Heart Murmur Classification Using a Capsule Neural Network.

The healthcare industry has made significant progress in the diagnosis of heart conditions due to the use of intelligent detection systems such as electrocardiograms, cardiac ultrasounds, and abnormal sound diagnostics that use artificial intelligence (AI) technology, such as convolutional neural networks (CNNs). Over the past few decades, methods for automated segmentation and classification of heart sounds have been widely studied. In many cases, both experimental and clinical data require electrocardiography (ECG)-labeled phonocardiograms (PCGs) or several feature extraction techniques from the mel-scale frequency cepstral coefficient (MFCC) spectrum of heart sounds to achieve better identification results with AI methods. Without good feature extraction techniques, the CNN may face challenges in classifying the MFCC spectrum of heart sounds. To overcome these limitations, we propose a capsule neural network (CapsNet), which can utilize iterative dynamic routing methods to obtain good combinations for layers in the translational equivariance of MFCC spectrum features, thereby improving the prediction accuracy of heart murmur classification. The 2016 PhysioNet heart sound database was used for training and validating the prediction performance of CapsNet and other CNNs. Then, we collected our own dataset of clinical auscultation scenarios for fine-tuning hyperparameters and testing results. CapsNet demonstrated its feasibility by achieving validation accuracies of 90.29% and 91.67% on the test dataset.

Systematic Myostatin Expression Screening Platform for Identification and Evaluation of Myogenesis-Related Phytogenic in Pigs.

Skeletal muscle growth in livestock impacts meat quantity and quality. Concerns arise because certain feed additives, like beta-agonists, may affect food safety. Skeletal muscle is a specialized tissue consisting of nondividing and multinucleated muscle fibers. Myostatin (MSTN), a protein specific to skeletal muscle, is secreted and functions as a negative regulator of muscle mass by inhibiting the proliferation and differentiation of myoblasts. To enhance livestock muscle growth, phytogenic feed additives could be an alternative as they inhibit MSTN activity. The objective of this study was to establish a systematic screening platform using MSTN activity to evaluate phytogenics, providing scientific evidence of their assessment and potency. In this study, we established a screening platform to monitor myostatin promoter activity in rat L8 myoblasts. Extract of Glycyrrhiza uralensis (GUE), an oriental herbal medicine, was identified through this screening platform, and the active fractions of GUE were identified using a process-scale liquid column chromatography system. For in vivo study, GUE as a feed additive was investigated in growth-finishing pigs. The results showed that GUE significantly increased body weight, carcass weight, and lean content in pigs. Microbiota analysis indicated that GUE did not affect the composition of gut microbiota in pigs. In summary, this established rodent myoblast screening platform was used to identify a myogenesis-related phytogenic, GUE, and further demonstrated that the active fractions and compounds inhibited MSTN expression. These findings suggest a novel application for GUE in growth performance enhancement through modulation of MSTN expression. Moreover, this well-established screening platform holds significant potential for identifying and assessing a diverse range of phytogenics that contribute to the process of myogenesis.

CrowbarLimbs: A Fatigue-Reducing Virtual Reality Text Entry Metaphor.

Text entry remains challenging in virtual environments, where users may quickly experience physical fatigue in some body parts using existing methods. In this paper, we propose "CrowbarLimbs," a novel virtual reality (VR) text entry metaphor with two deformable extended virtual limbs. By using a crowbar-like metaphor and placing the virtual keyboard at a user-preferred location based on the user's physical stature, our method can assist the user in placing their hands and arms in a comfortable posture, thus effectively reducing the physical fatigue in various body parts, such as hands, wrists, and elbows. In an initial user study, we found that CrowbarLimbs achieved text entry speed, accuracy, and system usability comparable to those of previous VR typing methods. To investigate the proposed metaphor in more depth, we further conducted two additional user studies to explore the ergonomically user-friendly shapes of CrowbarLimbs and virtual keyboard locations. The experimental results indicate that the shapes of CrowbarLimbs have significant effects on the fatigue ratings in various body parts and text entry speed. Furthermore, placing the virtual keyboard near the user and at half their height can lead to a satisfactory text entry rate of 28.37 words per minute.

Adsorption and purification of biogas inside graphitic nanopores: molecular dynamics simulation approach.

