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Background. The poor prognosis of the highly malignant tumor osteosarcoma stems from its drug resistance and therefore exploring its resistance mechanisms will help us identify more effective treatment options. However, the effects of miR-125b-5p on drug resistance in osteosarcoma cells are still unclear. Methods. To study the effects of miR-125b-5p on drug resistance in osteosarcoma cells. Osteosarcoma-resistant miR-125b-5p was obtained from the databases GeneCards and g:Profiler. CCK8, western blot, and transwell were applied for the detection of the miR-125b-5p effects on proliferation, migration, invasion, apoptosis, and drug resistance in osteosarcoma. Bioinformatics is aimed at demonstrating the targeting factor miR-125b-5p, performing protein interaction enrichment analysis by Metascape, and finally validating by binding sites. Results. Upregulation of miR-125b-5p restrains proliferation, migration, and invasion of osteosarcoma and promotes apoptosis. In addition, miR-125b-5p can restore drug sensitivity in drug-resistant osteosarcoma. miR-125-5p restrains the signal transducer and inhibits the transcription 3 (STAT3) expression activator via targeting its 3 ′ -UTR. STAT3 affects drug-resistant osteosarcoma to regulate the ABC transporter. Conclusion. miR-125b-5p/STAT3 axis mediates the drug resistance of osteosarcoma by acting on ABC transporter.

Tumor-derived extracellular vesicles (EVs) hold the potential to substantially improve noninvasive early diagnosis of cancer. However, analysis of nanosized EVs in blood samples has been hampered by lack of effective, rapid, and standardized methods for isolating and detecting EVs. To address this difficulty, here we use the electric-hydraulic analogy to design cascaded microfluidic circuits for pulsatile filtration of EVs via integration of a cell-removal circuit and an EV-isolation circuit. The microfluidic device is solely driven by a pneumatic clock pulse generator, allowing for preprogrammed, clog-free, gentle, high-yield, and high-purity isolation of EVs directly from blood within 30 minutes. We demonstrate its clinical utility by detecting protein markers of isolated EVs from patient blood using a polyethylene glycol–enhanced thermophoretic aptasensor, with 91% accuracy for diagnosis of early-stage breast cancer. The cascaded microfluidic circuits can have broad applications in the field of EV research.

The potential phosphorylation motifs of human SIRT3 were predicted by searching the data base using the combination of software Netphos2.0 server and Automotif server

Local mice xenograft tumor radiation settings showing the images of xenograft tumors derived from HCT116 cells harboring Thr150/Ser159 mutant or wild type SIRT3

Clonogenic survival ability of HCT116 cells via MnSOD activation

Western blot of mitochondrial acetylated proteins from irradiated MDA-231 or U87 cells harboring wild-type or Thr150/Ser159 mutant SIRT3.

MnSOD activity in MCF10A cells harboring mock, wild type or Thr150/Ser159 mutant SIRT3 following irradiation

Western blot analysis of SIRT3 and acetylated mitochondrial proteins of human breast cancer MDA-231 cells and glioblastoma U87 cells

The zone of proximal development (ZPD) and the scaffolding theory are very different, both in terms of their theoretical origins and connotations, and can even be said to be very different. However, during the development of the two concepts, some scholars have misunderstood them, resulting in the two being mistaken for similar concepts and therefore often confused. Professor James Lantolf from Pennsylvania State University (State College, USA) was interviewed by Professor Lili Qin from Dalian University of Foreign Studies (Dalian, China) and provides an in-depth analysis of these issues. The interview begins with the theoretical roots, connotations and definitions of the ZPD and scaffolding concepts, and then unravels the story of how they have been “mistakenly loved for life”, and ultimately it is made clear that the two concepts are completely different in their practical application to language teaching and should not continue to be used interchangeably.

Omicron (B.1.1.529), the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising concerns about the effectiveness of antibody therapies and vaccines1,2. Here we examined whether sera from individuals who received two or three doses of inactivated SARS-CoV-2 vaccine could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2 out of 60) and 95% (57 out of 60) for individuals who had received 2 and 3 doses of vaccine, respectively. For recipients of three vaccine doses, the geometric mean neutralization antibody titre for Omicron was 16.5-fold lower than for the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in triple vaccinees, half of which recognized the receptor-binding domain, and showed that a subset (24 out of 163) potently neutralized all SARS-CoV-2 variants of concern, including Omicron. Therapeutic treatments with representative broadly neutralizing monoclonal antibodies were highly protective against infection of mice with SARS-CoV-2 Beta (B.1.351) and Omicron. Atomic structures of the Omicron spike protein in complex with three classes of antibodies that were active against all five variants of concern defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to a class of antibodies that bind on the right shoulder of the receptor-binding domain by altering local conformation at the binding interface. Our results rationalize the use of three-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are rational targets for a universal sarbecovirus vaccine.

