APOE ε4 allele modifies the associations of toxic metals and their mixture with cognitive impairment among older adults.

BACKGROUND: The evidence of interactive effect of the toxic metal (TM) mixture and apolipoprotein E (APOE) ε4 gene on cognitive impairment in older adults is scarce. We aimed to explore whether the associations of single TMs and their mixture with cognitive impairment depend on APOE ε4 in Chinese community-dwelling older people. METHODS: A total of 1148 older adults from a subset of the baseline survey of a cohort study were included. Blood arsenic (As), cadmium (Cd), lead (Pb), strontium (Sr), and vanadium (V) were detected by inductively coupled plasma mass spectrometry. APOE gene (rs429358, rs7412) polymorphisms were analyzed by the Polymerase Chain Reaction instrument. Mixed effects logistic regression was applied to estimate the relationships of single TMs and APOE genotype with cognitive impairment. Weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were performed to examine joint impacts of the TM mixture, as well as the interaction of the TM mixture with APOE ε4 genotype on cognitive impairment. RESULTS: Pb displayed a significant linear association with an increased odds of cognitive impairment after adjustment for covariates (Ptrend = 0.045). While APOE genotype did not show a significant correlation with cognitive impairment. WQS showed that the TM mixture was associated with an increased risk of cognitive impairment by 31.0% (OR=1.31, 95% CI: 0.92, 1.87) while no significance was found. BKMR exhibited a significant linear association between the TM mixture and cognitive impairment. Moreover, both WQS and BKMR indicated that Pb contributed the most to cognitive impairment within the mixture. Significant interactions of Pb or the TM mixture and APOE genotype on cognitive impairment were observed, contributing to 38.1% and 38.2% of total effects, respectively. CONCLUSIONS: APOE ε4 allele amplifies the associations of single Pb or the TM mixture with cognitive impairment. These findings may help to develop precision prevention.

Bacteriophage-cocktail hydrogel dressing to prevent multiple bacterial infections and heal diabetic ulcers in mice.

Bacteriophage (phage) has been reported to reduce the bacterial infection in delayed-healing wounds and, as a result, aiding in the healing of said wounds. In this study we investigated whether the presence of phage itself could help repair delayed-healing wounds in diabetic mice. Three strains of phage that target Salmonella enterica, Escherichia coli, and Pseudomonas aeruginosa were used. To prevent the phage liquid from running off the wound, the mixture of phage (phage-cocktail) was encapsulated in a porous hydrogel dressing made with three-dimensional printing. The phage-cocktail dressing was tested for its phage preservation and release efficacy, bacterial reduction, cytotoxicity with 3T3 fibroblast, and performance in repairing a sterile full-thickness skin wound in diabetic mice. The phage-cocktail dressing released 1.7%-5.7% of the phages embedded in 24 h, and reduced between 37%-79% of the surface bacteria compared with the blank dressing (p <.05). The phage-cocktail dressing exhibited no sign of cytotoxicity after 3 days (p <.05). In vivo studies showed that 14 days after incision, the full-thickness wound treated with a phage-cocktail dressing had a higher wound healing ratio compared with the blank dressing and control (p <.01). Histological analysis showed that the structure of the skin layers in the group treated with phage-cocktail dressing was restored in an orderly fashion. Compared with the blank dressing and control, the repaired tissue in the phage-cocktail dressing group had new capillary vessels and no sign of inflammation in its dermis, and its epidermis had a higher degree of re-epithelialization (p <.05). The slow-released phage has demonstrated positive effects in repairing diabetic skin wounds.

Association between labor epidural analgesia and gut microbiota: A prospective cohort study.

Background: Labor epidural analgesia (LEA) may influence gut microbiota. We explored the association between LEA and gut microbiota for both mothers and their newborns. Methods: In this prospective cohort study, parturients aged 25-35 years with a gestational age of 37-42 weeks and planned vaginal delivery were recruited. Twenty-one parturients received LEA (the LEA group), and 24 did not (the control group). Maternal and neonatal fecal samples were collected, and the gut microbiota profiles were analyzed using the 16S rRNA gene sequencing. The impact of LEA on gut microbiota was assessed using the general liner models. Results: We showcased the gut microbiota profile from the phyla to species levels based on data on 45 mother-newborn dyads. The results of α- and ß-diversity suggested significant changes in gut microbiota between the LEA and control groups. After adjusting for baseline confounders, the administration of LEA had positive correlations with R. ilealis (ß = 91.87, adjusted P = 0.007) in mothers; LEA also had negative correlations with A. pittii (ß = -449.36, adjusted P = 0.015), P. aeruginosa (ß = -192.55, adjusted P = 0.008), or S. maltophilia (ß = -142.62, adjusted P = 0.001) in mothers, and with Muribaculaceae (ß = -2702.77, adjusted P = 0.003) in neonates. Conclusion: LEA was associated with changes in maternal and neonatal gut microbiota, and future studies are still required to assess their impact on clinical outcomes and explore the mechanisms.