Biogas is one of the most common sources of biomass energy. Due to the associated environmental pollution and costs, desulfurization, and purification are the most important challenges of biogas power generation. Using all-atom molecular dynamics (MD), we systematically simulated the isothermal adsorption behavior of biogas (comprising CH4, CO2, H2O, H2S, and H2) in graphite (Gr) slit nanopores. The impact of slit width, system temperature, and moisture content on the adsorption energy, adsorption ratio, and diffusion coefficient of biogas molecules was investigated. Simulation results revealed that due to strong interactions between graphite and H2S, graphite slits of width d = 48 ~ 80 Å displayed significant selective adsorption of H2S molecules. At temperatures between 300 and 500 K, Gr slits can effectively separate H2S in biogas. Moreover, as the moisture content of biogas (vol%) increases from 0 to 20%, the formation and interactions of hydrogen bonds between water molecules create H2O films accumulating on the Gr surface and taking up the adsorption sites, which reduces the amount of hydrogen sulfide that can be adsorbed. Our findings provide important insights into the material design for biogas purification. A schematic representation of molecular interactions between adsorbates and the wall for biogas mixtures (comprising CH4, CO2, H2O, H2S, and H2) inside graphitic nanopores.

Frequency-domain analysis of transient visual evoked potentials in schizophrenia.

PURPOSE: Frequency-domain measures were applied to characterize neural deficits in individuals with schizophrenia using transient visual evoked potentials (tVEP). These measures were compared with conventional time-domain measures to elucidate underlying neurophysiological mechanisms and examine the value of frequency analysis. METHODS: Four frequency bands of activity identified in previous work were explored with respect to magnitude (spectral power), timing (phase), a combined measure, magnitude-squared coherence (MSC), and compared to amplitudes and times of prominent deflections in the response. RESULTS: Band 2 power/MSC (14-28 Hz) captured the major deflections in the waveform and its power predicted N75-P100 amplitude for patients and controls. Band 3 power/MSC (30-40 Hz) correlated highly with the earliest deflection (P60-N75), reflecting input to primary visual cortex (V1) and produced the largest magnitude effect. Phase of the 24th harmonic component predicted P100 peak time for patients and controls and yielded the largest group difference. Cluster analyses including time- and frequency-domain measures identified subgroups of patients with differential neurophysiological effects. A small but significant difference in visual acuity was found between groups that appears to be neurally based: Acuity (range 0.63-1.6) was not correlated with any tVEP measures in controls nor with input timing to V1 (P60 peak time) in patients, but was correlated with later tVEP measures in patients. All but two of the patients were on antipsychotic medication: Medication level (chlorpromazine equivalents) was correlated negatively with tVEP time measures and positively with certain magnitude measures yielding responses similar to controls at high levels. CONCLUSIONS: Overall, frequency-domain measures were shown to be objective and recommended as an alternative to conventional, subjective time-domain measures for analyzing tVEPs and in distinguishing between groups (patients vs. controls and patient subgroups). The findings implicated a loss of excitatory input to V1 in schizophrenia. Acuity as measured in the current study reflected disease status, and medication level was associated with improved tVEP responses. These novel tVEP techniques may be useful in revealing neurophysiological processes affected in schizophrenia and as a clinical tool.

Granulocytic MDSC with Deficient CCR5 Alleviates Lipogenesis and Inflammation in Nonalcoholic Fatty Liver Disease.

C-C chemokine receptor type 5 (CCR5) positively contributes to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a common metabolic liver disease associated with chronic inflammation. CCR5 signaling also facilitates the immunosuppressive activity of a group of immature myeloid cells known as granulocytic myeloid-derived suppressor cells (g-MDSCs). While both hepatocyte and g-MDSC express CCR5, how CCR5 coordinates these two distinct cell types in the hepatic microenvironment remains largely unknown. Here, we used in vivo and ex vivo approaches to define the molecular details of how CCR5 mediates the crosstalk between hepatocytes and g-MDSCs in a mouse model of NAFLD. Global CCR5-deficient mice exhibited more severe steatosis, increased hepatic gene expression of lipogenesis, and exacerbated liver damage in diet-induced obesity. Either NAFLD or CCR5-deficiency per se is causative for the increase of g-MDSCs. Purified g-MDSCs have a higher survival rate in the fatty liver microenvironment, and blockade of CCR5 significantly decreases g-MDSCs' expression of anti-inflammatory factors. On the other hand, the null of CCR5 signaling increases hepatocytes' expression of lipogenic genes in the NAFLD microenvironment. Most importantly, inhibiting g-MDSCs' CCR5 signaling in the fatty liver microenvironment dramatically reduces STAT3 signaling, lipogenic, and pro-inflammatory gene expression in primary hepatocytes. Adoptive cell transfer experiments further demonstrate that CCR5-deficient g-MDSCs mitigate hepatic lipogenic gene expression without facilitating pro-inflammatory cytokine production and liver damage in NAFLD mice. These results suggest that targeting g-MDSCs' CCR5 signaling might serve as a potential therapeutic strategy for NAFLD.

