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Abstract Background An increasing number of studies have focused on ailanthone (aila) due to its antitumor activity. However, the role of ailanthone in glioblastoma(GBM) has not been investigated before. This study aims to explore the biological function and the underlying mechanism of ailanthone in GBM. Methods The microarray analysis was used to screen out down-stream long non-coding RNAs (lncRNAs) targeted by ailanthone. Real-time PCR(RT-PCR) assay was used to examine LINC01956 expression levels. Colony-formation, Methylthiazolyldiphenyl-tetrazolium bromide(MTT), cell-cycle, organoids culture and in-vivo tumorigenesis assays were used to examine cell growth in vitro and in vivo. Boyden assay was used to examine cell invasion ability in vitro. RNA immunoprecipitation and RNA-protein pull-down assays were used to examine the interaction between LINC01956 and FUS protein. Chromatin Immunoprecipitation(ChIP) assay was used to examine HIF1-α-binding sites in the LINC01956 promoter. Results Ailanthone decreased GBM cell growth in vitro and in vivo via inducing ferroptosis. Ailanthone treatment exhibited blood‒brain barrier(BBB) permeability and specifically targeted the tumor area. LINC01956 was identified as a down-stream target of Ailanthone. LINC01956 exerted as an onco-lncRNA in GBM. M2 polarization of macrophages induced by exosomes derived from glioma cells overexpressing LINC01956 accelerated GBM progression. Mechanistically, we found that LINC01956 bound to FUS and reduced its ubiquitination. LINC01956 evoked nuclear translocation of phosphorylated (p)-β-catenin by recruiting FUS. Furthermore, under hypoxic conditions, LINC01956 was regulated by HIF-1α. Ailanthone decreased the expression of LINC01956 via suppressing HIF-1α. Conclusion Taken together, our data revealed for the first time that ailanthone regulated HIF-1α/LINC01956/FUS/β-catenin signaling pathway and thereby inhibited GBM progression.

Abstract Wind sensors have always played an irreplaceable role in environmental information monitoring and are expected to operate with lower power consumption to extend service lifetime. Here, we propose a breeze wake-up anemometer (B-WA) based on a rolling-bearing triboelectric nanogenerator (RB-TENG) with extremely low static power. The B-WA consists of two RB-TENGs, a self-waking-up module (SWM), a signal processing module (SPM), and a wireless transmission unit. The two RB-TENGs are employed for system activation and wind-speed sensing. Once the ambient wind-speed exceeds 2 m/s, the wake TENG (W-TENG) and the SWM can wake up the system within 0.96 s. At the same time, the SPM starts to calculate the signal frequency from the measured TENG (M-TENG) to monitor the wind speed with a sensitivity of 9.45 Hz/(m/s). After the wind stops, the SWM can switch off the B-WA within 0.52 s to decrease the system energy loss. In quiescent on-duty mode, the operating power of the B-WA is less than 30 nW, which can greatly extend the service lifetime of the B-WA. By integrating triboelectric devices and rolling bearings, this work has realized an ultralow quiescent power and self-waked-up wireless wind-speed monitoring system, which has foreseeable applications in remote weather monitoring, IoT nodes, and so on.

The membrane-proximal external region (MPER) represents a highly conserved region of the Human Immunodeficiency Virus (HIV) envelope glycoprotein (env) targeted by several broadly neutralizing antibodies (bnAbs). In this study, we employed single genome amplification to amplify 34 full-length env sequences from the 2005 plasma sample of CBJC504, a chronic HIV-1 clade B infected individual. We identified three amino acid changes (N671S, D674N, and K677R) in the MPER. A longitudinal analysis revealed that the proportion of env sequences with MPER mutations increased from 26.5 % in 2005 to 56.0 % in 2009, and the sequences with the same mutation clustered together. Nine functional pseudoviruses were generated from the 34 env sequences to examine the effect of these mutations on neutralizing activity. Pseudoviruses carrying N674 or R677 mutations demonstrate increased sensitivity to autologous plasma and monoclonal antibodies 2F5, 4E10, and 10E8. Reverse mutations were performed in env including N674, R677, D659, and S671/N677 mutations, to validate the impact of the mutations on neutralizing sensitivity. Neutralization assays indicated that the N671S mutation increased neutralization sensitivity to 2F5 and 10E8. The amino acid R at position 677 increased viral resistance to 10E8, whereas N enhanced viral resistance to 4E10 and 10E8. It has been proposed that critical amino acids in the extra-MPER and the number of potential N-like glycosylation sites (PNGSs) in the V1 loop may have an impact on neutralizing activity. Understanding the mutations and evolution of MPER in chronically infected patients with HIV-1 is crucial for the design and development of vaccines that trigger bnAbs against MPER.

BackgroundLong-term non-progressors (LTNPs) with HIV infection can naturally control viral replication for up to a decade without antiretroviral therapy (ART), but the underlying mechanisms of this phenomenon remain elusive.MethodsTo investigate the relevant immune and inflammatory factors associated with this natural control mechanism, we collected plasma samples from 16 LTNPs, 14 untreated viral progressors (VPs), 17 successfully ART-treated patients (TPs), and 16 healthy controls (HCs). The OLINK immune response panel and inflammation panel were employed to detect critical proteins, and the plasma neutralizing activity against a global panel of pseudoviruses was assessed using TZM-bl cells.ResultsThe combination of IL17C, IL18, DDX58, and NF2 contributed to discriminating LTNPs and VPs. IL18 and CCL25 were positively associated with CD4+ T cell counts but negatively correlated with viral load. Furthermore, CXCL9 and CXCL10 emerged as potential supplementary diagnostic markers for assessing the efficacy of antiretroviral therapy (ART). Finally, TNFRSF9 displayed positive correlations with neutralization breadth and Geometry Median Titer (GMT) despite the lack of significant differences between LTNPs and VPs.ConclusionIn summary, this study identified a set of biomarkers in HIV-infected individuals at different disease stages. These markers constitute a potential network for immune balance regulation in HIV infection, which is related to the long-term control of HIV by LTNPs. It provides important clues for further exploring the immune regulatory mechanism of HIV.

ObjectiveCurrent evidence on the association between dietary vitamin E intake and the risk of Parkinson's disease (PD) is limited. The aim of the study was to explore the association of dietary vitamin E intake with PD in the United States among adults over 40 years.MethodsWe conducted a cross-sectional study with data collected from National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018. A total of the sample of 13,340 participants were included. To identify the different characteristics of the participants, we utilized propensity score matching (PSM) to reduce the effects of selection bias and confounding variables. Weighted univariate and multivariable logistic regression were used to examine the association between dietary vitamin E intake and PD before and after matching. Then, restricted cubic spline (RCS) was used to visually describe the possible non-linear relationships. Finally, we employed the subgroup analysis to further investigate the relationship between dietary vitamin E intake and PD.ResultsAccording to the weighted univariate and multivariable logistic regression analysis, vitamin E intake was inversely associated with the risk of PD before and after matching. The results of RCS analysis revealed no non-linear inverse relationship between vitamin E intake and PD before and after matching. The subgroup analysis showed that age may influence the negative association between vitamin E and PD (P < 0.05 for interaction).ConclusionAmong participants over 40 years of age, vitamin E intake was negatively associated with the risk of PD. Our data may support the supplementation of vitamin E to be used as an intervention strategy for the occurrence of PD.

