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Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease. The association between diabetes mellitus and fracture risk is unclear. Currently, T2DM is not an independent risk factor for low-energy fractures in elderly patients. This study aimed to explore the association between T2DM and the risk of hip and vertebral fractures. PubMed, MEDLINE, and Cochrane library databases were searched for articles on T2DM and fracture risk. The final study sample from the literature was determined using predefined inclusion criteria, and a meta-analysis, including heterogeneity testing, publication bias analysis, and subgroup analysis, of relevant data was undertaken using STATA software. Seventeen studies, involving 365,185 participants, 6539 hip fracture events, and 1381 vertebral fracture events were included in this research. The adjusted relative risk of T2DM and hip or vertebral fracture were 1.46 (95% confidence interval [CI] 1.31–1.61) and 1.00 (95% CI 0.81–1.18), respectively, which showed that T2DM is positively related to hip fracture although not significantly associated with vertebral fractures. T2DM was positively associated with an increased risk of hip fracture but not with vertebral fracture. Bone health in patients with T2DM requires more attention, and further research is warranted.

Dietary supplementation with sea cucumber saponins (SCS) and exercise have been confirmed to be effective in preventing the development of obesity and its related diseases. However, the combined effectiveness of these interventions has not been explored. Here, we studied whether the beneficial influences of exercise could be further enhanced by dietary supplementation with SCS in high-fat diet-fed KM (Kunming) mice. Mice were randomly divided into four groups, including the high-fat diet group (HF), the SCS group (HF-S), the exercise group (HF-E), and the combination of dietary SCS and exercise group (HF-S + E). There were eight mice in every group. The results demonstrated that the combination of dietary SCS and exercise could synergistically reduce fat accumulation. In particular, white adipose tissue decreased by 63% in the HF-S + E group compared with that in the HF group. SCS supplementation with exercise also improved peripheral markers, such as serum parameters and hepatic TG levels. Further mechanical testing indicated that the combined effects of dietary SCS and exercise on inhibiting fat accumulation might be attributed to the inhibition of lipid synthesis in the liver and the activation of lipolysis in white adipose tissue to increase energy consumption.

Since the outbreak of SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, the viral genome has acquired numerous mutations with the potential to increase transmission. One year after its emergence, we now further analyze emergent SARS-CoV-2 genome sequences in an effort to understand the evolution of this virus.

Air pollution reduction policies can simultaneously mitigate CO2 emissions in the industrial sector, but the extent of these co-benefits is understudied. We analyse the potential co-benefits for SO2, NOx, particulate matter (PM) and CO2 emission reduction in major industrial sectors in China. We construct and analyse a firm-level database covering nearly 80,000 observations and use scenario simulations to estimate the co-benefits. The findings show that substantial co-benefits could be achieved with three specific interventions. Energy intensity improvement can reduce SO2, NOx, PM and CO2 emissions for non-power sectors by 26–44%, 19–44%, 25–46% and 18–50%, respectively. Reductions from scale structure adjustment such as phasing out small firms and developing large ones can amount to 1–8%, 1–6%, 2–20% and 0.2–3%. Electrification can reduce emissions by 19–25%, 4–28%, 20–29% and 11–12% if the share of electricity generated from non-fossil fuel sources is 70%. Since firm heterogeneity is essential to realize the co-benefits and directly determines the magnitudes of these benefits, stricter and sensible environmental policies targeting industrial firms can accelerate China’s sustainable transformation. Energy intensity improvement, scale structure adjustment and electrification measures in major industrial sectors can substantially and simultaneously reduce CO2, NOx, SO2 and particulate matter emissions.

Dendrobine has been reported to reduce blood lipid levels and apoptosis. The present study was designed to observe the effect of dendrobine in a model of ERS using vascular endothelial cells and to reveal the biological mechanisms and pathways responsible for the therapeutic effects of dendrobine on AS. Human umbilical vein endothelial cells (HUVECs) were pre-treated with various concentrations of dendrobine, followed by treatment with tunicamycin (TM) for the establishment of the cell models of ERS. The proliferation and apoptosis of HUVECs were detected by bromodeoxyuridine staining and flow cytometry, respectively. The target binding association was verified through dual luciferase reporter assay. It was found that TM treatment resulted in a low expression of miR-381-3p. Dendrobine treatment not only promoted the proliferation, but also inhibited the apoptosis of HUVECs induced by TM. The reduced expression of 78-kDa glucose-regulated protein, inositol-requiring enzyme 1, caspase-4, C/EBP homologous protein and caspase-3 was also observed following treatment with dendrobine. Dendrobine reduced the apoptosis of endothelial cells in the model of ERS by increasing miR-381-3p expression, and partially restored the cell proliferation level. This effect was significantly reduced after the expression of miR-381-3p was blocked. On the whole, the present study demonstrated that dendrobine upregulated miR-381-3p expression to inhibit apoptosis induced by ERS in HUVECs and this process was found to be mediated by caspase-4. The findings of the present study may provide new insight into the causes of endothelial cell apoptosis during AS and reveal the potent therapeutic effects of dendrobine in AS., GRAPHICAL ABSTRACT

