Anti-OX40 Antibody Combined with HBc VLPs Delays Tumor Growth in a Mouse Colon Cancer Model.

Objective: Combination immunotherapy strategies targeting OX40, a co-stimulatory molecule that can enhance antitumor immunity by modulating the proliferation, differentiation, and effector function of tumor-infiltrating T cells, have attracted much attention for their excellent therapeutic effects. In this study, we aimed to evaluate the antitumor efficacy of combined anti-OX40 and hepatitis B core virus-like particles (HBc VLPs) therapy using a mouse colon cancer model. Methods: Humanized B-hOX40 mice were injected subcutaneously with MC38 colon tumor cells and treated with HBc VLPs+anti-hOX40 antibody. Tumor growth was monitored. Flow cytometric analysis was performed to evaluate the populations of T cell subsets in the tumors. Results: The combination of anti-OX40 with HBc VLPs resulted in a significant delay in tumor growth, suggesting that a potent antitumor immunity was induced by the combination therapy. Further studies revealed that HBc VLPs+anti-OX40 treatment induced a significant increase in effector T cells (Teffs) and a significant decrease in regulatory T cells (Tregs) in the tumor microenvironment (TME), which accounted for the synergistic antitumor effect of anti-OX40 in combination with HBc VLPs. Conclusion: Combination therapy of anti-hOX40 and HBc VLPs provides synergistic antitumor activity in colon cancer-bearing mice, which may represent a potential design strategy for cancer immunotherapy.

Altered functional connectivity of brainstem nuclei in new daily persistent headache: Evidence from resting-state functional magnetic resonance imaging.

OBJECTIVES: The new daily persistent headache (NDPH) is a rare primary headache disorder. However, the underlying mechanisms of NDPH remain incompletely understood. This study aims to apply seed-based analysis to explore the functional connectivity (FC) of brainstem nuclei in patients with NDPH using resting-state functional magnetic resonance imaging (MRI). METHODS: The FC analysis from the region of interest (ROI) to whole brain voxels was used to investigate 29 patients with NDPH and 37 well-matched healthy controls (HCs) with 3.0 Tesla MRI. The 76 nuclei in the brainstem atlas were defined as ROIs. Furthermore, we explored the correlations between FC and patients' clinical characteristics and neuropsychological evaluations. RESULTS: Patients with NDPH exhibited reduced FC in multiple brainstem nuclei compared to HCs (including right inferior medullary reticular formation, right mesencephalic reticular formation, bilateral locus coeruleus, bilateral laterodorsal tegmental nucleus-central gray of the rhombencephalon, median raphe, left medial parabrachial nucleus, periaqueductal gray, and bilateral ventral tegmental area-parabrachial pigmented nucleus complex) and increased FC in periaqueductal gray. No significant correlations were found between the FC of these brain regions and clinical characteristics or neuropsychological evaluations after Bonferroni correction (p > 0.00016). CONCLUSIONS: Our results demonstrated that patients with NDPH have abnormal FC of brainstem nuclei involved in the perception and regulation of pain and emotions.

Optimising the manufacturing of a ß-Ti alloy produced via direct energy deposition using small dataset machine learning.

Successful additive manufacturing involves the optimisation of numerous process parameters that significantly influence product quality and manufacturing success. One commonly used criteria based on a collection of parameters is the global energy distribution (GED). This parameter encapsulates the energy input onto the surface of a build, and is a function of the laser power, laser scanning speed and laser spot size. This study uses machine learning to develop a model for predicting manufacturing layer height and grain size based on GED constituent process parameters. For both layer height and grain size, an artificial neural network (ANN) reduced error over the data set compared with multi linear regression. Layer height predictions using ANN achieved an R2 of 0.97 and a root mean square error (RMSE) of 0.03 mm, while grain size predictions resulted in an R2 of 0.85 and an RMSE of 9.68 µm. Grain refinement was observed when reducing laser power and increasing laser scanning speed. This observation was successfully replicated in another α + ß Ti alloy. The findings and developed models show why reproducibility is difficult when solely considering GED, as each of the constituent parameters influence these individual responses to varying magnitudes.

Promoting bond durability by a novel fabricated bioactive dentin adhesive.