Radiocontrast medium induces histamine release in association with upregulation of miR­19a­3p and miR­362­3p expression.

In Taiwan, the use of radiocontrast medium for clinical image diagnosis recently surpassed one million times and the overall prevalence of radiocontrast hypersensitivity was ~7%. A microRNA (miRNA/miRs) is a small non-coding RNA molecule that mostly plays a suppressor role in cells. However, the roles of miRNA expression in radiocontrast-induced mast cells activation remains to be elucidated. The aim of the present study was to investigate the role of miRNA on radiocontrast-induced mast cell activation. Computed tomography radiocontrast, ultravist and mouse mast cell line, P815, were used in the present study. Cell viability was detected by CCK-8 experiment. Levels of histamine and ß-hexosaminidase were measured by ELISA. miRNA expression was detected by miRNA sequencing and reverse transcription-quantitative PCR. The results showed that ultravist could increase histamine release and reduce intracellular ß-hexosaminidase levels of mast cells. A total of 102 miRNAs could be significantly upregulated by ultravist stimulation. Selected candidate miRNAs for the validation included miR-19a-3p and miR-362-3p which were also increased expression following stimulation with ultravist. In conclusion, ultravist could induce mast cell activation through upregulation of miR-19a-3p and miR-362-3p. Thus, miR-19a-3p and miR-362-3p could be promising candidates for development as novel targets for preventing radiocontrast-induced allergy in the future.

Blocking SLC7A11 attenuates the proliferation of esophageal squamous cell carcinoma cells.

The role of ferroptosis-associated gene SLC7A11 in esophageal cancer progression is largely unknown, therefore, the effects of blocking SLC7A11 on esophageal squamous cell carcinoma (ESCC) cells are evaluated. Results showed that SLC7A11 was overexpressed in ESCC tissues both in mRNA and protein levels. Blocking SLC7A11 using Erastin suppressed the proliferation and colony formation of ESCC cells, decreased cellular ATP levels, and improved ROS production. Sixty-three SLC7A11-binding proteins were identified using the IP-MS method, and these proteins were enriched in four signaling pathways, including spliceosome, ribosome, huntington disease, and diabetic cardiomyopathy. The deubiquitinase inhibitors PR-619, GRL0617, and P 22077 could reduce at least 40% protein expression level of SLC7A11 in ESCC cells, and PR-619 and GRL0617 exhibited suppressive effects on the cell viability and colony formation ability of KYSE30 cells, respectively. Erastin downregulated GPX4 and DHODH and also reduced the levels of ß-catenin, p-STAT3, and IL-6 in ESCC cells. In conclusion, SLC7A11 was overexpressed in ESCC, and blocking SLC7A11 using Erastin mitigated malignant phenotypes of ESCC cells and downregulated key ferroptosis-associated molecules GPX4 and DHODH. The therapeutic potential of targeting SLC7A11 should be further evaluated in the future.

Quantitative evaluation of vertical control in orthodontic camouflage treatment for skeletal class II with hyperdivergent facial type.

