Antioxidant Carbon Dots and Ursolic Acid Co-Encapsulated Liposomes Composite Hydrogel for Alleviating Adhesion Formation and Enhancing Tendon Healing in Tendon Injury.

Background: The formation of adhesion after tendon injury represents a major obstacle to tendon repair, and currently there is no effective anti-adhesion method in clinical practice. Oxidative stress, inflammation, and fibrosis can occur in tendon injury and these factors can lead to tendon adhesion. Antioxidant carbon dots and ursolic acid (UA) both possess antioxidant and anti-inflammatory properties. In this experiment, we have for the first time created RCDs/UA@Lipo-HAMA using red fluorescent carbon dots and UA co-encapsulated liposomes composite hyaluronic acid methacryloyl hydrogel. We found that RCDs/UA@Lipo-HAMA could better attenuate adhesion formation and enhance tendon healing in tendon injury. Materials and Methods: RCDs/UA@Lipo-HAMA were prepared and characterized. In vitro experiments on cellular oxidative stress and fibrosis were performed. Reactive oxygen species (ROS), and immunofluorescent staining of collagens type I (COL I), collagens type III (COL III), and α-smooth muscle actin (α-SMA) were used to evaluate anti-oxidative and anti-fibrotic abilities. In vivo models of Achilles tendon injury repair (ATI) and flexor digitorum profundus tendon injury repair (FDPI) were established. The major organs and blood biochemical indicators of rats were tested to determine the toxicity of RCDs/UA@Lipo-HAMA. Biomechanical testing, motor function analysis, immunofluorescence, and immunohistochemical staining were performed to assess the tendon adhesion and repair after tendon injury. Results: In vitro, the RCDs/UA@Lipo group scavenged excessive ROS, stabilized the mitochondrial membrane potential (ΔΨm), and reduced the expression of COL I, COL III, and α-SMA. In vivo, assessment results showed that the RCDs/UA@Lipo-HAMA group improved collagen arrangement and biomechanical properties, reduced tendon adhesion, and promoted motor function after tendon injury. Additionally, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the RCDs/UA@Lipo-HAMA group increased; the levels of cluster of differentiation 68 (CD68), inducible Nitric Oxide Synthase (iNOS), COL III, α-SMA, Vimentin, and matrix metallopeptidase 2 (MMP2) decreased. Conclusion: In this study, the RCDs/UA@Lipo-HAMA alleviated tendon adhesion formation and enhanced tendon healing by attenuating oxidative stress, inflammation, and fibrosis. This study provided a novel therapeutic approach for the clinical treatment of tendon injury.

Epidemiological characteristics and outcomes of special-cause burns: analysis of 33,619 burn patients in a major regional burn center in China from 2004 to 2021.

Special-cause burn injuries are usually more severe and difficult to manage, and often contribute to a high mortality in severely injured patients. The aim of this study was to present the epidemiological characteristics of special-cause burn in a major regional burn center in China between 2004 and 2021 and determine the risk factors associated with the mortality of burn patients. A total of 33,619 burn patients were included the study, among which 4,452 (13.2%) were special-cause burn patients. Compared to the thermal burn group, the special-cause burn patients were usually male, elder, married and III-IV degree of burn with onset of upper extremity in summer and autumn. Moreover, a greater proportion of patients in the special-cause burn group underwent surgical treatment and amputation and had a higher median hospital stay and treatment costs. During the multivariate logistic regression, older age, male, unmarried, winter, III-IV degree of burn, ≥ 3 burn sites, and larger total body surface area (TBSA) of burn were significantly associated with higher burn mortality (all P < 0.05), however, patients with special-cause burn injuries have not increased odds for mortality (P > 0.05). These results suggested that special cause-burn patients suffer more severe injuries, resulting in longer hospital stays and higher health care expenditures, but it did not significantly increase the mortality risk. Therefore, burn clinicians should not only have the responsibility to cure burns, but also need to know and popularize burn epidemiological characteristic and precaution.

The Hemagglutinin of Influenza A Virus Induces Ferroptosis to Facilitate Viral Replication.

Ferroptosis is a novel form of cell death caused by the accumulation of lipid peroxides in an iron-dependent manner. However, the precise mechanism underlying the exploitation of ferroptosis by influenza A viruses (IAV) remains unclear. The results demonstrate that IAV promotes its own replication through ferritinophagy by sensitizing cells to ferroptosis, with hemagglutinin identified as a key trigger in this process. Hemagglutinin interacts with autophagic receptors nuclear receptor coactivator 4 (NCOA4) and tax1-binding protein 1 (TAX1BP1), facilitating the formation of ferritin-NCOA4 condensates and inducing ferritinophagy. Further investigation shows that hemagglutinin-induced ferritinophagy causes cellular lipid peroxidation, inhibits aggregation of mitochondrial antiviral signaling protein (MAVS), and suppresses the type I interferon response, thereby contributing to viral replication. Collectively, a novel mechanism by which IAV hemagglutinin induces ferritinophagy resulting in cellular lipid peroxidation, consequently impairing MAVS-mediated antiviral immunity, is revealed.