Purpose:Bladder cancer treatment remains a major clinical challenge due to therapy resistance and a high recurrence rate. Profiling intratumor heterogeneity can reveal the molecular mechanism of bladder cancer recurrence.Experimental Design:Here, we performed single-cell RNA sequencing and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on tumors from 13 patients with low recurrence risk, high recurrence risk, and recurrent bladder cancer.Results:Our study generated a comprehensive cancer-cell atlas consisting of 54,971 single cells and identified distinct cell subpopulations. We found that the cancer stem-cell subpopulation is enriched during bladder cancer recurrence with elevated expression of EZH2. We further defined a subpopulation-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the NCAM1 gene, thereby inactivating the cell invasive and stemness transcriptional program. Furthermore, taking advantage of this large single-cell dataset, we elucidated the spectrum of epithelial–mesenchymal transition (EMT) in clinical samples and revealed distinct EMT features associated with bladder cancer subtypes. We identified that TCF7 promotes EMT in corroboration with single-cell ATAC with high-throughput sequencing (scATAC-seq) analysis. Additionally, we constructed regulatory networks specific to recurrent bladder cancer.Conclusions:Our study and analytic approaches herein provide a rich resource for the further study of cancer stem cells and EMT in the bladder cancer research field.

Supplementary Data from Single-Cell Analyses Reveal Mechanisms of Cancer Stem Cell Maintenance and Epithelial–Mesenchymal Transition in Recurrent Bladder Cancer

Supplementary Figure 1. BET inhibition reduces MYC expression and MYC-dependent transcription; Supplementary Figure 2. BET inhibition impairs proliferation and survival of CRC cells; Supplementary Figure 3. Phosphorylation status of ERK in CRC cell lines; Supplementary Figure 4. BET inhibition sensitizes CRC cells to inhibitors of the MAPK pathway; Supplementary Figure 5. The combination of JQ1 and trametinib impairs colony formation in CRC cells; Supplementary Figure 6. Depletion of BRD4 sensitizes CRC cells to trametinib; Supplementary Figure 7. Knockdown of KRAS recapitulates the ability of MAPK pathway inhibitors to sensitize CRC cells to JQ1; Supplementary Figure 8. Response to JQ1 {plus minus} trametinib in DLD1 and derivative lines; Supplementary Figure 9. Response to JQ1 {plus minus} trametinib in RKO and derivative lines; Supplementary Figure 10. (A) MYC mRNA levels in RKO cells treated with 500 nmol/L JQ1 {plus minus} 50 nmol/L trametinib for 2 days; Supplementary Figure 11. Co-targeting of BET proteins and MEK effectively shifts expression of apoptotic regulators to promote apoptosis; Supplementary Figure 12. The combination of JQ1 and trametinib induced CRC xenograft tumor Regression; Supplementary Table 1. Real-time PCR primers used in this study; Supplementary Table 2. Genotypes and IC50 values for JQ1 and trametinib in CRC cell lines.

Few studies have investigated learners’ emotional experiences and the interactions between emotion, cognition, and activity in the flipped foreign language classroom (i.e., a mixed teaching mode that combines in-class teaching and off-class self-directed learning). This study, from the perspective of perezhivanie (a concept from sociocultural theory), addressed these research gaps by exercising a longitudinal narrative study on a total of 32 Chinese-as-the-first-language university students of English who attended a 15-week English course with this teaching design. Among them, eight focal students were randomly selected for further evidence of the characteristics of the interactions between emotion, cognition, and activity. The results showed that the participants experienced more of positive emotions than negative emotions in the flipped classroom (FC) context, which supports the efficacy of the pedagogy. But most importantly, complex interactions between emotion, cognition, and activity were revealed. Generally, (negative) positive emotion, cognition, and activity were interconnected; however, what is also evident is that learners’ emotions either promoted or inhibited their cognitive functions, and positive and negative emotions did not necessarily correspond to positive and negative activities, respectively. This is due to the presence of dynamic, developmental, and historical sociocultural mediators in learners perezhivanija, be it teacher, peers, technology, teaching materials, teaching activities in an FC, or the learners’ previous English learning anecdotes, etc.

Purpose: Bladder cancer treatment remains a major clinical challenge due to therapy resistance and a high recurrence rate. Profiling intratumor heterogeneity can reveal the molecular mechanism of bladder cancer recurrence. Experimental Design: Here, we performed single-cell RNA sequencing and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on tumors from 13 patients with low recurrence risk, high recurrence risk, and recurrent bladder cancer. Results: Our study generated a comprehensive cancer-cell atlas consisting of 54,971 single cells and identified distinct cell subpopulations. We found that the cancer stem-cell subpopulation is enriched during bladder cancer recurrence with elevated expression of EZH2. We further defined a subpopulation-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the NCAM1 gene, thereby inactivating the cell invasive and stemness transcriptional program. Furthermore, taking advantage of this large single-cell dataset, we elucidated the spectrum of epithelial–mesenchymal transition (EMT) in clinical samples and revealed distinct EMT features associated with bladder cancer subtypes. We identified that TCF7 promotes EMT in corroboration with single-cell ATAC with high-throughput sequencing (scATAC-seq) analysis. Additionally, we constructed regulatory networks specific to recurrent bladder cancer. Conclusions: Our study and analytic approaches herein provide a rich resource for the further study of cancer stem cells and EMT in the bladder cancer research field.

