Search

Abstract Hyperbilirubinaemia is a prevalent condition during the neonatal period, and if not promptly and effectively managed, it can lead to severe bilirubin-induced neurotoxicity. Sunflower seeds are a nutrient-rich food source, particularly abundant in linoleic acid. Here, we provide compelling evidence that lactating maternal mice fed a sunflower seed diet experience enhanced neurological outcomes and increased survival rates in hyperbilirubinemic offspring. We assessed histomorphological indices, including cerebellar Nissl staining, and Calbindin staining, and hippocampal hematoxylin and eosin staining. Furthermore, we observed the transmission of linoleic acid, enriched in sunflower seeds, to offspring through lactation. The oral administration of linoleic acid-rich sunflower seed oil by lactating mothers significantly prolonged the survival time of hyperbilirubinemic offspring mice. Mechanistically, linoleic acid counteracts the bilirubin-induced accumulation of ubiquitinated proteins and neuronal cell death by activating autophagy. Collectively, these findings elucidate the novel role of a maternal linoleic acid-supplemented diet in promoting child health.

Abstract The long-term trends in maternal and child health (MCH) in China and the national-level factors that may be associated with these changes have been poorly explored. This study aimed to assess trends in MCH indicators nationally and separately in urban and rural areas and the impact of public policies over a 30‒year period. An ecological study was conducted using data on neonatal mortality rate (NMR), infant mortality rate (IMR), under-five mortality rate (U5MR), and maternal mortality ratio (MMR) nationally and separately in urban and rural areas in China from 1991 to 2020. Joinpoint regression models were used to estimate the annual percentage changes (APC), average annual percentage changes (AAPC) with 95% confidence intervals (CIs), and mortality differences between urban and rural areas. From 1991 to 2020, maternal and child mortalities in China gradually declined (national AAPC [95% CI]: NMRs − 7.7% [− 8.6%, − 6.8%], IMRs − 7.5% [− 8.4%, − 6.6%], U5MRs − 7.5% [− 8.5%, − 6.5%], MMRs − 5.0% [− 5.7%, − 4.4%]). However, the rate of decline nationally in child mortality slowed after 2005, and in maternal mortality after 2013. For all indicators, the decline in mortality was greater in rural areas than in urban areas. The AAPCs in rate differences between rural and urban areas were − 8.5% for NMRs, − 8.6% for IMRs, − 7.7% for U5MRs, and − 9.6% for MMRs. The AAPCs in rate ratios (rural vs. urban) were − 1.2 for NMRs, − 2.1 for IMRs, − 1.7 for U5MRs, and − 1.9 for MMRs. After 2010, urban‒rural disparity in MMR did not diminish and in NMR, IMR, and U5MR, it gradually narrowed but persisted. MCH indicators have declined at the national level as well as separately in urban and rural areas but may have reached a plateau. Urban‒rural disparities in MCH indicators have narrowed but still exist. Regular analyses of temporal trends in MCH are necessary to assess the effectiveness of measures for timely adjustments.

Abstract The purpose of this study was to develop and validate a physiologically based pharmacokinetic (PBPK) model combined with an EGFR occupancy (EO) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and the intracranial time-course of EGFR (T790M and L858R mutants) engagement in patient populations. The PBPK model was also used to investigate the key factors affecting OSI pharmacokinetics (PK) and intracranial EGFR engagement, analyze resistance to the target mutation C797S, and determine optimal dosing regimens when used alone and in drug-drug interactions (DDIs). A population PBPK-EO model of OSI was developed using physicochemical, biochemical, binding kinetic, and physiological properties, and then validated using nine clinical PK studies, observed EO study, and two clinical DDI studies. The PBPK-EO model demonstrated good consistency with observed data, with most prediction-to-observation ratios falling within the range of 0.7 to 1.3 for plasma AUC, Cmax, Ctrough and intracranial free concentration. The simulated time-course of C797S occupancy by the PBPK model was much lower than T790M and L858R occupancy, providing an explanation for OSI on-target resistance to the C797S mutation. The PBPK model identified ABCB1 CLint,u, albumin level, and EGFR expression as key factors affecting plasma Ctrough and intracranial EO for OSI. Additionally, PBPK-EO simulations indicated that the optimal dosing regimen for OSI in patients with brain metastases is either 80 mg once daily (OD) or 160 mg OD, or 40 mg or 80 mg twice daily (BID). When used concomitantly with CYP enzyme perpetrators, the PBPK-EO model suggested appropriate dosing regimens of 80 mg OD with fluvoxamine (FLUV) itraconazole (ITR) or fluvoxamine (FLUC) for co-administration and an increase to 160 mg OD with rifampicin (RIF) or efavirenz (EFA). In conclusion, the PBPK-EO model has been shown to be capable of simulating the pharmacokinetic concentration–time profiles and the time-course of EGFR engagement for OSI, as well as determining the optimum dosing in various clinical situations.

Summary: Self-grooming is an innate stereotyped behavior influenced by sense and emotion. It is considered an important characteristic in various disease models. However, the neural circuit mechanism underlying sensory-induced and emotion-driven self-grooming remains unclear. We found that the ventral zona incerta (Ziv) was activated during spontaneous self-grooming (SG), corn oil-induced sensory self-grooming (OG), and tail suspension-induced stress self-grooming (TG). Optogenetic excitation of Ziv parvalbumin (PV) neurons increased the duration of SG. Conversely, optogenetic inhibition of ZivPV neurons significantly reduced self-grooming in all three models. Furthermore, glutamatergic inputs from the primary sensory cortex activated the Ziv and contributed to OG. Activation of GABAergic inputs from the central amygdala to the Ziv increased SG, OG, and TG, potentially through local negative regulation of the Ziv. These findings suggest that the Ziv may play a crucial role in processing sensory and emotional information related to self-grooming, making it a potential target for regulating stereotyped behavior.

Abstract Circulating tumor DNA (ctDNA) has been widely used as a minimally invasive biomarker in clinical routine. However, a number of factors such as panel design, sample quality, patients' disease stages are known to influence ctDNA detection sensitivity. In this study, we systematically evaluated common factors associated with the variability of ctDNA detection in plasma and investigated ctDNA abundance in bronchoalveolar lavage (BAL). Whole exome profiling was conducted on 61 tumor tissue samples to identify tumor‐specific variants, which were then used to design personalized assay MarRyDa® for ctDNA detection. DNA extracted from BAL fluid and plasma were genotyped using MarRyDa® platform. Our analysis showed that histological subtypes and disease stages had significant differences in ctDNA detection rate. Furthermore, we found that DNA purified from BAL supernatants contains the highest levels of ctDNA compared with BAL precipitates and plasma; therefore, utilizing BAL supernatants for tumor detection might provide additional benefits. Finally, we demonstrated that tumor cellularity played significant roles in the design of personalized ctDNA panel which eventually impacts ctDNA detection sensitivity. We suggest setting a flexible criteria for sample quality control and utilization of BAL might benefit more patients in clinics.