CCAAT/Enhancer-Binding Protein Delta Regulates Glioblastoma Survival through Catalase-Mediated Hydrogen Peroxide Clearance.

It has long been documented that cancer cells show increased and persistent oxidative stress due to increased reactive oxygen species (ROS), which is necessary for their increased proliferative rate. Due to the high levels of ROS, cancer cells also stimulate the antioxidant system, which includes the enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), to eliminate ROS. However, overexpressed antioxidant enzymes often lead to drug resistance and therapeutic failure. Glioblastoma (GBM) is the most aggressive brain tumor and has the poorest prognosis. The transcription factor CCAAT/enhancer-binding protein delta (CEBPD) is highly expressed in GBM and correlates with drug resistance, prompting us to elucidate its role in GBM cell survival. In this study, we first demonstrated that loss of CEBPD significantly inhibited GBM cell viability and increased cell apoptosis. Furthermore, the expression of CAT was attenuated through promoter regulation following CEBPD knockdown, accelerating intracellular hydrogen peroxide (H2O2) accumulation. In addition, mitochondrial function was impaired in CEBPD knockdown cells. Together, we revealed the mechanism by which CEBPD-mediated CAT expression regulates H2O2 clearance for GBM cell survival.

Identification of Crucial Amino Acids in Begomovirus C4 Proteins Involved in the Modulation of the Severity of Leaf Curling Symptoms.

Begomoviruses frequently inflict upward or downward leaf curling symptoms on infected plants, leading to severe economic damages. Knowledge of the underlying mechanism controlling the leaf curling severity may facilitate the development of alternative disease management strategies. In this study, through genomic recombination between Ageratum yellow vein virus Nan-Tou strain (AYVV-NT) and Tomato leaf curl virus Tai-Chung Strain (TLCV-TC), which caused upward and downward leaf curling on Nicotiana benthamiana, respectively, it was found that the coding region of C4 protein might be involved in the determination of leaf curling directions. Sequence comparison and mutational analysis revealed that the cysteine and glycine at position 8 and 14 of AYVV-TC C4 protein, respectively, are involved in the modulation of leaf curling symptoms. Cross-protection assays further demonstrated that N. benthamiana inoculated with AYVV-carrying mutations of the aforementioned amino acids exhibited attenuated leaf curling symptoms under the challenge of wild-type AYVV-NT. Together, these findings revealed a new function of begomovirus C4 proteins involved in the modulation of leaf curling severity during symptom formation and suggested potential applications for managing viral diseases through manipulating the symptoms.

The Effect of University Students' Emotional Intelligence, Learning Motivation and Self-Efficacy on Their Academic Achievement-Online English Courses.

The COVID-19 pandemic has had a significant impact on education worldwide. The disease first hit China and numerous Chinese cities then started to conduct online courses. Therefore, this study aims to explore the effect of the Shanghai students' emotional intelligence, learning motivation, and self-efficacy on their academic achievement when they participated in online English classes during the latter phase of the pandemic in China. Furthermore, the research also examines whether the students' emotional intelligence can influence their academic achievement through the mediation effect of their learning motivation and self-efficacy. Social Cognitive Theory (SCT) and the social cognitive Expectancy-Value Model were employed to build the research framework, and the method of structural equation modeling (SEM) was utilized to conduct the model verification. Ten universities in Shanghai, China were selected for sampling. In total, 450 students were surveyed of which 404 questionnaires were valid. The results show that the students' emotional intelligence did not directly affect their academic achievement. Nevertheless, the students' emotional intelligence had a positive effect on their learning motivation and self-efficacy. In addition, mediation analysis showed that the relation between emotional intelligence and academic achievement was sequentially mediated by learning motivation and self-efficacy.

Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation.

BACKGROUND: Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. METHODS: RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo. RESULTS: Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid ß-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ. CONCLUSION: Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM.

The Role of Aldehyde-Functionalized Crosslinkers on the Property of Chitosan Hydrogels.