BACKGROUND: In this study, we sought to quantify the influence of vertical control assisted by a temporary anchorage device (TAD) on orthodontic treatment efficacy for skeletal class II patients with a hyperdivergent facial type and probe into the critical factors of profile improvement. METHODS: A total of 36 adult patients with skeletal class II and a hyperdivergent facial type were included in this retrospective case-control study. To exclude the effect of sagittal anchorage reinforcement, the patients were divided into two groups: a maxillary maximum anchorage (MMA) group (N = 17), in which TADs were only used to help with anterior tooth retraction, and the MMA with vertical control (MMA + VC) group (N = 19), for which TADs were also used to intrude the maxillary molars and incisors. The treatment outcome was evaluated using dental, skeletal, and soft-tissue-related parameters via a cephalometric analysis and cast superimposition. RESULTS: A significant decrease in ANB (P < 0.05 for both groups), the retraction and uprighting of the maxillary and mandibular incisors, and the retraction of protruded upper and lower lips were observed in both groups. Moreover, a significant intrusion of the maxillary molars was observed via the cephalometric analysis (- 1.56 ± 1.52 mm, P < 0.05) and cast superimposition (- 2.25 ± 1.03 mm, P < 0.05) of the MMA + VC group but not the MMA group, which resulted in a remarkable decrease in the mandibular plane angle (- 1.82 ± 1.38°, P < 0.05). The Z angle (15.25 ± 5.30°, P < 0.05) and Chin thickness (- 0.97 ± 0.45°, P < 0.05) also improved dramatically in the MMA + VC group, indicating a better profile and a relaxed mentalis. Multivariate regression showed that the improvement in the soft tissue was closely related to the counterclockwise rotation of the mandible plane (P < 0.05). CONCLUSIONS: TAD-assisted vertical control can achieve intrusion of approximately 2 mm for the upper first molars and induce mandibular counterclockwise rotation of approximately 1.8°. Moreover, it is especially important for patients without sufficient retraction of the upper incisors or a satisfactory chin shape.

Structural evolution and bonding properties of Nb1-2Gen-/0 (n = 3-7) clusters: Anion photoelectron spectroscopy and theoretical calculations.

This study presents a collaborative experimental and theoretical investigation into the structures and electronic properties of niobium-doped germanium clusters. Anion photoelectron spectra for Nb1-2Gen- (n = 3-7) clusters were acquired using 266 nm photon energies, enabling the determination of adiabatic detachment energies and vertical detachment energies. In conjunction with these experimental measurements, density functional theory (DFT) calculations were conducted to validate the experimentally obtained electron detachment energies and elucidate the geometric and electronic structures of each anionic cluster. The agreement between DFT calculations and experimental data establishes a solid foundation for assessing the structural evolution and electronic properties of niobium-doped germanium clusters. It is noted that both neutral and anionic clusters exhibit predominantly similar overall structural characteristics, with the exception of Nb2Ge6- and Nb2Ge6. Furthermore, this investigation emphasizes the exceptional chemical stability of the D3d symmetric chair-shaped structure in Nb2Ge6-, providing insights into its bonding characteristics.

Gender associations between phthalate exposure and biomarkers of oxidative stress: A prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p < .05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children.

Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson's disease.

The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson's disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1ß, which is subsequently secreted into the extracellular space. This secreted IL-1ß then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.

Ultrarobust Actuator Comprising High-Strength Carbon Fibers and Commercially Available Polycarbonate with Multi-Stimulus Responses and Programmable Deformation.

Polymer-based actuators have gained extensive attention owing to their potential applications in aerospace, soft robotics, etc. However, poor mechanical properties, the inability of multi-stimuli response and programmable deformation, and the costly fabrication procedure have significantly hindered their practical application. Herein, these issues are overcome via a simple and scalable one-step molding method. The actuator is fabricated by hot-pressing commercial unidirectional carbon fiber/epoxy prepregs with a commodity PC membrane. Notable CTE differences between the CF and PC layers endow the bilayer actuator with fast and reliable actuation deformation. Benefiting from the high strength of CF, the actuator exhibits excellent mechanical performance. Moreover, the anisotropy of CF endows the actuator with design flexibility. Furthermore, the multifunction of CF makes the actuator capable of responding to thermal, optical, and electrical stimulation simultaneously. Based on the bilayer actuator, we successfully fabricated intelligent devices such as light-driven biomimetic flowers, intelligent grippers, and gesture-simulating apparatuses, which further validate the programmability and multi-stimuli response characteristics of this actuator. Strikingly, the prepared gripper possesses a grasping capacity approximately 31.2 times its own weight. It is thus believed that the concept presented paves the way for building next-generation robust robotics.

Mouse serum albumin induces neuronal apoptosis and tauopathies.

The elderly frequently present impaired blood-brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders.

Controlling the Selectivity of Electrocatalytic NO Reduction through pH and Potential Regulation on Single-Atom Catalysts.

