Assessment of interactions between elemental carbon and metals in black carbon: Hydroxyl radical generation and glutathione depletion.

Elemental carbon (EC) and metals are two important parts of atmospheric black carbon (BC). However, little information is available regarding the interaction between them and its impacts on the reactive oxygen species (ROS) formation and physiological antioxidants depletion. In this study, we chose six most frequently detected metals (Cu(Ⅱ), Fe(Ⅲ), Mn(Ⅱ), Cr(Ⅲ), Pb(Ⅱ) and Zn(Ⅱ)) in BC and examined their interactions with EC in the ROS generation and glutathione (GSH) oxidation. Results showed that only Cu(Ⅱ) and EC synergically promoted the GSH oxidation and hydroxyl radical (•OH) generation. Other five metals had negligible effects on the GSH oxidation regardless of the presence or absence of EC. The synergistic interaction between Cu(Ⅱ) and EC could be attributed to the superior electrical conductivity of EC. In the process, EC transferred electrons from the adjacent GSH to Cu(Ⅱ) through its graphitic carbon framework to yield Cu(Ⅰ) and GSH radical. Cu(Ⅰ) further reacted with dioxygen to generate •OH, which eventually led to the oxidation of GSH. Our results revealed a new driving force inducing the ROS formation and GSH depletion as well as provided novel insights into the risk assessment of BC.

Optimal Timing of Starting Growing Rod Treatment for Early-onset Scoliosis.

BACKGROUND CONTEXT: Growing rod (GR) systems require periodical surgical intervention and may cause associated complications, as well as worsened sagittal plane deformity. Generally, the risk of complications decreases with increment in age at the time of the index surgery with GR construct placement. However, the optimal timing to begin GR treatment has not reached a consensus yet. PURPOSE: This study was performed to investigate the effect of age at the index GR surgery on the complication rates and formulate clinical guidelines for the optimal timing to begin GR treatment for EOS patients. STUDY DESIGN: Kaplan-Meier analysis was used to determine complication occurrence as a function of the age at the index surgery and to determine the survival rates for the procedures. The receiver operator characteristic (ROC) curve was used to determine optimal cut-off values for the optimal timing of index surgery based on whether complication occurred or not. PATIENT SAMPLE: 54 patients who met the criteria were enrolled in this study. OUTCOME MEASURES: The following spinal parameters were measured: major coronal Cobb angle, global kyphosis (GK), and coronal balance (CB). CB was defined as the horizontal distance from the C7 plumb line to the center sacral vertical line. METHODS: All patients had completed GR treatment and had a minimum 1-year follow-up duration after the final surgical intervention. Patient data were collected as follows: age at the index surgery, gender, diagnosis, type of GR construct, and the number of lengthening procedures. The standing full-spine radiographs were obtained before and after the index surgery, before and after each lengthening procedures, before and after the final surgical intervention, and at the latest follow-up. Complications were categorized as implant, alignment, and general. RESULTS: Kaplan-Meier analysis of complications demonstrated a declining trend in complication rates with increasing age at the index surgery. The absence of perioperative complications was targeted, we constructed the ROC curve and the cut-off value was 71.0 months. Age at the index surgery was therefore categorized into two groups: younger-age group (≤ 71.0 months) and advanced-age group (> 71.0 months). There was a higher complication rate for the younger-age group than versus the advanced-age group (61.5% vs 22.0%, P=0.011). PJK as a major alignment-related complication, was more frequent in the younger-age group than in the advanced-age group (30.8% vs 4.9%, P=0.025). But the advanced-age group exhibited significantly more severe deformities before GR surgery compared to the younger-age group. CONCLUSIONS: This study shows that the elevated risk of complications observed in the younger-age group, which can be attributed to the younger age at the index surgery and the increased number of lengthening procedures during treatment. We suggest deferring the initiation of GR treatment until after the age of six years for EOS patients. We hope it will serve as a basis for GR technique in the treatment of EOS, with the ultimate goal of enhancing treatment outcomes for this challenging disorder.

Association Between Vertebral Endplate Defects and Patient-reported Symptoms: An Immunohistochemical Study Investigating the COX-2/PGE-2/EP-4 Axis.

