KMT2D mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory T cell trafficking via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-ß1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-ß1 axis.

How Does Escherichia coli Allocate Proteome?

Microorganisms are shown to actively partition their intracellular resources, such as proteins, for growth optimization. Recent experiments have begun to reveal molecular components unpinning the partition; however, quantitatively, it remains unclear how individual parts orchestrate to yield precise resource allocation that is both robust and dynamic. Here, we developed a coarse-grained mathematical framework that centers on guanosine pentaphosphate (ppGpp)-mediated regulation and used it to systematically uncover the design principles of proteome allocation in Escherichia coli. Our results showed that the cellular ability of resource partition lies in an ultrasensitive, negative feedback-controlling topology with the ultrasensitivity arising from zero-order amino acid kinetics and the negative feedback from ppGpp-controlled ribosome synthesis. In addition, together with the time-scale separation between slow ribosome kinetics and fast turnovers of ppGpp and amino acids, the network topology confers the organism an optimization mechanism that mimics sliding mode control, a nonlinear optimization strategy that is widely used in man-made systems. We further showed that such a controlling mechanism is robust against parameter variations and molecular fluctuations and is also efficient for biomass production over time. This work elucidates the fundamental controlling mechanism of E. coli proteome allocation, thereby providing insights into quantitative microbial physiology as well as the design of synthetic gene networks.

Multi-omics and pharmacological characterization of patient-derived glioma cell lines.

Glioblastoma (GBM) is the most common brain tumor and remains incurable. Primary GBM cultures are widely used tools for drug screening, but there is a lack of genomic and pharmacological characterization for these primary GBM cultures. Here, we collect 50 patient-derived glioma cell (PDGC) lines and characterize them by whole genome sequencing, RNA sequencing, and drug response screening. We identify three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Drug response profiling reveals that PN subtype PDGCs are sensitive to tyrosine kinase inhibitors, whereas OXPHOS subtype PDGCs are sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably form tumors in vivo upon intracranial transplantation into immunodeficient mice, whereas most MES subtype PDGCs fail to form tumors in vivo. In addition, PDGCs cultured by serum-free medium, especially long-passage PDGCs, carry MYC/MYCN amplification, which is rare in GBM patients. Our study provides a valuable resource for understanding primary glioma cell cultures and clinical translation and highlights the problems of serum-free PDGC culture systems that cannot be ignored.

Tailoring the electrode material and structure of rocking-chair capacitive deionization for high-performance desalination.

With the gradually increasing requirement for freshwater, capacitive deionization (CDI) as a burgeoning desalination technique has gained wide attention owing to its merits of easy operation, high desalination efficiency, and environmental friendliness. To enhance the desalination performance of CDI, different CDI architectures are designed, such as membrane CDI, hybrid CDI, and flow-electrode CDI. However, these CDI systems have their own drawbacks, such as the high cost of membranes, capacity limitation of carbon materials and slurry blockage, which severely limit their practical application. Notably, rocking-chair CDI (RCDI) composed of symmetric electrode materials delivers excellent desalination performance because of its special dual chamber structure, which can not only break through the capacity limitations of carbon materials, but also deliver a continuous desalination process. Although RCDI showcases high promise for efficient desalination, few works systematically summarize the advantages and applications of RCDI in the desalination field. This review offers a thorough analysis of RCDI, focusing on its electrode materials, structure designs and desalination applications. Furthermore, the desalination performances of RCDI and other CDI architectures are compared to demonstrate the advantages of RCDI and the prospect of RCDI is elucidated.

Outcome of patients with complete cleft lip and alveolus: 20-year follow-up.

BACKGROUND: Patients with cleft have functional and aesthetic impairment, and typically require several interventions as they grow. Long-term evaluation following a treatment protocol is essential, but such reports on patients with complete cleft lip and alveolus (CLA) are sparse in the literature. METHODS: A retrospective review was conducted to all patients with complete CLA born between January 1995 and August 2002 and treated at our center. Patients who received continuous multidisciplinary team care until 20 years of age were included, and patients with cleft palate and syndromic abnormalities were excluded. Facial bone growth was evaluated using cephalometric analysis. RESULTS: Eighty-seven and 11 patients with unilateral and bilateral CLA (UCLA and BCLA) were included respectively. All patients received one-stage cheiloplasty with primary rhinoplasty. Revisional lip/nose surgery was performed in 21.8 and 27.3% during growing age, and in 51.7 and 72.7% after skeletal maturity. Orthognathic surgery was performed in 20.7 and 27.3%. Compared with UCLA patients, BCLA had larger number of operations (3.0 versus 3.7, p = 0.03) and higher chance of receiving alveolar bone grafting twice (1.1% versus 36.4%, p < 0.01). Patients with complete CLA had less hypoplastic maxilla, and received smaller number of operations than complete cleft lip and palate. CONCLUSION: Complete CLA is a less severe form of cleft, but the patients still require multiple interventions. This review revealed certain suboptimal results, and modifications have been made in the treatment protocol. Longitudinal follow-up and periodic assessment help to establish an ideal therapeutic strategy and improve overall cleft care.