Electrocatalytic nitrogen oxide reduction (NOxRR) emerges as an effective way to bring the disrupted nitrogen cycle back into balance. However, efficient and selective NOxRR is still challenging partly due to the complex reaction mechanism, which is influenced by experimental conditions such as pH and electrode potential. Here, we have studied the enzyme-inspired iron single-atom catalysts (Fe-N4-C) and identified that the selectivity roots in the first step of the nitric oxide reduction. Combining the constrained molecular dynamics (MD) simulations with the quasi-equilibrium approximation, the effects of electrode potential and pH on the reaction free energy were considered explicitly and predicted quantitatively. Systematic heat maps for selectivity between single-N and N-N-coupled products in a wide pH-potential space are further developed, which have reproduced the experimental observations of NOxRR. The approach presented in this study allows for a realistic simulation of the electrocatalytic interfaces and a quantitative evaluation of interfacial effects. Our results in this study provide valuable and straightforward guidance for selective NOx reduction toward desired products by precisely designing the experimental conditions.

The functional role of circRNA CHRC through miR-431-5p/KLF15 signaling axis in the progression of heart failure.

Pathological myocardial hypertrophy is a common early clinical manifestation of heart failure, with noncoding RNAs exerting regulatory influence. However, the molecular function of circular RNAs (circRNAs) in the progression from cardiac hypertrophy to heart failure remains unclear. To uncover functional circRNAs and identify the core circRNA signaling pathway in heart failure, we construct a global triple network (microRNA, circRNA, and mRNA) based on the competitive endogenous RNA (ceRNA) theory. We observe that cardiac hypertrophy related circRNA (circRNA CHRC), within the ceRNA network, is down-regulated in both transverse aortic constriction (TAC) mice and Ang-II--treated primary mouse cardiomyocytes. Silencing circRNA CHRC increases cross-sectional cell area, atrial natriuretic peptide, and ß-myosin heavy chain levels in primary mouse cardiomyocytes. Further screening reveals that circRNA CHRC targets the miR-431-5p/KLF15 axis implicated in heart failure progression in vivo and in vitro. Immunoprecipitation with anti-Ago2-RNA confirms the interaction between circRNA CHRC and miR-431-5p, while miR-431-5p mimics reverse Klf15 activation caused by circRNA CHRC overexpression. In summary, circRNA CHRC attenuates cardiac hypertrophy via sponging miR-431-5p to maintain the normal level of Klf15 expression.

Tannic acid-poloxamer self-assembled nanoparticles for advanced atherosclerosis therapy by regulation of macrophage polarization.

Atherosclerosis (AS) is a significant contributor to cardiovascular events. Advanced AS is particularly concerning, as it leads to the formation of high-risk vulnerable plaques. Current treatments for AS focus on antithrombotic and lipid-lowering interventions, which are effective in treating early-stage AS. Recent studies have shown that macrophage polarization plays a crucial role in the development of AS. This study presents a new biomedical application of natural tannic acid as an anti-inflammatory nanoplatform for advanced AS. Tannic acid-poloxamer nanoparticles (TPNP) are fabricated through self-assembly of tannic acid (TA) and poloxamer. TPNP has the potential to provide effective treatment for advanced AS. According to in vitro studies, TPNP has been found to suppress the inflammatory response in lipopolysaccharide-stimulated macrophages by scavenging reactive oxygen species (ROS), downregulating the expression levels of inflammatory cytokines (such as interleukin-10 and tumor necrosis factor-α) and regulating polarization of macrophages. In vivo studies further reveal that TPNP can retard the development of advanced atherosclerotic plaques by reducing ROS production and promoting M2 macrophage polarization in the aorta of ApoE-/- mice. Overall, these findings suggest that TPNP could be used to develop natural multifunctional nanoplatforms for molecular therapy of AS and other inflammation-related diseases.

KLF10/CBS increases the sensitivity of gastric carcinoma cells to methionine restriction by promoting sulfur transfer pathway.