BACKGROUND CONTEXT: Vertebral endplate defects are often implicated in degenerative disc disorders, yet their connection to patient-reported symptoms remains unclear. COX-2 and PGE-2 are known for their roles in inflammation and pain, with EP-4 receptor involvement in pain signaling. Examining their expression in vertebral endplate tissues may provide insights into pathomechanism of low back pain. PURPOSE: To investigate the association between endplate defects and patient-reported symptoms and to further clarify the role of the COX-2/PGE-2/EP-4 axis in the pathogenesis of chronic low back pain. STUDY DESIGN/SETTING: Retrospective study PATIENT SAMPLE: A total of 71 patients who had undergone single-level L4/5 or L5/S1 modified laminectomy decompression preserving proximal upper laminae and transforaminal lumbar interbody fusion surgery were included in this study, including 18 patients diagnosed with lumbar disc herniation, 19 with lumbar disc herniation accompanied by degenerative lumbar spinal stenosis, and 34 with degenerative spondylolisthesis. OUTCOME MEASURES: Demographic data, Pfirrmann grade, Modic changes, endplate defect score, visual analog scale (VAS) for back and leg pain, and Oswestry Disability Index (ODI) before surgery, 3-month and 6-month follow-up, and the percentage of immune-positive cells (COX-2, PGE-2, and EP-4) in endplate tissue sections. METHODS: Patients were divided into Defect and Non-defect groups according to endplate morphology on lumbar MR. All intraoperative endplate specimens were immediately fixed in 10% formaldehyde, and then embedded in paraffin 3 days later for tissue sections. The outcome measures were compared between the Defect group and Non-defect group. Data were analyzed using independent t-tests and χ² tests. Pearson's rank correlation test was used to assess correlations between patient-reported symptoms and the percentage of immune-positive cells in the groups. Multivariable logistic regression models using the forward stepwise likelihood ratio method were used to identify the factors that were independently associated with endplate defects. RESULTS: The age of Defect group was significantly higher than that of Non-defect group (52.5±7.7 vs. 57.2±9.1. P=0.024). There were no significant differences in gender, diagnosis, BMI, comorbidities, or surgical level between the two groups. Modic changes (Type Ⅱ/Type Ⅲ) were more common in patients of Defect group than Non-defect group (38.5% vs. 11.1%, P<0.001), and so was disc degeneration (Pfirrmann grade Ⅳ/Ⅴ) (69.2% vs. 33.3%, P<0.001). Defect group had significantly higher VAS-Back (6.5±2.0 vs. 4.9±1.6, P<0.001) and ODI scores (62.9±10.7 vs. 45.2±14.8, P<0.001) than Non-defect group, while there was no significant differences between the two groups during the 3 and 6-month follow-up after surgery. Histologically, Defect group was characterized by upregulation of COX-2, PGE-2, and EP-4 in endplate tissue sections. Both in Defect and Non-defect groups, VAS-Back showed moderate positive correlations with the expressions of COX-2 (r=0.643; r=0.558, p both<0.001), PGE-2 (r=0.611; r=0.640, p both<0.001), and EP-4 (r=0.643; r=0.563, p both<0.001). Multivariate regression analyses reveled that percentage of COX-2-positive cells was associated with endplate defects (OR=1.509, 95%CI [1.048∼2.171], P=0.027), as well as percentage of PGE-2-positive (OR=1.291, 95%CI [1.106∼1.508], P=0.001) and EP-4-positive cells (OR=1.284, 95%CI [1.048∼2.171], P=0.003). CONCLUSIONS: Patients with endplate defects had worse quality of life, more severe disc degeneration and Modic changes, and up-regulated COX-2/PGE-2/EP-4 axis expression in cartilage endplates in patients with defected endplates. Inflammatory factors may significantly contribute to the onset and progression of chronic low back pain in patients with endplate defects, consequently impacting patient-reported symptoms.

The association between albumin-corrected calcium and prognosis in patients with cardiac arrest: a retrospective study based on the MIMIC-IV database.

