-sectional area of the target intervertebral space were also compared between the groups. Finally, we evaluated bone graft size and interbody fusion rates at 6 and 12 months post-surgery using the Brantigan scoring system. Results The ULIF group had significantly shorter operative times compared to the Endo-TLIF group (P 0.05). Furthermore, both groups exhibited postoperative increases in vertebral canal volume compared to baseline (P 0.05). Interbody fusion rates were comparable between the two groups at both 6 and 12 months after surgery (P > 0.05). Lastly, the ULIF group had a significantly larger area of bone graft than the Endo-TLIF group (P

Abstract Sepsis is a major global health problem, causing a significant burden of disease and death worldwide. Risk stratification of sepsis patients, identification of severe patients and timely initiation of treatment can effectively improve the prognosis of sepsis patients. We procured gene expression datasets for sepsis (GSE54514, GSE65682, GSE95233) from the Gene Expression Omnibus and performed normalization to mitigate batch effects. Subsequently, we applied weighted gene co-expression network analysis to categorize genes into modules that exhibit correlation with macrophage activity. To pinpoint macrophage-associated genes (MAAGs), we executed differential expression analysis and single sample gene set enrichment analysis. We then established a prognostic model derived from four MAAGs that were significantly differentially expressed. Functional enrichment analysis and immune infiltration assessments were instrumental in deciphering the biological mechanisms involved. Furthermore, we employed principal component analysis and conducted survival outcome analyses to delineate molecular subgroups within sepsis. Four novel MAAGs—CD160, CX3CR1, DENND2D, and FAM43A—were validated and used to create a prognostic model. Subgroup classification revealed distinct molecular profiles and a correlation with 28-day survival outcomes. The MAAGs risk score was developed through univariate Cox, LASSO, and multivariate Cox analyses to predict patient prognosis. Validation of the risk score upheld its prognostic significance. Functional enrichment implicated ribonucleoprotein complex biogenesis, mitochondrial matrix, and transcription coregulator activity in sepsis, with an immune infiltration analysis indicating an association between MAAGs risk score and immune cell populations. The four MAAGs exhibited strong diagnostic capabilities for sepsis. The research successfully developed a MAAG-based prognostic model for sepsis, demonstrating that such genes can significantly stratify risk and reflect immune status. Although in-depth mechanistic studies are needed, these findings propose novel targets for therapy and provide a foundation for future precise clinical sepsis management.

Abstract Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3β, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1β, IL-6, JAG2, KCNJ2, MALT1, β-MHC, NF-κB, PCK1, PLCβ1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.

Abstract Although various new biomaterials have enriched the methods for peri-implant inflammation treatment, their efficacy is still debated, and secondary operations on the implant area have also caused pain for patients. Recently, strategies that regulate macrophage polarization to prevent or even treat peri-implantitis have attracted increasing attention. Here, we prepared a laser-drilled and covered with metal organic framework-miR-27a agomir nanomembrane (L-MOF-agomir) implant, which could load and sustain the release of miR-27a agomir. In vitro, the L-MOF-agomir titanium plate promoted the repolarization of LPS-stimulated macrophages from M1 to M2, and the macrophage culture supernatant promoted BMSCs osteogenesis. In a ligation-induced rat peri-implantitis model, the L-MOF-agomir implants featured strong immunomodulatory activity of macrophage polarization and alleviated ligation-induced bone resorption. The mechanism of repolarization function may be that the L-MOF-agomir implants promote the macrophage mitochondrial function and metabolism reprogramming from glycolysis to oxidative phosphorylation. Our study demonstrates the feasibility of targeting cell metabolism to regulate macrophage immunity for peri-implantitis inhibition and provides a new perspective for the development of novel multifunctional implants. Graphical Abstract