Purpose: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and pulmonary EGFRm+ (T790M and L858R mutants) inhibition in Caucasian, Japanese, and Chinese populations. The PBPK model was also utilized to investigate inter-ethnic and inter-patient differences in OSI pharmacokinetics (PK) and determine optimal dosing regimens.Methods: Population PBPK models of OSI for healthy and disease populations were developed using physicochemical and biochemical properties of OSI and physiological parameters of different groups. And then the PBPK models were validated using the multiple clinical PK and drug-drug interaction (DDI) study data.Results: The model demonstrated good consistency with the observed data, with most of prediction-to-observation ratios of 0.8–1.25 for AUC, Cmax, and Ctrough. The PBPK model revealed that plasma exposure of OSI was approximately 2-fold higher in patients compared to healthy individuals, and higher exposure observed in Caucasians compared to other ethnic groups. This was primarily attributed to a lower CL/F of OSI in patients and Caucasian. The PBPK model displayed that key factors influencing PK and EGFRm+ inhibition differences included genetic polymorphism of CYP3A4, CYP1A2 expression, plasma free concentration (fup), albumin level, and auto-inhibition/induction on CYP3A4. Inter-patient PK variability was most influenced by CYP3A4 variants, fup, and albumin level. The PBPK simulations indicated that the optimal dosing regimen for patients across the three populations of European, Japanese, and Chinese ancestry was OSI 80 mg once daily (OD) to achieve the desired range of plasma Ctrough (328–677 nmol/L), as well as 80 mg and 160 mg OD for desirable pulmonary EGFRm+ inhibition (>80%).Conclusion: In conclusion, this study’s PBPK simulations highlighted potential ethnic and inter-patient variability in OSI PK and EGFRm+ inhibition between Caucasian, Japanese, and Chinese populations, while also providing insights into optimal dosing regimens of OSI.

ABSTRACT: The meat production of broilers is crucial to economic benefits of broiler industries, while the slaughter performance of broilers is directly determined by skeletal muscle development. Hence, the broiler breeding for growth traits shows a great importance. As a kind of small noncoding RNA, microRNA (miRNA) can regulate the expression of multiple genes and perform a wide range of regulation in organisms. Currently, more and more studies have confirmed that miRNAs are closely associated with skeletal muscle development of chickens. Based on our previous miR-seq analysis (accession number: PRJNA668199), miR-460b-5p was screened as one of the key miRNAs probably involved in the growth regulation of chickens. However, the regulatory effect of miR-460b-5p on the development of chicken skeletal muscles is still unclear. Therefore, miR-460b-5p was further used for functional validation at the cellular level in this study. The expression pattern of miR-460b-5p was investigated in proliferation and differentiation stages of chicken primary myoblasts. It was showed that the expression level of miR-460b-5p gradually decreased from the proliferation stage (GM 50%) to the lowest at 24 h of differentiation. As differentiation proceeded, miR-460b-5p expression increased significantly, reaching the highest and stabilizing at 72 h and 96 h of differentiation. Through mRNA quantitative analysis of proliferation marker genes, CCK-8 and Edu assays, miR-460b-5p was found to significantly facilitate the transition of myoblasts from G1 to S phase and promote chicken myoblast proliferation. mRNA and protein quantitative analysis of differentiation marker genes, as well as the indirect immunofluorescence results of myotubes, revealed that miR-460b-5p significantly stimulated myotube development and promote chicken myoblast differentiation. In addition, the target relationship was validated for miR-460b-5p according to the dual-luciferase reporter assay and mRNA quantitative analysis, which indicates that miR-460b-5p was able to regulate RBM19 expression by specifically binding to the 3′ UTR of RBM19. In summary, miR-460b-5p has positive regulatory effects on the proliferation and differentiation of chicken myoblasts, and RBM19 is a target gene of miR-460b-5p.

The Pacific white shrimp, Penaeus vannamei, is highly susceptible to white spot syndrome virus (WSSV). Our study explored the transcriptomic responses of P. vannamei from resistant and susceptible families, uncovering distinct expression patterns after WSSV infection. The analysis revealed a higher number of differentially expressed genes (DEGs) in the susceptible family following WSSV infection compared to the resistant family, when both were evaluated against their respective control groups, indicating that the host resistance of the family line influences the transcriptome. The results also showed that subsequent to an identical duration following WSSV infection, there were more DEGs in P. vannamei with a high viral load than in those with a low viral load. To identify common transcriptomic responses, we profiled DEGs across families at 96 and 228 h post-infection (hpi). The analysis yielded 64 up-regulated and 37 down-regulated DEGs at 96 hpi, with 33 up-regulated and 34 down-regulated DEGs at 228 hpi, showcasing the dynamics of the transcriptomic response over time. Real-time RT-PCR assays confirmed significant DEG expression changes post-infection. Our results offer new insights into shrimp’s molecular defense mechanisms against WSSV.

White spot disease (WSD) outbreaks pose a significant threat to the Pacific white shrimp (Litopenaeus vannamei) farming industry. The causative agent is the white spot syndrome virus (WSSV). There are no effective treatments for WSD so far. Therefore, understanding the resistance mechanisms of L. vannamei against the WSSV is crucial. C-type lectins (CTLs) are important pattern recognition receptors (PRRs) that promote agglutination, phagocytosis, encapsulation, bacteriostasis, and antiviral infections. This study cloned the C-type lectin domain family 4 member F (LvCLEC4F) from L. vannamei. LvCLEC4F contains a 492 bp open reading frame (ORF) encoding a protein of 163 amino acids, including a carbohydrate recognition domain (CRD). Following a challenge with the WSSV, the expression profile of LvCLEC4F was significantly altered. Using RNA interference (RNAi) technology, it was found that LvCLEC4F promotes WSSV replication and affects the expression levels of genes related to the regulation of apoptosis, signaling and cellular stress response, and immune defense. Meanwhile, the hemolymph agglutination phenomenon in vivo was weakened when LvCLEC4F was knocked down. These results indicated that LvCLEC4F may play an important role in the interaction between L. vannamei and WSSV.

Abstract Background Metabolic syndrome (MetS), a clustering of traditional cardiovascular risk factors (CVRF), is currently one of the major global public health burdens. However, associations between MetS and non-traditional CVRF represented by uric acid (UA), homocysteine (HCY) and hypersensitive C-reactive protein (HsCRP) have not been well explored in the elderly population, especially when considering body mass index (BMI). Methods Participants from the Shanghai Elderly Cardiovascular Health (SHECH) study cohort in 2017 were analyzed. MetS was defined using the modified American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Logistic regression models were used to assess associations of non-traditional CVRF, BMI with MetS. Results Of the 4360 participants analyzed, 2378 (54.5%) had MetS, the mean (SD) UA was 331 (86) µmol/L, and the median (IQR) HCY and HsCRP were 15 (13–18) µmol/L and 1.0 (0.5–2.1) mg/L, respectively. Participants with higher non-traditional CVRF tended to have a higher significant risk of MetS (P 0.05). BMI mediated 43.89% (95%CI: 30.38–57.40%), 37.34% (95% CI: 13.86–60.83%) and 30.99% (95%CI: 13.16–48.83%) of associations of hyperuricemia (HUA), hyperhomocysteinemia (HHCY) and high HsCRP (HHsCRP) with MetS, respectively. Abnormal non-traditional CVRF combined with overweight/obesity greatly increased MetS risk (adjusted OR(95%CI): HUA + Overweight: 5.860(4.059-8.461); 6.148(3.707–10.194); HHCY + Overweight: 3.989(3.107-5.121); HHCY + Obese: 5.746(4.064–8.123); HHsCRP + Overweight: 4.026(2.906-5.580); HHsCRP + Obese: 7.717(4.508–13.210)). Conclusions In the Chinese elderly population, HUA, HHCY, and HHsCRP were all significantly and independently associated with MetS, supporting the potential of focusing on non-traditional CVRF interventions for preventing and controlling MetS. BMI played moderate mediating roles in associations between non-traditional CVRF and MetS, and abnormal non-traditional CVRF combined with overweight/obesity had significant synergistic effects on MetS risk, highlighting the importance of better weight management in the elderly population.