BACKGROUND: Cardiac arrest (CA) is one of the leading causes of death globally, characterized by high incidence and mortality. It is of particular significance to determine the prognosis of patients with CA early and accurately. Therefore, we aim to investigate the correlation between albumin-corrected calcium (ACC) and the prognosis in patients diagnosed with CA. METHODS: We retrospectively collected data from medical information mart for intensive care IV database. Patients were divided into two groups (survival and non-survival groups), according to the 90-day prognosis. In the Restricted cubic spline (RCS) analysis, the cut-off values (8.86 and 10.32) were obtained to categorize patients into three groups: low ACC group (< 8.86), moderate ACC group (8.86-10.32), and high ACC group (> 10.32). The least absolute shrinkage and selection operator with a ten-fold cross-validation regression analysis was performed to identify variables linked to the mortality. The inverse probability treatment weighting (IPTW) was used to address the confounding factors, and a weighted cohort was generated. RCS, Kaplan-Meier curve, and Cox regression analyses were used to explore the relationship between ACC and the mortality. Sensitivity analysis was employed to validate the stability of the results. RESULTS: Cut-off values for ACC of 8.86 and 10.32 were determined. RCS analyses showed that there was an overall non-linear trend relationship between ACC and the risk of 90-day and 360-day mortalities. After IPTW adjustment, compared to the moderate ACC group, the 90-day and 360-day mortalities in the high ACC group were higher (P < 0.05). The Cox analyses before and after IPTW adjustment showed that both low ACC and high ACC group were independent risk factors for 90-day and 360-day all-cause mortality in patients with CA (P < 0.05). The results obtained from sensitivity analyses indicated the stability of the findings. The Kaplan-Meier survival curves indicated that 90- and 360-day cumulative survival rates in the low ACC and high ACC groups were lower than that in the moderate ACC group (χ2 = 11.350, P = 0.003; χ2 = 14.110, P = 0.001). CONCLUSION: Both low ACC (< 8.86) and high ACC groups (> 10.32) were independent risk factors for 90-day and 360-day all-cause mortality in patients with CA (P < 0.05). For those CA patients with high and low ACC, it deserved the attention of clinicians.

Interfacial charge transfer in sheet Ni2P-FePx heterojunction to promote the study of electrocatalytic oxygen evolution.

The substantial expense associated with catalysts significantly hampers the progress of electrolytic water-based hydrogen production technology. There is an urgent need to find non-precious metal catalysts that are both cost-effective and highly efficient. Here, the porous Ni2P-FePx nanomaterials were successfully prepared by hydrothermal method, nickel foam as the base, iron nitrate solution as the caustic agent and iron source, and finally phosphating at low temperature. The obtained porous Ni2P-FePx nanosheets showed excellent catalytic activity under alkaline PH = 14, and an overpotential of merely 241 mV was required to achieve a current density of 50 mA cm-2. The morphology of the nanosheet can still be flawlessly presented on the screen after 50 h of working at high current density.

Low concentrations of TNF-α in vitro transform the phenotype of vascular smooth muscle cells and enhance their survival in a three-dimensional culture system.

BACKGROUND: Vascular smooth muscle cells (VSMCs) are commonly used as seed cells in tissue-engineered vascular constructions. However, their variable phenotypes and difficult to control functions pose challenges. This study aimed to overcome these obstacles using a three-dimensional culture system. METHODS: Calf VSMCs were administered tumor necrosis factor-alpha (TNF-α) before culturing in two- and three-dimensional well plates and polyglycolic acid (PGA) scaffolds, respectively. The phenotypic markers of VSMCs were detected by immunofluorescence staining and western blotting, and the proliferation and migration abilities of VSMCs were detected by CCK-8, EDU, cell counting, scratch, and Transwell assays. RESULTS: TNF-α rapidly decreased the contractile phenotypic markers and elevated the synthetic phenotypic markers of VSMCs, as well as markedly increasing the proliferation and migration ability of VSMCs under two- and three-dimensional culture conditions. CONCLUSIONS: TNF-α can rapidly induce a phenotypic shift in VSMCs and change their viability on PGA scaffolds.

Carrageenan maintains the contractile phenotype of vascular smooth muscle cells by increasing macromolecular crowding in vitro.