Resveratrol (Res) is a plant extract with strong anti-inflammatory, antioxidant and anti-aging biological activities. However, Res is limited by its disadvantages, such as poor solubility, rapid metabolism and low bioavailability. In this study, the Resveratrol-loaded TEMPO-oxidized cellulose aerogel (RLTA) drug delivery system was prepared by the method of “dissolution-freeze-drying” and characterized by a series of analysis. Then the blood biochemical indexes and HE staining were measured and analyzed in animal experiments. The in vivo results showed that RLTA can decrease the levels of TNF-α and IL-6 inflammatory factors in the synovial fluid. Furthermore, the molecular mechanism was investigated through the analysis of silent information regulator 2 homolog 1 (Sirt1) protein expression, which suggested that RLTA could upregulate the expression of Sirt1 and mediate the P38 signaling pathway, thereby inhibiting the expression of COX-2 and MMP13 which can suppress the levels of IL-6 and TNF-α inflammatory factor. These results reveal that cellulose aerogel is a promising candidate for drug delivery and RLTA has great potential application for the treatment of sports osteoarthritis.

Background As an integral ingredient of human sociality, prosocial behavior requires learning what acts can benefit or harm others. However, it remains unknown how individuals adjust prosocial learning to avoid punishment or to pursue reward. Given that arginine vasopressin (AVP) is a neuropeptide that has been involved in modulating various social behaviors in mammals, it could be a crucial neurochemical facilitator that supports prosocial learning. Methods In 50 placebo controls and 54 participants with AVP administration, we examined the modulation of AVP on the prosocial learning characterized by reward and punishment framework, as well as its underlying neurocomputational mechanisms combining computational modeling, event-related potentials and oscillations. Results We found a self-bias that individuals learn to avoid punishment asymmetrically more severely than reward-seeking. Importantly, AVP increased behavioral performances and learning rates when making decisions to avoid losses for others and to obtain gains for self. These behavioral effects were underpinned by larger responses of stimulus-preceding negativity (SPN) to anticipation, as well as higher punishment-related feedback-related negativity (FRN) for prosocial learning and reward-related P300 for proself benefits, while FRN and P300 neural processes were integrated into theta (4–7 Hz) oscillation at the outcome evaluation stage. Conclusions These results suggest that AVP context-dependently up-regulates altruism for concerning others' losses and reward-seeking for self-oriented benefits. Our findings provide insight into the selectively modulatory roles of AVP in prosocial behaviors depending on learning contexts between proself reward-seeking and prosocial punishment-avoidance.

Few studies have investigated learners' emotional experiences and the interactions between emotion, cognition, and activity in the flipped foreign language classroom (i.e., a mixed teaching mode that combines in-class teaching and off-class self-directed learning). This study, from the perspective of

Preceding works tend to explicate affordance through supposing what is happening here and now. They seldom relate it to actual social, diachronic activities, such as foreign language learning. To tackle this issue, this study explores how students actualize affordances in technology-enriched language learning environment (TELLE) by examining their perezhivanija (lived and emotional experience), a term borrowed from sociocultural theory. Because an individual’s social life is a developing process or a perezhivanie Perezhivanie is the singular form of perezhivanija. , it is necessary to base the research in a dynamic development of language learning to figure out how the affordances are actualized. Narrative interviews were adopted to collect data from three Chinese college students who learn English as a foreign language in a Northeastern university in China. The results showed that due to the students’ different past perezhivanija in English learning, their present interpretations of the perceived affordances in TELLE varied. This influenced hugely in their actions taken during their English learning in college to actualize the affordances. The findings indicated that the actualization of affordances is historical, dynamic and developmental instead of static. It does not lie in the autonomy of the students or the teachers, but in the institutional and cultural legitimacy of technology use in student’s social life. The paper contributes to the application of affordance theory in foreign language learning and provides implications to language teaching practice in TELLE.

Abstract Sepsis is considered to be a systemic inflammatory response, which results in organ dysfunction. LncRNA nuclear-enriched abundant transcript 1 (NEAT1) involved in sepsis progression has been reported. However, the underlying mechanism of NEAT1 in sepsis-induced inflammatory response remains to be revealed. In this study, NEAT1 and POU domain class 2 transcription factor 1 (POU2F1) were highly expressed in LPS-induced septic RAW264.7 cells, opposite to miR-31-5p expression. Furthermore, we found that NEAT1 silencing inhibited LPS-induced inflammatory response and cell proliferation, and promoted cell apoptosis. Subsequently, we found that miR-31-5p interacted with NEAT1 and targeted the 3′UTR of POU2F1, and in LPS-induced RAW264.7 cells, the inhibition of NEAT1 silencing was reversed by miR-31-5p knockdown, while POU2F1 downregulation could cover the functions of miR-31-5p knockdown. In a word, this study indicates that NEAT1 inhibits the LPS-induced progression of sepsis in RAW264.7 cells by modulating miR-31-5p/POU2F1 axis, suggesting that NEAT1 will be the potential therapeutic target for sepsis.