OBJECTIVE: To prepare a bioactive dentin adhesive and investigate its effect on promoting bonding durability of dentin. METHODS: The mineralization of the bioactive glass with high phosphorus (10.8 mol% P2O5-54.2 mol% SiO2-35 mol% CaO, named PSC) and its ability to induce type I collagen mineralization were observed by SEM and TEM. The Control-Bond and the bioactive dentin adhesive containing 20 wt% PSC particles (PSC-Bond) were prepared, and their degree of conversion (DC), microtensile bond strength (µTBS), film thickness and mineralization performance were evaluated. To evaluate the bonding durability, dentin bonding samples were prepared by Control-Bond and PSC-Bond, and mineralizated in simulated body fluid for 24 h, 3 months, and 6 months. Then, the long-term bond strength and microleakage at the adhesive interface of dentin bonding samples were evaluated by microtensile testing and semiquantitative ELIASA respectively. RESULTS: The PSC showed superior mineralization at 24 h and induced type I collagen mineralization to some extent under weakly alkaline conditions. For PSC-Bond, DC was 62.65 ± 1.20%, µTBS was 39.25 ± 4.24 MPa and film thickness was 17.00 ± 2.61 µm. PSC-Bond also formed hydroxyapatite and maintained good mineralization at the bonding interface. At 24 h, no significant differences in µTBS and interface microleakage were observed between the Control-Bond and PSC-Bond groups. After 6 months of aging, the µTBS was significantly higher and the interface microleakage was significantly lower of PSC-Bond group than those of Control-Bond group. SIGNIFICANCE: PSC-Bond maintained bond strength stability and reduced interface microleakage to some extent, possibly reducing the occurrence of secondary caries, while maintaining long-term effectiveness of adhesive restorations.

ACOT7 promotes retinoblastoma resistance to vincristine by regulating fatty acid metabolism reprogramming.

The rate of vincristine (VCR) resistance in the treatment of retinoblastoma (RB) is relatively high, and the exact role and mechanism of autophagy and fatty acid (FA) metabolism in RB are still unknown. The aim of this study was to elucidate the molecular mechanism by which acyl-CoA thioesterase 7 (ACOT7) regulates FA metabolism and autophagy, which may lead to potential therapeutic strategies for RB. In the present study, the relationship between FA metabolism and cellular drug sensitivity was evaluated through ACOT7 overexpression or inhibition tests in RB-resistant cells. The lipase inhibitor orlistat and the autophagy inhibitor CQ were used to determine the effects of ACOT7 on FA metabolism, autophagy, and cellular drug sensitivity, as well as the therapeutic value of ACOT7 targeting. The results showed that ACOT7 was upregulated in VCR-resistant RB cells, significantly enhancing cell resistance and indicating that ACOT7 may serve as a biomarker for VCR resistance in RB cells. Knockdown of ACOT7 inhibited FA metabolism and reduced cell viability in VCR-resistant RB cells. The effect of ACOT7 overexpression was opposite to that of ACOT7 knockdown, and ACOT7 overexpression promoted autophagy in VCR-resistant RB cells. After treatment with orlistat or CQ, FA metabolism in VCR-resistant RB cells decreased, cell viability and autophagy were inhibited, EMT was inhibited, and the sensitivity of RB cells to VCR was increased. In conclusion, ACOT7 knockdown can mediate FA metabolism to inhibit autophagy and the migration of RB cells, thereby improving the sensitivity of RB cells to VCR.

Revealing the Heterogeneous Bubble Nucleation at Individual Silica Nanoparticles.

Deep understanding of the bubble nucleation process is universally important in systems, from chemical engineering to materials. However, due to its nanoscale and transient nature, effective probing of nucleation behavior with a high spatiotemporal resolution is prohibitively challenging. We previously reported the measurement of a single nanobubble nucleation at a nanoparticle using scanning electrochemical cell microscopy, where the bubble nucleation and formation were inferred from the voltammetric responses. Here, we continue the study of heterogeneous bubble nucleation at interfaces by regulating the local nanostructures using silica nanoparticles with a distinct surface morphology. It is demonstrated that, compared to the smooth spherical silica nanoparticles, the raspberry-like nanoparticles can further significantly reduce the nucleation energy barrier, with a critical peak current about 23% of the bare carbon surfaces. This study advances our understanding of how surface nanostructures direct the heterogeneous nucleation process and may offer a new strategy for surface engineering in gas involved energy conversion systems.