Accessory proteins play important roles in the interaction between coronaviruses and their hosts. Accordingly, a comprehensive study of the compositional diversity and evolutionary patterns of accessory proteins is critical to understanding the host adaptation and epidemic variation of coronaviruses. Here, we developed a standardized genome annotation tool for coronavirus (CoroAnnoter) by combining open reading frame prediction, transcription regulatory sequence recognition and homologous alignment. Using CoroAnnoter, we annotated 39 representative coronavirus strains to form a compositional profile for all of the accessary proteins. Large variations were observed in the number of accessory proteins of 1–10 for different coronaviruses, with SARS-CoV-2 and SARS-CoV having the most (9 and 10, respectively). The variation between SARS-CoV and SARS-CoV-2 accessory proteins could be traced back to related coronaviruses in other hosts. The genomic distribution of accessory proteins had significant intra-genus conservation and inter-genus diversity and could be grouped into 1, 4, 2 and 1 types for alpha-, beta-, gamma-, and delta-coronaviruses, respectively. Evolutionary analysis suggested that accessory proteins are more conservative locating before the N-terminal of proteins E and M (E-M), while they are more diverse after these proteins. Furthermore, comparison of virus-host interaction networks of SARS-CoV-2 and SARS-CoV accessory proteins showed that they share multiple antiviral signaling pathways, those involved in the apoptotic process, viral life cycle and response to oxidative stress. In summary, our study provides a tool for coronavirus genome annotation and builds a comprehensive profile for coronavirus accessory proteins covering their composition, classification, evolutionary pattern and host interaction.

This study tested the hypothesis that autistic traits influence the neuronal habituation that underlies the processing of others’ pain. Based on their autism-spectrum quotient (AQ), two groups of participants were classified according to their autistic traits: High-AQ and Low-AQ groups. Their event-related potentials in response to trains of three identical audio recordings, exhibiting either painful or neutral feelings of others, were compared during three experimental tasks. (1) In a Pain Judgment Task, participants were instructed to focus on pain-related cues in the presented audio recordings. (2) In a Gender Judgment Task, participants were instructed to focus on non-pain-related cues in the presented audio recordings. (3) In a Passive Listening Task, participants were instructed to passively listen. In the High-AQ group, an altered empathic pattern of habituation, indexed by frontal-central P2 responses of the second repeated painful audio recordings, was found during the Passive Listening Task. Nevertheless, both High-AQ and Low-AQ groups exhibited similar patterns of habituation to hearing others’ voices, both neutral and painful, in the Pain Judgment and Gender Judgment Tasks. These results suggest altered empathic neuronal habituation in the passive processing of others’ vocal pain by individuals with autistic traits.

The presence of sulfur dioxide (SO2) in the air is a global concern because of its severe environmental and public health impacts. Recent evidence from satellite observations shows rapid changes in the spatial distribution of global SO2 emissions, but such features are generally missing in global emission inventories that use a bottom-up method due to the lack of up-to-date information, especially in developing countries. Here, we rely on the latest data available on emission activities, control measures, and emission factors to estimate global SO2 emissions for the period 1960-2014 on a 0.1° × 0.1° spatial resolution. We design two counterfactual scenarios to isolate the contributions of emission activity growth and control measure deployment on historical SO2 emission changes. We find that activity growth has been the major factor driving global SO2 emission changes overall, but control measure deployment is playing an increasingly important role. With effective control measures deployed in developed countries, the predominant emission contributor has shifted from developed countries in the early 1960s (61%) to developing countries at present (83%). Developing countries show divergency in mitigation strategies and thus in SO2 emission trends. Stringent controls in China are driving the recent decline in global emissions. A further reduction in SO2 emissions would come from a large number of developing nations that currently lack effective SO2 emission controls.

Introduction. Neonatal infection with Cronobacter sakazakii can cause severe intestinal damage and necrotizing enterocolitis (NEC). The inflammasome and Toll-like receptors mediate intestinal damage caused by other intestinal pathogens causing NEC, but the exact mechanism is unclear. Aim. We evaluated the molecular mechanisms underlying C. sakazakii -induced NEC. Methodology. The effects of C. sakazakii treatment on two cell lines and a Sprague–Dawley rat model of NEC were evaluated by a cell death assay, western blot and real-time PCR analyses of the NLRP3 inflammasome and downstream factors, and observation of cell and intestinal damage. Results. C. sakazakii caused cellular damage in vitro, as well as intestinal damage in an animal model. NLRP3, caspase-1, TLR4 and MyD88, as well as the downstream factor IL-1β, were upregulated in C. sakazakii -infected J774A.1 and HT-29 cells. Western blotting showed that C. sakazakii-infected J774A.1 and HT-29 cells and the NEC rat model had higher expression levels of N-terminal gasdermin D (GSDMD) compared with those in the control groups. C. sakazakii and its components promote NF-κB expression via the TLR4/MyD88 signalling pathway, thereby regulating the NLRP3 inflammasome and mediating GSDMD cleavage, resulting in pyroptosis-induced intestinal damage. Conclusion. We found that C. sakazakii upregulates NF-κB via TLR4/MyD88 to promote activation of the NLRP3 inflammasome, leading to the up-regulation of downstream caspase-1, release of IL-1β, GSDMD-mediated pyroptosis and development of NEC. These findings clarify the mechanisms by which C. sakazakii contributes to NEC.