Abstract Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder and seriously affects quality of life globally. Moxibustion is widely used to treat neurodegenerative diseases in the clinic and has achieved a beneficial clinical effect. However, strict control and high-quality randomized controlled trials are still lacking. Therefore, this trial aims to evaluate the clinical efficacy and safety of moxibustion in patients with PD and preliminarily explore the underlying mechanism. Methods This is a randomized, single-blind and placebo-controlled trial design in which 70 eligible participants will be randomly divided into a moxibustion group and a sham moxibustion group. Baihui (DU20) and Sishenchong (EX-HN1) are selected for both groups. The treatment will be performed for 30 min per session, two sessions a week for 8 weeks. The mean change in MDS-UPDRS scores (including MDS-UPDRS II, III subscale scores and total scores) from baseline to the observation points will be the primary outcome. The secondary outcomes will include scores on the Parkinson’s Disease Questionnaire-39 (PDQ-39), Fatigue Severity Scale (FSS), Parkinson Disease Sleep Scale (PDSS), Montreal Cognitive Assessment (MoCA), and Self-Rating Depression Scale (SDS) as well as the Wexner constipation score. All the above outcomes will be assessed at 4 and 8 weeks. Laboratory blood biochemical analysis and functional magnetic resonance imaging (fMRI) will be conducted at baseline and at the end of treatment to explore the potential mechanisms of moxibustion in regulating PD. Discussion In conclusion, the results of this trial will reveal whether moxibustion is effective for treating motor and nonmotor symptoms in PD. This trial will also preliminarily explore the underlying mechanism of the regulatory effect of moxibustion in PD, which will contribute to providing a theoretical basis for the treatment of PD. Trial registration ClinicalTrials.gov ChiCTR2000029745. Registered on 9 August 2021.

Functional tissue engineering strategies provide innovative approach for the repair and regeneration of damaged cartilage. Hydrogel is widely used because it could provide rapid defect filling and proper structure support, and is biocompatible for cell aggregation and matrix deposition. Efforts have been made to seek suitable scaffolds for cartilage tissue engineering. Here Alg-DA/Ac-β-CD/gelatin hydrogel was designed with the features of physical and chemical multiple crosslinking and self-healing properties. Gelation time, swelling ratio, biodegradability and biocompatibility of the hydrogels were systematically characterized, and the injectable self-healing adhesive hydrogel were demonstrated to exhibit ideal properties for cartilage repair. Furthermore, the new hydrogel design introduces a pre-gel state before photo-crosslinking, where increased viscosity and decreased fluidity allow the gel to remain in a semi-solid condition. This granted multiple administration routes to the hydrogels, which brings hydrogels the ability to adapt to complex clinical situations. Pulsed electromagnetic fields (PEMF) have been recognized as a promising solution to various health problems owing to their noninvasive properties and therapeutic potentials. PEMF treatment offers a better clinical outcome with fewer, if any, side effects, and wildly used in musculoskeletal tissue repair. Thereby we propose PEMF as an effective biophysical stimulation to be 4th key element in cartilage tissue engineering. In this study, the as-prepared Alg-DA/Ac-β-CD/gelatin hydrogels were utilized in the rat osteochondral defect model, and the potential application of PEMF in cartilage tissue engineering were investigated. PEMF treatment were proven to enhance the quality of engineered chondrogenic constructs in vitro, and facilitate chondrogenesis and cartilage repair in vivo. All of the results suggested that with the injectable self-healing adhesive hydrogel and PEMF treatment, this newly proposed tissue engineering strategy revealed superior clinical potential for cartilage defect treatment.

In this study, we investigate a delayed reaction-diffusion predator-prey system with the effect of toxins. We first investigate whether the internal equilibrium exists. We then provide certain requirements for the presence of Turing and Hopf bifurcations by examining the corresponding characteristic equation. We also study Turing-Hopf and Hopf bifurcations brought on by delays. Finally, numerical simulations that exemplify our theoretical findings are provided. The quantitatively obtained properties are in good agreement with the findings that the theory had predicted. The effects of toxins on the system are substantial, according to theoretical and numerical calculations.

Abstract Background Seagrasses are higher marine flowering plants that evolved from terrestrial plants, but returned to the sea during the early evolution of monocotyledons through several separate lineages. Thus, they become a good model for studying the adaptation of plants to the marine environment. Sequencing of the mitochondrial (mt) genome of seagrasses is essential for understanding their evolutionary characteristics. Results In this study, we sequenced the mt genome of two endangered seagrasses (Zostera japonica and Phyllospadix iwatensis). These data and data on previously sequenced mt genomes from monocotyledons provide new evolutionary evidence of genome size reduction, gene loss, and adaptive evolution in seagrasses. The mt genomes of Z. japonica and P. iwatensis are circular. The sizes of the three seagrasses (including Zostera marine) that have been sequenced to date are smaller than that of other monocotyledons. Additionally, we found a large number of repeat sequences in seagrasses. The most abundant long repeat sequences were 31–40 bp repeats. Our study also found that seagrass species lost extensive ribosomal protein genes during evolution. The rps7 gene and the rpl16 gene of P. iwatensis are exceptions to this trend. The phylogenetic analysis based on the mt genome strongly supports the previous results. Furthermore, we identified five positive selection genes (atp8, nad3, nad6, ccmFn, and matR) in seagrasses that may be associated with their adaptation to the marine environment. Conclusions In this study, we sequenced and annotated the mt genomes of Z. japonica and P. iwatensis and compared them with the genome of other monocotyledons. The results of this study will enhance our understanding of seagrass adaptation to the marine environment and can inform further investigations of the seagrass mt genome.

Abstract Background Several methods can assist in detecting early esophageal cancer (EEC) and staging esophageal cancer (EC) invasion depth. Objective To evaluate the accuracy of magnifying endoscopy with narrow-band imaging (ME-NBI) plus endoscopic ultrasonography (EUS) for diagnosing EC. Methods We searched the PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases for relevant studies. The Quality Assessment of Diagnostic Accuracy Studies 2 (QADAS2) was used to assess the studies’ methodological quality. The sensitivity, specificity, positive likelihood (LR+), negative likelihood (LR−), and diagnostic odds ratio (DOR) were calculated, and the summary receiver operating characteristic (SROC) curves were drawn to evaluate the diagnostic performance. Results Seven studies were included. The meta-analysis suggested that the pooled sensitivity, specificity, LR+, LR−, and DOR of ME-NBI plus EUS for diagnosing EC were 0.947 (95% confidence interval [CI], 0.901–0.975), 0.894 (95% CI, 0.847–0.931), 7.989 (95% CI, 4.264–14.970), 0.066 (95% CI, 0.035–0.124), and 137.96 (95% CI, 60.369–315.27), respectively. Those values for staging the invasive depth were 0.791 (95% CI, 0.674–0.881), 0.943 (95% CI, 0.906–0.968), 13.087 (95% CI, 7.559–22.657), 0.226 (95% CI, 0.142–0.360), and 61.332 (95% CI, 27.343–137.57). The areas under the curves (AUCs) for diagnosis and staging were 0.97 and 0.95, respectively. Conclusions ME-NBI plus EUS might be an adequate diagnostic and staging modality for EC. Due to the study limitations, more large-scale, high-quality studies are needed to confirm the diagnostic accuracy of ME-NBI plus EUS.

IntroductionThe novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been posing a severe threat to global public health. Although broadly neutralizing antibodies have been used to prevent or treat corona virus disease 2019 (COVID-19), new emerging variants have been proven resistant to these antibodies.MethodsIn this study, we isolated receptor binding domain (RBD)-specific memory B cells using single-cell sorting method from two COVID-19 convalescents and expressed the antibody to test their neutralizing activity against diverse SARS-CoV-2 variants. Then, we resolved antibody-RBD complex structures of potent RBD-specific neutralizing antibodies by X-ray diffraction method. Finally, we analyzed the whole antibody repertoires of the two donors and studied the evolutionary pathway of potent neutralizing antibodies.Results and discussionWe identified three potent RBD-specific neutralizing antibodies (1D7, 3G10 and 3C11) from two COVID-19 convalescents that neutralized authentic SARS-CoV-2 WH-1 and Delta variant, and one of them, 1D7, presented broadly neutralizing activity against WH-1, Beta, Gamma, Delta and Omicron authentic viruses. The resolved antibody-RBD complex structures of two antibodies, 3G10 and 3C11, indicate that both of them interact with the external subdomain of the RBD and that they belong to the RBD-1 and RBD-4 communities, respectively. From the antibody repertoire analysis, we found that the CDR3 frequencies of the light chain, which shared high degrees of amino acid identity with these three antibodies, were higher than those of the heavy chain. This research will contribute to the development of RBD-specific antibody-based drugs and immunogens against multiple variants.