Frailty and all-cause and cancer-related mortality in cancer patients: A prospective cohort study.

PURPOSE: To evaluate the associations between frailty and all-cause and cancer-related mortality. Additionally, the objective is to compare the magnitude of these associations between older adults and younger adults. METHODS: We gathered baseline data from NHANES (1999-2018) and developed a cumulative index consisting of 39 items to evaluate frailty. The National Death Index database was utilized to track the survival status of individuals. The Cox regression model was employed to estimate the associations between frailty status and all-cause and cancer-related mortality. RESULTS: Ultimately, 3398 cancer patients were included in the analysis, comprising 910 younger adults and 2488 older adults. Compared to non-frail patients, the elevated all-cause and cancer-related mortality among pre-frail patients was not statistically significant (HRs = 1.312, 95%CI: 0.956-1.800, P = 0.092; HRs = 1.462, 0.811-2.635, P = 0.207). However, a significant elevation of both all-cause and cancer-related mortality risk was observed among frail patients (HRs = 2.213, 1.617-3.030, P < 0.001; HRs = 2.463, 95%CI = 1.370-4.429, P = 0.003). Frailty individuals demonstrated a more pronounced association with the prediction of all-cause mortality in younger (HRs = 2.230, 1.073-4.634, P = 0.032) than in older adults (HRs = 2.090, 1.475-2.960, P < 0.001). Sensitivity analysis consistently revealed robust results. RCS plots suggested a progressively escalating dose-response correlation between frailty and both all-cause and cancer-related mortality risk. CONCLUSIONS: Pre-frailty did not result in an increase in mortality risks compared to non-frailty. However, frailty caused a higher all-cause and cancer-related mortality risk than non-frailty. Identifying those at risk and implementing targeted interventions may contribute to extending healthy life expectancy, regardless of age.

Isoliquiritigenin alleviates experimental autoimmune encephalomyelitis by modulating inflammatory and neuroprotective reactive astrocytes.

Multiple sclerosis (MS) is an autoimmune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS) that poses significant treatment challenges. Currently, it is believed that inflammatory and neuroprotective reactive astrocytes, along with other resident CNS cells and immune cells, contribute to the pathophysiology of MS. In our study, we found that isoliquiritigenin (ILG), a bioactive chalcone compound, significantly reduces the clinical scores of experimental autoimmune encephalomyelitis (EAE) by 44 % (P < 0.05). Additionally, ILG significantly decreases the pathological scores of spinal cord inflammation and demyelination by 61 % and 65 %, respectively (both P < 0.0001). Furthermore, ILG affects the populations of CD4, Th1, Th17, and Treg cells in vivo. More importantly, ILG significantly promotes the activation of astrocytes in EAE (P < 0.0001). Additionally, ILG treatment indirectly inhibits inflammatory reactive astrocytes and promotes neuroprotective reactive astrocytes. It reduces spleen levels of TNFα, IL1α, C1qa, IL1ß, and IL17A by 95 % (P < 0.001), 98 % (P < 0.01), 46 % (P < 0.05), 97 % (P < 0.001), and 60 % (P < 0.001), respectively. It also decreases CNS levels of TNFα, IL1α, C1qa, IL1ß, and IL17A by 53 % (P < 0.05), 88 % (P < 0.05), 64 % (P < 0.01), 57 % (P < 0.05), and 60 % (P < 0.001), respectively. These results indicate that ILG exerts an immunoregulatory effect by inhibiting the secretion of pro-inflammatory cytokines. Consequently, ILG inhibits inflammatory reactive astrocytes, promotes neuroprotective reactive astrocytes, alleviates inflammation and improves EAE. These findings provide a theoretical basis and support for the application of ILG in the prevention and treatment of MS.

A randomized prospective study comparing the effect of low-volume bowel preparations for colonoscopy preparation in China.