With the implementation of the global two-carbon policy, energy saving and CO2 emission reduction have become important developmental goals of the automobile manufacturing industry. At present, the combination of high temperature for the automobile gear steel and short carburizing time is the most direct carbon reduction countermeasure for gear production enterprises. However, the problem of abnormally coarsened austenite grains often occurs in the high-temperature carburization of gear steel. With the increase in carburizing temperature, the degree of mixing crystals becomes serious. As a requirement of gear manufacturing enterprises, microalloying is carried out on the carburized gear steel. Upon the addition of microalloying elements, the second-phase particles are precipitated during heating, and the pinning effect is generated to prevent the movement of austenite grain boundaries, thus preventing the abnormal growth of austenite grains. Although the second-phase particles precipitate at the usual carburizing temperature, the partial solid solution of particles appears. In this work, the effects of the heating temperature and holding time on the austenite grain size of gear steel are studied to clarify the mechanisms of complex austenite grain growth and second-phase particle precipitation for the realization of fine austenite grain size after high-temperature carburization. The influence of the contents of microalloying elements (Nb, Al) on the pinning effect, precipitation position, and solution temperature of the second-phase particles (Nb (C, N)/AlN) are also discussed. Austenite grain growth models, critical sizes of austenite grain abnormal growth, and pinning force models of second-phase particles are summarized. The austenite grain growth model is based on the Beck equation, and the most common models are the modified Sellars and Arrhenius models. For the study of the inhibition effect on austenite grains, the pinning force model is used to study the critical size of austenite by modifying the dimensionless constant (A) of the Zener equation mainly through the pinning effect (Pz) produced by all particles on the grain boundary. After the experimental data are obtained, the trend of austenite growth can be predicted accurately by fitting the curve using the mathematical method. The precipitated second-phase particles are generally distributed along the grain boundary. Nb (C, N) particles have a higher solution temperature than AlN particles, so they are more stable at high temperatures. When the temperature exceeds the grain coarsening temperature, the precipitated particles become dissolved or coarsened. The mixed crystal structure generally starts to appear at about 1000 ℃, and adding the appropriate amount of microalloying elements can increase the coarsening temperature.

Abstract Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds promise for reduced toxicity in HSC gene therapy. Here we test the ability of an antibody-drug conjugate targeting CD117 (CD117-ADC) to enable engraftment in a non-human primate lentiviral gene therapy model of hemoglobinopathies. Following single-dose CD117-ADC, a >99% depletion of bone marrow CD34 + CD90 + CD45RA- cells without lymphocyte reduction is observed, which results are not inferior to multi-day myeloablative busulfan conditioning. CD117-ADC, similarly to busulfan, allows efficient engraftment, gene marking, and vector-derived fetal hemoglobin induction. Importantly, ADC treatment is associated with minimal toxicity, and CD117-ADC-conditioned animals maintain fertility. In contrast, busulfan treatment commonly causes severe toxicities and infertility in humans. Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans.

To address CD19 loss from lymphoma after anti-CD19 chimeric antigen receptor (CAR) T cell therapy, we designed a bicistronic construct encoding an anti-CD19 CAR and an anti-CD20 CAR. We detected deletions from the expected bicistronic construct sequence in a minority of transcripts by mRNA sequencing. Loss of bicistronic construct transgene DNA was also detected. Deletions of sequence were present at much higher frequencies in transduced T cell mRNA versus gamma-retroviral vector RNA. We concluded that these deletions were caused by intramolecular template switching of the reverse transcriptase enzyme during reverse transcription of gamma-retroviral vector RNA into transgene DNA of transduced T cells. Intramolecular template switching was driven by repeated regions of highly similar nucleic acid sequence within CAR sequences. We optimized the sequence of the bicistronic CAR construct to reduce repeated regions of highly similar sequences. This optimization nearly eliminated sequence deletions. This work shows that repeated regions of highly similar nucleic acid sequence must be avoided in complex CAR constructs. We further optimized the bicistronic construct by lengthening the linker of the anti-CD20 single-chain variable fragment. This modification increased CD20-specific interleukin-2 release and reduced CD20-specific activation-induced cell death. We selected an optimized anti-CD19/CD20 bicistronic construct for clinical development.