OBJECTIVE To investigate the characteristics and risk factors of endotracheal intubation-related pressure injury (EIRPI) in patients admitted to the ICU and provide a basis for EIRPI prevention and treatment. METHODS A total of 156 patients with endotracheal intubation who were admitted to ICU at a first-class hospital from January to December 2018 were enrolled in this study. Investigators collected and analyzed data and outcomes such as patient characteristics (demographic and clinical), endotracheal catheter-related factors, and the assessment and features of pressure injuries. RESULTS The incidence of EIRPI was 23.7%. The most commonly affected site was the lip (76.7%). The incidence was affected by endotracheal intubation types, endotracheal catheter indwelling time, subglottic suction, catheter fixation, and fixator types (P < .05). In addition, the moisture, mobility, and friction/shear Braden subscale scores were also correlated with the incidence of pressure injury (P < .05). Long endotracheal catheter indwelling time, the use of catheters with subglottic suction, high Braden moisture subscale score, low Braden mobility subscale score, and low Braden friction and shear subscale scores were predictive factors for EIRPI (P < .05). CONCLUSIONS Patients in the ICU are at higher risk of developing EIRPI. Early identification of risk factors and timely intervention are the keys to preventing EIRPI.

As one of the most imperative antioxidants in higher plants, carotenoids serve as accessory pigments to harvest light for photosynthesis as well as photoprotectors for plants to adapt to high light stress. Phytoene synthase (PSY) is the entry enzyme and also the major rate-limiting enzyme in the carotenoid pathway. Here, we report a dehydration-responsive element-binding protein (DREB) transcription factor member in Nicotiana tabacum K326, NtDREB-1BL1, which regulates carotenoids biosynthesis by binding to the NtPSY promoter. The NtDREB-1BL1 transcript was widely distributed in leaves by Real-time PCR. Confocal image revealed that NtDREB-1BL1 was localized in the nucleus. The chromatin immunoprecipitation (ChIP) with the qPCR technique indicated that NtDREB-1BL1 could anchor the promoter region of NtPSY. Overexpression (NtDREB-1BL1 OE) and RNA interference (NtDREB-1BL1 RNAi) of NtDREB-1BL1 were performed to evaluate its biological function in N. tabacum. Both carotenoid and chlorophyll contents increased in transgenic plants of NtDREB-1BL1 OE compared with wild-type (WT) plants, with the augment of the genes involved in carotenoid biosynthesis. In contrast, the contents of carotenoid and chlorophyll significantly decreased in transgenic plants of NtDREB-1BL1 RNAi compared to WT, along with the decline in the expression of genes related to carotenoid biosynthesis. Moreover, transgenic plants of NtDREB-1BL1 OE exhibited enhanced tolerance under drought stress, with the weakened tolerance of drought stress in transgenic plants of NtDREB-1BL1 RNAi. In conclusion, our results illustrated the new role of transcription factor NtDREB-1BL1 in improving carotenoid biosynthesis through regulating NtPSY expression.

ObjectiveTumor spread through air spaces (STAS) has recently been reported as a novel invasive pattern in lung adenocarcinoma. Thus, this study aimed to investigate the clinicopathological and radiological features in invasive lung adenocarcinoma with tumor STAS.MethodsData of 503 invasive lung adenocarcinoma patients who underwent surgery between 1 January 2015 and 31 December 2021 were collected. The correlations between STAS presence and clinicopathological and radiological characteristics were analyzed. Statistical analysis was performed using SPSS 22.0.ResultsAmong the 503 patients with invasive adenocarcinoma, 247 (47.9%) and 262 (52.1%) patients were positive and negative for STAS, respectively. Compared to STAS-negative adenocarcinoma, STAS was more common in papillary, micropapillary, and solid tumors (p < 0.01); STAS was associated with advanced pT (p = 0.024), pN (p < 0.001), and pTNM (p < 0.001) stage, more lymph node metastases (p < 0.01), more pleural invasion (p < 0.01), and more neurovascular invasion (p = 0.025). The maximum diameter (p < 0.01), the maximum diameters of the solid component (p < 0.01), and the consolidation/tumor ratio (CTR, p < 0.01) were significantly larger in STAS-positive than in STAS-negative adenocarcinoma. Other common computed tomography (CT) features of adenocarcinomas, i.e., lobulation (p < 0.01), spiculation (p < 0.01), vacuole (p < 0.01), air bronchogram (p = 0.020), vascular convergence (p < 0.01), and pleural indentation (p < 0.01) were significantly associated with STAS. In a multivariable analysis, the maximal diameter of the solid component (odds ratio [OR], 2.505; 95% confidence interval [CI], 1.886–3.329), vacuole (OR, 3.301; 95% CI, 1.822–5.980), and spiculation (OR, 2.162; 95% CI, 1.221–3.829) were independent predictors of STAS. The area under the curve (AUC) of the maximal diameter of the solid component was 0.757 (95% CI, 0.714–0.799; p < 0.001), the sensitivity was 73.9%, and the specificity was 69.1% at a cutoff value of 1.18 cm.ConclusionSTAS was significantly correlated with several invasive clinicopathological and radiological characteristics, and the maximal diameter was an independent predictor of STAS. These results will prove helpful in identifying STAS-positive adenocarcinoma by CT before surgical resection.