Abstract Tissue dynamics play critical roles in many physiological functions and provide important metrics for clinical diagnosis. Capturing real-time high-resolution 3D images of tissue dynamics, however, remains a challenge. This study presents a hybrid physics-informed neural network algorithm that infers 3D flow-induced tissue dynamics and other physical quantities from sparse 2D images. The algorithm combines a recurrent neural network model of soft tissue with a differentiable fluid solver, leveraging prior knowledge in solid mechanics to project the governing equation on a discrete eigen space. The algorithm uses a Long-short-term memory-based recurrent encoder-decoder connected with a fully connected neural network to capture the temporal dependence of flow-structure-interaction. The effectiveness and merit of the proposed algorithm is demonstrated on synthetic data from a canine vocal fold model and experimental data from excised pigeon syringes. The results showed that the algorithm accurately reconstructs 3D vocal dynamics, aerodynamics, and acoustics from sparse 2D vibration profiles.

Introduction: Investigating the genetic footprints of historical temperature selection can get insights to the local adaptation and feasible influences of climate change on long-term population dynamics. Object: Chicken is a significative species to study genetic adaptation on account of its similar domestication track related to human activity with the most diversified varieties. Yet, few studies have demonstrated the genetic signatures of its adaptation to naturally tropical and frigid environments. Method: Here, we generated whole genome resequencing of 119 domesticated chickens in China including the following breeds which are in order of breeding environmental temperature from more tropical to more frigid: Wenchang chicken (WCC), green-shell chicken (GSC), Tibetan chicken (TBC), and Lindian chicken (LDC). Results: Our results showed WCC branched off earlier than LDC with an evident genetic admixture between WCC and LDC, suggesting their closer genetic relationship. Further comparative genomic analyses solute carrier family 33 member 1 (SLC33A1) and thyroid stimulating hormone receptor (TSHR) genes exhibited stronger signatures for positive selection in the genome of the more tropical WCC. Furthermore, genotype data from about 3,000 African local ecotypes confirmed that allele frequencies of single nucleotide polymorphisms (SNPs) in these 2 genes appeared strongly associated with tropical environment adaptation. In addition, the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) gene exhibited a strong signature for positive selection in the LDC genome, and SNPs with marked allele frequency differences indicated a significant relationship with frigid environment adaptation. Conclusion: Our findings partially clarify how selection footprints from environmental temperature stress can lead to advantageous genomic adaptions to tropical and frigid environments in poultry and provide a valuable resource for selective breeding of chickens.

Abstract The ubiquitin‐proteasome system assumes a critical role in numerous cellular processes, and among its components, deubiquitinases (DUBs) have emerged as essential regulators. With roughly 100 DUBs encoded within the human genome, these enzymes can be categorized into two main types: cysteine protease DUBs and metalloproteinase DUBs, based on the catalytic mechanism of the active site. DUBs exert significant influence over specific substrates implicated in cancer progression, establishing them as closely associated with various malignancies, including breast carcinoma, prostate cancer, and chronic myeloid leukemia. Consequently, the targeted inhibition of DUBs presents an enticing therapeutic strategy for cancer treatment. Here, we delve into the functional roles of DUBs in different cancer types and provide a thorough overview of the anticancer properties exhibited by DUB inhibitors. This knowledge will propel the development and clinical application of DUB inhibitors, opening promising avenues for tumor treatment.

Abstract Background and aims Non-alcoholic fatty liver disease (NAFLD) is associated with a greater risk of developing cardiovascular disease and have adverse impacts on the cardiac structure and function. Little is known about the effect of non-obese NAFLD upon cardiac function. We aimed to compare the echocardiographic parameters of left ventricle (LV) between non-obese NAFLD group and control group, and explore the correlation of non-obese NAFLD with LV diastolic dysfunction. Methods and results In this cross-sectional study, 316 non-obese inpatients were enrolled, including 72 participants with NAFLD (non-obese NAFLD group) and 244 participants without NAFLD (control group). LV structural and functional indices of two groups were comparatively analyzed. LV diastolic disfunction was diagnosed and graded using the ratio of the peak velocity of the early filling (E) wave to the atrial contraction (A) wave and E value. Compared with control group, the non-obese NAFLD group had the lower E/A〔(0.80 ± 0.22) vs (0.88 ± 0.35), t = 2.528, p = 0.012〕and the smaller LV end-diastolic diameter〔(4.51 ± 0.42)cm vs (4.64 ± 0.43)cm, t = 2.182, p = 0.030〕. And the non-obese NAFLD group had a higher prevalence of E/A

Abstract Background Radiotherapy is a commonly used tool in clinical practice to treat solid tumors. However, due to the unique microenvironment inside the tumor, such as high levels of GSH, overexpressed H2O2 and hypoxia, these factors can seriously affect the effectiveness of radiotherapy. Results Therefore, to further improve the efficiency of radiotherapy, a core–shell nanocomposite CeO2–MnO2 is designed as a novel radiosensitizer that can modulate the tumor microenvironment (TME) and thus improve the efficacy of radiation therapy. CeO2–MnO2 can act as a radiosensitizer to enhance X-ray absorption at the tumor site while triggering the response behavior associated with the tumor microenvironment. According to in vivo and in vitro experiments, the nanoparticles aggravate the killing effect on tumor cells by generating large amounts of ROS and disrupting the redox balance. In this process, the outer layer of MnO2 reacts with GSH and H2O2 in the tumor microenvironment to generate ROS and release oxygen, thus alleviating the hypoxic condition in the tumor area. Meanwhile, the manganese ions produced by degradation can enhance T1-weighted magnetic resonance imaging (MRI). In addition, CeO2–MnO2, due to its high atomic number oxide CeO2, releases a large number of electrons under the effect of radiotherapy, which further reacts with intracellular molecules to produce reactive oxygen species and enhances the killing effect on tumor cells, thus having the effect of radiotherapy sensitization. In conclusion, the nanomaterial CeO2–MnO2, as a novel radiosensitizer, greatly improves the efficiency of cancer radiation therapy by improving the lack of oxygen in tumor and responding to the tumor microenvironment, providing an effective strategy for the construction of nanosystem with radiosensitizing function. Conclusion In conclusion, the nanomaterial CeO2–MnO2, as a novel radiosensitizer, greatly improves the efficiency of cancer radiation therapy by improving the lack of oxygen in tumor and responding to the tumor microenvironment, providing an effective strategy for the construction of nanosystems with radiosensitizing function.

This meta-analysis was conducted to systematically evaluate the short-term efficacy and safety of the three-dimensional (3D) reconstruction visualization technology (3D-RVT) technique for hepatectomy. A systematic literature search was used to gather information on the 3D reconstruction visualization technology technique for hepatectomy from retrospective cohort studies and comparative studies. The retrieval period was up to March 2022. Publications and conference papers in English were manually searched and references in bibliographies traced. After evaluating the quality of selected studies, a meta-analysis was conducted using Review Manager 5.1 software. We included 12 studies comprising 2053 patients with liver disease. Our meta-results showed that 3D-RVT significantly shortened operation times [weighted mean differences (WMD) = −29.36; 95% confidence interval (CI): −55.20 to −3.51; P = 0.03], reduced intraoperative bleeding [WMD = −93.53; 95% CI: −152.32 to −34.73; P = 0.002], reduced blood transfusion volume [WMD = −66.06; 95% CI: −109.13 to −22.99; P = 0.003], and shortened hospital stays [WMD = −1.90; 95% CI: −3.05 to −0.74; P = 0.001]. Additionally, the technique reduced the use of hepatic inflow occlusion and avoided overall postoperative complications [odds ratio (OR) = 0.60; 95% CI: 0.46 to 0.79; P

This study presents a novel method that combines a computational fluid-structure interaction model with an interpretable deep-learning model to explore the fundamental mechanisms of seal whisker sensing. By establishing connections between crucial signal patterns, flow characteristics, and attributes of upstream obstacles, the method has the potential to enhance our understanding of the intricate sensing mechanisms. The effectiveness of the method is demonstrated through its accurate prediction of the location and orientation of a circular plate placed in front of seal whisker arrays. The model also generates temporal and spatial importance values of the signals, enabling the identification of significant temporal-spatial signal patterns crucial for the network’s predictions. These signal patterns are further correlated with flow structures, allowing for the identification of important flow features relevant for accurate prediction. The study provides insights into seal whiskers’ perception of complex underwater environments, inspiring advancements in underwater sensing technologies.