Atherosclerosis is a significant risk factor for coronary heart disease (CHD) and myocardial infarction (MI). Atherosclerosis develops during foam cell generation, which is caused by an imbalance in cholesterol uptake, esterification, and efflux. LOX-1, SR-A1, and CD36 all increased cholesterol uptake. ACAT1 and ACAT2 promote free cholesterol (FC) esterification to cholesteryl esters (CE). The hydrolysis of CE to FC was aided by nCEH. FC efflux was promoted by ABCA1, ABCG1, ADAM10, and apoA-I. SR-BI promotes not only cholesterol uptake but also FC efflux. Circular RNAs (circRNAs), which are single-stranded RNAs with a closed covalent circular structure, have emerged as promising biomarkers and therapeutic targets for atherosclerosis due to their highly tissue, cell, and disease state-specific expression profiles. Numerous studies have shown that circRNAs regulate foam cell formation, acting as miRNA sponges to influence atherosclerosis development by regulating the expression of SR-A1, CD36, ACAT2, ABCA1, ABCG1, ADAM10, apoA-I, SR-B1. Several circRNAs, including circ-Wdr91, circ 0004104, circRNA0044073, circRNA_0001805, circDENND1B, circRSF1, circ 0001445, and circRNA 102682, are potential biomarkers for atherosclerosis to better evaluate cardiovascular risk. It is difficult to deliver synthetic therapeutic circRNAs to the desired target tissues. Nanotechnology, such as GA-RM/GZ/PL, may be an important solution to this problem. In this review, we focus on the potential role and mechanism of circRNA/miRNA axis in foam cell formation in the hopes of discovering new targets for the diagnosis, prevention, and treatment of atherosclerosis.

Abstract Backgrounds The role of cytoreductive radical prostatectomy (cRP) for bone‐metastatic prostate cancer (bmPCa) remains controversial. We aimed to figure out whether cRP and lymph node dissection (LND) can benefit bmPCa. Methods 11,271 PCa patients with bone metastatic burden from 2010 to 2019 were identified using SEER‐Medicare. Overall survival (OS) and cancer‐specific survival (CSS) rates were visualized using Kaplan–Meier plots. Multivariable Cox regression analyses were constructed to examine the effects of cRP and LND on survival, after stratifying to age, prostate specific antigen (PSA), clinical stages, Gleason score, metastatic burden, radiotherapy, and chemotherapy status. Results 317 PCa patients underwent cRP and cRP was increasingly performed for bmPCa from 2010 (2.2%) to 2019 (3.0%) (p

Abstract Background Ilicis chinensis folium extract (ICFE) is a powder extracted and processed with Ilex chinensis Sims (ICS) which has numerous bioactivities and is conventionally used in traditional Chinese medicine. Nonetheless, there has been no definitive study evaluating ICFE’s application as a feed supplement for broilers. This research sought to determine the chemical composition and evaluate how dietary ICFE supplementation affects the growth performance, serum metrics, intestinal structure, and antioxidant capacity of broilers. Methods A total of 360 one-day-old broiler chicks were assigned to four treatments (with 9 replicates of 10 chicks, each) of dietary supplementation with ICFE at 0, 250, 500, and 1,000 mg /kg for 42 days. Results Ten polyphenolic compounds and two triterpenoid glycosides were detected by HPLC. In the grower stage and overall, broilers supplemented with 500 and 1,000 mg/kg ICFE exhibited a higher ADFI (P