BackgroundThe coronavirus disease 2019 (COVID-19) has been spreading astonishingly and caused catastrophic losses worldwide. The high mortality of severe COVID-19 patients is an serious problem that needs to be solved urgently. However, the biomarkers and fundamental pathological mechanisms of severe COVID-19 are poorly understood. The aims of this study was to explore key genes related to inflammasome in severe COVID-19 and their potential molecular mechanisms using random forest and artificial neural network modeling.MethodsDifferentially expressed genes (DEGs) in severe COVID-19 were screened from GSE151764 and GSE183533 via comprehensive transcriptome Meta-analysis. Protein-protein interaction (PPI) networks and functional analyses were conducted to identify molecular mechanisms related to DEGs or DEGs associated with inflammasome (IADEGs), respectively. Five the most important IADEGs in severe COVID-19 were explored using random forest. Then, we put these five IADEGs into an artificial neural network to construct a novel diagnostic model for severe COVID-19 and verified its diagnostic efficacy in GSE205099.ResultsUsing combining P value < 0.05, we obtained 192 DEGs, 40 of which are IADEGs. The GO enrichment analysis results indicated that 192 DEGs were mainly involved in T cell activation, MHC protein complex and immune receptor activity. The KEGG enrichment analysis results indicated that 192 GEGs were mainly involved in Th17 cell differentiation, IL-17 signaling pathway, mTOR signaling pathway and NOD-like receptor signaling pathway. In addition, the top GO terms of 40 IADEGs were involved in T cell activation, immune response-activating signal transduction, external side of plasma membrane and phosphatase binding. The KEGG enrichment analysis results indicated that IADEGs were mainly involved in FoxO signaling pathway, Toll-like receptor, JAK-STAT signaling pathway and Apoptosis. Then, five important IADEGs (AXL, MKI67, CDKN3, BCL2 and PTGS2) for severe COVID-19 were screened by random forest analysis. By building an artificial neural network model, we found that the AUC values of 5 important IADEGs were 0.972 and 0.844 in the train group (GSE151764 and GSE183533) and test group (GSE205099), respectively.ConclusionThe five genes related to inflammasome, including AXL, MKI67, CDKN3, BCL2 and PTGS2, are important for severe COVID-19 patients, and these molecules are related to the activation of NLRP3 inflammasome. Furthermore, AXL, MKI67, CDKN3, BCL2 and PTGS2 as a marker combination could be used as potential markers to identify severe COVID-19 patients.

Osteoporosis and degenerative endocrine diseases are some of the major causes of disability in the elderly. The feedback loop in the endocrine system works to control the release of hormones and maintain the homeostasis of metabolism, thereby regulating the function of target organs. The breakdown of this feedback loop results in various endocrine and metabolic disorders, such as osteoporosis, type II diabetes, hyperlipidemia, etc. The direct regulation of redox homeostasis is one of the most attractive strategies to redress the imbalance of the feedback loop. The biophysical regulation of redox homeostasis can be achieved through engineered dynamic hydrogel niches, with which cellular mechanics and redox homeostasis are intrinsically connected. Mechanotransduction-dependent redox signaling is initiated by cell surface protein assemblies, cadherins for cell–cell junctions, and integrins for cell–ECM interactions. In this review, we focused on the biophysical regulation of redox homeostasis via the tunable cell–ECM interactions in the engineered dynamic hydrogel niches. We elucidate processes from the rational design of the hydrogel matrix to the mechano-signaling initiation and then to the redox response of the encapsulated cells. We also gave a comprehensive summary of the current biomedical applications of this strategy in several degenerative endocrine disease models.

Abstract Ferroptosis is a type of cell death induced by the iron-dependent accumulation of lipid hydroperoxides and reactive oxygen species (ROS) in cells. Inhibiting ferroptosis is important for improving the survival of transplanted bone marrow-derived mesenchymal stem cells (BMSCs). Although it is known that NOP2/Sun RNA methyltransferase 5 (NSUN5) post-transcriptionally regulates ferroptosis in BMSCs through RNA methylation, the precise mechanisms underlying these effects have not been reported. In this study, we demonstrate that NSUN5 is downregulated in erastin-induced ferroptosis in BMSCs. Ferroptosis was inhibited by the overexpression of NSUN5 or ferritin heavy chain/light-chain (FTH1/FTL) and was enhanced by NSUN5 knockdown. RNA immunoprecipitation experiments revealed that NSUN5 binds to FTH1/FTL, while NSUN5 depletion reduced the levels of 5-methylcytosine in FTH1/FTL RNA and increased intracellular iron concentrations, resulting in the downregulation of glutathione peroxidase 4 (GPX4) and the accumulation of ROS and lipid peroxidation products. Co-immunoprecipitation experiments demonstrated that the recognition of FTH1 and FTL by NSUN5 is dependent on the recruitment of tumor necrosis factor receptor-associated protein 1 (TRAP1). These results suggested that the NSUN5-FTH1/FTL pathway mediates ferroptosis in BMSCs and that the therapeutic targeting of components of this pathway may promote resistance to ferroptosis and improve the survival of transplanted BMSCs.

Seed development is a crucial phase in the life cycle of seed-propagated plants. As the only group of angiosperms that evolved from terrestrial plants to complete their life cycle submerged in marine environments, the mechanisms underlying seed development in seagrasses are still largely unknown. In the present study, we attempted to combine transcriptomic, metabolomic, and physiological data to comprehensively analyze the molecular mechanism that regulates energy metabolism in Zostera marina seeds at the four major developmental stages. Our results demonstrated that seed metabolism was reprogrammed with significant alteration of starch and sucrose metabolism, glycolysis, the tricarboxylic acid cycle (TCA cycle), and the pentose phosphate pathway during the transition from seed formation to seedling establishment. The interconversion of starch and sugar provided energy storage substances in mature seeds and further acted as energy sources to support seed germination and seedling growth. The glycolysis pathway was active during Z. marina germination and seedling establishment, which provided pyruvate for TCA cycle by decomposing soluble sugar. Notably, the biological processes of glycolysis were severely inhibited during Z. marina seed maturation may have a positive effect on seed germination, maintaining a low level of metabolic activity during seed maturation to preserve seed viability. Increased acetyl-CoA and ATP contents were accompanied with the higher TCA cycle activity during seed germination and seedling establishment, indicating that the accumulations of precursor and intermediates metabolite that can strengthen the TCA cycle and facilitate energy supply for Z. marina seed germination and seedling growth. The large amount of oxidatively generated sugar phosphate promotes fructose 1,6-bisphosphate synthesis to feed back to glycolysis during seed germination, indicating that the pentose phosphate pathway not only provides energy for germination, but also complements the glycolytic pathway. Collectively, our findings suggest these energy metabolism pathways cooperate with each other in the process of seed transformation from maturity to seedling establishment, transforming seed from storage tissue to highly active metabolic tissue to meet the energy requirement seed development. These findings provide insights into the roles of the energy metabolism pathway in the complete developmental process of Z. marina seeds from different perspectives, which could facilitate habitat restoration of Z. marina meadows via seeds.

BackgroundAlthough non-motor symptoms of Parkinson’s disease (PD) are serious, effective treatments are still lacking. Acupuncture may have clinical benefits for non-motor symptoms of PD patients, but high-quality evidence supporting this possibility is still limited. Hence, we conducted this meta-analysis to evaluate the effect of acupuncture treatment on non-motor symptoms in patients with PD.MethodsRandomized controlled trials (RCTs) of acupuncture treatment for PD were retrieved from the following electronic databases: Medline (OVID), Embase (OVID), Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese BioMedical Literature Database, Chonqing VIP (CQVIP), and Wangfang database. Studies evaluating non-motor symptoms of PD were retrieved. Methodological quality was assessed using the Cochrane Handbook for Systematic Reviews of Interventions.ResultsA total of 27 RCTs were included, among which 8 outcomes related to non-motor symptoms were evaluated. The results showed that acupuncture combined with medication had benefits for PD-related insomnia relative to medication alone or sham acupuncture [standardized mean difference (SMD) = 0.517; 95% confidence interval (CI) = 0.242–0.793; p = 0.000], and acupuncture treatment had benefits at 8 weeks (SMD = 0.519; 95% CI = 0.181–0.857; p = 0.003). Regarding depression, acupuncture treatment was more effective (SMD = −0.353; 95% CI = −0.669 to −0.037; p = 0.029) within 2 months (SMD = −0.671; 95% CI = −1.332 to −0.011; p = 0.046). Regarding cognition, quality of life, and Unified Parkinson’s Disease Rating Scale (UPDRS) I and II scores, acupuncture treatment was effective [SMD = 0.878, 95% CI = 0.046–1.711, p = 0.039; SMD = −0.690, 95% CI = −1.226 to −0.155, p = 0.011; weighted mean difference (WMD) = −1.536, 95% CI = −2.201 to −0.871, p = 0.000; WMD = −2.071, 95% CI = −3.792 to −0.351, p = 0.018; respectively]. A significant difference was not found in terms of PD-related constipation. Only one study evaluated PD-related fatigue.ConclusionThe results of the analysis suggested that acupuncture treatment could ameliorate the symptoms of depression, quality of life, cognition, total mentation, behavior and mood, and activities of daily living in PD patients. Nevertheless, more prospective, well-designed RCTs with larger sample sizes are required to confirm our findings.