We conducted this mixed-method study by focusing on the influx relationship among teacher beliefs, agency, and resilience during the pandemic and exploring the relationships and tensions among these constructs or capacities. Specifically, we surveyed 93 language teachers across seven different regions in China and collected their perceptions and beliefs about challenges and solutions during the first wave of the pandemic. In a further step, we interviewed six participants, analyzed the transcripts of the interviews, and then explored how their agency and resilience emerged and developed during the pandemic. From the quantitative statistics, we reported teacher beliefs about emotional, physical, mentoring, and support challenges in emergency remote teaching and their adopted strategies to handle these challenges during the pandemic. We also reported significant correlations among different perceived challenges and solutions. From the qualitative analysis, we found that language teacher beliefs, agency, and resilience co-evolved from intrapersonal and interpersonal reflections through temporal and contextual affordances. Drawing from the sociocultural theory, we contributed a theoretical framework for studying language teacher beliefs, agency, and resilience. We discussed our findings around the global traits that language teachers are required to develop in the increasingly complex world and also offered implications for language teacher education programs.

To unveil the role and regulatory mechanism of miR-146a-5p in sepsis. A sepsis cell model was established via lipopolysaccharide (LPS)-induction in dendritic cells (DCs). The maturation of DCs was evaluated via flow cytometry. Gene expression was measured through reverse-transcription quantitative polymerase chain reaction (RT-qPCR). The concentrations of inflammation biomarkers were revealed via enzyme-linked immunosorbent assay (ELISA). The pathological and histological changes in lungs in the sepsis mice model were analyzed via hematoxylin and eosin (HE) staining. In this study, the miR-146a-5p level was elevated in the serum of sepsis patients and LPS-induced DCs but decreased in the serums of cured sepsis patients. Furthermore, miR-146a-5p deletion alleviated the activation of T cells and attenuated the imbalance of Th17/Treg. Besides, ATG7 was validated as a target of miR-146a-5p. ATG7 elevation enhanced lactate production and glucose uptake in LPS-triggered DCs. Additionally, upregulation of ATG7 suppressed the protein levels of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), phospho protein kinase B (p-AKT), and phosphorylated signal transducer and activator for transcription 3 (p-STAT3). In addition, miR-146a-5p downregulation alleviated T-cell activation, inflammation, lactate production, and glucose uptake in sepsis mice. Moreover, the lung injury due to sepsis was also attenuated as a result of miR-146a-5p silencing. MiR-146a-5p aggravates sepsis through DCs activation and glycolysis via targeting ATG7.

As one of the most imperative antioxidants in higher plants, carotenoids serve as accessory pigments to harvest light for photosynthesis as well as photoprotectors for plants to adapt to high light stress. Phytoene synthase (PSY) is the entry enzyme and also the major rate-limiting enzyme in the carotenoid pathway. Here, we report a dehydration-responsive element-binding protein (DREB) transcription factor member in

Background Long non-coding RNA (lncRNA) exerts a regulatory role in the occurrence and progression of tumors. This study aimed at probing into the function and mechanism of lncRNA DICER1 antisense RNA 1 (DICER1-AS1) in colorectal cancer (CRC). Methods The expressions of DICER1-AS1, miR-296-5p and STAT3 mRNA were tested by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8 (CCK-8) assay was employed to detect cell proliferation, and Transwell was used to detect cell migration and invasion. In addition, the expressions of apoptosis-related proteins Bax and Bcl2 were detected by Western blot. Interactions between DICER1-AS1 and miR-296-5p, and miR-296-5p and STAT3 were predicted and determined by bioinformatics analysis, luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay. Results The expressions of DICER1-AS1 and STAT3 mRNA were significantly up-regulated while miR-296-5p expression was remarkably down-regulated in CRC tissues and cell lines. Over-expression of DICER1-AS1 or transfection of miR-296-5p inhibitors could promote the proliferation, migration and invasion and inhibit apoptosis of CRC cells, whereas knockdown of DICER1-AS1 or transfection of miR-296-5p mimics had the opposite effects. Additionally, DICER1-AS1 could down-regulate miR-296-5p expression via sponging it. DICER1-AS1 also enhanced the expression of STAT3, which was identified as a target gene of miR-296-5p. Conclusion DICER1-AS1 acts as an oncogenic lncRNA in CRC via modulating miR-296-5p/STAT3 axis. Our results provide a new direction for the diagnosis and treatment of CRC.

Expression levels and changes of serum cystatin C (C's C) and soluble vascular endothelial growth factor receptor 1 (sVEGFR1) in treatment of patients with glomerulus nephritis (GN) were investigated. The medical records of 88 patients with GN who were diagnosed in Weifang People's Hospital from March 2014 to June 2017 were collected, and their medical records were considered as a study group. The study group was divided into secondary glomerulonephritis (SGN) group (52 cases) and primary glomerulonephritis (PGN) group (36 cases). Physical examination data of 50 healthy volunteers who were examined in the same hospital during the same period were considered as a control group. The correlation between expression of serum C's C and expression of sVEGFR1 of patients with GN was compared. Expression levels of serum C's C and sVEGFR1 of patients before treatment in the study group were higher than those in the control group (P

This research examines whether prior research may not have detected cultural-specificity in the role of controlling and autonomy-supportive parenting in children's adjustment because of reliance on between-individual analyses. In two longitudinal studies (