3D bioprinting bioglass to construct vascularized full-thickness skin substitutes for wound healing.

Constructing three-dimensional (3D) bioprinted skin tissues that accurately replicate the mechanical properties of native skin and provide adequate oxygen and nutrient support remains a formidable challenge. In this study, we incorporated phosphosilicate calcium bioglasses (PSCs), a type of bioactive glass (BG), into the bioinks used for 3D bioprinting. The resulting bioink exhibited mechanical properties and biocompatibility that closely resembled those of natural skin. Utilizing 3D bioprinting technology, we successfully fabricated full-thickness skin substitutes, which underwent comprehensive evaluation to assess their regenerative potential in treating full-thickness skin injuries in rats. Remarkably, the skin substitutes loaded with PSCs exhibited exceptional angiogenic activity, as evidenced by the upregulation of angiogenesis-related genes in vitro and the observation of enhanced vascularization in wound tissue sections in vivo. These findings conclusively demonstrated the outstanding efficacy of PSCs in promoting angiogenesis and facilitating the repair of full-thickness skin wounds. The insights garnered from this study provide a valuable reference strategy for the development of skin tissue grafts with potent angiogenesis-inducing capabilities.

Mapping brain functional networks topological characteristics in new daily persistent headache: a magnetoencephalography study.

BACKGROUND: The brain functional network topology in new daily persistent headache (NDPH) is not well understood. In this study, we aim to assess the cortical functional network topological characteristics of NDPH using non-invasive neural signal recordings. METHODS: Resting-state magnetoencephalography (MEG) was used to measure power fluctuations in neuronal oscillations from distributed cortical parcels in 35 patients with NDPH and 40 healthy controls (HCs). Their structural data were collected by 3T MRI. Functional connectivity (FC) of neural networks from 1 to 80 Hz frequency ranges was analyzed with topographic patterns and calculated network topological parameters with graph theory. RESULTS: In the delta (1-4 Hz) and beta (13-30 Hz) bands, the lateral occipital cortex and superior frontal gyrus FC were increased in NDPH groups compared to HCs. Graph theory analysis revealed that the NDPH had significantly increased global efficiency in the delta band and decreased nodal clustering coefficient (left medial orbitofrontal cortex) in the theta (4-8 Hz) band. The clinical characteristics had a significant correlation with network topological parameters. Age at onset of patients showed a positive correlation with global efficiency in the delta band. The degree of depression of patients showed a negative correlation with the nodal clustering coefficient (left medial orbitofrontal cortex) in the theta band. CONCLUSION: The FC and topology of NDPH in brain networks may be altered, potentially leading to cortical hyperexcitability. Moreover, medial orbitofrontal cortex is involved in the pathophysiological mechanism of depression in patients with NDPH. Increased FC observed in the lateral occipital cortex and superior frontal gyrus during resting-state MEG could serve as one of the imaging characteristics associated with NDPH.

Effects of Conservative Oxygen Therapy versus Conventional Oxygen Therapy on the Mortality in ICU Patients: A Meta-Analysis.

Objective: To compare the effects of conservative oxygen therapy and conventional oxygen therapy on the mortality of critically ill patients in ICU. Methods: Searching for randomized controlled clinical trials (RCT) on the effect of conservative oxygen therapy and conventional oxygen therapy on the mortality of critically ill patients in computer databases, including PubMed, Embase, Cochrane Library, CNKI, VIP, and Wanfang, with postdate before August 2022. We have two researchers evaluating the quality of the literature included and extracting data as per the inclusion and exclusion criteria and then analyzed it with RevMan 5.4 statistical software. Primary outcome included short-term mortality (28-day mortality or ICU mortality); secondary outcome included 90-day mortality, ICU length of stay, hospital length of stay, incidence of new organ dysfunction in ICU, incidence of new infection in ICU, and incidence of ICUAW. Results: A total of 5779 subjects were included in 10 articles, including 2886 in the conservative oxygen therapy group and 2893 in the conventional oxygen therapy group. The meta-analysis showed that conservative oxygen therapy had an advantage over conventional oxygen therapy in terms of short-term mortality (P=0.03). Subgroup analysis based on different conservative oxygen targets showed that this advantage was statistically significant when the target is set above 90% (RR = 0.76, 95% CI = 0.62∼0.94, P=0.01), while there was no significant difference between conservative oxygen therapy and conventional oxygen therapy when the target is set below 90% (RR = 0.95, 95% CI = 0.79∼1.16, P=0.63). In addition, in terms of the incidence of new infections in the ICU (P=0.03) and the incidence of ICUAW (P=0.03), conservative oxygen therapy also had advantages over conventional oxygen therapy, and the difference was statistically significant. But in terms of 90-day mortality (P=0.61), ICU length of stay (P=0.96), hospital length of stay (P=0.47), and incidence of new organ dysfunction in ICU (P=0.61), there was no significant difference between conservative oxygen therapy and conventional oxygen therapy. Conclusion: Compared with conventional oxygen therapy, conservative oxygen therapy can reduce the short-term mortality of severe patients, especially when the conservative oxygen therapy target is set above 90%. And it can also reduce the incidence of ICU new infections and ICUAW, while having no effect on 90-day mortality, ICU length of stay, and hospital length of stay.