BACKGROUND: The contractile phenotype of vascular smooth muscle cells (VSMCs) results in good diastolic and contractile capacities, and its altered function is the main pathophysiological basis for diseases such as hypertension. VSMCs exist as a synthetic phenotype in vitro, making it challenging to maintain a contractile phenotype for research. It is widely recognized that the common medium in vitro is significantly less crowded than in the in vivo environment. Additionally, VSMCs have a heightened sense for detecting changes in medium crowding. However, it is unclear whether macromolecular crowding (MMC) helps maintain the VSMCs contractile phenotype. PURPOSE: This study aimed to explore the phenotypic, behavioral and gene expression changes of VSMCs after increasing the crowding degree by adding carrageenan (CR). METHODS: The degree of medium crowding was examined by a dynamic light scattering assay; VSMCs survival and activity were examined by calcein/PI cell activity and toxicity and CCK-8 assays; VSMCs phenotypes and migration were examined by WB and wound healing assays; and gene expression was examined by transcriptomic analysis and RT-qPCR. RESULTS: Notably, 225 µg/mL CR significantly increased the crowding degree of the medium and did not affect cell survival. Simultaneously, CR significantly promoted the contraction phenotypic marker expression in VSMCs, shortened cell length, decreased cell proliferation, and inhibited cell migration. CR significantly altered gene expression in VSMCs. Specifically, 856 genes were upregulated and 1207 genes were downregulated. These alterations primarily affect the cellular ion channel transport, microtubule movement, respiratory metabolism, amino acid transport, and extracellular matrix synthesis. The upregulated genes were primarily involved in the cytoskeleton and contraction processes of VSMCs, whereas the downregulated genes were mainly involved in extracellular matrix synthesis. CONCLUSIONS: The in vitro study showed that VSMCs can maintain the contractile phenotype by sensing changes in the crowding of the culture environment, which can be maintained by adding CR.

Development of an attenuated potato virus Y mutant carrying multiple mutations in helper-component protease for cross-protection.

Tobacco (Nicotiana tabacum) is one of the major cash crops in China. Potato virus Y (PVY), a representative member of the genus Potyvirus, greatly reduces the quality and yield of tobacco leaves by inducing veinal necrosis. Mild strain-mediated cross-protection is an attractive method of controlling diseases caused by PVY. Currently, there is a lack of effective and stable attenuated PVY mutants. Potyviral helper component-protease (HC-Pro) is a likely target for the development of mild strains. Our previous studies showed that the residues lysine at positions 124 and 182 (K124 and K182) in HC-Pro were involved in PVY virulence, and the conserved KITC motif in HC-Pro was involved in aphid transmission. In this study, to improve the stability of PVY mild strains, K at position 50 (K50) in KITC motif, K124, and K182 were separately substituted with glutamic acid (E), leucine (L), and arginine (R), resulting in a triple-mutant PVY-HCELR. The mutant PVY-HCELR had attenuated virulence and did not induce leaf veinal necrosis symptoms in tobacco plants and could not be transmitted by Myzus persicae. Furthermore, PVY-HCELR mutant was genetically stable after six serial passages, and only caused mild mosaic symptoms in tobacco plants even at 90 days post inoculation. The tobacco plants cross-protected by PVY-HCELR mutant showed high resistance to the wild-type PVY. This study showed that PVY-HCELR mutant was a promising mild mutant for cross-protection to control PVY.

miR-101-3p-mediated role of PDZK1 in hepatocellular carcinoma progression and the underlying PI3K/Akt signaling mechanism.

BACKGROUND: The molecular targets and associated mechanisms of hepatocellular carcinoma (HCC) have been widely studied, but the roles of PDZK1 in HCC are unclear. Therefore, the aim of this study is to explore the role and associated mechanisms of PDZK1 in HCC. RESULTS: It was found that the expression of PDZK1 in HCC tissues was higher than that in paired paracancerous tissues. High expression of PDZK1 was associated with lymph node metastasis, degree of differentiation, and clinical stage. Upregulation of PDZK1 in HCC cells affected their proliferation, migration, invasion, apoptosis, and cell cycle, and also induced PI3K/AKT activation. PDZK1 is a downstream target gene of miR-101-3p. Accordingly, increase in the expression of miR-101-3p reversed the promotive effect of PDZK1 in HCC. Moreover, PDZK1 was found to accelerate cell proliferation and promote the malignant progression of HCC via the PI3K/AKT pathway. CONCLUSION: Our study indicated that the miR-101-3p/PDZK1 axis plays a role in HCC progression and could be beneficial as a novel biomarker and new therapeutic target for HCC treatment.