Abstract Backgrounds and aims As a central event during liver fibrosis, hepatic stellate cells (HSC) have been thought to be a potential therapeutic target for liver fibrosis. Previous studies have shown that runt‐related transcription factor 2 (Runx2) is associated with the development of non‐alcoholic fatty liver disease, while its specific role in HSC activation and hepatic fibrosis remains elusive. Approach and results In this study, we found that Runx2 expression was significantly upregulated in human liver fibrosis with different aetiologies. Runx2 expression was also gradually elevated in mouse liver during fibrosis, and Runx2 was mainly expressed in the activated HSC. Knockdown of Runx2 in HSC markedly alleviated CCl4‐induced, 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine‐induced or methionine‐choline deficient (MCD)‐induced liver fibrosis, while hepatic overexpression of Runx2 via HBAAV‐Runx2 or VA‐Lip‐Runx2 injection exacerbated CCl4‐induced liver fibrosis. In vitro analysis demonstrated that Runx2 promoted HSC activation and proliferation, whereas Runx2 knockdown in HSC suppressed these effects. RNA‐seq and Runx2 ChIP‐seq analysis demonstrated that Runx2 could promote integrin alpha‐V (Itgav) expression by binding to its promoter. Blockade of Itgav attenuated Runx2‐induced HSC activation and liver fibrosis. Additionally, we found that cytokines (TGF‐β1, PDGF, EGF) promote the expression and nuclear translocation of Runx2 through protein kinase A (PKA) in HSC. Conclusions Runx2 is critical for HSC activation via transcriptionally regulating Itgav expression during liver fibrosis, and may be a promising therapeutic target for liver fibrosis.

Comparisons of genomic and methylomic changes during the conservation of indigenous chicken breeds in China provide insight into conservation programmes for these breeds and their adaptations to unique environments.

Objective: Sorafenib is a first-line drug for advanced hepatocellular carcinoma (HCC). Unfortunately, most patients with HCC do not respond to sorafenib, mainly because of the frequent development of drug resistance. Bilirubin is an end metabolite of heme catabolism and an indicator of liver function, but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear. In the current study, we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC. Methods: A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC. Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin, and cell proliferation, apoptosis, and signaling pathways were assayed. The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts. Results: Serum levels of bilirubin (including total, direct, and indirect bilirubin) negatively correlated with the overall survival of patients with HCC treated with sorafenib (P < 0.05). Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells (P < 0.05). Mechanically, bilirubin inhibited sorafenib-induced activation of GSK-3β and subsequent downstream MCL-1 degradation. Conclusions: Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC, and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment.

Abstract Stretchable organic light‐emitting diodes (OLEDs) are important components for flexible/wearable electronics. However, the efficiency of the existing stretchable OLEDs is still much lower as compared with their rigid counterparts, one of the main reasons being the lack of ideal flexible transparent electrodes. Herein, we propose and develop a printed embedded metal composite electrode (PEMCE) strategy that enables the fabrication of ultra‐thin, highly flexible transparent electrodes with robust mechanical properties. With the flexible transparent electrodes serves as the anodes, flexible/stretchable white OLEDs have been successfully constructed, achieving a current efficiency of up to 77.4 cd A−1 and a maximum luminance of 34 787 cd m−2. The current efficiency of the resulting stretchable OLEDs is the highest ever reported for flexible/stretchable white OLEDs, which is about 1.2 times higher than that of the reference rigid devices based on ITO/glass electrodes. The excellent optoelectronic properties of the printed embedded transparent electrodes and the light extraction effect of the Ag‐mesh account for the significant increase in current efficiency. Remarkably, the electroluminescence performance still retains ~83% of the original luminance even after bending the device 2000 cycles at a radii of ~0.5 mm. More importantly, the device can withstand tensile strains of up to ~100%, and even mechanical deformation of 90% tensile strain does not result in a significant loss of electroluminescence performance with current efficiency and luminance maintained at over 85%. The results confirm that the PEMCE strategy is effective for constructing ultra‐flexible transparent electrodes, showing great promise for use in a variety of flexible/stretchable electronics.

Undifferentiated pleomorphic sarcoma (UPS) is a rare and aggressive soft tissue tumor with a high degree of malignancy and rapid progression, usually occurring in the extremities, retroperitoneum, and abdomen, whereas it rarely arises in the mediastinum, and is treated mainly by surgical resection. The prognosis of patients with advanced sarcoma is poor, and doxorubicin monotherapy is the standard first-line chemotherapy for most advanced soft tissue sarcomas (STS), but the prognosis is generally unsatisfactory. Immune checkpoint inhibitors (ICIs) have been established as therapies for many solid cancers in recent years; however, evidence on the efficacy of ICIs in undifferentiated sarcoma is scarce, mostly consisting of small studies, and no ICIs are currently approved for use in sarcomas. We report a case of a middle-aged man with primary mediastinal UPS with high PD-L1 expression (TPS was approximately 80%) and TLS positive. The patient was treated with sequential tislelizumab monotherapy maintenance after 6 cycles of tislelizumab combined with epirubicin, efficacy evaluation was partial remission (PR), progression-free survival (PFS) was 8.5 months, and grade 1 fatigue was identified as an adverse event.

Subglottic stenosis (SGS) is a rare yet potentially life-threatening condition that requires prompt identification and treatment. One of the primary symptoms of SGS is a respiratory sound that is tonal. To better understand the effect of SGS on expiratory sound, we used direct noise calculation to simulate sound production in a simplified axisymmetric configuration that included the trachea, the vocal folds, the supraglottal tract, and an open environmental space. This study focused on flow-sustained tones and explored the impact of various parameters, such as the SGS severity, the SGS distance, the flowrate, and the glottal opening size. It was found that the sound pressure level (SPL) of the expiratory sound increased with flowrate. SGS had little effect on the sound until its severity approached 75% and SPL increased rapidly as the severity approached 100%. The results also revealed that the tonal components of the sound predominantly came from hole tones and tract harmonics and their coupling. The spectra of the sound were greatly influenced by constricting the glottis, which suggests that respiratory tasks that involve maneuvers to change the glottal opening size could be useful in gathering more information on respiratory sound to aid in the diagnosis of subglottic stenosis.

Intestinal microorganisms are closely related to the health, development, and production performance of animals and can also provide basic information for us to fully understand and explore the germplasm characteristics and traits of local chicken breeds. In this experiment, we used five local Chinese chicken breeds as research materials; metagenomic sequencing technology was used to explore the differences in the composition of intestinal microorganisms in different breeds, and it was found that each local chicken breed had unique unigenes, of which Silkies had the most, with a total of 12,948. GO and KEGG analyses found that the biological processes most enriched by differential functional genes include genetic coding, macromolecular transport, protein synthesis, and molecular functions such as glycoprotein binding, protein hydrolysis, etc. Each breed is enriched with specific pathways, such as Anyi tile-like gray chickens, which are enriched with pathways related to disease resistance, while Gamecocks’ enrichment is related to amino acid metabolism. Random Forest and LEfSe analyses revealed specific species of intestinal microorganisms in the cecum of different breeds, such as Exiguobacterium, which is associated with melanin deposition in Silkies. Therefore, we infer that gut microorganisms are closely related to the formation of chicken breed characteristics, and the results of this experiment can provide a theoretical basis for the discovery of high-quality traits and the improvement of feeding conditions in the future.