Smoking has become a major cause of chronic obstructive pulmonary disease through weakening of the respiratory mucus-ciliary transport system, impairing cough reflex sensitivity, and inducing inflammation. Recent researches have indicated that hydrogen sulfide is essential in the development of various lung diseases. However, the effect and mechanism of hydrogen sulfide on cigarette smoke-induced chronic obstructive pulmonary disease have not been reported. In this study, rats were treated with cigarette smoke to create a chronic obstructive pulmonary disease model followed by treatment with a low concentration of hydrogen sulfide. Pulmonary function, histopathological appearance, lung edema, permeability, airway remodeling indicators, oxidative products/antioxidases levels, inflammatory factors in lung, cell classification in bronchoalveolar lavage fluid were measured to examine the effect of hydrogen sulfide on chronic obstructive pulmonary disease model. The results showed that hydrogen sulfide effectively improved pulmonary function and reduced histopathological changes, lung edema, and permeability. Airway remodeling, oxidative stress, and inflammation were also reduced by hydrogen sulfide treatment. To understand the mechanisms, we measured the expression of TGF-β1, TGF-βIand TGF-βII receptors and Smad7 and phosphorylation of Smad2/Smad3. The results indicated that the TGF-β1 and Smad were activated in cigarette smoke-induced chronic obstructive pulmonary disease model, but inhibited by hydrogen sulfide. In conclusion, this study showed that hydrogen sulfide treatment alleviated cigarette smoke-induced chronic obstructive pulmonary disease through inhibition of the TGF-β1/Smad pathway. Impact statement COPD has become a severe public health issue in the world and smoking has become a major cause of COPD. As a result, it is a demandingly needed to explore new potential therapy for cigarette smoke-associated COPD. The present study suggested that H2S treatment improved pulmonary function and reduced histopathological changes, lung edema, permeability, inflammation, airway remodeling and oxidative injury in a COPD model induced by cigarette smoke. Although additional studies are required to elucidate the pharmacodynamics, pharmacokinetics, and pharmacology of H2S in the cigarette smoke-associated COPD, our findings provide an experimental basis for the potential clinical application of H2S in COPD treatment.

Our proclivity toward high-fidelity transmission of knowledge is one of the key mechanisms that underpins our success as a species. This study evaluated overimitation within children with hearing impairments (who had either a cochlear implant or a hearing aid) in relation to those with normal hearing. A total of seventy-two 4-year-old children were shown how to operate novel objects using a series of causally irrelevant actions, followed by causally relevant action. We measured the degree to which children reproduced the irrelevant actions as an indicator of imitative fidelity. Children with either hearing impairments or normal hearing replicated the irrelevant actions at rates above the baseline. However, imitative fidelity of the former group was significantly lower. In addition, children with hearing impairments were also less likely to identify and achieve the outcome by performing the relevant act. This study advances our understanding of social learning in children with hearing impairments and proposes potential weakness of social-cognitive skills within this population.

Scavenging reactive oxygen species (ROS) by antioxidants is an important therapy to neurodegenerative diseases. In this work, a new chalcone compound (E)-3-(3,4 -dichlorophenyl)-1-(3,4-dihydroxyphenyl)-prop-2-en-1-one (A1) with potent antioxidant activity in PC12 cells was found. The MTT assay showed that A1 at 10 μM had no apparent cytotoxicity in PC12 cells. DPPH assay exhibited A1 could scavenge ROS directly. Treatment with A1 could elevate the population of viable cells in a dose-dependent manner. Furthermore, A1 protected PC12 cells against H2O2-induced apoptosis. At the molecular level, A1 conferred cytoprotection against oxidative damage in PC12 cells via up-regulation of the expression of HO-1 and GCLC proteins. These findings suggest compound A1 to be a promising antioxidant for the treatment oxidative stress-related diseases.

Lung cancer is a common cancer with high mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for the majority. The clinical treatment effect of NSCLC is not ideal. The aim of this study was to investigate the inhibitory effect of sea cucumber peptide (SCP) on NSCLC and its mechanism. The results showed that SCP could effectively inhibit the proliferation, migration and invasion of A549 cells. In addition, SCP can also inhibit the formation of pleural effusion and tumor growth in lung cancer mice, reduce liver and kidney injury, increase the levels of IL-2 and IL-12, decrease the levels of IL-6 and TNF-α, and prolong the survival time of mice. The microRNA sequencing and immunohistochemistry of mouse tumors showed that the tumor suppressor gene TUSC2 targeted by miR-378a-5p was involved in the inhibition of tumor growth by SCP. This study provides an experimental basis for the further development of SCP as an anti-tumor nutritional supplement, and provides a new idea for exploring the molecular mechanism of food derived active peptides in anti-tumor applications.

Lung adenocarcinoma (LUAD) is the main subtype of non-small cell lung cancer with a poor survival prognosis. In our study, gene expression, DNA methylation, and clinicopathological data of primary LUAD were utilized to identify potential prognostic markers for LUAD, which were recruited from The Cancer Genome Atlas (TCGA) database. Univariate regression analysis showed that there were 21 methylation-associated DEGs related to overall survival (OS), including 9 down- and 12 up-regulated genes. The 12 up-regulated genes with hypomethylation may be risky genes, whereas the other 9 down-regulated genes with hypermethylation might be protective genes. By using the Step-wise multivariate Cox analysis, a methylation-associated 6-gene (consisting of CCL20, F2, GNPNAT1, NT5E, B3GALT2, and VSIG2) prognostic signature was constructed and the risk score based on this gene signature classified patients into high- or low-risk groups. Patients of the high-risk group had shorter OS than those of the low-risk group in both the training and validation cohort. Multivariate Cox analysis and the stratified analysis revealed that the risk score was an independent prognostic factor for LUAD patients. The methylation-associated gene signature may serve as a prognostic factor for LUAD patients and the represent hypermethylated or hypomethylated genes might be potential targets for LUAD therapy.