Chitosan has been utilized as a popular biopolymer to fabricate hydrogels for biomedical applications. However, chitosan hydrogels are generally too brittle to mimic the deformability of the extracellular matrix in many tissues and organs. In particular, the role of the varied crosslinkers in determining the elasticity of chitosan hydrogels is lack of discussion. Here, three aldehyde-functionalized crosslinkers (i.e., aldehyde-modified poly(xylitol sebacate)-co-poly(ethylene glycol) (APP), glutaraldehyde (GA), and polydextran aldehyde (PDA)) are used to react with quaternized chitosan (QCS) through imine bonds to form hydrogels. The microstructures, mechanical performances, and cytocompatibility of the three hydrogels are systematically investigated. The APP/QCS hydrogels presented the best compressive and stretch properties among the three hydrogels. The mechanical property and antibacterial activity of APP/QCS hydrogels can be further modulated using varied QCS amounts, where more QCS contributed higher stiffness and stretchability as well as better bacterial inhibition to the APP/QCS hydrogels. Taken together, it is demonstrated that the inherent elastomeric characteristic of APP crosslinker provides the desirable elasticity and stretchability to QCS hydrogels compared to the other aldehyde-functionalized crosslinkers of GA and PDA. This strategy of using multivalent elastomeric crosslinkers to fabricate deformable chitosan hydrogels can expand the use of chitosan hydrogels in tissue engineering applications.

Correlation between neutrophil-to-lymphocyte ratio and postoperative mortality in elderly patients with hip fracture: a meta-analysis.

INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) is a crucial prognosis predictor following several major operations. However, the association between NLR and the outcome after hip fracture surgery is unclear. In this meta-analysis, we investigated the correlation between NLR and postoperative mortality in geriatric patients following hip surgery. METHOD: PubMed, Embase, Cochrane library, and Google Scholar were searched for studies up to June 2021 reporting the correlation between NLR and postoperative mortality in elderly patients undergoing surgery for hip fracture. Data from studies reporting the mean of NLR and its 95% confidence interval (CI) were pooled. Both long-term (≥ 1 year) and short-term (≤ 30 days) mortality rates were included for analysis. RESULT: Eight retrospective studies comprising a total of 1563 patients were included. Both preoperative and postoperative NLRs (mean difference [MD]: 2.75, 95% CI: 0.23-5.27; P = 0.03 and MD: 2.36, 95% CI: 0.51-4.21; P = 0.01, respectively) were significantly higher in the long-term mortality group than in the long-term survival group. However, no significant differences in NLR were noted between the short-term mortality and survival groups (MD: - 1.02, 95% CI: - 3.98 to 1.93; P = 0.5). CONCLUSION: Higher preoperative and postoperative NLRs were correlated with a higher risk of long-term mortality following surgery for hip fracture in the geriatric population, suggesting the prognostic value of NLR for long-term survival. Further studies with well-controlled confounders are warranted to clarify the predictive value of NLR in clinical practice in geriatric patients with hip fracture.

Approaching precision public health by automated syndromic surveillance in communities.

BACKGROUND: Sentinel physician surveillance in communities has played an important role in detecting early signs of epidemics. The traditional approach is to let the primary care physician voluntarily and actively report diseases to the health department on a weekly basis. However, this is labor-intensive work, and the spatio-temporal resolution of the surveillance data is not precise at all. In this study, we built up a clinic-based enhanced sentinel surveillance system named "Sentinel plus" which was designed for sentinel clinics and community hospitals to monitor 23 kinds of syndromic groups in Taipei City, Taiwan. The definitions of those syndromic groups were based on ICD-10 diagnoses from physicians. METHODS: Daily ICD-10 counts of two syndromic groups including ILI and EV-like syndromes in Taipei City were extracted from Sentinel plus. A negative binomial regression model was used to couple with lag structure functions to examine the short-term association between ICD counts and meteorological variables. After fitting the negative binomial regression model, residuals were further rescaled to Pearson residuals. We then monitored these daily standardized Pearson residuals for any aberrations from July 2018 to October 2019. RESULTS: The results showed that daily average temperature was significantly negatively associated with numbers of ILI syndromes. The ozone and PM2.5 concentrations were significantly positively associated with ILI syndromes. In addition, daily minimum temperature, and the ozone and PM2.5 concentrations were significantly negatively associated with the EV-like syndromes. The aberrational signals detected from clinics for ILI and EV-like syndromes were earlier than the epidemic period based on outpatient surveillance defined by the Taiwan CDC. CONCLUSIONS: This system not only provides warning signals to the local health department for managing the risks but also reminds medical practitioners to be vigilant toward susceptible patients. The near real-time surveillance can help decision makers evaluate their policy on a timely basis.