Seeing Your Stories: Visualization for Narrative Medicine.

Importance: Narrative medicine (NM), in which patient stories play a crucial role in their diagnosis and treatment, can potentially support a more holistic approach to patient care than traditional scientific ones. However, there are some challenges in the implementation of narrative medicine, for example, differences in understanding illnesses between physicians and patients and physicians' increased workloads and overloaded schedules. This paper first presents a review to explore previous visualization research for narrative medicine to bridge the gap between visualization researchers and narrative medicine experts and explore further visualization opportunities. Highlights: The review is conducted from 2 perspectives: (a) the contexts and domains in which visualization has been explored for narrative medicine and (b) the forms and solutions applied in these studies. Four applied domains are defined, including understanding patients from narrative records, medical communication, medical conversation training in education, and psychotherapy and emotional wellness enhancement. Conclusions: A future work framework illustrates some opportunities for future research, including groups of specific directions and future points for the 4 domains and 3 technological exploration opportunities (combination of narrative and medical data visualization, task-audience-based visual storytelling, and user-centered interactive visualization). Specifically, 3 directions of future work in medical communication (asynchronous online physician-patient communication, synchronous face-to-face medical conversation, and medical knowledge dissemination) were concluded.

Object-centered family interactions for young autistic children: a diary study.

Autistic Children often struggle with social interaction and communication, studies have found that many of them prefer to interact with objects than people. However, there is a lack of research exploring the specific characteristics and factors involved in interactions within families with autistic children where objects are the center of the interaction. This paper describes the process and findings of a diary study exploring how young autistic children interact with their families through objects in natural scenarios. A one-week diary study was conducted with six families with young autistic children. Diary videos were recorded onsite and coded later according to a social interaction behavior scheme with corresponding diary entries. Qualitative data analysis was conducted to reveal possible patterns. Results revealed ongoing difficulties in establishing and maintaining family interaction and identified influential factors of object-centered family interaction. The most prevalent pattern observed was parents taking the lead in interactions, followed by the child's confirmation response. Remarkably, daily necessities emerged as potential physical mediums for enhancing family interactions, opening avenues for exploring tangible designs in human-computer interaction. These findings offer valuable implications for future research and the development of innovative designs that promote enriching interactions for autistic children and their families.

Transformation risk and associated survival outcome of marginal zone lymphoma: A nationwide study.

Histological transformation into an aggressive B-cell lymphoma indicates a poor survival outcome for patients with indolent marginal zone lymphoma (MZL), which has been less studied. Large-scale data with long-term follow-up to investigate MZL transformation is limited. Here, by reporting a US-Nationwide cohort of 30,619 MZL patients diagnosed between 2000 and 2019, we found that transformation occurred in 2.08% (N = 624) of MZL cases, with the transformation incidence of 3.1 per 1,000 person-years. Advanced Ann Arbor stage, nodal MZL (NMZL) and splenic MZL (SMZL) were associated with an elevated risk of transformation. Certain subtype-specific characteristics, such as non-gastric extra-nodal MZL (vs. gastric, HR, 1.51, 95%CI 1.13-2.04; p = 0.006), and receiving splenectomy for SMZL (HR, 2.04, 95%CI 1.28-3.26; p = 0.003), also indicated a higher risk of transformation. Besides, transformation independently increased the overall mortality risk (HR, 1.38, 95%CI 1.24-1.53, p < 0.001), especially the higher lymphoma-caused mortality risk (HR, 3.21, 95%CI 2.81-3.67, p < 0.001). Transformation was also associated with a higher percentage of lymphoma-caused deaths. The post-transformation prognostic analyses demonstrated that female gender and age ≥ 65 years independently affected patients' mortalities. These findings, based on the largest cohort to date, contribute to a better understanding of transformed MZL, and provide valuable reference points for guidelines and patient counseling.

Light-Induced Dynamic Manipulation of Liquid Metal Droplets in the Ambient Atmosphere.