Objective: To explore the immune characteristics and short-term prognosis of children with autoimmune encephalitis (AE), then to analyse the relationship between them. Methods: A total of 78 children with AE were identified through the clinic database and inpatient consults in Tianjin Children’s Hospital (238 Long-Yan Road, Bei-Chen District, Tianjin, China) from January 2018 to January 2021. Based on the recent follow-up (one-year follow-up) of the modified Rankin Scale (mRS) prognosis score, they were divided into a good prognosis group (59 cases, mRS Results: The differences in age, consciousness disorder, limb dyskinesia, cognitive impairment, onset type, mRS score at admission, and immune function status during remission between the two groups were statistically significant (p < 0.05). The mRS score of the good prognosis group at admission was significantly lower than that of the poor prognosis group (2.65 ± 0.76 vs 3.05 ± 0.71, p ＜ 0.05). IgA (0.61 ± 0.19 vs 0.87 ± 0.25, p < 0.001), IgG (8.17 ± 1.12 vs 9.02 ± 1.39, p = 0.001). IgM (1.01 ± 0.26 vs 1.23 ± 0.33, p < 0.001) in the good prognosis group were significantly lower than those in the poor prognosis group, while CD4 (36.35 ± 8.74 vs 23.89 ± 6.97, p < 0.001) and CD4/CD8 (1.68 ± 0.32 vs 1.01 ± 0.24, p = 0.001) were significantly higher than those in the poor prognosis group. Spearman correlation analysis showed that the mRS score at admission was significantly negatively correlated with CD4/CD8 (r ＝−0.775, p < 0.001), but not significantly correlated with other immune function indexes. Binary logistic regression showed that age (OR = 0.385; 95% CI = 0.200–0.741), consciousness disorder (OR = 39.3569; 95% CI = 4.073–380.262), limb movement disorder (OR = 17.107; 95% CI = 2.769–105.701), and abnormal immune function in remission (OR = 0.050; 95% CI = 0.007–0.372) were risk factors for poor prognosis in children with AE. Conclusion: There is a close correlation between mRS and immune function index CD4/CD8 in children with AE when they are admitted to the hospital. Young age, disturbance of consciousness, limb dyskinesia, and abnormal immune function in remission are risk factors for poor prognosis of children with AE. More attention should be paid in clinical treatment.

Background With the increasing incidence of osteoporosis, vitamin K and calcium have been linked to bone mineral density (BMD) and undercarboxylated osteocalcin (UcOC) in many studies, but the results of studies of the combined effect of vitamin K and calcium on BMD and UcOC in humans have been inconsistent. We conducted a systematic review of randomized controlled trials to assess the effect of this combination treatment on BMD and UcOC in humans. Methods A search for articles was conducted using PubMed, Embase, and the Cochrane Library database up to March 2021 (no language restrictions). We also reviewed the reference lists of the relevant publications and reviews to locate additional publications. The standard mean difference (SMD) was used as the primary measure of effect size. Our main endpoints were lumbar BMD, femoral neck BMD, hip BMD, total femoral BMD, and UcOC from baseline to end point. We performed subgroup analysis, heterogeneity testing, and assessment of publication bias. Results A total of 1346 patients from 10 randomized controlled trials were included in the meta-analysis. The forest plot analysis revealed that vitamin K combined with calcium was associated with a higher lumbar spine BMD compared to controls. The SMD was 0.20 [95% confidence interval (CI): 0.07 to 0.32]. Vitamin K and calcium supplementation led to a significant decrease in UcOC (SMD: − 1.71, 95% CI: − 2.45 to − 0.96). Subgroup analysis showed that vitamin K2 and vitamin K1 had SMDs of 0.30 (95% CI: 0.10 to 0.51) and SMDs of 0.14 (95% CI: − 0.02 to 0.29), and calcium dosages of ≤ 1000 mg/d or > 1000 mg/d had SMDs of 0.19 (95% CI: 0.05 to 0.32) and 0.26 (95% CI: − 0.04 to 0.55). Conclusion The combination of vitamin K and calcium has a positive effect on lumbar BMD and decreases the level of UcOC. Registration: The protocol for this meta-analysis was registered at the International Prospective Register of Systematic Reviews (CRD42021251825).

Previous reports demonstrated that aristolochic acids (AAs) exposure-induced nephrotoxicity, mutations, and tumorigenesis are mainly due to aristolochic acid I (AAI). Notably, the chemical structure of aristolochic acid IVa (AAIVa), which exists at higher levels in many Aristolochiaceae herbs, is extremely similar to AAI. In lack of toxicological data, it is unknown whether AAIVa exposure leads to aristolochic acid nephropathy (AAN), mutations, and tumorigenesis as of AAI. To answer these questions, mice were administered AAIVa by single or repeated long-term gavage, while AAI was used as a positive control. We found that single gavage of 40 mg/kg of AAIVa exhibited no obvious toxicity. Also, there were no tumors or death in mice administrated with 1 and 10 mg/kg of AAIVa for 6 months followed by a 12-month recovery time. There were no noteworthy alterations in gene mutation frequency in the kidney, liver, and stomach between the AAIVa and control mice. Fascinatingly, AA-associated mutational signatures, adenine-to-thymine (A>T) transversions, were absent in AAIVa-treated mice. Nonetheless, 10 mg/kg of AAIVa triggered lymphocytic infiltration and slight fibrous hyperplasia in the kidney at the 6th month; however, these were alleviated at the 12th and 18th months. On the contrary, AAI (positive control) caused severe diffuse fibrosis, tubular atrophy, necrosis, tumors in the forestomach and kidney, and death after the 6th month. It seems that long-term AAIVa exposure induced mild renal lesions could be due to the activation of the canonical or noncanonical transforming growth factor-β (TGFβ) pathway. Overall, these findings suggest that the mutagenicity and carcinogenic risk of AAIVa are very low.