A pH-neutral bioactive glass empowered gelatin-chitosan-sodium phytate composite scaffold for skull defect repair.

The ideal skull defect repairing material should have good biocompatibility and mechanical properties, and contribute to osteogenesis. In this study, we designed and fabricated biodegradable, bioactive and mechanically robust porous scaffolds composed completely of biological materials. We used a gelatin-chitosan blend as the matrix, sodium phytate instead of toxic glutaraldehyde for cross-linking, and the pH-neutral bioactive glass (PSC) to improve biological activity and mechanical properties. The chitosan-gelatin-30%PSC/sodium phytate composite scaffold avoided the problems of high toxicity in conventional cross-linking agents with glutaraldehyde, the poor mechanical support of the pure chitosan or gelatin scaffold, and the mismatch of the degradation rate with bone repair, becoming a promising new candidate for skull defect repair.

Micro-structural white matter abnormalities in new daily persistent headache: a DTI study using TBSS analysis.

BACKGROUND: New daily persistent headache (NDPH) is a rare primary headache disorder characterized by daily and persistent sudden onset headaches. The pathogenesis of NDPH remains unclear, and there are few white matter imaging studies related to NDPH. The purpose of this study was to investigate the micro-structural abnormalities of white matter in NDPH and provided insights into the pathogenesis of this disease based on tract-based spatial statistics (TBSS). METHODS: Twenty-one patients with NDPH and 25 healthy controls (HCs) were included in this study. T1 structural and diffusion magnetic resonance imaging (MRI) were acquired from all participants. Differences in the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) between patients with NDPH and HCs were investigated using TBSS analysis. RESULTS: Significantly decreased FA, increased MD and RD were found in patients with NDPH compared to HCs. White matter regions overlaid with decreased FA, increased MD and RD were found in 16 white matter tracts from the Johns Hopkins University ICBM-DTI-81 White-Matter Atlas and Johns Hopkins University White-Matter Tractography Atlas. Specifically, these white matter regions included the right anterior thalamic radiation (ATR), body of the corpus callosum (BCC), bilateral cingulum, left hippocampal cingulum (CGH), left corticospinal tract (CST), forceps major, fornix, left inferior fronto-occipital fasciculus (IFOF), bilateral inferior longitudinal fasciculus (ILF), left posterior limb of the internal capsule (PLIC), right retrolenticular part of the internal capsule (RPIC), splenium of the corpus callosum (SCC), right superior longitudinal fasciculus (SLF) and left uncinate fasciculus (UF). After Bonferroni correction, there were no correlations between the FA, MD, AD and RD values and the clinical characteristics of patients with NDPH (p > 0.05/96). CONCLUSION: The results of our research indicated that patients with NDPH might have widespread abnormalities in the white matter of the brain.

Reinforcing Hydrogel by Nonsolvent-Quenching-Facilitated In Situ Nanofibrosis.

Nanofibrous hydrogels are pervasive in load-bearing soft tissues, which are believed to be key to their extraordinary mechanical properties. Enlighted by this phenomenon, a novel reinforcing strategy for polymeric hydrogels is proposed, where polymer segments in the hydrogels are induced to form nanofibers in situ by bolstering their controllable aggregation at the nanoscale level. Poly(vinyl alcohol) hydrogels are chosen to demonstrate the virtue of this strategy. A nonsolvent-quenching step is introduced into the conventional solvent-exchange hydrogel preparation approach, which readily promotes the formation of nanofibrous hydrogels in the following solvent-tempering process. The resultant nanofibrous hydrogels demonstrate significantly improved mechanical properties and swelling resistance, compared to the conventional solvent-exchange hydrogels with identical compositions. This work validates the hypothesis that bundling polymer chains to form nanofibers can lead to nanofibrous hydrogels with remarkably enhanced mechanical performances, which may open a new horizon for single-component hydrogel reinforcement.