Bone morphogenetic protein (BMP-2) has been approved by the FDA to promote bone regeneration, but uncertain osteogenic effect and dose-dependent side effects may occur. Osteoimmunomodulation plays an important role in growth factor-based osteogenesis. Here, we explored how proinflammatory signals affect the dose-dependent osteogenic potential of BMP-2. We observed that the expression level of local IL-1β did not increase with the dose of BMP-2 in the mouse osteogenesis model. A low dose of BMP-2 could not promote new bone formation, but trigger the release of IL-1β from M1 macrophages. As the dose of BMP-2 increased, the IL-1β expression and M1 infiltration in local microenvironment were inhibited by IL-1Ra from MSCs under osteogenic differentiation induced by BMP-2, and new bone tissues formed, even excessively. Anti-inflammatory drugs (Dexamethasone, Dex) promoted osteogenesis via inhibiting M1 polarization and enhancing BMP-2-induced MSC osteo-differentiation. Thus, we suggest that the osteogenic effect of BMP-2 involves macrophage-MSC interaction that is dependent on BMP-2 dose and based on IL-1R1 ligands, including IL-1β and IL-1Ra. The dose of BMP-2 could be reduced by introducing immunoregulatory strategies.

Background: An increasing amount of evidence suggests that telomere length (TL) at birth can predict lifespan and is associated with chronic diseases later in life, but newborn TL may be affected by environmental pollutants. Neonicotinoids (NEOs) are widely used worldwide, and despite an increasing number of studies showing that they may have adverse effects on birth in mammals and even humans, few studies have examined the effect of NEO exposure on newborn TLs. Objective: To investigate the effects of prenatal exposure to NEOs and the interactions between NEOs and sampling season on newborn TL. Methods: We conducted a prospective cohort study of 500 mother-newborn pairs from the Guangxi Zhuang Birth Cohort. Ultraperformance liquid chromatographymass spectrometry was used to detect ten NEOs in maternal serum, and fluorescence quantitative PCR was used to estimate the newborn TL. A generalized linear model (GLM) was used to evaluate the relationships between individual NEO exposures and TLs , and quantile g-computation (Qgcomp) model and Bayesian kernel machine regression (BKMR) model were used to evaluate the combined effect of mixtures of components. Results: The results of the GLM showed that compared with maternal TMX levels < LOD, maternal TMX levels < median were negatively correlated with newborn TL (-6.93%, 95% CI%: −11.92%, −1.66%), and the decrease in newborn TL was more pronounced in girls (-9.60%, 95% CI: −16.84%, −1.72%). Moreover, different kinds of maternal NEO exposure had different effects on newborn TL in different sampling seasons, and the effect was statistically significant in all seasons except in autumn. Mixed exposure analysis revealed a potential positive trend between NEOs and newborn TL, but the association was not statistically significant. Conclusion: Prenatal exposure to TMX may shorten newborn TL, and this effect is more pronounced among female newborns. Furthermore, the relationship between NEO exposure and TL may be modified by the sampling season.

Background: The Jiawei Kongsheng Zhenzhong pill (JKZP), a Chinese herbal prescription comprised of eight Chinese crude drugs, has been historically employed to treat neurological and psychological disorders. Nevertheless, the ambiguous material basis severely hindered its progress and application.Purpose: The current study aimed to establish a rapid analytical method for identifying the chemical components of the JKZP aqueous extract and the components absorbed into the rat serum to investigate the quality markers (Q-markers) responsible for the neuroprotective effects of JKZP.Methods: The qualitative detection of the chemical components, prototype components, and metabolites of the aqueous extracts of JKZP, as well as the serum samples of rats that were administered the drug, was performed using the ultra-performance liquid chromatography- quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) technology. This analysis combined information from literature reports and database comparisons. Moreover, the study was conducted to anticipate the potential Q-markers for the neuroprotective effects of JKZP based on the “five principles” of Q-marker determination.Results: A total of 67 compounds and 111 serum components (comprising 33 prototypes and 78 metabolites) were detected and identified. Combining the principles of quality transmission and traceability, compound compatibility environment, component specificity, effectiveness, and measurability, the study predicted that five key compounds, namely, senkyunolide H, danshensu, echinacoside, loganin, and 3,6′-disinapoyl sucrose, may serve as potential pharmacological bases for the neuroprotective effects of JKZP.Conclusion: To summarize, the UPLC-Q-TOF-MS/MS technique can be employed to rapidly and accurately identify compounds in JKZP. Five active compounds have been predicted to be the Q-markers for the neuroprotective effects of JKZP. This discovery serves as a reference for improving quality, advancing further research and development, and utilizing Chinese herbal prescriptions.