The aim of the present study was to examine whether adiponectin could inhibit cardiomyocyte senescence induced by D‑galactose (D‑gal), and whether it functioned via the adiponectin receptor 1 (AdipoR1)/adaptor protein phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) signaling pathway. For this purpose, the expression levels of adiponectin, AdipoR1 and APPL1 in mouse plasma and myocardial tissues were detected via reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. An adiponectin‑overexpression plasmid was transfected into D‑gal‑treated H9c2 cells prior to the detection of AdipoR1 and APPL1 expression by RT‑qPCR. Senescence‑associated β‑galactose staining was then performed to observe cellular senescence following the transfection of small interfering RNAs (si) targeting AdipoR1 and APPL1 into D‑gal‑treated H9c2 cells overexpressing adiponectin. Commercial kits were used to detect reactive oxygen species (ROS) production and malondialdehyde (MDA) content in the different groups. The expression levels of heme oxygenase (HO)‑1 and high mobility group box 1 (HMGB1) were examined by western blot analysis. The results revealed that the expression levels of adiponectin, AdipoR1 and APPL1 were downregulated in aged mouse plasma, myocardial tissues and D‑gal‑treated cardiomyocytes. It was also observed that AdipoR1 and APPL1 expression levels were significantly upregulated following the overexpression of adiponectin into D‑gal‑treated cardiomyocytes. Moreover, adiponectin overexpression reduced cellular senescence induced by D‑gal and the expression of p16 and p21; these effects were reversed following transfection with si‑AdipoR1 and si‑APPL1. Adiponectin also downregulated the levels of ROS and MDA in D‑gal‑treated H9c2 cells via AdipoR1/APPL1. Additionally, the release of HO‑11/HMGB1 was affected by adiponectin via AdipoR1/APPL1, and adiponectin/AdipoR1/APPL1 suppressed ROS production via HO‑1/HMGB1. On the whole, the present study demonstrated that adiponectin played an inhibitory role in cardiomyocyte senescence via the AdioR1/APPL1 signaling pathway and inhibited the levels of oxidative stress in senescent cardiomyocytes via the HO‑1/HMGB1 signaling pathway.

Acute renal injury (ARI) is a life-threatening condition and a main contributor to end-stage renal disease, which is mainly caused by ischemia-reperfusion (I/R). miR-106b-5p is a kidney function-related miRNA; however, whether miR-106b-5p regulates the progression of ARI remains unclear. The present study thus aimed to examine the effects of miR-106b-5p antagonist on the regulation of ARI progression. It was found that miR-106b-5p expression was upregulated in the renal tissue of rats with I/R-induced ARI and in NRK-52E rat renal proximal tubular epithelial cells subjected to hypoxia-reoxygenation (H/R). In vitro, H/R induction suppressed the proliferation, and promoted the apoptosis and autophagy of NRK-52E cells, whereas miR-106b-5p antagonist (inhibition of miR-106b-5p) promoted the proliferation, and attenuated the apoptosis and autophagy of NRK-52E cells under the H/R condition. Dual luciferase reporter gene assay validated that transcription factor 4 (TCF4) was a target of miR-106b-5p. It was further found that TCF4 overexpression promoted the proliferation, and inhibited the apoptosis and autophagy of NRK-52E cells subjected to H/R. Moreover, the effects of miR-106b-5p antagonist on NRK-52E cell proliferation, apoptosis and autophagy were mediated through the regulation of TCF4. In vivo, miR-106b-5p antagonist reduced the severity of renal injury, decreased cell proliferation in renal tissues and lowered the serum creatinine (Scr) and blood urea nitrogen (BUN) levels in the blood samples from rats with I/R-induced ARI. On the whole, the findings presented herein demonstrate that miR-106b-5p antagonist attenuates ARI by promoting the proliferation, and suppressing the apoptosis and autophagy of renal cells via upregulating TCF4.

Although the physical effects of air pollution on humans are well documented, there may be even greater impacts on the emotional state and health. Surveys have traditionally been used to explore the impact of air pollution on people’s subjective well-being (SWB). However, the survey techniques usually take long periods to properly match the air pollution characteristics from monitoring stations to each respondent’s SWB at both disaggregated spatial and temporal levels. Here, we used air pollution data to simulate fixed-scene images and psychophysical process to examine the impact from only air pollution on SWB. Findings suggest that under the atmospheric conditions in Beijing, negative emotions occur when PM2.5 (particulate matter with a diameter less than 2.5 µm) increases to approximately 150 AQI (air quality index). The British observers have a stronger negative response under severe air pollution compared with Chinese observers. People from different social groups appear to have different sensitivities to SWB when air quality index exceeds approximately 200 AQI., Air pollution can affect people’s emotional status and well-being. Here, the authors simulate fixed-scene images to show that under the atmospheric conditions in Beijing, negative emotions occur when air quality index of PM2.5 increases to approximately 150.

Summary Multi-targeted kinase inhibitors, such as sorafenib, have been used in various malignancies, but their efficacy in clinical applications varies among individuals and lacks pretherapeutic prediction measures. We applied the concept of “click chemistry” to pathological staining and established a drug-loaded probe staining assay. We stained the cells and different types of pathological sections and demonstrated that the assay was reliable. We further verified in cells, cell-derived xenograft model, and clinical level that the staining intensity of the probe could reflect drug sensitivity. The stained samples from 300 patients who suffered from hepatocellular carcinoma and used the sorafenib probe also indicated that staining intensity was closely related to clinical information and could be used as an independent marker without undergoing sorafenib therapy for prognosis. This assay provided new ideas for multi-target drug clinical trials, pre-medication prediction, and pathological research., Graphical Abstract, Highlights • The assay could be used for the rapid sensitivity detection of multi-target drugs • The assay could serve as an auxiliary technology for NGS and PDX • Sorafenib had multiple unknown primary contribution targets • Drug-probe staining could be used as an independent diagnostic and prognostic marker, Drugs; Medical Biochemistry; Biochemical Assay