AIM: To evaluate the effect of sodium picosulfate/magnesium citrate (SPMC) and 3 L split-dose polyethylene glycol (PEG) with or without dimethicone on bowel preparation before colonoscopy. METHODS: In this multicenter, prospective, randomized, controlled study conducted from April 2021 to December 2021, consecutive adult patients scheduled for colonoscopy were prospectively randomized into four groups: SPMC, SPMC plus dimethicone, 3 L PEG, and 3 L PEG plus dimethicone. Primary endpoint was colon cleansing based on Boston Bowel Preparation Scale (BBPS). Secondary endpoints were bubble score, time to cecal intubation, adenoma detection rate (ADR), patient safety and compliance, and adverse events. RESULTS: We enrolled 223 and 291 patients in SPMC and 3 L PEG group, respectively. The proportion with acceptable bowel cleansing, total BBPS score and cecal intubation time were similar in all four subgroups (p > 0.05). Patient-reported acceptability and tolerability was significantly greater in SPMC than 3 L PEG group (p < 0.001); adverse events were significantly lower in SPMC than latter group (p < 0.001). ADR in both groups was greater than 30%. CONCLUSION: SPMC had significantly higher acceptability and tolerability than 3 L PEG, however, was similar in terms of bowel-cleansing effect and cecal intubation time and hence can be used before colonoscopy preparation.

Reg2 treatment is protective but the induced Reg2 autoantibody is destructive to the islets in NOD mice.

Regenerating family protein 2 (Reg2) is a trophic factor which stimulates ß-cell replication and resists islet destruction. However, Reg2 also serves as an islet autoantigen, which makes it complicated to judge the effectiveness in treating diabetes. How Reg2 treatment behaves in non-obese diabetic (NOD) mice is to be investigated. NOD mice were treated with recombinant Reg2 protein, Complete Freund's adjuvant (CFA) + PBS and CFA+Reg2 vaccinations, CFA+PBS- and CFA+Reg2-immunized antisera, and single chain variable fragment (scFv)-Reg2 and mIgG2a-Reg2 antibodies. Glycemic level, bodyweight, serum Reg2 antibody titer, glucose tolerance, and insulin secretion were determined. Islet morphological characteristics, insulitis, cell apoptosis, islet cell components, and T cell infiltration were analyzed by histological examinations. The autoantigenicity of constructed Reg2C and Reg2X fragments was determined in healthy BALB/c mice, and the bioactivity in stimulating cell proliferation and survival was assessed in insulinoma MIN6 cells. Reg2 administration alleviated diabetes in NOD mice with improved glucose tolerance and insulin secretion but elevated serum Reg2 autoantibodies. Histomorphometry showed reduced inflammatory area, TUNEL signal and CD8 + T cell infiltration, and increased ß-cell proportion in support of the islet-protective effect of Reg2 treatment. CFA+PBS and CFA+Reg2 immunizations prevented diabetic onset and alleviated insulitis while injections of the antisera offered mild protections. Antibody treatments accelerated diabetic onset without increasing the overall incidence. Reg2C fragment depletes antigenicity, but reserves protective activity in streptozotocin (STZ)-treated MIN6 cells. In conclusion, Reg2 treatment alleviates type 1 diabetes (T1D) by preserving islet ß-cells, but induces Reg2 autoantibody production which poses a potential risk of accelerating diabetic progression.

Combined use of chemical dust suppressant and herbaceous plants for tailings dust control.

Tailings dust can negatively affect the surrounding environment and communities because the tailings are vulnerable to wind erosion. In this study, the effects of halides (sodium chloride [NaCl], calcium chloride [CaCl2], and magnesium chloride hexahydrate [MgCl2·6H2O]), and polymer materials (polyacrylamide [PAM], polyvinyl alcohol [PVA], and calcium lignosulfonate [LS]) were investigated for the stabilization of tailings for dust control. Erect milkvetch (Astragalus adsurgens), ryegrass (Lolium perenne L.), and Bermuda grass (Cynodon dactylon) were planted in the tailings and sprayed with chemical dust suppressants. The growth status of the plants and their effects on the mechanical properties of tailings were also studied. The results show that the weight loss of tailings was stabilized by halides and polymers, and decreased with increasing concentration and spraying amount of the solutions. The penetration resistance of tailings stabilized by halides and polymers increased with increasing concentration and spraying amount of the solutions. Among the halides and polymers tested, the use of CaCl2 and PAM resulted in the best control of tailings dust, respectively. CaCl2 solution reduces the adaptability of plants and therefore makes it difficult for grass seeds to germinate normally. PAM solutions are beneficial for the development of herbaceous plants. Among the three herbaceous species, ryegrass exhibited the best degree of development and was more suitable for growth in the tailings. The ryegrass plants planted in the tailings sprayed with PAM grew the best, and the root-soil complex that formed increased the shear strength of the tailings.

