Carfilzomib activates ER stress and JNK/p38 MAPK signaling to promote apoptosis in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers in the world, which is frequently diagnosed at a late stage. HCC patients have a poor prognosis due to the lack of an efficacious therapeutic strategy. Approved drug repurposing is a way for accelerating drug discovery and can significantly reduce the cost of drug development. Carfilzomib (CFZ) is a second-generation proteasome inhibitor, which is highly efficacious against multiple myeloma and has been reported to possess potential antitumor activities against multiple cancers. However, the underlying mechanism of CFZ on HCC is still unclear. Here, we show that CFZ inhibits the proliferation of HCC cells through cell cycle arrest at the G2/M phase and suppresses the migration and invasion of HCC cells by inhibiting epithelial-mesenchymal transition. We also find that CFZ promotes reactive oxygen species production to induce endoplasmic reticulum (ER) stress and activate JNK/p38 MAPK signaling in HCC cells, thus inducing cell death in HCC cells. Moreover, CFZ significantly inhibits HCC cell growth in a xenograft mouse model. Collectively, our study elucidates that CFZ impairs mitochondrial function and activates ER stress and JNK/p38 MAPK signaling, thus inhibiting HCC cell and tumor growth. This indicates that CFZ has the potential as a therapeutic drug for HCC.

Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization.

OBJECTIVES: Acute lung injury (ALI) is a highly inflammatory condition with the involvement of M1 alveolar macrophages (AMs) polarization, eventually leading to the development of non-cardiogenic edema in alveolar and interstitial regions, accompanied by persistent hypoxemia. Given the significant mortality rate associated with ALI, it is imperative to investigate the underlying mechanisms of this condition so as to identify potential therapeutic targets. The therapeutic effects of the inhibition of bromodomain containing protein 4 (BRD4), an epigenetic reader, has been proven with high efficacy in ameliorating various inflammatory diseases through mediating immune cell activation. However, little is known about the therapeutic potential of BRD4 degradation in acute lung injury. METHODS: This study aimed to assess the protective efficacy of ARV-825, a novel BRD4-targeted proteolysis targeting chimera (PROTAC), against ALI through histopathological examination in lung tissues and biochemical analysis in bronchoalveolar lavage fluid (BALF). Additionally, the underlying mechanism by which BRD4 regulated M1 AMs was elucidated by using CUT & Tag assay. RESULTS: In this study, we found the upregulation of BRD4 in a lipopolysaccharide (LPS)-induced ALI model. Furthermore, we observed that intraperitoneal administration of ARV-825, significantly alleviated LPS-induced pulmonary pathological changes and inflammatory responses. These effects were accompanied by the suppression of M1 AMs. In addition, our findings revealed that the administration of ARV-825 effectively suppressed M1 AMs by inhibiting the expression of IRF7, a crucial transcriptional factor involved in M1 macrophages. CONCLUSION: Our study suggested that targeting BRD4 using ARV-825 is a potential therapeutic approach for ALI.

Research on Delamination Damage Quantification Detection of CFRP Bending Plate Based on Lamb Wave Mode Control.

The carbon-fiber-reinforced polymer (CFRP) bending structure is widely used in aviation. The emergence and spread of delamination damage will decrease the safety of in-service bending structures. Lamb waves can effectively identify delamination damage as a high-damage-sensitivity detection tool. For this present study, the signal difference coefficient (SDC) was introduced to quantify delamination damage and evaluate the sensitivity of A0-mode and S0-mode Lamb waves to delamination damage. The simulation results show that compared with the S0-mode Lamb wave, the A0-mode Lamb wave exhibits higher delamination damage sensitivity. The delamination damage can be quantified based on the strong correlation between the SDC and the delamination damage size. The control effect of the linear array PZT phase time-delay method on the Lamb wave mode was investigated by simulation. The phase time-delay method realizes the generation of a single-mode Lamb wave, which can separately excite the A0-mode and S0-mode Lamb wave to identify delamination damage of different sizes. The A0-mode Lamb wave was excited by the developed one-dimensional miniaturized linear comb transducer (LCT), which was used to conduct the detection experiment on the CFRP bending plate with delamination damage sizes of Φ6.0 mm, Φ10.0 mm, and Φ15.0 mm. The experimental results verify the correctness of the simulation. According to the Hermite interpolation results of the finite-element simulation data, the relationship between the delamination damage size and the SDC was fitted by the Gaussian function and Rational function, which can accurately quantify the delamination damage. The absolute error of the delamination damage quantification with Gaussian and Rational fitting expression does not exceed 0.8 mm and 0.7 mm, and the percentage error is not more than 8% and 7%. The detection and signal processing methods employed in the present research are easy to operate and implement, and accurate delamination damage quantification results have been obtained.