SARS-CoV-2 has caused the COVID-19 pandemic. B.1.617 variants (including Kappa and Delta) have been transmitted rapidly in India. The transmissibility, pathogenicity, and neutralization characteristics of these variants have received considerable interest. In this study, 22 pseudotyped viruses were constructed for B.1.617 variants and their corresponding single amino acid mutations. B.1.617 variants did not exhibit significant enhanced infectivity in human cells, but mutations T478K and E484Q in the receptor binding domain led to enhanced infectivity in mouse ACE2-overexpressing cells. Furin activities were slightly increased against B.1.617 variants and cell-cell fusion after infection of B.1.617 variants were enhanced. Furthermore, B.1.617 variants escaped neutralization by several mAbs, mainly because of mutations L452R, T478K, and E484Q in the receptor binding domain. The neutralization activities of sera from convalescent patients, inactivated vaccine-immunized volunteers, adenovirus vaccine-immunized volunteers, and SARS-CoV-2 immunized animals against pseudotyped B.1.617 variants were reduced by approximately twofold, compared with the D614G variant.

Introduction: Atorvastatin (ATO) is often used to reduce blood lipids and prevent atherosclerosis, but excessive use of ATO will lead to hepatotoxicity. This paper investigated the effects of astragaloside IV (AS IV), which has multiple biological functions, on ATO-induced hepatotoxicity and the underlying mechanism. Methods: ATO treatment induced a rat model of hepatotoxicity, followed by AS IV treatment. Colorimetric kits were used to detect rat liver function indexes including aspartate aminotransferase (AST), alanine transaminase (ALT), malondialdehyde (MDA), and reduced glutathione (GSH). Reactive oxygen species (ROS) level was determined by 2′, 7′-Dichlorodihydrofluorescein diacetate kit. The liver fibrosis and F4/80 expression were detected by Sirius red staining and immunochemistry. Mitochondrial electron transport chain complex I and complex IV activities were examined. The level of mitochondrial membrane potential (MMP) was detected by JC-1 staining. The inflammatory factor levels were detected by quantitative real-time polymerase chain reaction. Western blot detected apoptosis-related proteins and AMPK/SIRT1-related proteins. Results: ATO increased ALT, AST, MDA, and ROS levels and decreased GSH content but was subsequently reversed by AS IV. AS IV alleviated liver tissue damage caused by ATO. AS IV elevated complex I and complex IV activity and promoted MMP levels in ATO rats. ATO promoted inflammatory factor release in SD rats but was then suppressed by AS IV. AS IV inhibited Bax, cleaved caspase-3 but up-regulated Bcl-2 in ATO-induced rats. ATO inhibited SIRT1 expression and AMPK phosphorylation, which was subsequently promoted by AS IV. Conclusion: AS IV inhibits ATO-induced hepatotoxicity by activating the AMPK/SIRT1 pathway.

Long non-coding RNAs have been confirmed closely related to the metastasis and angiogenesis of breast cancer (BC). LINC01857 can promote the growth and metastasis of BC cells. The present work focused on exploring the role of LINC01857 in BC metastasis and angiogenesis and investigating the possible mechanisms. The results showed that LINC01857 and CENPQ were highly expressed in BC tissues and cells, while miR-2052 was contrarily expressed. In vitro study showed that low expression of linc01857 could inhibit the migration ability and vascularization of BC cells, and mir-2052 inhibitor partially restored the effect of si-LINC01857 on the migration ability and vascularization of BC cells. Likewise, inhibition of CENPQ can partially rescue the effects of miR-2052 inhibitor on the migration ability and vascularization of BC cells. In vivo studies showed that down-regulation of LINC01857 notably suppressed tumor growth and angiogenesis in nude mice. The miR-2052 inhibitor partially restored the effects of si-LINC01857. CENPQ suppression partially rescued the effects of the miR-2052 inhibitor. To conclude, LINC01857/miR-2052/CENPQ is the potential novel target for BC treatment.

The possible role of fatty acid translocase (CD36) in the treatment of obesity has gained increasing research interest since researchers recognized its coordinated function in fatty acid uptake and oxidation. However, the effect of CD36 deficiency on intracellular insulin signaling is complex and its impact may depend on different nutritional stresses. Therefore, we investigated the various effects of CD36 deletion on insulin signaling in C2C12 myotubes with or without palmitic acid (PA) overload. In the present work, we reported the upregulated expression levels of CD36 in the skeletal muscle tissues of obese humans and mice as well as in C2C12 myotubes with PA stimulation. CD36 knockdown using RNA interference showed that insulin signaling was impaired in CD36-deficient C2C12 cells in the absence of PA loading, suggesting that CD36 is essential for the maintenance of insulin action, possibly resulting from increased mitochondrial dysfunction and endoplasmic reticulum (ER) stress; however, CD36 deletion improved insulin signaling in the presence of PA overload due to a reduction in lipid overaccumulation. In conclusion, we identified differential roles of CD36 in regulating muscle insulin response under conditions with and without PA overload, which provides supportive evidence for further research into therapeutic approaches to diabetes.