An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.

Antimicrobial resistance is an ongoing "one health" challenge of global concern. The acyl-ACP synthetase (termed AasS) of the zoonotic pathogen Vibrio harveyi recycles exogenous fatty acid (eFA), bypassing the requirement of type II fatty acid synthesis (FAS II), a druggable pathway. A growing body of bacterial AasS-type isoenzymes compromises the clinical efficacy of FAS II-directed antimicrobials, like cerulenin. Very recently, an acyl adenylate mimic, C10-AMS, was proposed as a lead compound against AasS activity. However, the underlying mechanism remains poorly understood. Here we present two high-resolution cryo-EM structures of AasS liganded with C10-AMS inhibitor (2.33 Å) and C10-AMP intermediate (2.19 Å) in addition to its apo form (2.53 Å). Apart from our measurements for C10-AMS' Ki value of around 0.6 µM, structural and functional analyses explained how this inhibitor interacts with AasS enzyme. Unlike an open state of AasS, ready for C10-AMP formation, a closed conformation is trapped by the C10-AMS inhibitor. Tight binding of C10-AMS blocks fatty acyl substrate entry, and therefore inhibits AasS action. Additionally, this intermediate analog C10-AMS appears to be a mixed-type AasS inhibitor. In summary, our results provide the proof of principle that inhibiting salvage of eFA by AasS reverses the FAS II bypass. This facilitates the development of next-generation anti-bacterial therapeutics, esp. the dual therapy consisting of C10-AMS scaffold derivatives combined with certain FAS II inhibitors.

Microscopic Mechanism and Percolation Model of Dynamic Deposition of Elemental Sulfur Particles in Acidic Gas Reservoirs.

The dissolution of elemental sulfur in acidic gas leads to its precipitation as gas pressure decreases, thereby causing potential damage to the formation due to the deposition of sulfur particles. Previous sulfur deposition prediction models often relied on the solubility of sulfur in acidic gas and the stress state of sulfur particles to determine the occurrence of deposition, thus establishing predictive models. However, in the presence of complex geological conditions, the multiphase flow through porous media and the adsorption of particles on pore throat walls can also influence sulfur particle deposition to some degree. It is well known that sulfur particle deposition during gas reservoir development exhibits instability, with multiple factors influencing the deposited sulfur particles. Particularly noteworthy is the influence of airflow velocity, which can resuspend sulfur particles that are physically adsorbed on pore throat surfaces, thereby reintegrating them into the gas phase. Additionally, the dynamic deposition of larger sulfur particles involves a dynamic process. This study elucidates the dynamic process of sulfur deposition by considering the diverse transport dynamics of sulfur particles. Physical adsorption and desorption behaviors of sulfur particles are determined based on variations in reservoir conditions. The desorption status of sulfur particles with different particle sizes within the formation is established by evaluating the equilibrium between the force exerted on the pore throat wall and the suspension force generated by gas flow. The critical conditions for sulfur deposition in Yuanba gas reservoir were obtained by substituting on-site parameters into calculations. Moreover, a mathematical model is proposed to describe the dynamic deposition and migration of sulfur particles, adopting principles from continuous porous media porous flow theory, fluid flow mass conservation, as well as sulfur particle desorption and migration. The formulated model is solved, and its resulting solution process and outcomes hold significant implications for numerical simulation and predictive assessment of the development impact on gas reservoirs, particularly in later stages.

Disparities in medical recommendations from AI-based chatbots across different countries/regions.

This study explores disparities and opportunities in healthcare information provided by AI chatbots. We focused on recommendations for adjuvant therapy in endometrial cancer, analyzing responses across four regions (Indonesia, Nigeria, Taiwan, USA) and three platforms (Bard, Bing, ChatGPT-3.5). Utilizing previously published cases, we asked identical questions to chatbots from each location within a 24-h window. Responses were evaluated in a double-blinded manner on relevance, clarity, depth, focus, and coherence by ten experts in endometrial cancer. Our analysis revealed significant variations across different countries/regions (p < 0.001). Interestingly, Bing's responses in Nigeria consistently outperformed others (p < 0.05), excelling in all evaluation criteria (p < 0.001). Bard also performed better in Nigeria compared to other regions (p < 0.05), consistently surpassing them across all categories (p < 0.001, with relevance reaching p < 0.01). Notably, Bard's overall scores were significantly higher than those of ChatGPT-3.5 and Bing in all locations (p < 0.001). These findings highlight disparities and opportunities in the quality of AI-powered healthcare information based on user location and platform. This emphasizes the necessity for more research and development to guarantee equal access to trustworthy medical information through AI technologies.