Numerous studies have demonstrated an overlap between the processing of self-pain and others' pain, which suggests that psychological and neural representations are shared between the perception of physical pain and empathy for pain. As hearing emotional exclamations is a common way in which we regularly perceive and empathize with others' pain, the present study aimed to investigate the link between sensitivity to physical pain and the sounds made by others in pain. We recorded event-related potential (ERP) responses to another person's vocalizations (neutral or painful intonation) and identified electrophysiological responses associated with the processing of painful sounds. Additionally, individual pain sensitivity was characterized by a stimulus-response function that described the relationship between objective stimulus intensity and subjective pain intensity. Results showed that compared with hearing others' neutral sounds, hearing others' sounds of pain elicited more positive frontal-central N1 and N2 responses as well as more positive central-parietal P3 and late positive potential responses. These electrophysiological responses to hearing others' pain replicated electrophysiological responses to observing pictures and video clips of people in pain. Importantly, the neural responses to hearing others in pain were associated with physical pain sensitivity that was indexed by stimulus-response characteristics. The identified link between perception of one's own physical pain and the sounds of others in pain further supports the shared common psychological computations between processing one's own pain and empathizing with others' pain.

The present study aimed to investigate the alterations of psychophysiological responses to empathy for pain among patients with somatoform pain disorder (SPD). Behavioral and event-related potential (ERP) responses to pictures depicting hands or feet in different non-painful or painful situations were compared between 18 SPD patients and 18 healthy controls. Patients with SPD reported lower unpleasantness to the observation of others' pain than healthy controls, thus suggesting a reduced affective sharing to others' pain in SPD. While healthy controls showed significant different N2 and P3 responses between painful and non-painful stimulations, no significant difference was observed for patients with SPD. In addition, while both patients and controls showed enlarged late positive potential (LPP) response to painful stimulation than to non-painful stimulation, the differential LPP response was significantly smaller in patients than controls. These ERP results suggested a reduced response to empathy for pain in both early affective and late cognitive temporal stages in SPD. Mediation analysis further revealed that alexithymia mediated the effect of somatoform pain on empathic N2 responses, suggesting that the reduced early affective sharing process in SPD was mediated by their heightened alexithymia. To sum up, our results demonstrated the reduced psychophysiological responses to empathy for pain among patients with SPD, where the reduced affective sharing process could be explained by the concurrent alexithymia. While the altered empathy for pain exhibited by these patients with SPD could impact their social functioning, our study would provide some insights into interventions aimed at improving empathy-related social functioning.

While empathic responses of individuals with autism-spectrum disorder have been reported to be modulated by top-down attention, it remains unclear whether empathy for pain in typically developing individuals with autistic traits also involves such top-down modulation mechanisms. This study employed the autism-spectrum quotient (AQ) to quantify autistic traits in a group of 1,231 healthy adults. Two subset groups (High-AQ and Low-AQ groups) were randomly selected from the highest and lowest 10% AQ scores respectively. We explored whether participants in both groups would differ in their response to others’ pain when their attention was directed toward (A-P tasks) or away (A-N tasks) from pain cues in auditory and visual experimental modalities. Compared to Low-AQ individuals, High-AQ individuals exhibited more suppressed N1 and P2 amplitudes in response to painful vocal cues in auditory A-N tasks. This suggests suppressed attentional and emotional processes of empathy for pain when High-AQ individuals have their attention directed away from others’ pain cues. No significant difference was found between both groups in the auditory A-P task, nor in the visual A-P and A-N tasks. These results suggest that top-down attention modulation of cortical empathic responses to others’ vocal pain is influenced by autistic traits.

Pyrimethamine (Pyr), an antimalarial drug that targeting plasmodium dihydrofolate reductase (pDHFR), has been proved to have antitumor activity. However, its direct target on cancer cells remains unclear. Methotrexate (MTX) is a widely used anticancer drug that blocks human dihydrofolate reductase (hDHFR). In this work, we examined the anticancer effects of Pyr in vitro and in vivo. Our results showed that hDHFR and pDHFR have similar secondary and three-dimensional structures and that Pyr can inhibit the activity of hDHFR in lung cancer cells. Although Pyr and MTX can inhibit the proliferation of lung cancer cells by targeting DHFR, only Pyr can inhibit the epithelial–mesenchymal transition (EMT), metastasis and invasion of lung cancer cells. These results indicated that hDHFR is not the only target of Pyr. We further found that thymidine phosphorylase (TP), an enzyme that is closely associated with the EMT of cancer cells, is also a target protein of Pyr. The data retrieved from the Cancer Genome Atlas (TCGA) database revealed that TP overexpression is associated with poor prognosis of patients with lung cancer. In conclusion, Pyr plays a dual role in antitumor proliferation and metastasis by targeting DHFR and TP. Pyr may have potential clinical applications for the treatment of lung cancer.