PurposeThis study was conducted in order to properly understand whether prior seasonal human coronavirus (HCoV) immunity could impact the potential cross-reactivity of humoral responses induced by SARS-CoV-2 vaccine, thereby devising universal coronavirus vaccines for future outbreaks.MethodsWe performed enzyme-linked immunosorbent assay (ELISA) to quantify the immunoglobulin G (IgG) antibody levels to spike (S) protein and S1 subunit of HCoVs (HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E), and ELISA [anti-RBD and anti-nucleoprotein (N)], chemiluminescence immunoassay assays (anti-RBD), pseudovirus neutralization test, and authentic viral neutralization test to detect the binding and neutralizing antibodies to SARS-CoV-2 in the vaccinees.ResultsWe found that the antibody of seasonal HCoVs did exist before vaccination and could be boosted by SARS-CoV-2 vaccine. A further analysis demonstrated that the prior S and S1 IgG antibodies of HCoV-OC43 were positively correlated with anti-RBD and neutralization antibodies to SARS-CoV-2 at 12 and 24 weeks after the second vaccination, and the correlation is more statistically significant at 24 weeks. The persistent antibody levels of SARS-CoV-2 were observed in vaccinees with higher pre-existing HCoV-OC43 antibodies.ConclusionOur data indicate that inactivated SARS-CoV-2 vaccination may confer cross-protection against seasonal coronaviruses in most individuals, and more importantly, the pre-existing HCoV-OC43 antibody was associated with protective immunity to SARS-CoV-2, supporting the development of a pan-coronavirus vaccine.

The Mediterranean diet (MED), a dietary pattern rich in fruits and vegetables, whole grains, legumes, nuts, fish, and olive oil, has anti-oxidative and anti-inflammatory effects. Although some data suggest that MED adherence is associated with decreased manifestation of depressive symptoms, it remains necessary to further analyze this apparent non-linear association as well as the influence of different factors on the relationship between MED and depression. Here, we investigated associations between the alternate MED (aMED) score and depressive symptom via multivariate logistic regression, weighted generalized additive (GAM) and two-step linear regression models, analyzing data from the 2005–2018 National Health and Nutrition Examination Survey (NHANES). The most important factor relevant to aMED score that contributed to the prevalence of depressive symptom was assessed using random forest. Furthermore, we examined whether the relationship between aMED score and depressive symptom differs by age, race, sex, socioeconomic variables, lifestyle- and health-related variables, and chronic medical conditions, via subgroup analyses. A total of 19,477 participants (20–80 years of age) were included in this cross-sectional study. In crude and adjusted (1–5) multivariate logistic regression models, increased aMED score was noted to associate with non-depressive status, as defined using the Patient Health Questionnaire-9 (P < 0.05). Data analyses via GAM and two-piecewise linear regression revealed a non-linear association between aMED and depressive symptom, which had an inflection point of 3. Random forest results revealed that vegetable score contributes greatest to the relationship between aMED and depressive symptom. Subgroup analyses revealed that aMED score is significantly negatively related with depressive symptom in most different populations (P < 0.05) with the exception of high annual income, diabetes, borderline blood glucose level and Parkinson's disease (PD) (P > 0.05). In conclusion, we observed a non-linear association between aMED score and depressive symptom. Further studies are needed to validate our results.

Research works on the synergistic effect of surface modified bioactive molecules and bone metal implants have been highlighted. N-cadherin is regarded as a key factor in directing cell–cell interactions during the mesenchymal condensation preceding the osteogenesis in the musculoskeletal system. In this study, the N-cadherin mimetic peptide (Cad) was biofunctionalized on the titanium metal surface via the acryloyl bisphosphonate (Ac-BP). To learn the synergistic effect of N-cadherin mimetic peptide, when tethered with titanium substrates, on promoting osteogenic differentiation of the seeded human mesenchymal stem cells (hMSCs) and the osseointegration at the bone-implant interfaces. Results show that the conjugation of N-cadherin mimetic peptide with Ac-BP promoted the osteogenic gene markers expression in the hMSCs. The biofunctionalized biomaterial surfaces promote the expression of the Wnt/β-catenin downstream axis in the attached hMSCs, and then enhance the in-situ bone formation and osseointegration at the bone-implant interfaces. We conclude that this N-cadherin mimetic peptide tethered on Ti surface promote osteogenic differentiation of hMSCs and osseointegration of biomaterial implants in vitro and in vivo. These findings demonstrate the importance of the development-inspired surface bioactivation of metal implants and shed light on the possible cellular mechanisms of the enhanced osseointegration.

Magnetic field energy harvesters (MFEHs) from current-carrying structures/conductors are usually modelled as decoupled electromagnetic and electrical systems. The current-carrying structures may affect the performance of MFEH through the generation of the eddy current and the alteration of the magnetic reluctance. Moreover, the load circuit affects the current generated in the coil and therefore the flux density and eddy current generated. The effects of the current-carrying structure and the load circuit cannot be fully described by the decoupled models. This work develops a finite element model (FEM) that fully couples the electromagnetic and electrical systems by simulating both the magnetic field and eddy current distribution of an MFEH connected to an electrical circuit. The FEM first simulates the coil inductance and resistance of a magnetic field energy harvester (MFEH) placed close to a current-carrying structure exemplified by a rail track. The FEM then simulates the outputs of the MFEH connected to an electrical circuit consisting of a compensating capacitor and optimal load resistor determined by the first step. An MFEH was fabricated and tested under a section of current-carrying rail track. Both experiment and simulation show an increase of both coil resistance and inductance when the MFEH is placed close to the rail track. The good agreement between experimental and simulation results validates that the FEM can predict the full-matrix performances of the MFEH, including the coil parameters, power output and magnetic flux density under the influence of the current-carrying structure and the load circuit. Simulation results reveal that in addition to the permeability of the magnetic core, the electrical conductivity and magnetic permeability of the current-carrying structure considerably affect the performance of the MFEH, which cannot be predicted by decoupled models.

Background/ObjectivesNon-ergot dopamine agonist (NEDA) are recommended as the first-line treatment for patients with early Parkinson's disease (PD) because of their efficacy in treating PD motor symptoms. However, systematic evaluations of the risk of motor complications induced by NEDA and risk factors potentially associated with motor complications are still lacking.MethodsMedline, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched for potentially eligible randomized controlled trials. The incidence of motor complications (dyskinesia, motor fluctuations), impulsive-compulsive behaviors and adverse events and clinical disability rating scale (UPDRS) scores were evaluated using standard meta-analytic methods. Metaregression was conducted on the incidence of motor complications (dyskinesia) with treatment duration and NEDA dose as covariates.ResultsPatients treated with NEDA had significantly lower UPDRS total scores, motor scores and activity of daily living (ADL) scores than those receiving a placebo (weighted mean difference (WMD) −4.81, 95% CI −6.57 to −3.05; WMD −4.901, 95% CI −7.03 to −2.77; WMD −1.52, 95% CI −2.19 to −0.84, respectively). Patients in the NEDA and NEDA+open Levodopa (LD) groups had lower odds for dyskinesia than patients in the LD group (OR = 0.21, 95% CI: 0.15–0.29; OR = 0.31, 95% CI 0.24–0.42, respectively). Metaregressions indicated that the mean LD dose of the NEDA group increased, and the odds of developing dyskinesia increased (p = 0.012). However, the odds of developing dyskinesia in the NEDA group were not related to treatment duration (p = 0.308). PD patients treated with NEDA or NEDA+open LD had a lower risk of wearing-off implications than those treated with LD (all p < 0.05). No significant difference was found between the NEDA and placebo groups in impulsive-compulsive behavior development (p > 0.05). Patients in the NEDA group were more likely to suffer somnolence, edema, constipation, dizziness, hallucinations, nausea and vomiting than those in the placebo or LD group.ConclusionNEDA therapy reduces motor symptoms and improves ADLs in early PD. The odds of developing motor complications were lower with NEDA than with LD, and dyskinesia increased with increasing LD equivalent dose and was not influenced by NEDA treatment duration. Therefore, long-term treatment with an appropriate dosage of NEDA might be more suitable than LD for early PD patients.RegistrationPROSPERO CRD42021287172.