Reconfigurable Neuromorphic Computing: Materials, Devices, and Integration.

Neuromorphic computing has been attracting ever-increasing attention due to superior energy efficiency, with great promise to promote the next wave of artificial general intelligence in the post-Moore era. Current approaches are, however, broadly designed for stationary and unitary assignments, thus encountering reluctant interconnections, power consumption, and data-intensive computing in that domain. Reconfigurable neuromorphic computing, an on-demand paradigm inspired by the inherent programmability of brain, can maximally reallocate finite resources to perform the proliferation of reproducibly brain-inspired functions, highlighting a disruptive framework for bridging the gap between different primitives. Although relevant research has flourished in diverse materials and devices with novel mechanisms and architectures, a precise overview remains blank and urgently desirable. Herein, the recent strides along this pursuit are systematically reviewed from material, device, and integration perspectives. At the material and device level, one comprehensively conclude the dominant mechanisms for reconfigurability, categorized into ion migration, carrier migration, phase transition, spintronics, and photonics. Integration-level developments for reconfigurable neuromorphic computing are also exhibited. Finally, a perspective on the future challenges for reconfigurable neuromorphic computing is discussed, definitely expanding its horizon for scientific communities.

Enlarged perivascular spaces in patients with migraine: a case-control study based on 3T MRI.

OBJECTIVE: To explore whether MRI-visible enlarged perivascular spaces (EPVS) are associated with migraine and may serve as a predictor of migraine. Then further explore its correlation with migraine chronification. METHODS: A total of 231 participants (healthy control [HC] = 57, episodic migraine [EM] = 59, chronic migraine [CM] = 115) were included in this case-control study. A 3T MRI device and the validated visual rating scale were used to assess the grades of EPVS in centrum semiovale (CSO), midbrain (MB), and basal ganglia (BG). Comparisons between the two groups were made using the chi-square or Fisher's exact tests to initially determine whether high-grade EPVS were associated with migraine and migraine chronification. A multivariate logistic regression model was constructed to further investigate the role of high-grade EPVS in migraine. RESULTS: The prevalence of high-grade EPVS in CSO and MB were significantly higher in patients with migraine than in HCs (CSO: 64.94% vs. 42.11%, P = 0.002; MB: 55.75% vs. 29.82%, P = 0.001). Subgroup analysis showed no statistical difference between patients with EM and CM (CSO: 69.94% vs. 62.61%, P = 0.368; MB: 50.85% vs. 58.26%, P = 0.351). Individuals with high-grade EPVS in CSO (odds ratio [OR]: 2.324; 95% confidence interval [CI]: 1.136-4.754; P = 0.021) and MB (OR: 3.261; 95% CI: 1.534-6.935; P = 0.002) were more likely to suffer from migraine. INTERPRETATION: This case-control study showed that high-grade EPVS in CSO and MB in clinical practice with the underlying mechanism of dysfunction of the glymphatic system could be a predictor of migraine, but no significant correlation had been found with migraine chronification.

Circ-MALAT1 accelerates cell proliferation and epithelial mesenchymal transformation of colorectal cancer through regulating miR-506-3p/KAT6B axis.

Colorectal cancer (CRC) is a prevalent malignant tumor of the digestive tract. Circular RNAs may play important roles in the progression of CRC. In this study, we investigated the roles and mechanisms of action of circ-MALAT1 in CRC. Gene expression and protein abundance were determined using qRT-PCR and western blot, respectively. Cell proliferation and migration were assessed by MTT, clone formation, and wound-healing assays. The interactions among the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (circ-MALAT1), miR-506-3p, and lysine acetyltransferase 6B (KAT6B) were predicted using the StarBase software and confirmed by the luciferase activity assay. Circ-MALAT1 and KAT6B were upregulated, while miR-506-3p was downregulated in CRC cells. We validated that knocking down of circ-MALAT1 suppressed proliferation, migration, and epithelial-mesenchymal transition (EMT) of CRC cells, and these effects were abolished by miR-506-3p downregulation or KAT6B sufficiency. Our study suggests that circ-MALAT1 could sponge miR-506-3p to regulate the expression of KAT6B. Moreover, KAT6B sufficiency could neutralize miR-506-3p-dependent growth arrest, migration, and EMT. Circ-MALAT1 promotes cell proliferation, migration, and EMT of CRC cells via the miR-506-3p/KAT6B axis, thereby acting as a novel potential therapeutic target for the treatment of colorectal cancer.