Capture of acidic gas molecules in metallic nanopillar array surfaces.

To effectively capture the acidic fluid molecules in industrial exhaust, this study employed molecular dynamics to simulate the dynamic adsorption behavior of a mixture of carbon monoxide (CO), carbon dioxide (CO2), hydrogen sulfide (H2S), and water (H2O) molecules in gold (Au) nanoslits. We systematically examined the self-diffusion coefficient (DZ), average adsorption energy (Ea,av), and static adsorption amount (Nsa) of individual ingredients and a mixture of the adsorbates under various temperatures (T), concentrations (c), and array slit widths (d). The simulation results indicate that Au(110) has better capture capabilities with regard to H2O and H2S, followed by CO2 and then finally CO. Among the various slit structures, the design of array structures with slit widths 8.15 × 5.76 Å (case C) resulted in the highest average adsorption energy and static adsorption amount for all of the adsorbates. This is due to the fact that an appropriate slit width can increase the self-diffusion coefficient of the gas molecule and provide more stable adsorption sites to capture the adsorbates. Compared to the smooth surface structure, the nanopillar array structures significantly increased the self-diffusion coefficients and the adsorption energy of specific molecules. The comprehensive molecular model is helpful to predict atomistic-level adsorption behaviors for acidic gas molecules.

Correlation between the expression of cancer stem cell marker BMI1 and glioma prognosis.

B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) appears to be essential for promoting certain types of cancer, and its inhibition effectively reduced the stemness of cancer cells. Therefore, this study aimed to investigate the potential role of BMI1 in glioma. To this end, we first investigated BMI1 expression in brain tumors using microarray datasets in ONCOMINE, which indicated that BMI1 levels were not commonly increased in clinical brain tumors. Moreover, survival plots in PROGgeneV2 also showed that BMI1 expression was not significantly associated with reduced survival in glioma patients. Interestingly, stressful serum deprivation and anchorage independence growth conditions led to an increased BMI1 expression in glioma cells. A stress-responsive pathway, HDAC/Sp1, was further identified to regulate BMI1 expression. The HDAC inhibitor vorinostat (SAHA) prevented Sp1 binding to the BMI1 promoter, leading to a decreased expression of BMI1 and attenuating tumor growth of TMZ-resistant glioma xenografts. Importantly, we further performed survival analysis using PROGgeneV2 and found that an elevated expression of HDAC1,3/Sp1/BMI1 but not BMI1 alone showed an increased risk of death in both high- and low-grade glioma patients. Thus, HDAC-mediated Sp1 deacetylation is critical for BMI1 regulation to attenuate stress- and therapy-induced death in glioma cells, and the HDAC/Sp1 axis is more important than BMI1 and appears as a therapeutic target to prevent recurrence of malignant glioma cells persisting after primary therapy.

Formation of highly elastomeric and property-tailorable poly(glycerol sebacate)-co-poly(ethylene glycol) hydrogels through thiol-norbornene photochemistry.

Poly(glycerol sebacate) (PGS) is a synthetic biorubber that presents good biocompatibility, excellent elasticity and desirable mechanical properties for biomedical applications; however, the inherent hydrophobicity and traditional thermal curing of PGS restrict its use in the fabrication of hydrogels for advanced bioapplications. Here, we designed a new class of hydrophilic PGS-based copolymers that allow hydrogel formation through thiol-norbornene chemistry. Poly(glycerol sebacate)-co-polyethylene glycol (PGS-co-PEG) macromers were synthesized through a stepwise polycondensation reaction, and then the norbornene functional groups were introduced to the PGS-co-PEG structure to form norbornene-functionalized PGS-co-PEG (Nor_PGS-co-PEG). Nor_PGS-co-PEG macromers can be crosslinked using dithiols to prepare hydrogels in the presence of light and photoinitiators. The mechanical, swelling and degradation properties of Nor_PGS-co-PEG hydrogels can be controlled by altering the crosslinker amount. In particular, the elongation of Nor_PGS-co-PEG hydrogels can be modulated up to 950%. Nor_PGS-co-PEG can be processed using electrospinning and 3D printing techniques to generate microfibrous scaffolds and printed structures, respectively. In addition, the cytocompatibility of Nor_PGS-co-PEG was also demonstrated using in vitro cellular viability studies. These results indicate that Nor_PGS-co-PEG is a promising biomaterial with definable properties for scaffold manufacturing, presenting a great potential for biomedical applications.

AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-Mediated redox homeostasis.

Drug resistance is the main obstacle in the improvement of chemotherapeutic efficacy in glioblastoma. Previously, we showed that dehydroepiandrosterone (DHEA), one kind of androgen/neurosteroid, potentiates glioblastoma to acquire resistance through attenuating DNA damage. Androgen receptor (AR) activated by DHEA or other types of androgen was reported to promote drug resistance in prostate cancer. However, in DHEA-enriched microenvironment, the role of AR in acquiring resistance of glioblastoma remains unknown. In this study, we found that AR expression is significantly correlated with poor prognosis, and AR obviously induced the resistance to temozolomide (TMZ) treatment. Herein, we observed that ALZ003, a curcumin analog, induces FBXL2-mediated AR ubiquitination, leading to degradation. Importantly, ALZ003 significantly inhibited the survival of TMZ-sensitive and -resistant glioblastoma in vitro and in vivo. The accumulation of reactive oxygen species (ROS), lipid peroxidation and suppression of glutathione peroxidase (GPX) 4, which are characteristics of ferroptosis, were observed in glioblastoma cell after treatment of ALZ003. Furthermore, overexpression of AR prevented ferroptosis in the presence of GPX4. To evaluate the therapeutic effect in vivo, we transplanted TMZ-sensitive or -resistant U87MG cells into mouse brain followed by intravenous administration with ALZ003. In addition to inhibiting the growth of glioblastoma, ALZ003 significantly extended the survival period of transplanted mice, and significantly decreased AR expression in the tumor area. Taken together, AR potentiates TMZ resistance for glioblastoma, and ALZ003-mediated AR ubiquitination might open a new insight into therapeutic strategy for TMZ resistant glioblastoma.

Comparing Computer-Assisted and Teacher-Implemented Visual Matching Instruction for Children with ASD and/or Other DD.

This paper compared the effectiveness and efficiency of using computer-assisted instruction (CAI) and teacher-implemented instruction (TII) to teach visual matching skills to students with autism spectrum disorder and/or other developmental disabilities. Four school-aged students participated in this study with an alternating treatment design. The CAI incorporated discrete trial instruction with the gesture-tracking application, while the TII involved traditional one-to-one instruction using flashcards. The results indicated that all students acquired the target matching skills with generalization to similar untaught skills and maintained acquired skills at a high level for up to 5 weeks under both CAI and TII. Both CAI and TII were effective. However, CAI was more efficient than TII in regards to the prompts provided and the duration of instructional sessions. CAI also resulted in more student engagement in independent learning.

ANGPTL4 Induces TMZ Resistance of Glioblastoma by Promoting Cancer Stemness Enrichment via the EGFR/AKT/4E-BP1 Cascade.

Glioblastoma (GBM) is the most aggressive type of brain tumor, with strong invasiveness and a high tolerance to chemotherapy. Despite the current standard treatment combining temozolomide (TMZ) and radiotherapy, glioblastoma can be incurable due to drug resistance. The existence of glioma stem-like cells (GSCs) is considered the major reason for drug resistance. However, the mechanism of GSC enrichment remains unclear. Herein, we found that the expression and secretion of angiopoietin-like 4 protein (ANGPTL4) were clearly increased in GSCs. The overexpression of ANGPTL4 induced GSC enrichment that was characterized by polycomb complex protein BMI-1 and SRY (sex determining region Y)-box 2 (SOX2) expression, resulting in TMZ resistance in GBM. Furthermore, epidermal growth factor receptor (EGFR) phosphorylation induced 4E-BP1 phosphorylation that was required for ANGPTL4-induced GSC enrichment. In particular, ANGPTL4 induced 4E-BP1 phosphorylation by activating phosphoinositide 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) cascades for inducing stemness. To elucidate the mechanism contributing to ANGPTL4 upregulation in GSCs, chromatin immunoprecipitation coupled with sequencing (ChIP-Seq) revealed that specificity protein 4 (Sp4) was associated with the promoter region, -979 to -606, and the luciferase reporter assay revealed that Sp4 positively regulated activity of the ANGPTL4 promoter. Moreover, both ANGPTL4 and Sp4 were highly expressed in GBM and resulted in a poor prognosis. Taken together, Sp4-mediated ANGPTL4 upregulation induces GSC enrichment through the EGFR/AKT/4E-BP1 cascade.