Dynamic manipulation of liquid metal (LM) droplets, a material combining metallicity and fluidity, has recently revealed tremendous potential in developing unconstrained microrobots. LM manipulating techniques based on magnetic fields, electric fields, chemical reactions, and ion concentration gradients in liquid environments have advanced considerably, but dynamic manipulation in air remains a challenge. Herein, a photoresponsive pyroelectric superhydrophobic (PPS) platform is proposed for noncontact, flexible, and controllable manipulation in the ambient atmosphere. The PPS can generate additional free charges when illuminated by light, thus generating the driving force to manipulate liquid metal droplets. By using the synergistic effect of dielectrophoretic and electrostatic forces generated under light navigation, liquid metal droplets can achieve a series of complex motion behaviors, such as climbing slopes, going over steps, avoiding obstacles, crossing mazes, etc. We further extend the light control of liquid metal droplets to robots applied in electronic circuits, including circuit switching robots and circuit welding robots. This light strategy for manipulating liquid metal droplets provides insights into the development of intelligent, responsive interfaces and simultaneously provides possibilities for the application of liquid metals.

Functional characterization of terpene synthases SmTPS1 involved in floral scent formation in Salvia miltiorrhiza.

Plants attract beneficial insects and promote pollination by releasing floral scents. Salvia miltiorrhiza, as an insect-pollinated flowering plant, which has been less studied for its floral aroma substances. This study revealed that S. miltiorrhiza flowers produce various volatile terpenoids, including five monoterpenes and ten sesquiterpenes, with the sesquiterpene compound (E)-ß-caryophyllene being the most abundant, accounting for 28.1% of the total volatile terpenoids. Y-tube olfactometer experiments were conducted on the primary pollinator of S. miltiorrhiza, the Apis ceranas. The results indicated that (E)-ß-caryophyllene compound had an attractive effect on the Apis ceranas. By comparing the homologous sequences with the genes of (E)-ß-caryophyllene terpene synthases in other plants, the SmTPS1 gene was selected for further experiment. Subcellular localization experiments showed SmTPS1 localized in the cytoplasm, and its in vitro enzyme assay revealed that it could catalyze FPP into ß-Elemene, (E)-ß-caryophyllene and α-Humulene. Overexpression of SmTPS1 in S. miltiorrhiza resulted in a 5.29-fold increase in gene expression. The GC-MS analysis revealed a significant increase in the concentration of (E)-ß-caryophyllene in the transgenic plants, with levels 2.47-fold higher compared to the empty vector plants. Furthermore, Y-tube olfactometer experiments showed that the transgenic plants were significantly more attractive to Apis ceranas compared to the empty vector plants. Co-expression analysis suggested that four SmMYCs (SmMYC1, SmMYC5, SmMYC10, and SmMYC11) may be involved in the transcriptional regulation of SmTPS1. The yeast one-hybrid screen and the Dual luciferase assay indicated that SmMYC10 positively regulates the expression of SmTPS1. In conclusion, this study lays a foundation for the functional analysis and transcriptional regulation of terpene synthase genes in S. miltiorrhiza.

DNA damage-regulated autophagy modulator 1 prevents glioblastoma cells proliferation by regulating lysosomal function and autophagic flux stability.

Glioblastoma (GBM) is the most aggressive and life-threatening brain tumor, characterized by its highly malignant and recurrent nature. DNA damage-regulated autophagy modulator 1 (DRAM-1) is a p53 target gene encoding a lysosomal protein that induces macro-autophagy and damage-induced programmed cell death in tumor growth. However, the precise mechanisms underlying how DRAM-1 affects tumor cell proliferation through regulation of lysosomal function and autophagic flux stability remain incompletely understood. We found that DRAM-1 expressions were evidently down-regulated in high-grade glioma and recurrent GBM tissues. The upregulation of DRAM-1 could increase mortality of primary cultured GBM cells. TEM analysis revealed an augmented accumulation of aberrant lysosomes in DRAM-1-overexpressing GBM cells. The assay for lysosomal pH and stability also demonstrated decreasing lysosomal membrane permeabilization (LMP) and impaired lysosomal acidity. Further research revealed the detrimental impact of lysosomal dysfunction, which impaired the autophagic flux stability and ultimately led to GBM cell death. Moreover, downregulation of mTOR phosphorylation was observed in GBM cells following upregulation of DRAM-1. In vivo and in vitro experiments additionally illustrated that the mTOR inhibitor rapamycin increased GBM cell mortality and exhibited an enhanced antitumor effect.