[Correlation between Serum Interleukin-33, ß2-Microglobulin Levels and DS Stage in Patients with Multiple Myeloma].

OBJECTIVE: To investigate the correlation between serum interleukin-33 (IL-33), ß2microglobulin (ß2-MG) levels and Durie-Salmon (DS) stage in patients with multiple myeloma (MM). METHODS: 100 MM patients admitted to the First Affiliated Hospital of Fujian Medical University from March 2019 to January 2021 were selected and divided into stage I, stage II and stage III groups according to the DS staging system. A baseline data questionnaire of patients was designed, then the relevant baseline data and laboratory test results of patients were recorded. The levels of serum IL-33 and ß2-MG of all patients were detected, and the correlation between serum IL-33, ß2-MG levels and DS stage of MM patients was analyzed. RESULTS: Among the 100 patients with MM, there were 32 cases in stage I, 39 cases in stage II and 29 cases in stage III. The levels of serum CRP and ß2-MG of patients in stage III were significantly higher than those of patients in stage I and II, and the levels of serum CRP and ß2-MG of patients in stage II were significantly higher than those of patients in stage I, the differences were statistically significant (P <0.05). The level of serum IL-33 of patients in stage III was significantly lower than that of patients in stage I and II, and the level of serum IL-33 of patients in stage II was significantly lower than that of patients in stage I, the differences were statistically significant (P <0.05). There was no statistical significant difference in other data between groups (P >0.05). Kendall's tau-b correlation analysis showed that the levels of serum CRP and ß2-MG were positively correlated with DS stage in MM patients (r =0.534, 0.776), the level of serum IL-33 was negatively correlated with DS stage in MM patients (r =-0.759). Ordered logistic regression analysis and forest plot showed that the low level of serum IL-33 and the high level of ß2-MG were the influencing factors of high DS stage in MM patients (P <0.05 ). CONCLUSION: DS stage of MM patients is closely related to the levels of serum IL-33 and ß2-MG, that is, the lower the serum IL-33 level and the higher the ß2-MG level, and the higher the DS stage of MM patients.

3D bioprinting microgels to construct implantable vascular tissue.

Engineered implantable functional thick tissues require hierarchical vasculatures within cell-laden hydrogel that can mechanically withstand the shear stress from perfusion and facilitate angiogenesis for nutrient transfer. Yet current extrusion-based 3D printing strategies are unable to recapitulate hierarchical networks, highlighting the need for bioinks with tunable properties. Here, we introduce an approach whereby crosslinkable microgels enhance mechanical stability and induce spontaneous microvascular networks comprised of human umbilical cord vein endothelial cells (HUVECs) in a soft gelatin methacryoyl (GelMA)-based bioink. Furthermore, we successfully implanted the 3D printed multi-branched tissue, being connected from the rat carotid artery to the jugular vein direct surgical anastomosis. The work represents a significant step toward in the field of large vascularized tissue fabrication and may have implications for the treatment of organ failure in the future.

Babao Dan decreases hepatocarcinogenesis by inhibiting hepatic progenitor cells malignant transformation via down-regulating toll-like receptor 4.