As one of the most imperative antioxidants in higher plants, carotenoids serve as accessory pigments to harvest light for photosynthesis and photoprotectors for plants to adapt to high light stress. Here, we report a small subunit (SSU) of geranylgeranyl diphosphate synthase (GGPPS) in Nicotiana tabacum, NtSSU II, which takes part in the regulation carotenoid biosynthesis by forming multiple enzymatic components with NtGGPPS1 and downstream phytoene synthase (NtPSY1). NtSSU II transcript is widely distributed in various tissues and stimulated by low light and high light treatments. The confocal image revealed that NtSSU II was localized in the chloroplast. Bimolecular fluorescence complementation (BiFC) indicated that NtSSU II and NtGGPPS1 formed heterodimers, which were able to interact with phytoene synthase (NtPSY1) to channel GGPP into the carotenoid production. CRISPR/Cas9-induced ntssu II mutant exhibited decreased leaf area and biomass, along with a decline in carotenoid and chlorophyll accumulation. Moreover, the genes involved in carotenoid biosynthesis were also downregulated in transgenic plants of ntssu II mutant. Taken together, the newly identified NtSSU II could form multiple enzymatic components with NtGGPPS1 and NtPSY1 to regulate carotenoid biosynthesis in N. tabacum, in addition to the co-expression of genes in carotenoids biosynthetic pathways.

Omicron, the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. We examined whether sera from individuals who received two or three doses of inactivated vaccine, could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2/60) and 95% (57/60) for 2- and 3-dose vaccinees, respectively. For three-dose recipients, the geometric mean neutralization antibody titer (GMT) of Omicron was 15, 16.5-fold lower than that of the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in 3-dose vaccinees, half of which recognize the receptor binding domain (RBD) and show that a subset of them (24/163) neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron, potently. Therapeutic treatments with representative broadly neutralizing mAbs individually or antibody cocktails were highly protective against SARS-CoV-2 Beta infection in mice. Atomic structures of the Omicron S in complex with three types of all five VOC-reactive antibodies defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to one major class of antibodies bound at the right shoulder of RBD through altering local conformation at the binding interface. Our results rationalize the use of 3-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are a rational target for a universal sarbecovirus vaccine.One sentence summaryA sub-set of antibodies derived from memory B cells of volunteers vaccinated with 3 doses of an inactivated SARS-CoV-2 vaccine work individually as well as synergistically to keep variants, including Omicron, at bay.

Background. At present, the study has confirmed that the mesenchymal stem cell-derived exosomes (MCSs-Exo) possess cardio-protection in sepsis. Nevertheless, the molecular mechanism of the protection of MSCs-Exo in sepsis remains unknown. Therefore, this research is aimed at studying the molecular mechanism. Methods. The effects of MSCs-Exo and miR-146a-5p in LPS-induced cardiomyocytes (H9C2 cells) in vitro were verified by CCK-8, EdU assay, flow cytometry, Western blot assay, and RT-qPCR. The effect of MSCs-Exo in vivo was evaluated by CLP-induced sepsis model. The potential gene in MSCs-Exo was verified by bioinformatics analysis, and the potential target of miR-146a-5p was identified by bioinformatics analysis and luciferase reporter assay. At last, the function of miR-146a-5p and its target genes on LPS-induced cardiomyocytes (H9C2 cells) in vitro was validated by recuse experiment. Results. Our findings revealed that MSCs-Exo could effectively protect cardiomyocytes of inflammation model in vitro and myocardial tissues of sepsis model in vivo. Meanwhile, we found that miR-146a-5p was a potential gene in MSCs-Exo, and MYBL1 was the target gene of miR-146a-5p and negatively regulated by miR-146a-5p. In addition, miR-146a-5p overexpression promoted proliferation and inhibited apoptosis of LPS-induced cardiomyocytes. The rescue experiment demonstrated that miR-146a-5p could effectively repress the inflammatory response of cardiomyocytes via decreasing MYBL1 expression. Conclusion. This study suggests that miR-146a-5p-bearing MSC-derived exosomes may become an effective treatment for sepsis.

The histone demethylase JMJD1C is associated with human platelet counts. The JMJD1C knockout in zebrafish and mice leads to the ablation of megakaryocyte–erythroid lineage anemia. However, the specific expression, function, and mechanism of JMJD1C in megakaryopoiesis remain unknown. Here, we used cell line models, cord blood cells, and thrombocytopenia samples, to detect the JMJD1C expression. ShRNA of JMJD1C and a specific peptide agonist of JMJD1C, SAH-JZ3, were used to explore the JMJD1C function in the cell line models. The actin ratio in megakaryopoiesis for the JMJDC modulation was also measured. Mass spectrometry was used to identify the JMJD1C-interacting proteins. We first show the JMJD1C expression difference in the PMA-induced cell line models, the thrombopoietin (TPO)-induced megakaryocyte differentiation of the cord blood cells, and also the thrombocytopenia patients, compared to the normal controls. The ShRNA of JMJD1C and SAH-JZ3 showed different effects, which were consistent with the expression of JMJD1C in the cell line models. The effort to find the underlying mechanism of JMJD1C in megakaryopoiesis, led to the discovery that SAH-JZ3 decreases F-actin in K562 cells and increases F-actin in MEG-01 cells. We further performed mass spectrometry to identify the potential JMJD1C-interacting proteins and found that the important Ran GTPase interacts with JMJD1C. To sum up, JMJD1C probably regulates megakaryopoiesis by influencing the actin network.