The common and distinct brain basis associated with adult and adolescent risk-taking behavior: Evidence from the neuroimaging meta-analysis.

Risk-taking is a common, complex, and multidimensional behavior construct that has significant implications for human health and well-being. Previous research has identified the neural mechanisms underlying risk-taking behavior in both adolescents and adults, yet the differences between adolescents' and adults' risk-taking in the brain remain elusive. This study firstly employs a comprehensive meta-analysis approach that includes 73 adult and 20 adolescent whole-brain experiments, incorporating observations from 1986 adults and 789 adolescents obtained from online databases, including Web of Science, PubMed, ScienceDirect, Google Scholar and Neurosynth. It then combines functional decoding methods to identify common and distinct brain regions and corresponding psychological processes associated with risk-taking behavior in these two cohorts. The results indicated that the neural bases underlying risk-taking behavior in both age groups are situated within the cognitive control, reward, and sensory networks. Subsequent contrast analysis revealed that adolescents and adults risk-taking engaged frontal pole within the fronto-parietal control network (FPN), but the former recruited more ventrolateral area and the latter recruited more dorsolateral area. Moreover, adolescents' risk-taking evoked brain area activity within the ventral attention network (VAN) and the default mode network (DMN) compared with adults, consistent with the functional decoding analyses. These findings provide new insights into the similarities and disparities of risk-taking neural substrates underlying different age cohorts, supporting future neuroimaging research on the dynamic changes of risk-taking.

Lifibrate attenuates blood-brain barrier damage following ischemic stroke via the MLCK/p-MLC/ZO-1 axis.

Dysfunction of tight junction proteins-associated damage to the blood-brain barrier (BBB) plays an important role in the pathogenesis of ischemic stroke. Lifibrate, an inhibitor of cholinephosphotransferase (CPT), has been used as an agent for serum lipid lowering. However, the protective effects of Lifibrate in ischemic stroke and the underlying mechanism have not been clearly elucidated. Here, we employed an in vivo mice model of MCAO and an OGD/R model in vitro. In the mice models, neurological deficit scores and infarct volume were assessed. Evans Blue solution was used to detect the BBB permeability. The TEER was examined to determine brain endothelial monolayer permeability. Here, we found that Lifibrate improved neurological dysfunction in stroke. Additionally, increased BBB permeability during stroke was significantly ameliorated by Lifibrate. Correspondingly, the reduced expression of the tight junction protein ZO-1 was restored by Lifibrate at both the mRNA and protein levels. Using an in vitro model, we found that Lifibrate ameliorated OGD/R-induced injury in human bEnd.3 brain microvascular endothelial cells by increasing cell viability but reducing the release of LDH. Importantly, Lifibrate suppressed the increase in endothelial monolayer permeability and the reduction in TEER induced by OGD/R via the rescue of ZO-1 expression. Mechanistically, Lifibrate blocked activation of the MLCK/ p-MLC signaling pathway in OGD/R-stimulated bEnd.3 cells. In contrast, overexpression of MLCK abolished the protective effects of Lifibrate in endothelial monolayer permeability, TEER, as well as the expression of ZO-1. Our results provide a basis for further investigation into the neuroprotective mechanism of Lifibrate during stroke.

Case report: A novel variant (H49N) in Myelin Protein Zero gene is responsible for a patient with Charcot-Marie-Tooth disease.