Lycium ruthenicum Murr. (LR) is a perennial shrub commonly used as a nutritional food and medicine. Herein, we identified 12 anthocyanins from LR, with petunidin derivatives constituting approximately 97% of the total anthocyanin content. Furthermore, the potential mechanism of anthocyanins exerting neuroprotective effects in d-galactose (d-gal)-treated rats was explored. Behavioral results showed that anthocyanins relieved d-gal-induced memory disorder. Additionally, anthocyanins reduced receptor for advanced glycation end products (RAGE) and suppressed oxidative stress caused by d-gal. Anthocyanins suppressed microgliosis and astrocytosis and reduced the overexpression of nuclear factor kappa B (NF-κB), interleukin-1-β (IL-1β), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α). Moreover, anthocyanins lowered C-jun N-terminal kinase ( p-JNK), caspase-3 levels, and the B-cell lymphoma 2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) ratio. Thus, anthocyanins from LR attenuated memory disfunction, neuroinflammation, and neurodegeneration caused by d-gal, possibly through the RAGE/NF-κB/JNK pathway, representing a promising, safe candidate for prevention and therapy of neurodegenerative diseases.

Quaking (QKI) is an alternative splicing factor that can regulate circRNA formation in the progression of epithelial–mesenchymal transition, but the mechanism remains unclear. High expression of QKI is correlated with short survival time, metastasis, and high clinical stage and pathology grade in hepatocellular carcinoma (HCC). Here we report that transcription of the QKI gene was activated by the Yin-Yang 1 (YY1)/p65/p300 complex, in which YY1 bound to the super-enhancer and promoter of QKI, p65 combined with the promoter, and p300 served as a mediator to maintain the stability of the complex. This YY1/p65/p300 complex increased QKI expression to promote the malignancy of HCC as well as an increased circRNA formation in vitro and in vivo. Hyperoside is one of several plant-derived flavonol glycoside compounds. Through virtual screening and antitumor activity analysis, we found that hyperoside inhibited QKI expression by targeting the YY1/p65/p300 complex. Overall, our study suggests that the regulatory mechanism of QKI depends on the YY1/p65/p300 complex and that it may serve as a potential target for treatment of HCC. Significance: These findings identify the YY1/p65/p300 complex as a regulator of QKI expression, identifying several potential therapeutic targets for the treatment of HCC.

BACKGROUND: Vertically integrating anatomy into pathology curricula is beneficial for student-centered learning. This study investigates the effectiveness of this approach on student learning outcomes. ACTIVITY: Learners received a vertically integrated pathology curriculum; their pre- and post-course test data were collected. RESULTS AND DISCUSSION: Two-hundred thirty-two learners participated in the activity. Upon completing the activity, their average post-course performance was significantly better than that of a control group (P

Background: Inversion deformities caused by insufficient medial support are especially common when the PHILOS locking plate is used to treat proximal humeral fractures. Using finite element analysis, the present study aimed to compare the biomechanical properties of a PHILOS locking plate (PLP) and a PHILOS plate combined with a lateral intertubercular sulcus plate (PLP-LSP) in the fixation of proximal humeral fractures with loss of the medial column. We also present representative results for a 69-year-old female patient with a comminuted fracture of the proximal right humerus (Neer type four-part fracture) who underwent successful surgical treatment with a PHILOS plate combined with an auxiliary lateral intertubercular sulcus plate. Methods: After creating a three-dimensional finite element model of proximal humeral fracture with loss of the medial column, three implant models were established. A full-screw PHILOS plate (PLP) was used in Group A, while a PHILOS plate lacking medial screw support and an auxiliary plate were used in Group B (MPLP-LSP). A full-screw PHILOS plate and auxiliary plate were used in Group C (PLP-LSP). The three fixation models were applied to the proximal humerus fracture model, following which horizontal, compressive, and rotational loads were applied to the humerus model. We evaluated the structural stiffness and stress distribution of the implant and compared displacement and angle changes among the three models. Results: Displacement and angle changes were smallest in Group C (PLP-LSP). The implant model used in Group C also had the highest structural rigidity, endured less von Misses stress than the other two models , and had the strongest stability. In our clinical case, X-ray and computed tomography images obtained 3 months after the operation indicated that the fracture had healed, with good positioning of internal fixation and good functional recovery.Conclusion: A lateral intertubercular sulcus plate placed at the internodal grove not only aids in anatomical reduction but also provides effective lateral and medial support, thereby reducing stress on the PHILOS plate and providing better stability in patients with proximal humeral fractures.

Background: As society ages, the incidence of osteoporosis increases. In several studies, cadmium (Cd) is thought to be related to osteoporosis. However, there are conflicting reports about the relationship between Cd and the risk of osteoporosis and osteopenia. Therefore, the purpose of this meta-analysis was to explore the relationship between Cd and osteoporosis and osteopenia.Methods: Through a review of the literature, articles published in PubMed as of December 2020 were identified and the references of related publications and reviews were reviewed. Ultimately, 17 eligible articles were selected to determine the relationship between blood and urine Cd concentrations for the risk of osteoporosis or osteopenia. In this study, we performed a classification analysis, heterogeneity test, subgroup analysis, and evaluated publication bias.Results: A total of 17 studies were included, including seven on blood Cd and 10 on urine Cd. By combining the odds ratio (OR) and 95% confidence interval (CI) for the lowest and highest categories, the odds ratio of blood Cd concentration that increased the risk of osteoporosis or osteopenia was OR 1.21 (95% CI: 0.84–1.58) and that of urine Cd concentration that increased the risk of osteoporosis or osteopenia was OR 1.80 (95% CI: 1.42–2.18), and the results of the subgroup analysis were also consistent.Conclusions: Our research indicates that while urine cadmium (Cd) concentration may be related to increased risk of osteoporosis and osteopenia, blood Cd concentration may not. Therefore, compared to blood Cd concentration, urine Cd concentration may be more reliable as a risk factor for osteoporosis and osteopenia. This result should be interpreted with caution. Currently. research on the relationship between Cd concentration and osteoporosis and osteopenia is limited, thus, further large, high-quality prospective studies are required to elucidate the relationship between Cd concentration and osteoporosis and osteopenia.