The cervicovaginal microbiota plays a key role in the health and reproductive outcomes of women. In reality epidemiological studies have demonstrated that there is an association between the structure of cervicovaginal microbiota and reproductive health, although key mechanistic questions regarding these effects remain unanswered and understanding the interplay between the immune system and the structure of the cervicovaginal microbiota. Here, we review existing literature relating to the potential mechanisms underlying the interaction between vaginal microbes and the immune system; we also describe the composition and function of the microbiome and explain the mechanisms underlying the interactions between these microbial communities and various aspects of the immune system. Finally, we also discuss the diseases that are caused by disorders of the reproductive tract and how the immune system is involved. Finally, based on the data presented in this review, the future perspectives in research directions and therapeutic opportunities are explored.

The diversity of HIV-1 envelope (Env) glycoproteins affects the potency and breadth of broadly neutralizing antibodies (bNAbs), a promising alternative to antiretroviral drugs for the prevention and treatment of HIV-1 infection. To facilitate immunogen design and development of therapeutic neutralizing antibodies, we characterized viral evolution and monitored the changes in neutralizing activity/sensitivity of a long-term non-progressor patient with HIV-1 CRF07_BC infection. Fifty-nine full-length Env gene fragments were derived from four plasma samples sequentially harvested from the patient between 2016 and 2020. Sequencing of patient-derived Env genes revealed that potential N-linked glycosylation sites (PNGS) in V1 and V5 significantly increased over time. Further, 24 functional Env-pseudotyped viruses were generated based on Env gene sequences. While all 24 Env-pseudotyped viruses remained sensitive to concurrent and subsequent autologous plasma, as well as bNAbs, including 10E8, VRC01, and 12A21, Env-pseudotyped viruses corresponding to later sampling time were increasingly more resistant to autologous plasma and bNAbs. All 24 Env-pseudotyped viruses were resistant to bNAbs 2G12, PGT121, and PGT135. The neutralization breadth of plasma from all four sequential samples was 100% against the global HIV-1 reference panel. Immune escape mutants resulted in increased resistance to bNAb targeting of different epitopes. Our study identified known mutations F277W in gp41 and previously uncharacterized mutation S465T in V5 which may be associated with increased viral resistance to bNAbs.

Marine macrophytes (seagrasses and macroalgae) and their epiphytic microorganisms play an important role in the ecological and biochemical processes of coastal oceans. However, simultaneous comparative studies on the biodiversity and functions of epiphytic bacteria and fungi associated with marine macrophytes have not been conducted. In this study, high-throughput sequencing technology was used to describe the epiphytic bacterial and fungal communities of 11 common macroalgae and 2 seagrasses from an intertidal zone of northern China and compare them with seawater communities. The results showed that Proteobacteria and Bacteroidota were the dominant bacterial phyla in marine macrophytes, whereas Ascomycota, Chytridiomycota, and Basidiomycota were the dominant fungal phyla. The alpha diversity of the bacterial and fungal communities in seagrasses was the highest of all macrophyte samples. This may have been related to their ability to recruit microorganisms from multiple sources. Host phylogeny may influence bacterial community structure, and geographical differences may influence fungal community structure. The FAPROTAX data indicated that C metabolic microbes were enriched in marine macrophytes, while the FUNGuild data indicated that undefined saprotroph, which participated in organic matter degradation, were also enriched in marine macrophytes. These findings provide a theoretical basis regarding the epiphytic microorganisms of macrophytes and may offer new insights to support the improved ecological restoration of seagrass and macroalgae beds.

IntroductionCurrently, the commonly used surgical methods for cervical lesions include loop electrosurgical excision procedure (LEEP) and cold knife conization (CKC). However, the positive rate of surgical margins after LEEP is relatively high, which leads to disease recurrence and places further demand on clinical treatment. This study investigated factors related to positive margins after LEEP and established a scoring system to enhance preoperative risk assessment and surgical selection.Materials and MethodsA retrospective analysis of the clinical data of 411 patients undergoing LEEP surgery for cervical lesions in the First Affiliated Hospital of University of Science and Technology of China (USTC), from January 2016 to March 2021, was performed. Cases were divided into a negative margin group (349 cases) and a positive margin group according to postoperative pathology. In the positive group (62 cases), single-factor and multi-factor analyses screened influencing factors; a logistic and additive scoring system was established; furthermore, a ROC curve was used to evaluate scoring effectiveness.ResultsThe positive rate of resection margins after LEEP was 15.1%. Univariate analysis indicated a relationship to patient age, menopause, preoperative ThinPrep Cytology Test (TCT) results, lesion quadrant number under colposcopy, cervical biopsy, and the result of endocervical curettage (ECC). Multivariate analysis showed that age >35 y, menopause, preoperative TCT being high-grade squamous intraepithelial lesion (HSIL), four quadrants being involved under colposcopy, and ECC being HSIL were all independent influencing factors of positive margins after LEEP (P < 0.05). These were included with the above factors to establish a logistic and additive scoring system. When the logistic score was 17, the sensitivity and specificity of predicting positive margins after LEEP were 80.6 and 61.6%, respectively. When the additive score was 6, the sensitivity and specificity were 74.2 and 66.2%, respectively. Both scoring systems had good predictability (area under the curve AUC >0.75).ConclusionsThis study quantified factors influencing positive margins after LEEP and established a scoring system for evaluating patients before surgery to provide a basis for individualized treatment and selection of surgical methods.

Background/Objectives: Aerobic exercise and mind-body exercise, are vital for improving motor and non-motor functional performance of Parkinson’s disease (PD). However, evidence-based recommendations on which type of exercise is most suitable for each individual are still lacking. Therefore, we conduct a network meta-analysis to assess the relative efficacy of aerobic and mind-body exercise on motor function and non-motor symptoms in Parkinson’s disease and to determine which of these therapies are the most suitable.Design: A network meta-analysis and dose-response analysis.Setting and Participants: Medline, Embase (all via Ovid), and the Cochrane Central Register of Controlled Trials were comprehensively searched for related trials through April 2021.Measurements: Study quality was evaluated using the Cochrane Risk of Bias Tool. The effect sizes of continuous outcomes were calculated using mean differences (MDs) or standardized mean differences (SMDs). A network meta-analysis with a frequentist approach was conducted to estimate the efficacy and probability rankings of the therapies. The dose-response relationship was determined based on metaregression and SUCRA.Results: Fifty-two trials with 1971 patients evaluating six different therapies were identified. For the UPDRS-motor score and TUG score, yoga all ranked highest (SUCRA = 92.8%, 92.6%, respectively). The SUCRA indicated that walking may best improve the BBS score (SUCRA = 90.2%). Depression, cognitive and activities of daily living scores were significantly improved by yoga (SUCRA: 86.3, 95.1, and 79.5%, respectively). In the dose-response analysis, 60-min sessions, two times a week might be the most suitable dose of yoga for reducing the UPDRS-motor score of PD patients.Conclusion: Yoga and walking are important options for increasing functional mobility and balance function, and yoga might be particularly effective for decreasing depressive symptoms and cognitive impairment and improving activities of daily living in PD. The potential optimal dose of yoga for enhancing motor ability in PD patients is 60-min sessions, two times a week.Registration: PROSPERO CRD42021224823.