The association of stress perception on anxiety, depression and sleep quality in parents of children with burns: The moderating effect of social support.

OBJECTIVE: Few studies have explored the mental health status of parents of children with burns and the moderating effect of social support on them. METHODS: A survey was performed with parents of 112 burn-injured children at a burn center in China. Their perceived stress, anxiety, depression, sleep quality, and social support were measured by the Chinese Perceived Stress Scale, Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index, and Perceived Social Support Scale. RESULTS: ➀ The prevalence of anxiety (46.43%), depression (52.67%) and poor sleep quality (43.75%) of parents indicated that they experienced emotional and sleep disorders;➁ The perceived stress was positively correlated with sleep quality, anxiety and depression（P＜0.01), and negatively correlated with perceived social support (p＜0.05); ➂ Social support had a significant moderating effect on their perceived stress and anxiety, depression, but not on their sleep quality. With high social support, parental perceived stress had a significant positive association on anxiety and depression, while with low perceived social support, parental perceived stress had no significant association on anxiety and depression. CONCLUSION: Parents of burned children had increased stress, obvious symptoms of anxiety and depression, and poor sleep quality. Social support had a significant buffering effect on them under low pressure, and high pressure will hinder the buffering effect of social support on stress. Therefore, the ideal services to improve mental health should be provided for them to face different levels of stress.

Transition of allele-specific DNA hydroxymethylation at regulatory loci is associated with phenotypic variation in monozygotic twins discordant for psychiatric disorders.

BACKGROUND: Major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD) are complex genetic mental illnesses. Their non-Mendelian features, such as those observed in monozygotic twins discordant for SCZ or BPD, are likely complicated by environmental modifiers of genetic effects. 5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark in gene regulation, and whether it is linked to genetic variants that contribute to non-Mendelian features remains largely unexplored. METHODS: We combined the 5hmC-selective chemical labeling method (5hmC-seq) and whole-genome sequencing (WGS) analysis of peripheral blood DNA obtained from monozygotic (MZ) twins discordant for SCZ or BPD to identify allelic imbalances in hydroxymethylome maps, and examined association of allele-specific hydroxymethylation (AShM) transition with disease susceptibility based on Bayes factors (BF) derived from the Bayesian generalized additive linear mixed model. We then performed multi-omics integrative analysis to determine the molecular pathogenic basis of those AShM sites. We finally employed luciferase reporter, CRISPR/Cas9 technology, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), PCR, FM4-64 imaging analysis, and RNA sequencing to validate the function of interested AShM sites in the human neuroblastoma SK-N-SH cells and human embryonic kidney 293T (HEK293T) cells. RESULTS: We identified thousands of genetic variants associated with AShM imbalances that exhibited phenotypic variation-associated AShM changes at regulatory loci. These AShM marks showed plausible associations with SCZ or BPD based on their effects on interactions among transcription factors (TFs), DNA methylation levels, or other epigenomic marks and thus contributed to dysregulated gene expression, which ultimately increased disease susceptibility. We then validated that competitive binding of POU3F2 on the alternative allele at the AShM site rs4558409 (G/T) in PLLP-enhanced PLLP expression, while the hydroxymethylated alternative allele, which alleviated the POU3F2 binding activity at the rs4558409 site, might be associated with the downregulated PLLP expression observed in BPD or SCZ. Moreover, disruption of rs4558409 promoted neural development and vesicle trafficking. CONCLUSION: Our study provides a powerful strategy for prioritizing regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic factors in mediating SCZ or BPD susceptibility.

Prohibitin1 facilitates viral replication by impairing the RIG-I-like receptor signaling pathway.

IMPORTANCE: Type I interferon (IFN-I), produced by the innate immune system, plays an essential role in host antiviral responses. Proper regulation of IFN-I production is required for the host to balance immune responses and prevent superfluous inflammation. IFN regulatory factor 3 (IRF3) and subsequent sensors are activated by RNA virus infection to induce IFN-I production. Therefore, proper regulation of IRF3 serves as an important way to control innate immunity and viral replication. Here, we first identified Prohibitin1 (PHB1) as a negative regulator of host IFN-I innate immune responses. Mechanistically, PHB1 inhibited the nucleus import of IRF3 by impairing its binding with importin subunit alpha-1 and importin subunit alpha-5. Our study demonstrates the mechanism by which PHB1 facilitates the replication of multiple RNA viruses and provides insights into the negative regulation of host immune responses.

Living arrangements and depression of the older adults- evidence from the Chinese longitudinal healthy longevity survey.

