Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2.

OBJECTIVE: Glioma, a malignant primary brain tumor, is notorious for its high incidence rate. However, the clinical application of temozolomide (TMZ) as a treatment option for glioma is often limited due to resistance, which has been linked to hypoxic glioma cell-released exosomes. In light of this, the present study aimed to investigate the role of exosomal pyruvate kinase M2 (PKM2) in glioma cells that exhibit resistance to TMZ. METHODS: Sensitive and TMZ-resistant glioma cells were subjected to either a normoxic or hypoxic environment, and the growth patterns and enzymatic activity of glycolysis enzymes were subsequently measured. From these cells, exosomal PKM2 was isolated and the subsequent effect on TMZ resistance was examined and characterized, with a particular focus on understanding the relevant mechanisms. Furthermore, the intercellular communication between hypoxic resistant cells and tumor-associated macrophages (TAMs) via exosomal PKM2 was also assessed. RESULTS: The adverse impact of hypoxic microenvironments on TMZ resistance in glioma cells was identified and characterized. Among the three glycolysis enzymes that were examined, PKM2 was found to be a critical mediator in hypoxia-triggered TMZ resistance. Upregulation of PKM2 was found to exacerbate the hypoxia-mediated TMZ resistance. Exosomal PKM2 were identified and isolated from hypoxic TMZ-resistant glioma cells, and were found to be responsible for transmitting TMZ resistance to sensitive glioma cells. The exosomal PKM2 also contributed towards mitigating TMZ-induced apoptosis in sensitive glioma cells, while also causing intracellular ROS accumulation. Additionally, hypoxic resistant cells also released exosomal PKM2, which facilitated TMZ resistance in tumor-associated macrophages. CONCLUSION: In the hypoxic microenvironment, glioma cells become resistant to TMZ due to the delivery of PKM2 by exosomes. Targeted modulation of exosomal PKM2 may be a promising strategy for overcoming TMZ resistance in glioma.

Effects of vaginal microbiota transfer on the neurodevelopment and microbiome of cesarean-born infants: A blinded randomized controlled trial.

The microbiomes of cesarean-born infants differ from vaginally delivered infants and are associated with increased disease risks. Vaginal microbiota transfer (VMT) to newborns may reverse C-section-related microbiome disturbances. Here, we evaluated the effect of VMT by exposing newborns to maternal vaginal fluids and assessing neurodevelopment, as well as the fecal microbiota and metabolome. Sixty-eight cesarean-delivered infants were randomly assigned a VMT or saline gauze intervention immediately after delivery in a triple-blind manner (ChiCTR2000031326). Adverse events were not significantly different between the two groups. Infant neurodevelopment, as measured by the Ages and Stages Questionnaire (ASQ-3) score at 6 months, was significantly higher with VMT than saline. VMT significantly accelerated gut microbiota maturation and regulated levels of certain fecal metabolites and metabolic functions, including carbohydrate, energy, and amino acid metabolisms, within 42 days after birth. Overall, VMT is likely safe and may partially normalize neurodevelopment and the fecal microbiome in cesarean-delivered infants.

Role of pericytes in the development of cerebral cavernous malformations.

Cerebral cavernous malformation (CCM) is caused by loss-of-function mutations in CCM1, CCM2, or CCM3 genes of endothelial cells. It is characterized by pericyte deficiency. However, the role of pericytes in CCMs is not yet clarified. We found pericytes in Cdh5Cre ERT2 ;Ccm1 fl/fl (Ccm1 ECKO ) mice had a high expression of PDGFRß. The inhibition of pericyte function by CP-673451 aggravated the CCM lesion development. RNA-sequencing analysis revealed the molecular traits of pericytes, such as highly expressed ECM-related genes, especially Fn1. Furthermore, KLF4 coupled with phosphorylated SMAD3 (pSMAD3) promoted the transcription of fibronectin in the pericytes of CCM lesions. RGDS peptide, an inhibitor of fibronectin, decreased the lesion area in the cerebella and retinas of Ccm1 ECKO mice. Also, human CCM lesions had abundant fibronectin deposition, and pSMAD3- and KLF4-positive pericytes. These findings indicate that pericytes are essential for CCM lesion development, and fibronectin intervention may provide a novel target for therapeutic intervention in such patients.

Prevalence of eczema between cesarean-born and vaginal-born infants within 1 year of age: a systematic review and meta-analysis.