Gastric cancer metastasis is a major cause of poor prognosis. Our previous research showed that methionine restriction (MR) lowers the invasiveness and motility of gastric carcinoma. In this study, we investigated the particular mechanisms of MR on gastric carcinoma metastasis. In vitro, gastric carcinoma cells (AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45) were grown in an MR medium for 24 h. In vivo, BALB/c mice were given a methionine-free (Met-) diet. Transwell assays were used to investigate cell invasion and migration. The amounts of Krüppel like factor 10 (KLF10) and cystathionine ß-synthase (CBS) were determined using quantitative real-time PCR and Western blot. To determine the relationship between KLF10 and CBS, chromatin immunoprecipitation and a dual-luciferase reporter experiment were used. Hematoxylin-eosin staining was used to detect lung metastasis. Liquid chromatography-mass spectrometry was used to determine cystathionine content. MR therapy had varying effects on the invasion and migration of gastric carcinoma cells AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45. KLF10 was highly expressed in AGS cells but poorly expressed in KATO III cells. KLF10 improved MR's ability to prevent gastric carcinoma cell invasion and migration. In addition, KLF10 may interact with CBS, facilitating transcription. Further detection revealed that inhibiting the KLF10/CBS-mediated trans-sulfur pathway lowered Met-'s inhibitory effect on lung metastasis development. KLF10 transcription activated CBS, accelerated the trans-sulfur pathway, and increased gastric carcinoma cells' susceptibility to MR.

Bipolar hip arthroplasty using conjoined tendon preserving posterior lateral approach in treatment of displaced femoral neck fractures.

BACKGROUND: Hip fractures account for 23.8% of all fractures in patients over the age of 75 years. More than half of these patients are older than 80 years. Bipolar hemiarthroplasty (BHA) was established as an effective management option for these patients. Various approaches can be used for the BHA procedure. However, there is a high risk of postoperative dislocation. The conjoined tendon-preserving posterior (CPP) lateral approach was introduced to reduce postoperative dislocation rates. AIM: To evaluate the effectiveness and safety of the CPP lateral approach for BHA in elderly patients. METHODS: We retrospectively analyzed medical data from 80 patients with displaced femoral neck fractures who underwent BHA. The patients were followed up for at least 1 year. Among the 80 patients, 57 (71.3%) were female. The time to operation averaged 2.3 d (range: 1-5 d). The mean age was 80.5 years (range: 67-90 years), and the mean body mass index was 24.9 kg/m2 (range: 17-36 kg/m2). According to the Garden classification, 42.5% of patients were type Ⅲ and 57.5% of patients were type Ⅳ. Uncemented bipolar hip prostheses were used for all patients. Torn conjoined tendons, dislocations, and adverse complications during and after surgery were recorded. RESULTS: The mean postoperative follow-up time was 15.3 months (range: 12-18 months). The average surgery time was 52 min (range: 40-70 min) with an average blood loss of 120 mL (range: 80-320 mL). The transfusion rate was 10% (8 of 80 patients). The gemellus inferior was torn in 4 patients (5%), while it was difficult to identify in 2 patients (2.5%) during surgery. The posterior capsule was punctured by the fractured femoral neck in 3 patients, but the conjoined tendon and the piriformis tendon remained intact. No patients had stem varus greater than 3 degrees or femoral fracture. There were no patients with stem subsidence more than 5 mm at the last follow-up. No postoperative dislocations were observed throughout the follow-up period. No significance was found between preoperative and postoperative mean Health Service System scores (87.30 ± 2.98 vs 86.10 ± 6.10, t = 1.89, P = 0.063). CONCLUSION: The CPP lateral approach can effectively reduce the incidence of postoperative dislocation without increasing perioperative complications. For surgeons familiar with the posterior lateral approach, there is no need for additional surgical instruments, and it does not increase surgical difficulty.

Regulating TKT activity inhibits proliferation of human acute lymphoblastic leukemia cells.

Among pediatric blood cancers, acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy. Within ALL, T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10 to 15% of all pediatric cases, and ~25% of adult cases. For T-ALL, its recurrence and relapse after treatment remain problematic. Therefore, it is necessary to develop new therapies for T-ALL. Recent studies suggested regulating energy metabolism is a novel approach to inhibit tumor growth, likely a promising treatment. Transketolase (TKT) is an important enzyme for modulating glucose metabolize in the pentose phosphate pathway (PPP). In this study, we treated T-ALL cells with different doses of niclosamide and primary T-ALL PBMCs were analyzed by RNA sequencing. T-ALL cells treated with niclosamide were analyzed with the Western blotting and TKT activity assay. Metabolism of T-ALL cells was evaluated by ATP assay and seahorse analyses. Lastly, we used a T-ALL xenograft murine model to determine effects of TKT knockdown on T-ALL tumor growth. Tumor samples were analyzed by H&E and IHC stainings. We found that niclosamide reduced T-ALL cell viability, and reduced expressions of TKT, Transketolase-Like Protein 1/2 (TKTL1/2) and transaldolase. In addition, niclosamide inhibited TKT enzyme activity, aerobic metabolism and glycolysis, finally leading to lower production of ATP. TKT knockdown inhibited tumor growth of xenograft T-ALL mice. Findings showed that niclosamide inhibits T-ALL cell growth by inhibiting TKT and energy metabolism.