The quasi-steady flow assumption (QSFA) is commonly used in the field of biomechanics of phonation. It approximates time-varying glottal flow with steady flow solutions based on frozen glottal shapes, ignoring unsteady flow behaviors and vocal fold motion. This study examined the limitations of QSFA in human phonation using numerical methods by considering factors of phonation frequency, air inertance in the vocal tract, and irregular glottal shapes. Two sets of irregular glottal shapes were examined through dynamic, pseudo-static, and quasi-steady simulations. The differences between dynamic and quasi-steady/pseudo-static simulations were measured for glottal flow rate, glottal wall pressure, and sound spectrum to evaluate the validity of QSFA. The results show that errors in glottal flow rate and wall pressure predicted by QSFA were small at 100 Hz but significant at 500 Hz due to growing flow unsteadiness. Air inertia in the vocal tract worsened predictions when interacting with unsteady glottal flow. Flow unsteadiness also influenced the harmonic energy ratio, which is perceptually important. The effects of glottal shape and glottal wall motion on the validity of QSFA were found to be insignificant.

This study used a two-dimensional flow-structure-interaction computer model to investigate the effects of flow-separation-vortex-induced negative pressure on vocal fold vibration and flow dynamics during vocal fold vibration. The study found that negative pressure induced by flow separation vortices enhances vocal fold vibration by increasing aeroelastic energy transfer during vibration. The result showed that the intraglottal pressure was predominantly negative after flow separation before gradually recovering to zero at the glottis exit. When the negative pressure was removed, the vibration amplitude and flow rate were reduced by up to 20%, and the closing speed, flow skewness quotient, and maximum flow declination rate were reduced by up to 40%. The study provides insights into the complex interactions between flow dynamics, vocal fold vibration, and energy transfer during voice production.

Excessive oxidative stress is a major causative factor of endothelial dysfunction in hypertension. As an endogenous pro-oxidant, thioredoxin-interacting protein (TXNIP) contributes to oxidative damage in various tissues. The present study aimed to investigate the role of TXNIP in mediating endothelial dysfunction in hypertension. In vivo, an experimental model of acquired hypertension was established with two-kidney, one-clip (2K1C) surgery. The expression of TXNIP in the vascular endothelial cells of multiple vessels was significantly increased in hypertensive rats compared with sham-operated rats. Resveratrol, a TXNIP inhibitor, suppressed vascular oxidative damage and increased the expression and activity of eNOS in the aorta of hypertensive rats. Notably, impaired endothelium-dependent vasodilation was effectively improved by TXNIP inhibition in hypertensive rats. In vitro, we observed that Ang II increased the expression of TXNIP in primary human aortic endothelial cells (HAECs) and that TXNIP knockdown by RNA interference alleviated cellular oxidative stress damage and mitigated the impaired eNOS activation and intracellular nitric oxide (NO) production observed in Ang II-treated HAECs. However, inhibiting thioredoxin (TRX) with PX-12 completely blunted the protective effect of silencing TXNIP. In addition, TXNIP knockdown facilitated TRX expression and promoted TRX nuclear translocation to further activate AP1 and REF1. TRX overexpression exhibited favorable effects on eNOS/NO homeostasis in Ang II-treated HAECs. Thus, TXNIP contributes to oxidative stress and endothelial dysfunction in hypertension, and these effects are dependent on the antioxidant capacity of TRX, suggesting that targeting TXNIP may be a novel strategy for antihypertensive therapy.

Abstract Background Rodent ultrasonic vocalizations (USVs) are crucial to their social communication and a widely used translational tool for linking gene mutations to behavior. To maximize the causal interpretation of experimental treatments, we need to understand how neural control affects USV production. However, both the aerodynamics of USV production and its neural control remain poorly understood. Results Here, we test three intralaryngeal whistle mechanisms—the wall and alar edge impingement, and shallow cavity tone—by combining in vitro larynx physiology and individual-based 3D airway reconstructions with fluid dynamics simulations. Our results show that in the mouse and rat larynx, USVs are produced by a glottal jet impinging on the thyroid inner wall. Furthermore, we implemented an empirically based motor control model that predicts motor gesture trajectories of USV call types. Conclusions Our results identify wall impingement as the aerodynamic mechanism of USV production in rats and mice. Furthermore, our empirically based motor control model shows that both neural and anatomical components contribute to USV production, which suggests that changes in strain specific USVs or USV changes in disease models can result from both altered motor programs and laryngeal geometry. Our work provides a quantitative neuromechanical framework to evaluate the contributions of brain and body in shaping USVs and a first step in linking descending motor control to USV production.

IntroductionEsophageal squamous cell carcinoma (ESCC) is one of the most common cancers globally, with significant cell heterogeneity and poor prognosis. Distant metastasis in ESCC is one of the key factors that affects the prognosis of patients.Methods and resultsStarting with the analysis of ESCC single-cell sequencing data, we constructed a single-cell atlas of ESCC in detail and clarified the cell heterogeneity within tumor tissues. Through analysis of epithelial-mesenchymal transition (EMT) levels, gene expression, and pathway activation, we revealed the existence of a novel subpopulation of SAA1+ malignant cells in ESCC that are highly aggressive and closely associated with distant metastasis of ESCC. In vitro wound healing and transwell assays confirmed a strong invasion capacity of ESCC tumor cells with high expression of SAA1. Then, we constructed an effective and reliable prediction model based on the gene expression pattern of SAA1+ malignant cell subpopulations and confirmed that patients in the high-risk group had significantly worse prognosis than those in the low-risk group in the training cohort, internal verification cohort and external verification cohort.DiscussionThis manuscript contributes to exploration of the heterogeneity of ESCC tumor tissues and the search for new ESCC subpopulations with special biological functions. These results contribute to our understanding of the underlying mechanisms of distant metastasis of ESCC and thus provide a theoretical basis for improved therapies.

Abstract Background Diabetic nephropathy (DN) is a common complication of diabetes. Long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2) is reported to exert a protective role in DN by a previous study. The working mechanism underlying the protective role of CASC2 in DN progression was further explored in this study. Methods The expression of CASC2 and microRNA-135a-5p (miR-135a-5p) was determined by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation ability was assessed by Cell Counting Kit-8 (CCK8) assay and 5-ethynyl-29-deoxyuridine (EDU) assay. Enzyme-linked immunosorbent assay (ELISA) was conducted to analyze the production of inflammatory cytokines in the supernatant. Western blot assay was performed to analyze protein expression. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to verify the target relationship between miR-135a-5p and CASC2 or tissue inhibitors of metalloproteinase 3 (TIMP3). Results High glucose (HG) treatment reduced the expression of CASC2 in human glomerular mesangial cells (HMCs) in a time-dependent manner. CASC2 overexpression suppressed HG-induced proliferation, inflammation and fibrosis in HMCs. miR-135a-5p was validated as a target of CASC2, and CASC2 restrained HG-induced influences in HMCs partly by down-regulating miR-135a-5p. miR-135a-5p bound to the 3ʹ untranslated region (3ʹUTR) of TIMP3, and CASC2 positively regulated TIMP3 expression by sponging miR-135a-5p in HMCs. miR-135a-5p silencing inhibited HG-induced effects in HMCs partly by up-regulating its target TIMP3. CASC2 overexpression suppressed HG-induced activation of Jun N-terminal Kinase (JNK) signaling partly through mediating miR-135a-5p/TIMP3 signaling. Conclusions In conclusion, CASC2 alleviated proliferation, inflammation and fibrosis in DN cell model by sponging miR-135a-5p to induce TIMP3 expression.