Effects of exercise dose based on the ACSM recommendations on patients with post-stroke cognitive impairment: a systematic review and meta-analyses.

Purpose: This review aimed to assess the impact of different exercise dosages on cognitive function in individuals with post-stroke cognitive impairment (PSCI). Methods: Four electronic databases-Embase, PubMed, Web of Science, and Cochrane Library-were systematically searched from inception to 01 January 2024, focusing on the impact of exercise therapy on cognitive function in individuals with PSCI. Only randomized controlled trials meeting the criteria were included. The exercise therapy dose and adherence were evaluated following the American College of Sports Medicine (ACSM) guidelines, categorized into a high compliance group with ACSM recommendations and a low or uncertain compliance group. A random-effects model compared the effect of ACSM compliance on cognitive function in individuals with PSCI, with the effect size represented by the standardized mean difference (SMD) and a 95% confidence interval (CI). Results: In total, 18 studies meeting the criteria were included, with data from 1,742 participants. The findings suggested a beneficial effect of exercise on cognitive function in individuals with PSCI [SMD = 0.42, 95% CI (0.20, 0.65)]. Ten studies were categorized as the "high adherence group" and eight in the "low or uncertain adherence group" based on the ACSM recommendations. The subgroup analysis revealed that the SMD of the high compliance group was 0.46 (95% CI: 0.10, 0.82) (p = 0.01), while the SMD of the low or uncertain compliance group was 0.38 (95% CI: 0.07, 0.70) (p = 0.02). Conclusion: Our study indicates the beneficial impact of exercise for patients with PSCI over no exercise. Furthermore, high adherence to the exercise dose recommended by ACSM guidelines demonstrated a more substantial improvement in cognitive function than low or uncertain adherence in patients with PSCI. Systematic Review Registration: https:// www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42023487915.

Concentration-resistance relationship and PK/PD evaluation of danofloxacin against emergence of resistant Pasteurella multocida in an in vitro dynamic model.

AIMS: This study aimed to assess the pharmacokinetic/pharmacodynamic (PK/PD) targets of danofloxacin to minimize the risk of selecting resistant Pasteurella multocida mutants and to identify the mechanisms underlying their resistance in an in vitro dynamic model, attaining the optimum dosing regimen of danofloxacin to improve its clinical efficacy based on the mutant selection window (MSW) hypothesis. METHODS AND RESULTS: Danofloxacin at seven dosing regimens and 5 days of treatment were simulated to quantify the bactericidal kinetics and enrichment of resistant mutants upon continuous antibiotic exposure. The magnitudes of PK/PD targets associated with different efficacies were determined in the model. The 24 h area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratios (AUC24h/MIC) of danofloxacin associated with bacteriostatic, bactericidal and eradication effects against P. multocida were 34, 52, and 64 h. This translates to average danofloxacin concentrations (Cav) over 24 h being 1.42, 2.17, and 2.67 times the MIC, respectively. An AUC/MIC-dependent antibacterial efficacy and AUC/mutant prevention concentration (MPC)-dependent enrichment of P. multocida mutants in which maximum losses in danofloxacin susceptibility occurred at a simulated AUC24h/MIC ratio of 72 h (i.e. Cav of three times the MIC). The overexpression of efflux pumps (acrAB-tolC) and their regulatory genes (marA, soxS, and ramA) was associated with reduced susceptibility in danofloxacin-exposed P. multocida. The AUC24h/MPC ratio of 19 h (i.e. Cav of 0.8 times the MPC) was determined to be the minimum mutant prevention target value for the selection of resistant P. multocida mutants. CONCLUSIONS: The emergence of P. multocida resistance to danofloxacin exhibited a concentration-dependent pattern and was consistent with the MSW hypothesis. The current clinical dosing regimen of danofloxacin (2.5 mg kg-1) may have a risk of treatment failure due to inducible fluoroquinolone resistance.

Research Progress on Dental Age Estimation Based on MRI Technology.

Dental age estimation is a crucial aspect and one of the ways to accomplish forensic age estimation, and imaging technology is an important technique for dental age estimation. In recent years, some studies have preliminarily confirmed the feasibility of magnetic resonance imaging (MRI) in evaluating dental development, providing a new perspective and possibility for the evaluation of dental development, suggesting that MRI is expected to be a safer and more accurate tool for dental age estimation. However, further research is essential to verify its accuracy and feasibility. This article reviews the current state, challenges and limitations of MRI in dental development and age estimation, offering reference for the research of dental age assessment based on MRI technology.