This study aims to quantify the difference in prevalence of eczema between cesarean-born and vaginal-born infants within 1 year of age through a systematic review and meta-analysis. Six electronic databases were searched from inception to August 31, 2021. Studies were included if they reported the prevalence of eczema in infants within 1 year of age with specified mode of delivery. The quality of included studies was assessed using the Joanna Briggs Instrument Critical Appraisal Checklist. Pooled prevalence and odds ratio (OR) were estimated by meta-analyses of included studies. Meta-regression was conducted to explore factors affecting heterogeneity of the prevalence of eczema. Nine studies were included with 3,758 cesarean-born infants and 9,631 vaginal-born infants. The prevalence of eczema in cesarean-born infants [27.8%; 95% confidence interval (CI): 17.7-39.2] was higher than in vaginal-born infants (20.1%; 95% CI: 13.9-28.1), with a pooled OR of 1.31 (95% CI: 1.04-1.65). Subgroup analyses showed that the prevalence of eczema in cesarean-born infants varied according to country, study design, and method of ascertainment. Additionally, the pooled prevalence of eczema in vaginal-born infants differed by age at which eczema was identified. Meta-regression analysis showed that study design and eczema ascertainment method were significant sources of heterogeneity. CONCLUSION: About 28% of cesarean-born infants within 1 year of age developed eczema, significantly higher than the 20% rate or occurrence seen in vaginal-born infants. PROTOCOL REGISTRATION: CRD 42,020,152,437. WHAT IS KNOWN: • Eczema, a complex inflammatory cutaneous disorder characterized by immune mediated inflammation and epidermal barrier dysfunction, is one of the most common allergic disorders in infants. • Eczema may increase the risk of immune-mediated inflammatory disease such as food allergy, asthma, and allergic rhinitis, leading to psychological and social burdens on affected individuals and their families. • Mode of delivery may be associated with the risk of developing eczema, although further studies are needed to clarify such differences. WHAT IS NEW: • This is the first systematic review designed to estimate the prevalence of eczema in cesarean- and vaginal-born infants within 1 year of age. • Cesarean delivery may increase the risk of developing eczema in infants within the first year of life.

Association between perceived birth trauma and postpartum depression: A prospective cohort study in China.

OBJECTIVE: To assess the association between women's perceived birth trauma and risk of postpartum depression (PPD). METHODS: We conducted a prospective cohort study in China between December 2018 and November 2019. Women aged 18-45 years who had a singleton live birth at a university teaching hospital were enrolled after written consent was obtained. PPD was defined as a score of 13 or more on the Chinese version of the Edinburgh Postnatal Depression Scale. We used multiple log-binomial regression analysis to estimate the independent association between perceived birth trauma and PPD. RESULTS: A total of 650 eligible women were included in the final analysis. Of them, 245 (37.69%) had self-reported perceived birth trauma and 188 (28.92%) developed PPD. The PPD rate was 42.04% in women with perceived birth trauma, compared with 20.99% in women without perceived birth trauma (crude relative risk [RR] 2.46, 95% confidence interval [CI] 1.48-3.72). The increased risk of PPD for women with perceived birth trauma remained after adjustment for sociodemographic and obstetric factors (adjusted RR 2.13, 95% CI 1.69-3.28). CONCLUSION: Perceived birth trauma may be an important risk factor for PPD in Chinese women. Supportive care for women who perceived childbirth as a trauma may help to reduce the risk of PPD.

Classical and Bayesian Inference of an Exponentiated Half-Logistic Distribution under Adaptive Type II Progressive Censoring.

The point and interval estimations for the unknown parameters of an exponentiated half-logistic distribution based on adaptive type II progressive censoring are obtained in this article. At the beginning, the maximum likelihood estimators are derived. Afterward, the observed and expected Fisher's information matrix are obtained to construct the asymptotic confidence intervals. Meanwhile, the percentile bootstrap method and the bootstrap-t method are put forward for the establishment of confidence intervals. With respect to Bayesian estimation, the Lindley method is used under three different loss functions. The importance sampling method is also applied to calculate Bayesian estimates and construct corresponding highest posterior density (HPD) credible intervals. Finally, numerous simulation studies are conducted on the basis of Markov Chain Monte Carlo (MCMC) samples to contrast the performance of the estimations, and an authentic data set is analyzed for exemplifying intention.

2D oriented covalent organic frameworks for alcohol-sensory synapses.

Resistive random access memories (RRAMs) based on the electrochemical metallization mechanism (ECM) have potential applications in high-density data storage and efficient neuromorphic computing. However, the high variability of ECM devices still hinders their application in artificial intelligence owing to the random formation of conductive filaments (CFs). Here, we demonstrate 2D covalent organic framework (COF) RRAM with electroforming-free resistive switching behavior, low spatial/temporal variations, and excellent retention capability up to 105 s. The one-dimensional channels of the oriented COF-5 film can not only confine the shape of filaments but also modulate the transition direction of Ag ions. Moreover, alcohol vapors could activate the device to achieve gas-mediated multilevel resistive switching since COF materials can absorb small molecules through host guest interactions to vary the conductivity. An alcohol gas recognition system constructed by integrating the COF RRAM as a sensor and filter part with the k-nearest neighbors (KNN) algorithm as a classifier was demonstrated with a recognition accuracy of 87.2%. Furthermore, the effect of alcohol inhibition stimulation in the human nervous system is successfully emulated by the COF RRAM.