This report presents a case of Charcot-Marie-Tooth dominant intermediate D (CMTDID), a rare subtype of Charcot-Marie-Tooth disease, in a 52 years-old male patient. The patient exhibited mobility impairment, foot abnormalities (pes cavus), and calf muscle atrophy. Whole exome sequencing and Sanger sequencing suggested that a novel variant (NM_000530.8, c.145C>A/p.His49Asn) of MPZ may be the genetic lesion in the patient. The bioinformatic program predicted that the new variant (p.His49Asn), located at an evolutionarily conserved site of MPZ, was neutral. Our study expands the variant spectrum of MPZ and the number of identified CMTDID patients, contributing to a better understanding of the relationship between MPZ and CMTDID.

Intrinsic Defect-Driven Synergistic Synaptic Heterostructures for Gate-Free Neuromorphic Phototransistors.

The optoelectronic synaptic devices based on two-dimensional (2D) materials offer great advances for future neuromorphic visual systems with dramatically improved integration density and power efficiency. The effective charge capture and retention are considered as one vital prerequisite to realizing the synaptic memory function. However, the current 2D synaptic devices are predominantly relied on materials with artificially-engineered defects or intricate gate-controlled architectures to realize the charge trapping process. These approaches, unfortunately, suffer from the degradation of pristine materials, rapid device failure, and unnecessary complication of device structures. To address these challenges, an innovative gate-free heterostructure paradigm is introduced herein. The heterostructure presents a distinctive dome-like morphology wherein a defect-rich Fe7 S8 core is enveloped snugly by a curved MoS2 dome shell (Fe7 S8 @MoS2 ), allowing the realization of effective photocarrier trapping through the intrinsic defects in the adjacent Fe7 S8 core. The resultant neuromorphic devices exhibit remarkable light-tunable synaptic behaviors with memory time up to ≈800 s under single optical pulse, thus demonstrating great advances in simulating visual recognition system with significantly improved image recognition efficiency. The emergence of such heterostructures foreshadows a promising trajectory for underpinning future synaptic devices, catalyzing the realization of high-efficiency and intricate visual processing applications.

Signal amplification strategy of DNA self-assembled biosensor and typical applications in pathogenic microorganism detection.

Biosensors have emerged as ideal analytical devices for various bio-applications owing to their low cost, convenience, and portability, which offer great potential for improving global healthcare. DNA self-assembly techniques have been enriched with the development of innovative amplification strategies, such as dispersion-to-localization of catalytic hairpin assembly, and dumbbell hybridization chain reaction, which hold great significance for building biosensors capable of realizing sensitive, rapid and multiplexed detection of pathogenic microorganisms. Here, focusing primarily on the signal amplification strategies based on DNA self-assembly, we concisely summarized the strengths and weaknesses of diverse isothermal nucleic acid amplification techniques. Subsequently, both single-layer and cascade amplification strategies based on traditional catalytic hairpin assembly and hybridization chain reaction were critically explored. Furthermore, a comprehensive overview of the recent advances in DNA self-assembled biosensors for the detection of pathogenic microorganisms is presented to summarize methods for biorecognition and signal amplification. Finally, a brief discussion is provided about the current challenges and future directions of DNA self-assembled biosensors.

A rare case of a neonate with fallot-type absent pulmonary valve and occlusion of the left main bronchus.

Fallot-type absent pulmonary valve is a rare and complex congenital heart disease. Repair surgery for this condition during the neonatal period has a mortality rate of over 50%. We reported a neonate with Fallot-type absent pulmonary valve and occlusion of the left main bronchus. The patient's pulmonary artery had unusual anatomy of a type that has not previously been reported. This case report outlines a successful treatment strategy for patients with complex congenital heart disease and airway occlusion during the neonatal period and the effect of these unusual anatomical conditions on postoperative outcomes.