Atherosclerosis is the most common cause of cardiovascular disease and is accompanied by high mortality rates and a poor prognosis. Semaphorin 7A (Sema7A) and its receptor β1 integrin have been reported to participate in the development of atherosclerosis. However, the role of Sema7A and β1 integrin in endothelial cell injury and endothelial-to-mesenchymal transition (EMT) in atherosclerosis remains undetermined, to the best of our knowledge. The mRNA and protein expression levels of Sema7A and β1 integrin in HUVECs were analyzed using reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses, respectively. HUVECs were induced with 50 µg/ml oxidized low-density lipoprotein (ox-LDL) to establish an atherosclerosis cell model. Cell viability was measured using Cell Counting Kit-8 assay and the production of IL-1β, IL-6 and C-C motif chemokine ligand 2 was determined using ELISA. The expression levels of cell adhesion factors, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 were analyzed using RT-qPCR and western blot analyses. Cell apoptosis was detected using flow cytometry and western blotting. The levels of EMT-related markers were evaluated using RT-qPCR, western blotting and immunofluorescence staining. The results of the present study revealed that the expression levels of Sema7A and β1 integrin were significantly upregulated in ox-LDL-treated HUVECs. Treatment with ox-LDL significantly decreased cell viability, and increased the levels of inflammatory and adhesion factors, the cell apoptotic rate and the expression levels of EMT-related proteins. Knockdown of Sema7A reversed the ox-LDL-induced inflammatory responses and EMT, while the overexpression of β1 integrin reversed the Sema7A-mediated inhibitory effects on ox-LDL-treated HUVECs. In conclusion, the findings of the present study indicated that Sema7A and β1 integrin may play significant roles in atherosclerosis by mediating endothelial cell injury and EMT progression.

Background We investigated whether glycemic control affects the relation between endothelial dysfunction and coronary artery disease in patients with type 2 diabetes mellitus (T2DM). Methods In 102 type 2 diabetic patients with stable angina, endothelial function was evaluated using brachial artery flow-mediated dilation (FMD) with high-resolution ultrasound, and significant stenosis of major epicardial coronary arteries (≥ 50% diameter narrowing) and degree of coronary atherosclerosis (Gensini score and SYNTAX score) were determined. The status of glycemic control was assessed by blood concentration of glycated hemoglobin (HbA1c). Results The prevalence of significant coronary artery stenosis (67.9% vs. 37.0%, P = 0.002) and degree of coronary atherosclerosis (Gensini score: 48.99 ± 48.88 vs. 15.07 ± 21.03, P 0.05). Conclusion Poor glycemic control negatively influences the association of endothelial dysfunction and coronary artery disease in T2DM patients.

With the steady advancement of the United Nations Sustainable Development Goals (SDGs), how to build a sustainable environment for human settlements has become a hot topic of research for scholars from various countries. Rational space utilization and resource allocation are the keys to enhancing human well-being and achieving sustainable human settlements. A comprehensive human settlement environment evaluation system, which includes 14 indicators from the natural environment, infrastructure, and public services, was established in this study. The results showed that the habitat suitability area only accounted for 1.61% (2.05% after removing the nature reserve) and all centered on cities and radiated to the surrounding areas. A belt-like suitability distribution pattern of “Yi Jiang Liang He” (i.e., Brahmaputra, Lhasa, and Nianchu Rivers) is formed, and a point-like suitability distribution pattern of the Chamdo Karub District, Nagqu Seni District, and Ngari Shiquanhe Town are formed. The results of the driving factor analysis indicate that the level of public health development in infrastructure and various indicators in public services are the main factors influencing human settlement. There is not much difference in the natural environment in the populated regions, so the suitability of the natural environment is not a significant driving factor. In addition, the reliability of the assessment results was verified by a questionnaire survey of residents in the three regions, and the subjective satisfaction of the residents agreed with the ranking results of the objective evaluation. The evaluation results of this study provide theoretical and directional guidance for the improvement of human settlements on the Qinghai–Tibet Plateau. It will be a useful tool for evaluating human settlements in the region and has a reference significance for the formulation of macro-policy in high-altitude regions.

Individuals with autistic traits display impaired social interaction and communication in everyday life, but the underlying cognitive neural mechanisms remain very unclear and still remain controversial. The mind-blindness hypothesis suggests that social difficulties in individuals with autistic traits are caused by empathy impairment in individuals; however, the intense world theory suggests that these social difficulties are caused by sensory hyper-reactivity and sensory overload, rather than empathy impairment. To further test these two theories, this study investigated event-related potentials (ERPs) to explore the cognitive neural processing of repetitive expressions in individuals with autistic traits. This study employed the Mandarin version of the autism-spectrum quotient (AQ) to assess autistic traits in 2,502 healthy adults. Two subset groups were used, e.g., the participants of a high-AQ group were randomly selected among the 10% of individuals with the highest AQ scores; similarly, the participants in the low-AQ group were randomly selected from the 10% of participants with the lowest AQ scores. In an experiment, three different facial expressions (positive, neutral, or negative) of the same person were presented successively and pseudo-randomly in each trial. Participants needed to define the expression of the face that was presented last. The results showed that compared with the low-AQ group, the high-AQ group exhibited higher P1 amplitudes induced by the second and third presented expressions, as well as higher P3 amplitudes induced by the third presented negative expressions. This indicates that individuals with autistic traits may experience overly strong perception, attention, and cognitive evaluation to repetitive expressions, particularly negative expressions. This result supports the intense world theory more strongly than the mind-blindness hypothesis.