Background: Babao Dan (BBD) is a traditional Chinese medicine that has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the effect of BBD on the incidence of diethylnitrosamine (DEN)-initiated hepatocellular carcinoma formation in rats and explored its possible mechanism. Methods: To verify this hypothesis, BBD was administrated to rats at a dose of 0.5g/kg body weight per two days from the 9th to 12th week in HCC-induced by DEN. Liver injury biomarkers and hepatic inflammatory parameters were evaluated by histopathology as well as serum and hepatic content analysis. We applied immunohistochemical analysis to investigate the expression of CK-19 and SOX-9 in liver tissues. The expression of TLR4 was determined by immunohistochemical, RT-PCR, and western blot analysis. Furthermore, we also detected the efficacy of BBD against primary HPCs neoplastic transformation induced by LPS. Results: We observed that DEN could induce hepatocarcinogenesis, and BBD could obviously decrease the incidence. The biochemical and histopathological examination results confirmed that BBD could protect against liver injury and decrease inflammatory infiltration. Immunohistochemistry staining results showed that BBD could effectively inhibit the ductal reaction and the expression of TLR4. The results showed that BBD-serumcould obviously inhibit primary HPCs neoplastic transformation induced by regulating the TLR4/Ras/ERK signaling pathway. Conclusion: In summary, our results indicate that BBD has potential applications in the prevention and treatment of HCC, which may be related to its effect on hepatic progenitor cells malignant transformation via inhibiting the TLR4/Ras/ERK signaling pathway.

Mapping the aberrant brain functional connectivity in new daily persistent headache: a resting-state functional magnetic resonance imaging study.

BACKGROUND AND PURPOSE: The pathogenesis of new daily persistent headache (NDPH) is not fully understood. We aim to map aberrant functional connectivity (FC) in patients with NDPH using resting-state functional magnetic resonance imaging (MRI). METHODS: Brain structural and functional MRI data were acquired from 29 patients with NDPH and 37 well-matched healthy controls (HCs) in this cross-sectional study. Region of interest (ROI) based analysis was used to compare FC between patients and HCs, with 116 brain regions in the automated anatomical labeling (AAL) atlas were defined as seeds. The correlations between aberrant FC and patients' clinical characteristics, and neuropsychological evaluation were also investigated. RESULTS: Compared with HCs, patients with NDPH showed increased FC in the left inferior occipital gyrus, right thalamus and decreased FC in right lingual gyrus, left superior occipital gyrus, right middle occipital gyrus, left inferior occipital gyrus, right inferior occipital gyrus, right fusiform gyrus, left postcentral gyrus, right postcentral gyrus, right thalamus and right superior temporal gyrus. There were no correlation between FC of these brain regions and clinical characteristics, neuropsychological evaluation after Bonferroni correction (p > 0.05/266). CONCLUSIONS: Patients with NDPH showed aberrant FC in multiple brain regions involved in perception and regulation of emotion and pain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05334927.

Brain structure and cortical activity changes of new daily persistent headache: multimodal evidence from MEG/sMRI.

BACKGROUND: New daily persistent headache (NDPH) is a rare but debilitating primary headache disorder that poses a significant burden on individuals and society. Despite its clinical importance, the underlying pathophysiological mechanisms of NDPH remain unclear. In this study, we aimed to investigate the brain structural changes and neural activity patterns in patients with NDPH using multimodal brain imaging analysis of structural magnetic resonance imaging (sMRI) combined with magnetoencephalography (MEG). METHODS: Twenty-eight patients with NDPH and 37 healthy controls (HCs) were recruited for this study, and their structural and resting-state data were collected by 3.0 Tesla MRI and MEG. We analyzed the brain morphology using voxel-based morphometry and source-based morphometry. In each brain region, MEG sensor signals from 1 to 200 Hz were analyzed using an adapted version of Welch's method. MEG source localization was conducted using the dynamic statistical parametric mapping, and the difference of source distribution between patients with NDPH and HCs was examined. RESULTS: Our results revealed significant differences in the regional grey matter volume, cortical thickness, and cortical surface area between the two groups. Specifically, compared with HCs, patients with NDPH showed a significant decrease in cortical thickness of the left rostral cortex in the middle frontal gyrus, decreased cortical surface area of the left fusiform gyrus, decreased grey matter volume of the left superior frontal gyrus and the left middle frontal gyrus, and increased grey matter volume of the left calcarine. Furthermore, the power of the whole brain, bilateral frontal lobes, and right temporal lobe in the NDPH group were higher than that in HCs in the ripple frequency band (80-200 Hz). Functional and structural analysis suggested that there were structural changes and abnormal high frequency cortical activity in both frontal and temporal lobes in patients with NDPH. CONCLUSION: Our findings indicated that patients with NDPH have abnormalities in brain morphology, such as cortical area, cortical thickness, and grey matter volume, accompanied by abnormal cortical neural activity. Brain structural changes in the frontotemporal cortex and abnormalities in cortical ripple activity may be involved in the pathogenesis of NDPH.