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Cognitive impairment is one of the key non-motor symptoms of PD, affecting both mortality and quality of life. However, there are few experimental studies on the pathology and treatments of PD with mild cognitive impairment (PD-MCI) and PD dementia (PDD) due to the lack of representative models. To identify new strategies for developing representative models, we systematically summarized previous studies on PD-MCI and PDD and compared differences between existing models and diseases. Our initial search identified 5432 articles, of which 738 were duplicates. A total of 227 articles met our inclusion criteria and were included in the analysis. Models fell into three categories based on model design: neurotoxin-induced, transgenic, and combined. Although the neurotoxin-induced experimental model was the most common type that was used during every time period, transgenic and combined experimental models have gained significant recent attention. Unfortunately, there remains a big gap between ideal and actual experimental models. While each model has its own disadvantages, there have been tremendous advances in the development of PD models of cognitive impairment, and almost every model can verify a hypothesis about PD-MCI or PDD. Finally, our proposed strategies for developing novel models are as follows: a set of plans that integrate symptoms, biochemistry, neuroimaging, and other objective indicators to judge and identify that the novel model plays a key role in new strategies for developing representative models; novel models should simulate different clinical features of PD-MCI or PDD; inducible α-Syn overexpression and SH-SY5Y-A53T cellular models are good candidate models of PD-MCI or PDD.

Parkinson’s disease dementia (PDD) is a common complication of Parkinson’s disease that seriously affects patients’ health and quality of life. At present, the process and pathological mechanisms of PDD remain controversial, which hinders the development of treatments. An increasing number of clinical studies have shown that alpha-synuclein (α-syn), tau, beta-amyloid (Aβ), and iron are closely associated with PDD severity. Thus, we inferred the vicious cycle that causes oxidative stress (OS), due to the synergistic effects of α-syn, tau, Aβ, and, iron, and which plays a pivotal role in the mechanism underlying PDD. First, iron-mediated reactive oxygen species (ROS) production can lead to neuronal protein accumulation (e.g., α-syn andAβ) and cytotoxicity. In addition, regulation of post-translational modification of α-syn by iron affects the aggregation or oligomer formation of α-syn. Iron promotes tau aggregation and neurofibrillary tangles (NFTs) formation. High levels of iron, α-syn, Aβ, tau, and NFTs can cause severe OS and neuroinflammation, which lead to cell death. Then, the increasing formation of α-syn, Aβ, and NFTs further increase iron levels, which promotes the spread of α-syn and Aβ in the central and peripheral nervous systems. Finally, iron-induced neurotoxicity promotes the activation of glycogen synthase kinase 3β (GSK3β) related pathways in the synaptic terminals, which in turn play an important role in the pathological synergistic effects of α-syn, tau and Aβ. Thus, as the central factor regulating this vicious cycle, GSK3β is a potential target for the prevention and treatment of PDD; this is worthy of future study.

Background: The complicated molecular mechanisms underlying the therapeutic effect of electroacupuncture (EA) on ischemic stroke are still unclear. Recently, more evidence has revealed the essential role of the microRNA (miRNA)–mRNA networks in ischemic stroke. However, a systematic analysis of novel key genes, miRNAs, and miRNA–mRNA networks regulated by EA in ischemic stroke is still absent.Methods: We established a middle cerebral artery occlusion (MCAO) mouse model and performed EA therapy on ischemic stroke mice. Behavior tests and measurement of infarction area were applied to measure the effect of EA treatment. Then, we performed RNA sequencing to analyze differentially expressed genes (DEGs) and functional enrichment between the EA and control groups. In addition, a protein–protein interaction (PPI) network was built, and hub genes were screened by Cytoscape. Upstream miRNAs were predicted by miRTarBase. Then hub genes and predicted miRNAs were verified as key biomarkers by RT-qPCR. Finally, miRNA–mRNA networks were constructed to explore the potential mechanisms of EA in ischemic stroke.Results: Our analysis revealed that EA treatment could significantly alleviate neurological deficits in the affected limbs and reduce infarct area of the MCAO model mice. A total of 174 significant DEGs, including 53 upregulated genes and 121 downregulated genes, were identified between the EA and control groups. Functional enrichment analysis showed that these DEGs were associated with the FOXO signaling pathway, NF-kappa B signaling pathway, T-cell receptor signaling pathway, and other vital pathways. The top 10 genes with the highest degree scores were identified as hub genes based on the degree method, but only seven genes were verified as key genes according to RT-qPCR. Twelve upstream miRNAs were predicted to target the seven key genes. However, only four miRNAs were significantly upregulated and indicated favorable effects of EA treatment. Finally, comprehensive analysis of the results identified the miR-425-5p-Cdk1, mmu-miR-1186b-Prc1, mmu-miR-434-3p-Prc1, and mmu-miR-453-Prc1 miRNA–mRNA networks as key networks that are regulated by EA and linked to ischemic stroke. These networks might mainly take place in neuronal cells regulated by EA in ischemic stroke.Conclusion: In summary, our study identified key DEGs, miRNAs, and miRNA–mRNA regulatory networks that may help to facilitate the understanding of the molecular mechanism underlying the effect of EA treatment on ischemic stroke.

Seagrasses are marine flowering plants found in tropical and sub-tropical areas that live in coastal regions between the sea and land. All seagrass species evolved from terrestrial monocotyledons, providing the opportunity to study plant adaptation to sea environments. Here, we sequenced the chloroplast genomes (cpGenomes) of three Zostera species, then analyzed and compared their cpGenome structures and sequence variations. We also performed a phylogenetic analysis using published seagrass chloroplasts and calculated the selection pressure of 17 species within seagrasses and nine terrestrial monocotyledons, as well as estimated the number of shared genes of eight seagrasses. The cpGenomes of Zosteraceae species ranged in size from 143,877 bp (Zostera marina) to 152,726 bp (Phyllospadix iwatensis), which were conserved and displayed similar structures and gene orders. Additionally, we found 17 variable hotspot regions as candidate DNA barcodes for Zosteraceae species, which will be helpful for studying the phylogenetic relationships and interspecies differences between seagrass species. Interestingly, nine genes had positive selection sites, including two ATP subunit genes (atpA and atpF), two ribosome subunit genes (rps4 and rpl20), two DNA-dependent RNA polymerase genes (rpoC1 and rpoC2), as well as accD, clpP, and ycf2. These gene regions may have played key roles in the seagrass adaptation to diverse environments. The Branch model analysis showed that seagrasses had a higher rate of evolution than terrestrial monocotyledons, suggesting that seagrasses experienced greater environmental pressure. Moreover, a branch-site model identified positively selected sites (PSSs) in ccsA, suggesting their involvement in the adaptation to sea environments. These findings are valuable for further investigations on Zosteraceae cpGenomes and will serve as an excellent resource for future studies on seagrass adaptation to sea environments.

Abstract Background Radiation pneumonitis (RP) is a common side effect in lung cancer patients who received radiotherapy. Our previous study found genetic variations in DNA repair gene NEIL1 may be a predictor of RP in patients with esophageal cancer. So, we hypothesis genetic variations in NEIL1 gene could affect the risk of RP in lung cancer patients following radiotherapy. Methods Genetic variations rs4462560 G>C and rs7402844 C>G in NEIL1 gene were genotyped in 174 lung cancer patients received radio(chemo)therapy. Luciferase assay, real‐time PCR and Western blot were used to access the effect of the variants on NEIL1 in HELF and HEF cell lines which were transfected with plasmids containing rs4462560 G>C and rs7402844 C>G. Results Patients with rs4462560 CC genotype had a lower risk of RP grade ≥2 than GG genotype. Compared with the CC genotype, rs7402844 GG genotype was associated with an increased RP grade ≥2 risk. What is more, rs4462560 G decreased the relative luciferase activity of NEIL1 gene promoter compared with the negative control in vitro, while rs4462560 C can increase the relative luciferase activity. The mRNA and protein level of the NEIL1 gene in rs4462560 G were lower than rs4462560 C. Conclusions Genetic variants of NEIL1 are associated with RP risk through regulation of NEIL1 expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy.