Anion Photoelectron Spectroscopy and Quantum Chemistry Calculations of Gas-Phase TaSi17Ì and TaSi18Ì Clusters: Structural Determination, Bonding Characteristics, and Multiplicity of Structural Forms.

This study explores the structures and chemical bonding properties of TaSi17̅ and TaSi18̅ clusters by employing anion photoelectron spectroscopy and theoretical computations. Utilizing CALYPSO and ABCluster programs for initial structure prediction, B3LYP hybrid functional for optimization, and CCSD(T)/def2-TZVPPD level for energy calculations, the research identifies the most stable isomers of these clusters. Key findings include the identification of two coexisting low-energy isomers for TaSi17̅, exhibiting Ta-endohedral fullerene-like cage structures, and the lowest-energy structures of TaSi17̅ and TaSi18̅ anions can be considered as derived from the TaSi16̅ superatom cluster. The study enhances the understanding of group 14 element chemistry and guides the design of novel inorganic metallic compounds, potentially impacting materials science.

SARS-CoV-2 envelope protein impairs airway epithelial barrier function and exacerbates airway inflammation via increased intracellular Cl- concentration.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts the epithelial barrier and triggers airway inflammation. The envelope (E) protein, a core virulence structural component of coronaviruses, may play a role in this process. Pathogens could interfere with transepithelial Cl- transport via impairment of the cystic fibrosis transmembrane conductance regulator (CFTR), which modulates nuclear factor κB (NF-κB) signaling. However, the pathological effects of SARS-CoV-2 E protein on airway epithelial barrier function, Cl- transport and the robust inflammatory response remain to be elucidated. Here, we have demonstrated that E protein down-regulated the expression of tight junctional proteins, leading to the disruption of the airway epithelial barrier. In addition, E protein triggered the activation of Toll-like receptor (TLR) 2/4 and downstream c-Jun N-terminal kinase (JNK) signaling, resulting in an increased intracellular Cl- concentration ([Cl-]i) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl-]i contributed to the heightened airway inflammation through promoting the phosphorylation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, blockade of SGK1 or PDE4 alleviated the robust inflammatory response induced by E protein. Overall, these findings provide novel insights into the pathogenic role of SARS-CoV-2 E protein in airway epithelial damage and the ongoing airway inflammation during SARS-CoV-2 infection.

The Effect of Topical Vancomycin Powder Application on the Rate of Intervertebral Fusion Following Lumbar Fusion: A Retrospective Study.

PURPOSE: The occurrence of surgical site infection (SSI) after lumbar spinal fusion is a serious complication. Therefore, an increasing number of clinicians are applying vancomycin powder topically in the surgical field to reduce the incidence of SSI. However, there is concern that topical vancomycin powder application may affect intervertebral fusion. The purpose of this study was to analyse the effect of clinically relevant topical vancomycin doses on the rate of intervertebral fusion after lumbar fusion and to further investigate the effect of vancomycin powder on the prevention of SSI. METHODS: The clinical data of 192 patients with degenerative lumbar spine disease admitted from January 2019 to June 2022, all of whom underwent posterior lumbar fusion, were retrospectively analysed. According to the infection prevention protocol, they were divided into a vancomycin group and a control group (no vancomycin), and the vancomycin group was sub-divided into 0.5 g, 1.0 g, and 1.5 g vancomycin groups. General information and surgical evaluation indexes were compared between the control and vancomycin groups and intervertebral fusion was compared between the vancomycin groups at 6 months and 12 months, postoperatively. RESULTS: The rate of SSI in the vancomycin group was 0.0%, which was significantly lower than that in the control group (5.3%, P < 0.05), and intervertebral fusion was good in all 3 vancomycin groups at 6 months and 12 months postoperatively, with no statistically-significant differences (P > 0.05). CONCLUSIONS: Topical application of 0.5 g, 1.0 g, or 1.5 g vancomycin powder did not affect the rates of intervertebral fusion after lumbar fusion. In addition, topical application of vancomycin powder significantly reduced the rates of SSI.