The microbial communities associated with alkaline–surfactant–polymer (ASP)-flooded reservoirs have rarely been investigated. In this study, high-throughput sequencing was used to analyse the indigenous microbial communities in two different blocks, the water flooding after the alkaline–surfactant–polymer flooding block and the alkaline–surfactant–polymer flooding block, and to ascertain the optimal stage for the implementation of indigenous microbial oil recovery technology. The different displacement blocks had significant effects on the indigenous microbial community at the genus level according to an alpha diversity analysis and community composition. In water flooding after alkaline–surfactant–polymer flooding, the dominant genus of Pseudomonas exceeded 30%, increasing to 52.1% in alkaline–surfactant–polymer flooding, but alpha diversity decreased. Through a co-occurrence network analysis, it was found that the complexity of the water flooding after alkaline–surfactant–polymer flooding was higher than that of alkaline–surfactant–polymer flooding. This means that the water flooding ecosystem after alkaline–surfactant–polymer flooding was more stable and less susceptible to external environmental influences. In addition, there were significant differences in the functional redundancy of microbial communities in different blocks. In summary, the optimal stage for implementing local microbial oil recovery technology may be water flooding after alkaline–surfactant–polymer flooding.

Hydrogen peroxide (H2O2) is a prevalent reactive oxygen species (ROS) found in cells and takes a central role in plant development and stress adaptation. The root apical meristem (RAM) has evolved strong plasticity to adapt to complex and changing environmental conditions. Recent advances have made great progress in explaining the mechanism of key factors, such as auxin, WUSCHEL-RELATED HOMEOBOX 5 (WOX5), PLETHORA (PLT), SHORTROOT (SHR), and SCARECROW (SCR), in the regulation of RAM activity maintenance. H2O2 functions as an emerging signaling molecule to control the quiescent center (QC) specification and stem cell niche (SCN) activity. Auxin is a key signal for the regulation of RAM maintenance, which largely depends on the formation of auxin regional gradients. H2O2 regulates the auxin gradients by the modulation of intercellular transport. H2O2 also modulates the expression of WOX5, PLTs, SHR, and SCR to maintain RAM activity. The present review is dedicated to summarizing the key factors in the regulation of RAM activity and discussing the signaling transduction of H2O2 in the maintenance of RAM activity. H2O2 is a significant signal for plant development and environmental adaptation.

Osteoclast differentiation is critical for bone homeostasis. The authors show the negative feedback regulation of BRD9-mediated chromatin remodeling on osteoclastogenesis via interferon beta signaling and its therapeutic potential for bone diseases.

Abstract Background With better patient selection and the increasing experience in patients undergoing hyperthermic intraperitoneal chemotherapy (HIPEC) combined surgery, the rate of severe postoperative complications and mortality decreased significantly. However, leukopenia and neutropenia were still a particular concern, and their relation to sarcopenia was not clarified. Methods Data of consecutive patients who underwent HIPEC for gastrointestinal cancer were collected and analyzed retrospectively between September 2020 and August 2022. Sarcopenia was assessed using psoas muscle index (PMI) at the L3 level on preoperative computed tomography (CT). Results Among 103 patients enrolled, 37 (35.9%) were classified as sarcopenic. Most leukopenia and neutropenia occurred during the hospital leaving period after HIPEC and surgery. Before the first time of postoperative chemotherapy, the blood tests revealed 11 (29.73%) and 6 (9.09%) patients were diagnosed with neutropenia in sarcopenia and no sarcopenia groups, respectively. Logistic regression analysis revealed sarcopenia was independently associated with the increased risk of neutropenia (OR 5.58, 95% CI 1.70–18.29, p = 0.005). An incremental albumin level was protective against the occurrence of leukopenia and neutropenia. Conclusions Sarcopenia and low albumin level were significantly associated with an increased rate of delayed neutropenia after HIPEC in that disease setting and could be the preoperative risk predictors.