As wind power transmission gear key parts， because of irregular under strong wind and Martin shock loads， so that its work reliability decides the reliability of the wind turbine gearbox. As one of the four requirements of gear transmission， an appropriate gear clearance is a necessary condition for the normal operation of the gear pair， which is the key to reduce the impact， noise， air distance error and improve the service life of the wind turbine gearbox. For the error of the gear pair clearance in planetary gear which is the first planet transmission structure forms of wind power gearbox， through analysis on the planetary gear pair clearance from three aspects of the impact， parts manufacturing， assembly and measuring， the influence of the assembly process of the planetary gear pair clearance is confirmed， through choosing the middle-box and the main bearings， the problem of the planet wheel gear deviation is solved.

Abnormal fibroblast differentiation into myofibroblast is a crucial pathological mechanism of pulmonary fibrosis (PF). Super-enhancers, a newly discovered cluster of regulatory elements, are regarded as the regulators of cell identity. We speculate that abnormal activation of super-enhancers must be involved in the pathological process of PF. This study aims to identify potential pathogenic super-enhancer-driven genes in PF. Differentially expressed genes (DEGs) in PF mouse lungs were identified from a GEO dataset (GDS1492). We collected super-enhancers and their associated genes in human lung fibroblasts and mouse embryonic fibroblasts from SEA version 3.0, a network database that provides comprehensive information on super-enhancers. We crosslinked upregulated DEGs and super-enhancer-associated genes in fibroblasts to predict potential super-enhancer-driven pathogenic genes in PF. A total of 25 genes formed an overlap, and the protein-protein interaction network of these genes was constructed by the STRING database. An interaction network of transcription factors (TFs), super-enhancers, and associated genes was constructed using the Cytoscape software. Gene enrichment analyses, including KEGG pathway and GO analysis, were performed for these genes. Latent transforming growth factor beta (TGF-β) binding protein 2 (LTBP2), one of the predicted super-enhancer-driven pathogenic genes, was used to verify the predicted network’s accuracy. LTBP2 was upregulated in the lungs of the bleomycin-induced PF mouse model and TGF-β1-stimulated mouse and human fibroblasts. Myc is one of the TFs binding to the LTBP2 super-enhancer. Knockout of super-enhancer sequences with a CRISPR/Cas9 plasmid or inhibition of Myc all decreased TGF-β1-induced LTBP2 expression in NIH/3 T3 cells. Identifying and interfering super-enhancers might be a new way to explore possible therapeutic methods for PF.

The receptor for Colony Stimulating Factor 1 (CSF1), c-fms, is highly expressed on mature osteoclasts suggesting a role for this cytokine in regulating the function of these cells. Consistent with this idea, in vitro studies have documented a variety of effects of CSF1 in mature osteoclasts. To better define the role of CSF1 in these cells, we conditionally deleted c-fms in osteoclasts (c-fms-OC-/-) by crossing c-fmsflox/flox mice with mice expressing Cre under the control of the cathepsin K promoter. The c-fms-OC-/- mice were of normal weight and had normal tooth eruption. However, when quantified by DXA, bone mass was significantly higher in the spine and femur of female knock out mice and in the femurs of male knock out mice. MicroCT analyses of femurs showed that female c-fms-OC-/- mice had significantly increased trabecular bone mass with a similar trend in males and both sexes demonstrated significantly increased trabecular number and reduced trabecular spacing. Histomorphometric analysis of the femoral trabecular bone compartment demonstrated a trend towards increased numbers of osteoclasts, +26% in Noc/BPm and +22% in OcS/BS in the k/o animals but this change was not significant. However, when the cellular volume of osteoclasts was quantified, the c-fms-OC-/- cells were found to be significantly smaller than controls. Mature osteoclasts show a marked spreading response when exposed to CSF1 in a non-gradient fashion. However, osteoclasts freshly isolated from c-fms-OC-/- mice had a near complete abrogation of this response. C-fms-OC-/- mice treated with (1-34)hPTH 80 ng/kg/d in single daily subcutaneous doses for 29 days showed an attenuated anabolic response in trabecular bone compared to wild-type animals. Taken together, these data indicate an important non-redundant role for c-fms in regulating mature osteoclast function in vivo.

As a sensitive cold-shock protein, RNA binding protein motif 3 (RBM3) exhibits a neuroprotective function in the condition of brain injury. However, how RBM3 is involved in acute ischemic stroke by affecting stress granules (SGs) remains unclear. Here, we established an oxygen-glucose deprivation/reperfusion (OGD/R) model in rat primary cortical neurons and PC12 cells to explore the potential mechanism between RBM3 and SG formation in acute ischemic/reperfusion (I/R) condition. The immunofluorescence results showed that the SG formation significantly decreased in rat primary cortical neurons and PC12 cells during the reperfusion period after 6 h of OGD stimulation. The western blot results, flow cytometry analysis, and cell viability assessment showed that the RBM3 expression and ratio of cell viability significantly decreased, while the rate of apoptosis increased in PC12 cells during the reperfusion period after 6 h of OGD stimulation. Co-immunoprecipitation (Co-IP) and immunofluorescence indicated that RBM3 and GTPase-activating protein-binding protein 1 (G3BP1) colocalized cytoplasm of PC12 cells after 6 h of OGD stimulation when the SGs formation reached the highest level. Besides, overexpression and knockdown of the RBM3 were achieved via plasmid transfection and CRISPR-Cas9 technology, respectively. The results of overexpression and knockdown of RBM3 gene illustrated the pivotal role of RBM3 in affecting SG formation and apoptosis level in OGD-treated PC12 cells. In conclusion, RBM3 could combine with G3BP1 resulted in increasing stress granules generation in rat primary cortical neurons and PC12 cells after 6 h of oxygen-glucose deprivation (OGD) injury, which ultimately reduced the apoptosis in OGD-induced cells. Our study may enable a new promising target for alleviating ischemia-reperfusion injury in cells.

The modification of methyltransferase-like (METTL) enzymes plays important roles in various cellular responses by regulating microRNA expression. However, how m6A modification is involved in stress granule (SG) formation in the early stage of acute ischemic stroke by affecting the biogenesis processing of microRNAs remains unclear. Here, we established a middle cerebral artery occlusion (MCAO) model in rats and an oxygen-glucose deprivation/reperfusion (OGD/R) model in primary cortical neurons and PC12 cells to explore the potential mechanism between m6A modification and SG formation. The in vivo results showed that the level of infarction and apoptosis increased while SG formation decreased significantly within the ischemic cortex with improved reperfusion time after 2 h of ischemia. Consistent with the in vivo data, an inverse association between the apoptosis level and SG formation was observed in PC12 cells during the reperfusion period after 6 h of OGD stimulation. Both in vivo and in vitro results showed that the expression of METTL3 protein, m6A and miR-335 was significantly decreased with the reperfusion period. Overexpression of the METTL3 and METTL3 gene-knockdown in PC12 cells were achieved via plasmid transfection and CRISPR-Cas9 technology, respectively. Overexpression or knockdown of METTL3 in oxygen-glucose deprivation of PC12 cells resulted in functional maturation of miR-335, SG formation and apoptosis levels. In addition, we found that miR-335 enhanced SG formation through degradation of the mRNA of the eukaryotic translation termination factor (Erf1). In conclusion, we found that METTL3-mediated m6A methylation increases the maturation of miR-335, which promotes SG formation and reduces the apoptosis level of injury neurons and cells, and provides a potential therapeutic strategy for AIS.

Aurora kinase A (AURKA) is a cell cycle regulatory serine/threonine kinase that promotes cell cycle progression. It plays an important role in regulating the transition from G2 to M phase during mitosis. The association between the AURKA rs2273535 T>A polymorphism and cancer risk has been investigated, but the results remain inconsistent. To get a more accurate conclusion, we conducted a comprehensive meta-analysis of 36 case-control studies, involving 22,884 cancer cases and 30,497 healthy controls. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the association of interest. Pooled analysis indicated that the AURKA rs2273535 T>A polymorphism increased the overall risk of cancer (homozygous: OR = 1.17, 95% CI = 1.04-1.33; recessive: OR = 1.15, 95% CI = 1.05-1.25; allele: OR = 1.07, 95% CI = 1.02-1.13). Stratification analysis by cancer type further showed that this polymorphism was associated with an increased breast cancer risk. This meta-analysis indicated that the AURKA rs2273535 T>A polymorphism was associated with an overall increased cancer risk, especially breast cancer. Further validation experiments are needed to strengthen our conclusion.