Social Media Opinions on Working From Home in the United States During the COVID-19 Pandemic: Observational Study.

BACKGROUND: Since March 2020, companies nationwide have started work from home (WFH) owing to the rapid increase of confirmed COVID-19 cases in an attempt to help prevent the disease from spreading and to rescue the economy from the pandemic. Many organizations have conducted surveys to understand people's opinions toward WFH. However, the findings are limited owing to a small sample size and the dynamic topics over time. OBJECTIVE: This study aims to understand public opinions regarding WFH in the United States during the COVID-19 pandemic. METHODS: We conducted a large-scale social media study using Twitter data to portray different groups of individuals who have positive or negative opinions on WFH. We performed an ordinary least squares regression analysis to investigate the relationship between the sentiment about WFH and user characteristics including gender, age, ethnicity, median household income, and population density. To better understand the public opinion, we used latent Dirichlet allocation to extract topics and investigate how tweet contents are related to people's attitude. RESULTS: On performing ordinary least squares regression analysis using a large-scale data set of publicly available Twitter posts (n=28,579) regarding WFH during April 10-22, 2020, we found that the sentiment on WFH varies across user characteristics. In particular, women tend to be more positive about WFH (P<.001). People in their 40s are more positive toward WFH than those in other age groups (P<.001). People from high-income areas are more likely to have positive opinions about WFH (P<.001). These nuanced differences are supported by a more fine-grained topic analysis. At a higher level, we found that the most negative sentiment about WFH roughly corresponds to the discussion on government policy. However, people express a more positive sentiment when discussing topics on "remote work or study" and "encouragement." Furthermore, topic distributions vary across different user groups. Women pay more attention to family activities than men (P<.05). Older people talk more about work and express a more positive sentiment regarding WFH. CONCLUSIONS: This paper presents a large-scale social media-based study to understand the public opinion on WFH in the United States during the COVID-19 pandemic. We hope that this study can contribute to policymaking both at the national and institution or company levels to improve the overall population's experience with WFH.

Inorganic Perovskite Quantum Dot-Based Strain Sensors for Data Storage and In-Sensor Computing.

Although remarkable improvement has been achieved in stretchable strain sensors, challenges still exist in aspects including intelligent sensing, simultaneous data processing, and scalable fabrication techniques. In this work, a strain-sensitive device is presented by fabricating a CsPbBr3 quantum dots (QDs) floating-gate field-effect transistor (FET) sensing array on thin polyimide (PI) films. The FET exhibits an excellent on/off ratio (>103) and a large memory window (>2 V). With the introduction of CsPbBr3 QDs as the trapping layer, an additional UV response is obtained because of the photogenerated charge carriers that significantly enhance the source-drain current (IDS) of the device. At each electrical state, the IDS varies with the strains and the sensing range is from compressive +12.5% to tensile -10.8%. Excellent data retainability and mechanical durability demonstrate the high quality and reliability of the fabricated sensors. Furthermore, synapse functions including long-term potentiation (LTP), long-term depression (LTD), etc., are emulated at the device level. Linearity factor changes of LTP/LTD in different sensing scenarios demonstrate the reliability of the device and further confirm the different sensing mechanisms with/without UV illumination. Our results exhibit the potential of transistor-based devices for multifunctional intelligent sensing.

Modulation of Binary Neuroplasticity in a Heterojunction-Based Ambipolar Transistor.

To keep pace with the upcoming big-data era, the development of a device-level neuromorphic system with highly efficient computing paradigms is underway with numerous attempts. Synaptic transistors based on an all-solution processing method have received growing interest as building blocks for neuromorphic computing based on spikes. Here, we propose and experimentally demonstrated the dual operation mode in poly{2,2-(2,5-bis(2-octyldodecyl)-3,6-dioxo-2,3,5,6-tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl)dithieno[3,2-b]thiophene-5,5-diyl-alt-thiophen-2,5-diyl}(PDPPBTT)/ZnO junction-based synaptic transistor from ambipolar charge-trapping mechanism to analog the spiking interfere with synaptic plasticity. The heterojunction formed by PDPPBTT and ZnO layers serves as the basis for hole-enhancement and electron-enhancement modes of the synaptic transistor. Distinctive synaptic responses of paired-pulse facilitation (PPF) and paired-pulse depression (PPD) were configured to achieve the training/recognition function for digit image patterns at the device-to-system level. The experimental results indicate the potential application of the ambipolar transistor in future neuromorphic intelligent systems.