The associations between peripheral inflammatory and lipid parameters, white matter hyperintensity, and cognitive function in patients with non-disabling ischemic cerebrovascular events.

BACKGROUND: The global prevalence of VCI has increased steadily in recent years, but diagnostic biomarkers for VCI in patients with non-disabling ischemic cerebrovascular incidents (NICE) remain indefinite. The primary objective of this research was to investigate the relationship between peripheral serological markers, white matter damage, and cognitive function in individuals with NICE. METHODS: We collected clinical data, demographic information, and medical history from 257 patients with NICE. Using the MoCA upon admission, patients were categorized into either normal cognitive function (NCF) or VCI groups. Furthermore, they were classified as having mild white matter hyperintensity (mWMH) or severe WMH based on Fazekas scores. We then compared the levels of serological markers between the cognitive function groups and the WMH groups. RESULTS: Among 257 patients with NICE, 165 were male and 92 were female. Lymphocyte count (OR = 0.448, P < 0.001) and LDL-C/HDL-C (OR = 0.725, P = 0.028) were protective factors for cognitive function in patients with NICE. The sWMH group had a higher age and inflammation markers but a lower MoCA score, and lymphocyte count than the mWMH group. In the mWMH group, lymphocyte count (AUC = 0.765, P < 0.001) and LDL-C/HDL-C (AUC = 0.740, P < 0.001) had an acceptable diagnostic value for the diagnosis of VCI. In the sWMH group, no significant differences were found in serological markers between the NCF and VCI groups. CONCLUSION: Lymphocyte count, LDL-C/HDL-C were independent protective factors for cognitive function in patients with NICE; they can be used as potential biological markers to distinguish VCI in patients with NICE and are applicable to subgroups of patients with mWMH.

Curcumin relieves oxaliplatin-induced neuropathic pain via reducing inflammation and activating antioxidant response.

Oxaliplatin (OXA) has shown high effectiveness in the treatment of cancers, but its anticancer clinical effects often induce neurotoxicity leading to neuropathic pain. Oxidative damage and NLRP3 inflammasome play important roles in neuropathic pain development. Here, neuropathic pain mouse model was constructed by continuous intraperitoneal injection of OXA. OXA administration induced mechanical pain, spontaneous pain, thermal hyperalgesia and motor disability in mice. The spinal cord tissues of OXA mice exhibited the suppressed antioxidative response, the activated NLRP3 inflammasome mediated inflammatory responses, and the increased GSK-3ß activity. Next, we injected curcumin (CUR) intraperitoneally in OXA mice for seven consecutive days. CUR-treated mice showed increased mechanical pain thresholds, reduced number of spontaneous flinches, increased paw withdrawal latency, and restored latency to fall. While in the spinal cord, CUR treatment inhibited the NLRP3 inflammasome mediated inflammatory response, increased Nrf2/GPX4-mediated antioxidant responses, and decreased mitochondrial oxidative generation. Additionally, CUR combined with GSK-3ß through four covalent bonds and reduced GSK-3ß activity. In conclusion, our findings suggest that CUR treatment inhibits GSK-3ß activation, increases Nrf2 mediated antioxidant responses, inhibits oxidative damage and inflammatory reaction, and alleviates OXA-induced neuropathic pain.

Hyperforin ameliorates neuroinflammation and white matter lesions by regulating microglial VEGFR2 /SRC pathway in vascular cognitive impairment mice.