Hepatic arterial chemoembolization is an effective treatment for primary hepatocellular carcinoma (HCC) and can improve the survival rate of patients. Nevertheless, the long-term prognosis of patients with HCC is not optimistic. In recent years, tumor humoral detection has attracted extensive attention and is expected to become the main examination method for early tumor screening. Studies have found that serum LDH is an indicator with effective potential to predict tumor proliferation and progression, such as pancreatic cancer, esophageal cancer, nasopharyngeal cancer, etc., but the relationship between this indicator and the prognosis of HCC is still unclear. The purpose of this study was to clarify the relationship between serum LDH and the prognosis of patients with HCC, so as to provide an important scientific basis for prognosis judgment of HCC.

Cell-substrate adhesion is a critical aspect of many forms of cell migration. Cell adhesion to an extracellular matrix (ECM) generates traction forces necessary for efficient migration. One of the most well-studied structures cells use to adhere to the ECM is focal adhesions, which are composed of a multilayered protein complex physically linking the ECM to the intracellular actin cytoskeleton. Much of our understanding of focal adhesions, however, is primarily derived from in vitro studies in Metazoan systems. Though these studies provide a valuable foundation to the cell-substrate adhesion field, the evolution of cell-substrate adhesion machinery across evolutionary space and the role of focal adhesions in vivo are largely understudied within the field. Furthering investigation in these areas is necessary to bolster our understanding of the role cell-substrate adhesion machinery across Eukaryotes plays during cell migration in physiological contexts such as cancer and pathogenesis. In this review, we review studies of cell-substrate adhesion machinery in organisms evolutionary distant from Metazoa and cover the current understanding and ongoing work on how focal adhesions function in single and collective cell migration in an in vivo environment, with an emphasis on work that directly visualizes cell-substrate adhesions. Finally, we discuss nuances that ought to be considered moving forward and the importance of future investigation in these emerging fields for application in other fields pertinent to adhesion-based processes.

The electrochemical reduction of CO2 is an efficient method to convert CO2 waste into hydrocarbon fuels, among which methanol is the direct liquid fuel in the direct methanol fuel cells (DMFC). Copper is the most widely used catalyst for CO2 reduction reaction (CO2RR); the reaction is affected by the surface morphology of the copper. Here, the morphology effect and the mechanism of CO2RR on three typical low-index Cu (100), Cu (110) and Cu (111) surfaces are studied. According to our results, Cu (110) provides the optimum surface for the CO2RR via CO2 → *COOH → *CO → *CHO → *CH2O → *CH2OH → CH3OH pathway, where the reduction reaction of CO2 to *COOH is the potential-determining step (PDS). This is because Cu (110) has the highest d band center, which promotes the adsorption of *COOH.

Objective Inbreeding depression of reproduction is a major concern in the conservation of native chicken genetic resources. Here, based on the successful development of strongly inbred (Sinb) and weakly inbred (Winb) Langshan chickens, we aimed to evaluate inbreeding effects on reproductive traits and identify candidate genes involved in inbreeding depression of reproduction in Langshan chickens. Methods A two-sample t-test was performed to estimate the differences in phenotypic values of reproductive traits between Sinb and Winb chicken groups. Three healthy chickens with reproductive trait values around the group mean values were selected from each of the groups. Differences in ovarian and hypothalamus transcriptomes between the two groups of chickens were analyzed by RNA sequencing (RNA-Seq). Results The Sinb chicken group showed an obvious inbreeding depression in reproduction, especially for traits of age at the first egg and egg number at 300 days (p

PurposeTo explore the application value of an integrated emergency care model based on failure modes and effects analysis (FMEA) in patients with acute ischemic stroke (AIS).MethodsAccording to the convenience sampling method, 100 patients with AIS who visited the emergency department in our hospital from October 2018 to March 2019 were randomly selected as the control group and received routine emergency care mode intervention. Another 100 AIS patients who visited the emergency department from April to October 2019 were selected as the intervention group and received the integrated emergency care model based on FMEA. The total time spent from admission to completion of each emergency procedure [total time spent from admission to emergency physician reception (T0−1), total time spent from admission to stroke team reception (T0−2), total time spent from admission to imaging report out (T0−3), total time spent from admission to laboratory report out (T0−4), and total time spent from admission to intravenous thrombolysis (T0−5)] was recorded for both groups. The clinical outcome indicators (vascular recanalization rate, symptomatic intracerebral hemorrhage incidence, mortality rate) were observed for both groups. The National Institutes of Health Stroke Scale (NIHSS) score and Barthel score were evaluated for both groups after the intervention. The treatment satisfaction rate of the patients was investigated for both groups.ResultsThe total time of T0−1, T0−2, T0−3, T0−4, T0−5 in the intervention group (0.55 ± 0.15, 1.23 ± 0.30, 21.24 ± 3.01, 33.30 ± 5.28, 44.19 ± 7.02) min was shorter than that of the control group (1.22 ± 0.28, 4.01 ± 1.06, 34.12 ± 4.44, 72.48 ± 8.27, 80.31 ± 9.22) min (P < 0.05). The vascular recanalization rate in the intervention group (23.00%) was higher than that in the control group (12.00%) (P < 0.05). There was no statistical significance in the symptomatic intracerebral hemorrhage incidence and mortality rate in the two groups (P > 0.05). After intervention, the NIHSS score of the intervention group (2.95 ± 0.91) was lower than that of the control group (6.10 ± 2.02), and the Barthel score (77.58 ± 7.33) was higher than that of the control group (53.34 ± 5.12) (P < 0.05). The treatment satisfaction rate in the intervention group (95.00%) was higher than that of the control group (86.00%) (P < 0.05).ConclusionThrough FMEA, the failure mode that affects the emergency time of AIS patients is effectively analyzed and the targeted optimization process is proposed, which are important to enhance the efficiency and success rate of resuscitation of medical and nursing staff and improve the prognosis and life ability of patients.

Environmental factors, such as medication during pregnancy, are one of the major causes of autism spectrum disorder (ASD). Valproic acid (VPA) intake during pregnancy has been reported to dramatically elevate autism risk in offspring. Recently, researchers have proposed that VPA exposure could induce excitatory or inhibitory synaptic dysfunction. However, it remains to be determined whether and how alterations in the excitatory/inhibitory (E/I) balance contribute to VPA-induced ASD in a mouse model. In the present study, we explored changes in the E/I balance during different developmental periods in a VPA mouse model. We found that typical markers of pre- and postsynaptic excitatory and inhibitory function involved in E/I balance markedly decreased during development, reflecting difficulties in the development of synaptic plasticity in VPA-exposed mice. The expression of brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the formation and maturation of glutamatergic and GABAergic synapses during postnatal development, was severely reduced in the VPA-exposed group. Treatment with exogenous BDNF during the critical E/I imbalance period rescued synaptic functions and autism-like behaviors, such as social defects. With these results, we experimentally showed that social dysfunction in the VPA mouse model of autism might be caused by E/I imbalance stemming from BDNF deficits during the developmental stage.

Abstract Background Ruptured sinus of Valsalva aneurysm (SVA) is a rare cardiovascular disease in which some patients exhibit aortic valve insufficiency. SVA repair and valve replacement are usually required for treatment. Here, we report 5 cases of ruptured SVA with severe post-anaesthesia aortic regurgitation (AR). To the best of our knowledge, this is the first report of ruptured SVA with severe post-anaesthesia AR. Case presentation: From 2018 to 2020, there were 5 cases of ruptured SVA with severe AR after anaesthesia in our hospital. The main symptoms were palpitation and shortness of breath. Transthoracic echocardiography (TTE) with colour-flow Doppler showed ruptured aortic sinus aneurysms without AR. Post-anaesthesia echocardiography showed severe AR. Direct patch closure of the ruptured aneurysm resolved the left-to-right shunt and AR, and the aortic valve was not replaced. Conclusions Post-anaesthesia AR without obvious structural defects may occur in patients with ruptured SVAs. Valve replacement may not be necessary.