Assessing the duration of neutralizing antibodies (nAbs) following SARS-CoV-2 infection or vaccination is critical to evaluate the protective immunity and formulate public health strategies. In this study, SARS-CoV-2 Ab ELISA (enzyme-linked immunosorbent assay), chemiluminescent microparticle immunoassay (CMIA), as well as pseudovirus neutralization test (PVNT) were performed in two cohorts, convalescent patients (CP) from coronavirus disease 2019 (COVID-19) and BBIBP-CorV vaccinated population. It was found that nAbs and binding antibodies emerged at 14 days post the 1st dose of vaccination, reached peaks at 28 days after 2nd dose vaccination and then gradually declined over time. CP-6M (convalescent patients up to 6 months) from COVID-19 presented stronger nAbs or binding antibodies responses than vaccinees 90 days or 180 days after 2nd dose vaccination. CMIA or SARS-CoV-2 Ab ELISA correlated well with PVNT with high consistency in the two cohorts. It shown that nAbs and binding antibodies can keep 6 months both in CP and vaccinees. Most importantly, our data show the application of using CMIA and SARS-CoV-2 Ab ELISA as rapid screening tests for nAb titer and could be used as alternative strategies for quickly evaluating SARS-CoV-2 nAbs responses in vaccine research.

The JNK and P38α pathways play an important role in the sensitivity and outcomes of chemotherapy. We hypothesize that functional single nucleotide polymorphisms (SNPs) of genes of these pathways modulate outcomes of patients with advanced non–small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy (PBC). We selectively genotyped 11 independent, potentially functional SNPs of 9 genes in the JNK and P38α pathways first in a discovery group of 355 patients with advanced NSCLC treated with PBC, and we evaluated their associations with progression-free survival (PFS) and overall survival (OS) by Cox proportional hazards regression analysis. Then, resultant significant SNPs were further validated in a replication group of 355 patients. In both discovery and validation groups as well as their combined analysis, the MAPK14 rs3804451GA/AA genotypes showed a strong association with a reduced PFS (adjusted hazards ratio [HR] = 1.39; 95% confidence interval [CI] = 1.16–1.66; P = .0003) and OS (adjusted HR = 1.41; 95% CI = 1.11-1.80; P = .005) compared with the wild-type GG genotype. In contrast, patients with or without the MAPK14 rs3804451A allele had no significant difference in OS in response to tyrosine-kinase inhibitor treatment (adjusted HR = 0.86; 95% CI = 0.56-1.33; P = .505). The present study provides evidence that the MAPK14 rs3804451 G>A variant may modulate survival outcomes in patients with advanced NSCLC treated with PBC. Larger studies of additional patient populations are needed to validate our findings.

This letter presents a piezoelectric bimorph with auxetic (negative Poisson’s ratio) behaviors for increased power output in vibration energy harvesting. The piezoelectric bimorph comprises a 2D auxetic substrate sandwiched between two piezoelectric layers. The auxetic substrate is capable of introducing auxetic behaviors and thus increasing the transverse stress in the piezoelectric layers when the bimorph is subjected to a longitudinal stretching load. As a result, both 31- and 32-modes are simultaneously exploited to generate electric power, leading to an increased power output. The increasing power output principle was theoretically analyzed and verified by finite element (FE) modelling. The FE modelling results showed that the auxetic substrate can increase the transverse stress of a bimorph by 16.7 times. The average power generated by the auxetic bimorph is 2.76 times of that generated by a conventional bimorph.

A method was developed to pattern the surface of perfluorinated materials with graphene oxide thin film, and various biological applications of the patterned perfluorinated surface were illustrated. Perfluorinated surfaces such as Teflon, Cytop, and other perfluorinated materials are known to be both hydrophobic and oleophobic, with low adhesion for most materials. Modifying the perfluorinated surfaces has been difficult due to the extraordinary chemical inertness, which limits the applications of perfluorinated materials as anti-fouling substrates. Herein we successfully patterned Cytop surfaces with graphene oxide. Patterns of the graphene oxide thin film with feature dimension down to 40 microns were formed and remained stable on the Cytop surface against washing with water, ethanol and acetone. The graphene oxide thin film on the Cytop surface allowed non-specific protein adsorption. To illustrate the applications of the patterned Cytop surface, we used the patterned Cytop surface as the substrate to study the protein-protein interactions, stem cell culture, and stem cell proliferation.

This work presents a design approach that improves power management circuit (PMC) for energy harvesting applications so that more of the harvested energy can be utilized by the wireless sensor nodes (WSNs) to perform useful tasks. The proposed method is widely applicable to different circuits by setting an appropriate threshold voltage at the energy flow control interface of the circuit. Experimental results show that with a threshold voltage difference of around 20 mV, the energy output from the PMC can differ by more than 5%. This difference is significant over a long period of time as more tasks can be performed by the WSN with the extra energy.

Predictive industrial maintenance promotes proactive scheduling of maintenance to minimize unexpected device anomalies/faults. Almost all current predictive industrial maintenance techniques construct a model based on prior knowledge or data at build-time. However, anomalies/faults will propagate among sensors and devices along correlations hidden among sensors. These correlations can facilitate maintenance. This paper makes an attempt on predicting the anomaly/fault propagation to perform predictive industrial maintenance by considering the correlations among faults. The main challenge is that an anomaly/fault may propagate in multiple ways owing to various correlations. This is called as the uncertainty of anomaly/fault propagation. This present paper proposes a correlation-based event routing approach for predictive industrial maintenance by improving our previous works. Our previous works mapped physical sensors into a soft-ware-defined abstraction, called proactive data service. In the service model, anomalies/faults are encapsulated into events. We also proposed a service hyperlink model to encapsulate the correlations among anomalies/faults. This paper maps the anomalies/faults propagation into event routing and proposes a heuristic algorithm based on service hyperlinks to route events among services. The experiment results show that, our approach can reach 100% precision and 88.89% recall at most.

Photocrosslinked methacrylated hyaluronic acid (MeHA) hydrogels support chondrogenesis of encapsulated human mesenchymal stem cells (hMSCs). However, the covalent crosslinks formed via chain polymerization in these hydrogels are hydrolytically non-degradable and restrict cartilage matrix spatial distribution and cell spreading. Meanwhile, cells are known to remodel their surrounding extracellular matrix (ECM) by secreting catabolic enzymes, such as MMPs. Hydrogels that are created with bifunctional crosslinkers containing MMP degradable peptide sequences have been shown to influence hMSC differentiations. However, crosslinks formed in the MMP-degradable hydrogels of these previous studies are also prone to hydrolysis, thereby confounding the effect of MMP-mediated degradation. The objective of this study is to develop a MMP-sensitive but hydrolytically stable hydrogel scaffold and investigate the effect of MMP-mediated hydrogel degradation on the chondrogenesis of the encapsulated hMSCs. Hyaluronic acid macromers were modified with maleimide groups and crosslinked with MMP-cleavable peptides or control crosslinkers containing dual thiol groups. The chondrogenesis of the hMSCs encapsulated in the hydrolytically stable MMP-sensitive HA hydrogels were compared with that of the MMP-insensitive HA hydrogels. It was found that hMSCs encapsulated in the MMP-sensitive hydrogels switched to a more spreaded morphology while cells in the MMP-insensitive hydrogels remained in round shape. Furthermore, hMSCs in the MMP-sensitive hydrogels expressed higher level of chondrogenic marker genes but lower level of hypertrophic genes compared to cells in the MMP-insensitive hydrogels. As a result, more cartilage specific matrix molecules but less calcification was observed in the MMP-degradable hydrogels than in the MMP-insensitive hydrogels. Findings from this study demonstrate that cell-mediated scaffold degradation regulates the chondrogenesis and hypertrophy of hMSCs encapsulated in HA hydrogels.