Clinical manifestations and EEG findings in children infected with COVID-19 and exhibiting neurological symptoms.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection has many neurological manifestations, and its effects on the nervous system are increasingly recognized. There has been no systematic analysis of electroencephalography (EEG) characteristics in children exhibiting neurological symptoms of Coronavirus disease 2019 (COVID-19). The primary aim of this study was to describe the EEG characteristics caused by COVID-19 infection in children who were showing neurological symptoms and to assess the relationship between COVID-19-related EEG changes and clinical features in these children. METHOD: This study included 125 pediatric patients infected with SARS-CoV2 and showing neurological symptoms, and their continuous EEG was recorded. In addition, the demographic and clinical characteristics of these patients were analyzed and the correlation between the two was investigated. RESULTS: Abnormal EEG findings were detected in 31.20% (N = 39) of the patients. Abnormal discharges (43.59%) were the most common EEG abnormalities, followed by background abnormalities (41.03%). The proportion of patients diagnosed with febrile seizure was higher in the normal EEG group than in the abnormal EEG group (P = 0.002), while the opposite was true for epilepsy and encephalitis/encephalopathy (P = 0.016 and P = 0.003, respectively). The independent associated factors of abnormal EEG were age and total length of stay (P < 0.001 and P = 0.003, respectively). Non-specific EEG abnormalities were found in COVID-19-related encephalitis/encephalopathy. CONCLUSION: Our study corroborated that a small group of pediatric patients infected by COVID-19 and showing neurological symptoms may exhibit abnormal EEG. This study could help improve the understanding of clinical and EEG characteristics in children with COVID-19 and inform triage policies in other hospitals during the COVID-19 pandemic.

Abnormal characteristic static and dynamic functional network connectivity in idiopathic normal pressure hydrocephalus.

AIMS: Idiopathic Normal pressure hydrocephalus (iNPH) is a neurodegenerative disease characterized by gait disturbance, dementia, and urinary dysfunction. The neural network mechanisms underlying this phenomenon is currently unknown. METHODS: To investigate the resting-state functional connectivity (rs-FC) abnormalities of iNPH-related brain connectivity from static and dynamic perspectives and the correlation of these abnormalities with clinical symptoms before and 3-month after shunt. We investigated both static and dynamic functional network connectivity (sFNC and dFNC, respectively) in 33 iNPH patients and 23 healthy controls (HCs). RESULTS: The sFNC and dFNC of networks were generally decreased in iNPH patients. The reduction in sFNC within the default mode network (DMN) and between the somatomotor network (SMN) and visual network (VN) were related to symptoms. The temporal properties of dFNC and its temporal variability in state-4 were sensitive to the identification of iNPH and were correlated with symptoms. The temporal variability in the dorsal attention network (DAN) increased, and the average instantaneous FC was altered among networks in iNPH. These features were partially associated with clinical symptoms. CONCLUSION: The dFNC may be a more sensitive biomarker for altered network function in iNPH, providing us with extra information on the mechanisms of iNPH.

Long-lasting humoral and cellular memory immunity to vaccinia virus Tiantan provides pre-existing immunity against mpox virus in Chinese population.

Investigating immune memory to vaccinia virus and pre-existing immunity to mpox virus (MPXV) among the population is crucial for the global response to this ongoing mpox epidemic. Blood was sampled from vaccinees inoculated with vaccinia virus Tiantan (VTT) strain born before 1981 and unvaccinated control subjects born since 1982. After at least 40 years of the inoculation, 60% or 5% VTT vaccinees possess neutralizing antibodies (NAbs) to VTT or MPXV, with at least 50% having T cell memory to VTT protein antigens. Notably, 46.7% vaccinees show pre-existing T cell responses to MPXV. Broad pre-existing CD8+ T cell reactivities to MPXV are detected not only against conserved epitopes but also against variant epitopes between VTT and MPXV. Persistent NAbs and T cell memory to VTT among vaccinees, along with pre-existing T cells to MPXV among both vaccinees and the unvaccinated population, indicate a particular immune barrier to mpox.

Association of the LPA gene polymorphisms with coronary artery disease risk in the Xinjiang population of China: A case-control study.