Despite a growing preference for second-generation (2G) ethanol in industries, its application is severely restricted owing to a major obstacle of developing a suitable yeast strain for fermentation using feedstock biomasses. In this study, a yeast strain, Saccharomyces cerevisiae A31Z, for 2G bioethanol production was developed from an industrial strain, Angel, using metabolic engineering by the incorporation of gene clusters involved in the xylose metabolism combined with adaptive evolution for evolving its anti-inhibitory properties. This strain outcompeted its ancestors in xylose utilization and subsequent ethanol production and manifested higher tolerance against common inhibitors from lignocellulosic hydrolysates, and also it lowered the production of glycerol by-product. Furthermore, A31Z outperformed in ethanol production using industrial hydrolysate from dried distillers grains with solubles and whole corn. Overall, this study provided a promising path for improving 2G bioethanol production in industries using S. cerevisiae.

Abstract The anterior cingulate cortex (ACC) serves as a critical hub for the anxiety and pain perception. The large-conductance Ca2+-activated potassium channels, or BKCa channels, are ubiquitously expressed throughout the central nervous system including the cingulate cortex. However, what changes of cortical BKCa channels undergo in the ACC remains unknown in pain-related anxiety. In the present study, a significant upregulation of synaptic and non-synaptic BKCa channel accessory β4 subunits in the ACC was accompanied with pain-associated anxiety-like behaviors in the chronic compression of multiple dorsal root ganglia (mCCD) of the rat. NS1619, an opener of BKCa channels, significantly rescued the alteration of fAHP and AP duration of ACC pyramidal neurons in mCCD rats. The mRNA expression of BKCa β4 subunits was extremely upregulated in the ACC after mCCD with the increased amount of both synaptic and non-synaptic BKCa β4 subunit protein. Meanwhile, NS1619 reversed the enhanced AMPA receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) frequency and the attenuated PPR of ACC neurons in mCCD rats. Local activation of BKCa channels in the ACC reversed mechanical allodynia and anxiety-like behaviors. These results suggest that the upregulation of postsynaptic and presynaptic BKCa β4 subunit may contribute to neuronal hyperexcitability and the enhanced synaptic transmission in the ACC in neuropathic pain state, and then may result in anxiety-like behavior induced by neuropathic pain.

Summary: Terahertz (THz) frequency occupies a large portion of the electromagnetic spectrum that is between the infrared and microwave regions. Recent advances in THz application have stimulated interests regarding the biological effects within this frequency range. In the current study, we report that irradiation with a single-frequency THz laser on mice cortical neuron cultures increases excitatory synaptic transmission and neuronal firing activities. Microarray assay reveals gene expression dynamics after THz exposure, which is consistent with morphology and electrophysiology results. Besides, certain schedule of THz irradiation inhibits the proliferation of oligodendrocyte precursor cells (OPCs) and promotes OPC differentiation. Of note, the myelination process is enhanced after THz exposure. In summary, our observations suggest that THz irradiation can modulate the functions of different neuronal cells, with different sensitivity to THz. These results provide important understanding of the mechanisms that govern THz interactions with nervous systems and suggest THz wave as a new strategy for neuromodulation.

People residing near stable urban heat islands (UHIs) experience a high long-term heat exposure, and the health consequences of such islands may be more severe than those of an expanding UHI; however, these areas are hidden in the overall heat island and not focused on. We developed a novel approach to identify the locations and ranges of stable UHIs by considering multiple frequency urban heat islands (MFUHIs). The MFUHIs were identified through multi-temporal remote sensing data and morphological spatial pattern analysis (MSPA), and the approach was applied in the case area of Beijing, the capital city of China. Specifically, the MFUHIs in Beijing were classified according to the landscape characteristics, based on the field survey and remote sensing data. The landscape indicators included land-use types, biophysical parameters (normalised difference vegetation index (NDVI), proportion of water areas, and impervious surface area (ISA)) and 3-D metrics (building density and building heights), which were considered causative factors. The relationship between the land surface temperature and landscape indicators was examined using ordinary least-squares (OLS) regressions and the Area Weighted Contribution Index (AWCI). The results showed that the MFUHIs in Beijing have four key zones, in which the surface temperature is more than 9 ℃ higher than the average temperature of the urban area, and the air temperature is 3.3–8.5 ℃ higher than the built-up temperature in the non-UHI area. The OLS regression and spatial statistics of the landscape indicators and surface temperature indicated that the regions in which area where MFUHIs occur could be characterised by a relatively high degree of impervious surface coverage, lack of green space and water area, and presence of low-rise and high-density buildings. The average number of building-floors in MFUHIs was between 1.93 and 2.64, and the number of floors in the entire study area was less than 3.6. Moreover, the building-densities in the MFUHIs were 16.25% to 27.62% higher than that in the whole study area. According to the result of the AWCI and field survey, the MFUHIs were classified into transportation, historical block, commercial, and city village high-temperature centre. The main findings indicated that certain regions between the city centre and rural areas, in which sound planning is not implemented, are the hotspots of UHI mitigation and risk elimination regions. The proposed approach can help policymakers develop targeted mitigation strategies in urban planning.

Self-grooming is an innate, cephalo-caudal progression of body cleaning behaviors that are found in normal rodents but exhibit repetitive and stereotyped patterns in several mouse models, such as autism spectrum disorders (ASDs). It is also recognized as a marker of stress and anxiety. Mice with Shank3B gene knockout (KO) exhibit typical ASD-like behavioral abnormalities, including stereotyped self-grooming and increased levels of anxiety. However, the exact relationship between anxiety and stereotyped self-grooming in certain types of animal models is not clear. We selected three animal models with high anxiety to compare their self-grooming parameters. First, we confirmed that Shank3B KO mice (ASD model), acute restraint stress mouse model (stress model), and chronic inflammatory pain mouse model (pain model) all showed increased anxiety levels in the open field test (OFT) and elevated plus maze (EPM). We found that only the ASD model and the stress model produced increased total grooming duration. The pain model only exhibited an increasing trend of mean self-grooming duration. We used the grooming analysis algorithm to examine the self-grooming microstructure and assess the cephalo-caudal progression of grooming behavior. The results showed distinct self-grooming microstructures in these three models. The anxiolytic drug diazepam relieved the anxiety level and the total time of grooming in the ASD and stress models. The grooming microstructure was not restored in Shank3B KO mice but was partially relieved in the stress model, which suggested that anxiety aggravated stereotyped self-grooming duration but not the grooming microstructure in the ASD mouse model. Our results indicated that stereotyped behavior and anxiety may be shared by separate, but interacting, neural circuits in distinct disease models, which may be useful to understand the mechanisms and develop potential treatments for stereotyped behaviors and anxiety.