ObjectiveC1q/TNF-related proteins 1 (CTRP1) is a recently identified adiponectin associated with obesity-linked disorders and adverse cardiovascular events. The effect of CTRP1 on cardiac fibrosis has not yet been fully elucidated; thus, we aimed to explore this association.Materials and MethodsIn this experimental study, a mouse model of cardiac fibrosis was established by administeringisoproterenol (ISO) (subcutaneously injecting 10 mg/kg/day for 3 days and then 5 mg/kg/day for 11 days). Mice were also injected with recombinant CTRP1 protein (200 μg/kg) 14 days after the final ISO administration. Adult mouse fibroblasts were isolated and stimulated with transforming growth factor (TGF) β1, followed by treatment with recombinant CTRP1. Primary bone marrow-derived macrophages were isolated from C57BL/6J mice and treated with recombinant CTRP1 as well.ResultsCTRP1 level was increased in mouse plasma and heart tissue 2 weeks after ISO injection. Our findingsindicated that recombinant CTRP1 injection aggravated ISO-induced cardiac fibrosis and dysfunction. However,recombinant CTRP1 did not alter TGFβ1-induced fibroblast proliferation and activation or collagen transcription.Recombinant CTRP1 exacerbated ISO-induced macrophage infiltration and inflammatory response. We determinedthat macrophages treated with recombinant CTRP1 showed increased pro-inflammatory cytokine release. Fibroblastsco-cultured with macrophages treated with recombinant CTRP1 showed increased proliferation and collagentranscription. We also found that CTRP1 upregulated the NADPH oxidase 2 (NOX2)/p38 pathway in macrophages.When we inhibited p38 signaling, the pro-inflammatory effect of CTRP1 on macrophages was counteracted. Fibroblastsco-cultured with macrophages treated with a p38 inhibitor also showed limited proliferation and collagen transcription.Conclusion: Cardiac fibrosis was aggravated with the activation of the NOX2/p38 pathway in macrophages afterCTRP1 treatment.

Background/objective Bone marrow biopsy, the gold standard for the diagnosis of multiple myeloma (MM), has main limitation of the invasiveness. Here, we explored the diagnostic and prognostic values of circulating miR-1246 in patients with MM.Material and methods Ninety MM patients and 30 healthy donors (control group) were recruited in this study. The expression of miR-1246 in the peripheral blood samples was detected using qPCR. The receiver operating characteristic (ROC) curve was used to assess the diagnostic value of miR-1246 in MM. The Kaplan–Meier survival analyze was performed to evaluate the prognostic value of miR-1246.Results The expression level of serum miR-1246 from newly diagnosed MM patients was significantly higher than that of the control group. Circulating miR-1246 level was decreased after treatment in remission patients, but remained high levels in relapsed patients (P

Abstract Uncontrolled microglial activation is pivotal to the pathogenesis of Parkinson’s disease (PD), which can secrete Cathepsin L (CTSL) to affect the survival of neurons in the PD patients; however, the precise mechanism has yet to be determined. We demonstrated for the first time that CTSL was mostly released by exosomes derived from α-Syn-activated microglia, resulting in neuronal damage and death. The elevation of CTSL activity was blocked by GW4869, suggesting a critical role for exosomes in mediating CTSL release. Furthermore, the P2X7R/PI3K/AKT signalling pathway was identified as the underlying molecular mechanism since specific antagonists of this signalling pathway, P2X7R knockdown and exosome release inhibitors significantly reduced the injury to cultured mouse cortical neurons. Our study suggests that increased extracellular release of CTSL from α-Syn-activated microglia through exosomes amplifies and aggravates of the neurotoxic effect of microglia, implying that CTSL may be involved in a fresh mechanism of PD pathogenesis, and serve as a potential biomarker and a target for PD drug development.