AIM: To explore the neuroprotective potential of hyperforin and elucidate its underlying molecular mechanisms involved in its therapeutic effects against vascular cognitive impairment (VCI). METHODS: The active compounds and possible targets of Hypericum perforatum L. that may be effective against VCI were found by network pharmacology in this research. We utilized bilateral common carotid artery occlusion (BCCAO) surgery to induce a VCI mouse model. Morris water maze (MWM) and Y-maze tests were used to assess VCI mice's cognitive abilities following treatment with hyperforin. To evaluate white matter lesions (WMLs), we utilized Luxol fast blue (LFB) stain and immunofluorescence (IF). Neuroinflammation was assessed using IF, western blot (WB), and enzyme-linked immunosorbent assay (ELISA). The effects of hyperforin on microglia were investigated by subjecting the BV2 microglial cell line to oxygen-glucose deprivation/reperfusion (OGD/R) stimulation. The expressions of VEGFR2 , p-SRC, SRC, VEGFA, and inflammatory markers including IL-10, IL-1ß, TNF-α, and IL-6 were subsequently assessed. RESULTS: The VEGFR2 /SRC signaling pathway is essential for mediating the protective properties of hyperforin against VCI according to network pharmacology analysis. In vivo findings demonstrated that hyperforin effectively improved BCCAO-induced cognitive impairment. Furthermore, staining results showed that hyperforin attenuated WMLs and reduced microglial activation in VCI mice. The hyperforin treatment group's ELISA results revealed a substantial decrease in IL-1ß, IL-6, and TNF-α levels. According to the results of in vitro experiments, hyperforin decreased the release of pro-inflammatory mediators (TNF-α, IL-6, and IL-1ß) and blocked microglial M1-polarization by modulating the VEGFR2 /SRC signaling pathway. CONCLUSION: Hyperforin effectively modulated microglial M1 polarization and neuroinflammation by inhibiting the VEGFR2 /SRC signaling pathways, thereby ameliorating WMLs and cognitive impairment in VCI mice.

Engineering and application of LacI mutants with stringent expressions.

Optimal transcriptional regulatory circuits are expected to exhibit stringent control, maintaining silence in the absence of inducers while exhibiting a broad induction dynamic range upon the addition of effectors. In the Plac /LacI pair, the promoter of the lac operon in Escherichia coli is characterized by its leakiness, attributed to the moderate affinity of LacI for its operator target. In response to this limitation, the LacI regulatory protein underwent engineering to enhance its regulatory properties. The M7 mutant, carrying I79T and N246S mutations, resulted in the lac promoter displaying approximately 95% less leaky expression and a broader induction dynamic range compared to the wild-type LacI. An in-depth analysis of each mutation revealed distinct regulatory profiles. In contrast to the wild-type LacI, the M7 mutant exhibited a tighter binding to the operator sequence, as evidenced by surface plasmon resonance studies. Leveraging the capabilities of the M7 mutant, a high-value sugar biosensor was constructed. This biosensor facilitated the selection of mutant galactosidases with approximately a seven-fold improvement in specific activity for transgalactosylation. Consequently, this advancement enabled enhanced biosynthesis of galacto-oligosaccharides (GOS).

Macromolecular Crowding Enhances Matrix Protein Deposition in Tissue-Engineered Vascular Grafts.

Successful in vitro culture of small-diameter tissue-engineered vascular grafts (TEVGs) requires rapid deposition of biomacromolecules secreted by vascular smooth muscle cells in a polyglycolic acid mesh scaffold's three-dimensional (3D) porous environment. However, common media have lower crowding conditions than in vivo tissue fluids. In addition, during the early stages of construction, most of the biomolecules secreted by the cells into the medium are lost, which negatively affects the TEVG culture process. In this study, we propose the use of macromolecular crowding (MMC) to enhance medium crowding to improve the deposition and self-assembly efficiency of major biomolecules in the early stages of TEVG culture. The addition of carrageenan significantly increased the degree of MMC in the culture medium without affecting cell viability, proliferation, and metabolic activity. Protein analysis demonstrated that the deposition of collagen types I and III and fibronectin increased significantly in the cell layers of two-dimensional and 3D smooth muscle cell cultures after the addition of a MMC agent. Collagen type I in the culture medium decreased significantly compared with that in the medium without a MMC agent. Scanning electron microscopy demonstrated that MMC agents considerably enhanced the formation of matrix protein structures during the early stages of 3D culture. Hence, MMC modifies the crowding degree of the culture medium, resulting in the rapid formation of numerous matrix proteins and fiber structures. Impact Statement Small-diameter tissue-engineered vascular grafts (TEVGs) are one of the most promising means of treating cardiovascular diseases; however, the in vitro construction of TEVGs has some limitations, such as slow deposition of extracellular matrix (ECM), long culture period, and poor mechanical properties. We hypothesized that macromolecular crowding can increase the crowding of the culture medium to construct a more bionic microenvironment, which enhances ECM deposition in the medium to the cell layer and reduces collagen loss, accelerating and enhancing TEVG culture and construction in vitro.