The catalytic conversion of CO2 to C2 products through the CO2 reduction reaction (CO2RR) offers the possibility of preparing carbon-based fuels and valuable chemicals in a sustainable way. Herein, various Fen and Co5 clusters are designed to screen out the good catalysts with reasonable stability, as well as high activity and selectivity for either C2H4 or CH3CH2OH generation through density functional theory (DFT) calculations. The binding energy and cohesive energy calculations show that both Fe5 and Co5 clusters can adsorb stably on the N-doped carbon (NC) with one metal atom anchored at the center of the defected hole via a classical MN4 structure. The proposed reaction pathway demonstrates that the Fe5-NC cluster has better activity than Co5-NC, since the carbon–carbon coupling reaction is the potential determining step (PDS), and the free energy change is 0.22 eV lower in the Fe5-NC cluster than that in Co5-NC. However, Co5-NC shows a better selectivity towards C2H4 since the hydrogenation of CH2CHO to CH3CHO becomes the PDS, and the free energy change is 1.08 eV, which is 0.07 eV higher than that in the C-C coupling step. The larger discrepancy of d band center and density of states (DOS) between the topmost Fe and sub-layer Fe may account for the lower free energy change in the C-C coupling reaction. Our theoretical insights propose an explicit indication for designing new catalysts based on the transition metal (TM) clusters supported on N-doped carbon for multi-hydrocarbon synthesis through systematically analyzing the stability of the metal clusters, the electronic structure of the critical intermediates and the energy profiles during the CO2RR.

Due to the complexity of the biomolecules and titanium (Ti) combination, it is a challenge to modify the implant surface with biological cytokines. The study proposed a new method for immobilizing cytokines on implant surface to solve the problem of low osseointegration under type 2 diabetes mellitus (T2DM) condition. This new modified protein that connected Ti-binding artificial aptamer minTBP-1 with Insulin-like growth factor I (IGF-I), had a special strong affinity with Ti and a therapeutic effect on diabetic bone loss. According to the copies of minTBP-1, three proteins were prepared, namely minTBP-1-IGF-1, 2minTBP-1-IGF-1 and 3minTBP-1-IGF-1. Compared with the other modified proteins, 3minTBP-1-IGF-1 adsorbed most on the Ti surface. Additionally, this biointerface demonstrated the most uniform state and the strongest hydrophilicity. In vitro results showed that the 3minTBP-1-IGF-1 significantly increased the adhesion, proliferation, and mineralization activity of osteoblasts under T2DM conditions when compared with the control group and the other modified IGF-1s groups. Real-time PCR assay results confirmed that 3minTBP-1-IGF-1 could effectively promote the expression of osteogenic genes, that is, ALP, BMP-2, OCN, OPG, and Runx2. All these data indicated that the 3minTBP-1-IGF-1 had the most efficacious effect in promoting osteoblasts osteogenesis in diabetic conditions, and may be a promising option for further clinical use.

BackgroundThe immunotherapy of Glioma has always been a research hotspot. Although tumor associated microglia/macrophages (TAMs) proves to be important in glioma progression and drug resistance, our knowledge about how TAMs influence glioma remains unclear. The relationship between glioma and TAMs still needs further study.MethodsWe collected the data of TAMs in glioma from NCBI Gene Expression Omnibus (GEO) that included 20 glioma samples and 15 control samples from four datasets. Six genes were screened from the Differential Expression Gene through Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein–protein interaction (PPI) network and single-cell sequencing analysis. A risk score was then constructed based on the six genes and patients’ overall survival rates of 669 patients from The Cancer Genome Atlas (TCGA). The efficacy of the risk score in prognosis and prediction was verified in Chinese Glioma Genome Atlas (CGGA).ResultsSix genes, including CD163, FPR3, LPAR5, P2ry12, PLAUR, SIGLEC1, that participate in signal transduction and plasma membrane were selected. Half of them, like CD163, FPR3, SIGLEC1, were mainly expression in M2 macrophages. FPR3 and SIGLEC1 were high expression genes in glioma associated with grades and IDH status. The overall survival rates of the high risk score group was significantly lower than that of the low risk score group, especially in LGG.ConclusionJoint usage of the 6 candidate genes may be an effective method to diagnose and evaluate the prognosis of glioma, especially in Low-grade glioma (LGG).

The protein inhibitor of the activated STAT2 (PIAS2) has been implicated in many cellular processes and can also regulate viral replication in mammals. However, the role of PIAS2 in the highly pathogenic avian influenza virus (HPAIV) H5N1 replication in ducks is still unclear. Through liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay, we identified that duck PIAS2 (duPIAS2) was one protein that interacted with the nucleoprotein (NP) from the H5N1 HPAIV strain of DK212. Through confocal microscopy images and Co-IP assay, we confirmed NP could interact with duPIAS2. Overexpression of duPIAS2 in primary duck embryo fibroblast (DEF) cells was shown to promote DK212 replication, and knockdown of duPIAS2 could repress DK212 replication. We further found duPIAS2 could promote NP SUMOylation through duck SUMO1 (duSUMO1), and the potential SUMOylation sites of NP were at lysines 7, 48, and 87. Furthermore, duPIAS2 promoted the replication of DK212, here relying on the activity of its SUMO E3 ligase. Duck SENP1 (duSENP1), a deSUMOylation enzyme, could repress NP SUMOylation and also inhibit DK212 replication. Together, we identified duPIAS2 could interact with NP and that duPIAS2 promoted H5N1 HPAIV replication, which might be related to NP SUMOylation.

In mammals, tripartite motif 32 (TRIM32) is essential for regulating host innate immune responses to viral infections. However, the antiviral effect of TRIM32 in birds has not been reported. Here, we cloned the full-length duck TRIM32 (duTRIM32) cDNA from total spleen RNA of Peking duck. DuTRIM32 consists of 682 amino acids and has 95.5% similarity in amino acid sequences with chicken TRIM32 and 84.9% similarity with human TRIM32, respectively. DuTRIM32 mRNA was found to be ubiquitously expressed in all tested tissues from healthy ducks. Overexpression of duTRIM32 significantly activated the IFN-β promoter and upregulated the mRNA levels of IFN-β, IRF7, and Mx, which indicates that duTRIM32 is involved in the type I IFN pathway. Furthermore, duTRIM32 was found to directly interact with duck STING (duSTING) and to contribute to the expression of IFN-β mediated by duSTING. The mRNA level of duTRIM32 was significantly upregulated in the lungs and spleens of H5N6 highly pathogenic avian influenza virus (HPAIV) infected ducks 3 days post-infection (DPI). Furthermore, overexpression of duTRIM32 could inhibit the replication of H5N6 HPAIV in duck embryo fibroblasts (DEFs). Therefore, these results indicate that duTRIM32 is involved in the type I IFN pathway and exhibit an antiviral effect against H5N6 HPAIV infection.

Musculoskeletal pain (MSP) is one of the most severe complaints in women undergoing menopause. The prevalence of MSP varied when taking the menopausal state and age factor into consideration. This study investigated the prevalence of MSP in perimenopausal women and its association with menopausal state. The MEDLINE, Embase, Web of Science, and PubMed databases were searched from inception to July 2020, and 16 studies were retrieved for the current meta-analysis. The primary outcome measure was the MSP Odds Ratio (OR). The estimated overall prevalence of MSP among perimenopausal women was 71% (4144 out of 5836, 95% confidence interval (CI): 64%-78%). Perimenopausal women demonstrated a higher risk for MSP than premenopausal ones (OR: 1.63, 95% CI: 1.35-1.96, P=0.008, I2=59.7%), but similar to that in postmenopausal ones (OR: 1.07, 95% CI: 0.95–1.20, P=0.316, I2=13.4%). The postmenopausal women were at a higher risk of moderate/severe MSP than the premenopausal ones (OR: 1.45, 95% CI: 1.21-1.75, P=0.302, I2=16.5%) or the perimenopausal ones (OR: 1.40, 95% CI: 1.09–1.79, P=0.106, I2=55.4%). In conclusion, the perimenopause is a state during which women are particularly predisposed to develop MSP. As to moderate to severe degrees of MSP, the odds increase linearly with age, from premenopause to peri- and then to postmenopause.