Lipoprotein(a) is a well-known independent risk factor for coronary artery disease (CAD) and primarily determined by variation in the LPA gene coding for the apolipoprotein(a) moiety. Our study purpose was to evaluate the association between the human LPA gene polymorphisms and CAD in Han and Uyghur populations in Xinjiang, China. A case-control study was conducted with 831 Han people (392 CAD patients and 439 control subjects) and 829 Uygur people (513 CAD patients and 316 control subjects). All participants were genotyped for the same 3 single nucleotide polymorphisms (rs1801693, rs6923877, and rs9364559) of the LPA gene by a Real-time PCR instrument. In CAD patients, the levels of lipoprotein(a) were significantly higher in the Han population with the C/C genotype at the rs1801693 (P = .018) and the A/A genotype at the rs9364559 (P = .029) than in the Uyghur population. The polymorphisms rs1801693, rs6923877, and rs9364559 were found to be associated with CAD in the Han population. For men, the distribution of rs1801693 in genotypes, alleles and recessive model (CC vs CT + TT) showed a significant difference (all P < .05), and the difference in recessive model was retained after adjustment for covariates (odds ratio [OR]: 0.557, 95% confidence interval [CI]: 0.355-0.874, P = .011). But the distribution of rs6923877 in genotypes and dominant model (GG vs AG + AA) showed a significant difference (both P < .05) in both men and women, and the difference was kept in dominant model after adjustment (OR: 1.473, 95% CI:1.009-2.148, P = .045). For women, a significant difference was found in the distribution of rs9364559 in the alleles and dominant model (AA vs AG + GG) (for alleles: P = .021, for dominant model: P = .025, OR: 0.560, 95% CI:0.350-0.898, P = .016) after adjustment. Polymorphisms rs1801693, rs6923877, and rs9364559 of the LPA gene are associated with CAD in the Han population in Xinjiang Uygur Autonomous Region of China.

Effects of Apple Polyphenols and Taurine on Growth Performance, Tissue Morphology, and Lipid and Glucose Metabolism in Rice Field Eel (Monopterus albus) Fed High Oxidized Fish Oil.

The aim of this trial was to investigate the effects of apple polyphenols (AP) and taurine (TA) on the growth performance, tissue morphology, and lipid and glucose metabolism in rice field eel fed diets with high oxidized fish oil (OFO). A 10-week feeding experiment was conducted using juveniles (initial body weight 16.66 ± 0.02 g) fed five different diets. Three diets were formulated with various levels of OFO at 9.5, 600, and 800 meq·kg-1 and named as Control, POV600, and POV800 diet, respectively. The other two diets were POV600 and POV800 supplemented with 0.5% AP and 0.2% TA, respectively. Compared to the Control group, only the eels fed POV800 exhibited an increase in weight gain and specific growth rate along with a reduction in feed conversion ratio. AP and TA did not affect growth performance; juveniles fed AP, however, showed a decrease in liver weight. Both POV600 and POV800 decreased nuclei number and increased vacuoles size in the liver. POV800 damaged the intestinal structure integrity and reduced goblet cells number. AP repaired the liver damage on nuclei number and vacuoles size in fish fed with POV600 diet, while TA mitigated intestinal histopathological damage on intact structure and goblet cells number. The mRNA expression level of liver ampkα in fish fed AP was upregulated, while dietary TA upregulated the mRNA expression levels of liver ampkα and accα. In the muscle, POV600 downregulated mRNA expression levels of accα, cpt1, and lipin, whereas POV800 upregulated mRNA expression levels of accα, pparα, and lipin. Dietary AP and TA could counteract the effects of POV600 and POV800 diet on muscle lipid metabolism. Both POV600 and POV800 diets upregulated mRNA expression levels of liver pck1 and gsk3α. AP and TA both downregulated mRNA expression level of liver pck1, while only TA downregulated the expression of liver gsk3α. AP increased the mRNA expression level of gsk3α in muscle. In summary, inclusion of AP and TA did not affect growth performance but showed a potential to alleviate liver or intestinal damages induced by a high OFO diet. Dietary AP and TA were also found to regulate mRNA expression of genes related to lipid and glucose metabolism.

Immunogenicity and Safety of a SARS-CoV-2 Inactivated Vaccine KCONVAC in Chinese Children: Randomized, Double-blind, Placebo-controlled Phase 1 and 2 Trials.