Emergence of variants of concern (VOC) with altered antigenic structures and waning humoral immunity to SARS-CoV-2 are harbingers of a long pandemic. Administration of a third dose of an inactivated virus vaccine can boost the immune response. Here, we have dissected the immunogenic profiles of antibodies from 3-dose vaccinees, 2-dose vaccinees and convalescents. Better neutralization breadth to VOCs, expeditious recall and long-lasting humoral response bolster 3-dose vaccinees in warding off COVID-19. Analysis of 171 complex structures of SARS-CoV-2 neutralizing antibodies identified structure-activity correlates, revealing ultrapotent, VOCs-resistant and broad-spectrum antigenic patches. Construction of immunogenic and mutational heat maps revealed a direct relationship between “hot” immunogenic sites and areas with high mutation frequencies. Ongoing antibody somatic mutation, memory B cell clonal turnover and antibody composition changes in B cell repertoire driven by prolonged and repeated antigen stimulation confer development of monoclonal antibodies with enhanced neutralizing potency and breadth. Our findings rationalize the use of 3-dose immunization regimens for inactivated vaccines.One sentence summaryA third booster dose of inactivated vaccine produces a highly sifted humoral immune response via a sustained evolution of antibodies capable of effectively neutralizing SARS-CoV-2 variants of concern.

This research evaluated the role of high-status peers in youth’s academic engagement. Youth (mean age = 12.7 years) in the United States and China (N = 934) made social status (i.e., sociometric popularity, perceived popularity, and admiration) nominations of their peers in the fall and spring of their first year of middle school. They also reported on their academic engagement at these two time points. The academic engagement of peers that youth nominated as high in sociometric and perceived popularity, but not of peers they admired, was predictive of youth’s own academic engagement over time. Notably, this effect was evident over and above any initial similarity youth had with high-status peers they nominated (e.g., youth tended to nominate peers as high in sociometric popularity when they were similarly academically engaged to youth). It also did not differ in size in the United States and China. The results underscore the importance of high-status peers in youth’s academic engagement in two countries that differ in terms of their cultural and educational systems. (PsycINFO Database Record (c) 2019 APA, all rights reserved)

To accurately characterize cirrhosis, knowledge of the 3D fibrous structures is essential. Histology is the gold standard in cirrhosis screening, but it mainly provides structural information in 2D planes and destroys the 3D samples in the process. The aim of this study was to evaluate the potential of X-ray phase-contrast computed tomography (PCCT) with iodine staining for the 3D nondestructive visualization of internal structural details in entire cirrhotic livers with histopathologic correlation. In this study, cirrhotic livers induced by carbon tetrachloride (CCl4) in rats were imaged via PCCT and then histopathologically processed. Characteristics of the cirrhosis, i.e. abnormal nodules surrounded by annular fibrosis, were established and a 3D reconstruction of these structures was also performed via PCCT. Fibrosis area, septal width and nodular size were measured and the correlation for these quantitative measurements between PCCT and histopathologic findings was analyzed. The results showed that fibrous bands, small nodules and angio-architecture in cirrhosis were clearly presented in the PCCT images, with histopathologic findings as standard reference. In comparison with histopathology, PCCT was associated with a very close value for fibrosis area, septal width and nodular size. The quantitative measurements showed a strong correlation between PCCT and histopathology. Additionally, the 3D structures of fibrous bands and microvasculature were presented simultaneously. PCCT provides excellent results in the assessment of cirrhosis characteristics and 3D presentation of these feature structures compared with histopathology. Thus, the technique may serve as an adjunct nondestructive 3D modality for cirrhosis characterization.

As the largest group of structurally diverse metabolites, terpenoids are versatile natural compounds that act as metabolism mediators, plant volatiles, and ecological communicators. However, few terpenoid compounds have been identified in plant parts of sacred lotus (Nelumbo nucifera Gaertn.). To elucidate the molecular genetic basis of the terpene biosynthetic pathway, terpenes from different parts of the plant, including seeds (S), young leaves (YL), mature leaves (ML), white flowers (WF), yellow flowers (YF), and red flowers (RF), were identified by LC-MS/MS and the relative contents of the same terpenes in different parts were compared. The results indicate that all plant parts primarily consist of triterpenes, with only minor quantities of sesquiterpenes and diterpenes, and there were differences in the terpene content detected in different plant parts. To illustrate the biosynthesis of various terpenoids, RNA sequencing was performed to profile the transcriptomes of various plant parts, which generated a total of 126.95 GB clean data and assembled into 29,630 unigenes. Among these unigenes, 105 candidate unigenes are involved in the mevalonate (MVA) pathway, methyl-erythritol phosphate (MEP) pathway, terpenoid backbone biosynthesis pathway, and terpenoid synthases pathway. Moreover, the co-expression network between terpene synthase (TPS) and WRKY transcription factors provides new information for the terpene biosynthesis pathway.