BACKGROUND: It is important to extend the indication of severe acute respiratory syndrome coronavirus 2 vaccine to children to improve the vaccine intake rate and reduce infection in this population. METHODS: In 2 phase 1 and phase 2 randomized, double-blind and placebo-controlled trials, 84 and 480 Chinese healthy children 3 to 17 years old were enrolled, respectively, and randomized in 3:1 ratio to receive 2 doses of a severe acute respiratory syndrome coronavirus 2 inactivated vaccine, KCONVAC or placebo. The 2 doses were given 28 days apart. Adverse events (AEs) were recorded through Day 28 after each dosing. Live virus neutralizing antibody and receptor binding domain antibody (RBD-IgG) were tested before vaccination and after the second dose. RESULTS: Two doses of the vaccine, KCONVAC, elicited geometric mean titers of 142-150 for neutralizing antibody and 4154-4253 for RBD-IgG 28 days after the second dose. Seroconversion rates were 100% after 2 doses for both antibodies in both trials. The predominant AEs were injection-site pain, cough and fever. Most AEs were grade 1 or 2 in intensity. Five participants reported 6 vaccination-unrelated serious AEs in the phase 2 trial. CONCLUSIONS: Two doses of this study vaccine, KCONVAC, were well tolerated and immunogenic in children 3 to 17 years of age.

Platelet-Based Nanoparticles with Stimuli-Responsive for Anti-Tumor Therapy.

In addition to hemostasis and coagulation, years of studies have proved that platelets are involved in the whole process of tumor progression, including tumor invasion, intravasation, extravasation, and so on. It means that this property of platelets can be used in anti-tumor therapy. However, traditional platelet-based antitumor drugs often cause autologous platelet damage due to lack of targeting, resulting in serious side effects. Therefore, the researchers designed a variety of anti-tumor drug delivery systems based on platelets by targeting platelets or platelet membrane coating. The drug delivery systems have special response modes, which is crucial in the design of nanoparticles. These modes enhance the targeting and improve the anti-tumor effect. Here, we present a review of recent discoveries in the field of the crosstalk between platelets and tumors and the progress of platelet-based anti-tumor nanoparticles.

Sleep deprivation attenuates neural responses to outcomes from risky decision-making.

Sleep loss impacts a broad range of brain and cognitive functions. However, how sleep deprivation affects risky decision-making remains inconclusive. This study used functional MRI to examine the impact of one night of total sleep deprivation (TSD) on risky decision-making behavior and the underlying brain responses in healthy adults. In this study, we analyzed data from N = 56 participants in a strictly controlled 5-day and 4-night in-laboratory study using a modified Balloon Analogue Risk Task. Participants completed two scan sessions in counter-balanced order, including one scan during rested wakefulness (RW) and another scan after one night of TSD. Results showed no differences in participants' risk-taking propensity and risk-induced activation between RW and TSD. However, participants showed significantly reduced neural activity in the anterior cingulate cortex and bilateral insula for loss outcomes, and in bilateral putamen for win outcomes during TSD compared with RW. Moreover, risk-induced activation in the insula negatively correlated with participants' risk-taking propensity during RW, while no such correlations were observed after TSD. These findings suggest that sleep loss may impact risky decision-making by attenuating neural responses to decision outcomes and impairing brain-behavior associations.

A prognostic nomogram that includes MPV in esophageal squamous cell carcinoma.

BACKGROUND: Mean platelet volume (MPV), as a marker of platelet activity, has been shown to be an efficient prognostic biomarker in several types of cancer. Using MPV, this study aimed to create and validate a prognostic nomogram to the overall survival in esophageal squamous cell carcinoma (ESCC) patients. METHODS: The nomogram was constructed and tested using data from a retrospective study of 1893 patients who were randomly assigned to the training and testing cohorts with a 7:3 randomization. In order to screen out the optimal predictors for overall survival (OS), we conducted the LASSO-cox regression, univariate, and multivariate cox regression analyses. Subsequently, the predictive accuracy of the nomogram was validated in both the training and the testing cohorts. Finally, decision curve analysis (DCA) was used to confirm clinical validity. RESULTS: Age, MPV, nerve invasion, T stage, and N stage were found as independent prognostic variables for OS and were further developed into a nomogram. The nomogram's prediction accuracy for 1-, 3-, and 5-year OS was 0.736, 0.749, 0.774, and 0.724, 0.719, 0.704 in the training and testing cohorts, respectively. Furthermore, DCA results indicated that nomograms outperformed the AJCC 8th and conventional T, N staging systems in both the training and testing cohorts. CONCLUSIONS: The nomogram, in conjunction with MPV and standard clinicopathological markers, could improve the accuracy of prediction of OS in ESCC patients.