BACKGROUND: The mental health and living arrangements of older adults are worthy of attention. Previous studies have pointed out that the living arrangements may be related to older adults' depression. However, it has not been found that studies concern the relationship between actual living arrangements, living arrangement preferences, and the fit between living arrangement preferences and reality and depression in older adults, so we carried out this study. METHODS: The data from the Chinese longitudinal healthy longevity survey were used in this study. With the older adults' depression as the dependent variable and the living arrangement related variables as the independent variable, we constructed three binary-logistic regression analysis models to explore the potential relationship between living arrangement related variables and depression in older adults. RESULTS: We found that the actual living arrangements, living arrangement preferences, and the fit between living arrangement preferences and reality are significantly correlated with depression in older adults. Specifically, older adults living alone or only with the spouse are at greater risk of depression. Older adults who prefer living alone or only with the spouse are at relatively low risk of depression. Older adults whose living arrangement preferences do not match reality have a higher risk of depression. CONCLUSION: The living arrangement related variables are significantly correlated with depression in older adults. In addition to the actual living arrangements, living arrangement preferences and whether the living arrangement preferences fit with reality are also related to the depression of older adults.

Chronic stress and turnover intention of resident physicians after experiencing COVID-19.

BACKGROUND: Previous studies have explored the stress and turnover intention of healthcare workers, but as important backup talents in the healthcare system, resident physicians have received little attention from researchers, especially after experiencing COVID-19. Therefore, this study aims to evaluate the chronic stress and turnover intention of resident physicians after experiencing COVID-19. METHODS: From June to August 2022, we conducted a questionnaire survey on resident physicians in the Children's Hospital of Hebei Province through the online platform (Wenjuanxing) to evaluate their chronic stress and turnover intention after experiencing COVID-19. For the collected data, we used frequency and percentage to make the statistical description, the Chi-square test to make a univariate analysis on the scores of chronic stress and turnover intention scale, and binary logistic regression analysis to explore the influencing factors of turnover intention. RESULTS: Out of 143 respondents, we finally received 127 questionnaires, with a response rate of 88.81%. Among 127 respondents, 80.31% of resident physicians experienced varying degrees of chronic stress (mild: 36.22%, moderate: 35.43%, severe: 8.66%), and 74.80% of resident physicians showed varying degrees of turnover intention (mild: 23.62%, moderate: 37.79%, severe: 13.39%). Moreover, age (OR = 0.772, P = 0.042), identity (OR = 8.648, P = 0.021), and chronic stress levels (mild: OR = 6.938, P = 0.003; moderate: OR = 44.049, P < 0.003; severe: OR = 46.141, P = 0.004) can significantly affect turnover intention. CONCLUSION: In this study, we reported a relatively high proportion of resident physicians with high chronic stress and high turnover intention after experiencing COVID-19. We suggest that the relevant departments should pay more attention to the resident physicians' group and formulate corresponding measures to solve the problems faced by the resident physicians and ensure the stability of the health human resources.

Evaluation of the Mucosal Immunity Effect of Bovine Viral Diarrhea Virus Subunit Vaccine E2Fc and E2Ft.

Classified as a class B infectious disease by the World Organization for Animal Health (OIE), bovine viral diarrhea/mucosal disease is an acute, highly contagious disease caused by the bovine viral diarrhea virus (BVDV). Sporadic endemics of BVDV often lead to huge economic losses to the dairy and beef industries. To shed light on the prevention and control of BVDV, we developed two novel subunit vaccines by expressing bovine viral diarrhea virus E2 fusion recombinant proteins (E2Fc and E2Ft) through suspended HEK293 cells. We also evaluated the immune effects of the vaccines. The results showed that both subunit vaccines induced an intense mucosal immune response in calves. Mechanistically, E2Fc bonded to the Fc γ receptor (FcγRI) on antigen-presenting cells (APCs) and promoted IgA secretion, leading to a stronger T-cell immune response (Th1 type). The neutralizing antibody titer stimulated by the mucosal-immunized E2Fc subunit vaccine reached 1:64, which was higher than that of the E2Ft subunit vaccine and that of the intramuscular inactivated vaccine. The two novel subunit vaccines for mucosal immunity developed in this study, E2Fc and E2Ft, can be further used as new strategies to control BVDV by enhancing cellular and humoral immunity.

eIF4A3 Promotes RNA Viruses' Replication by Inhibiting Innate Immune Responses.

Viral infection activates the type I interferons (IFNs) and cellular antiviral responses. Eukaryotic initiation factor 4A-III (eIF4A3) has been shown to promote influenza A virus (IAV) replication by promoting viral mRNA splicing and spliced mRNA nuclear export. Here, we identified eIF4A3 as a negative regulator of virus-triggered type I IFN induction. Our study found that eIF4A3 promoted multiple RNA viruses' replication by binding to IFN regulatory factor 3 (IRF3) and impaired the interaction between tank-binding kinase 1 (TBK1) and IRF3, leading to attenuation of the phosphorylation of IRF3 by TBK1, the formation of IRF3 dimer, and the nuclear translocation of IRF3. This impaired its biological functions in the nucleus, which blocked IRF3 binding to interferon-stimulated response element (ISRE) and the interaction of IRF3 and CBP/p300, resulting in inhibiting the transcription of IFN-ß and downstream IFN-stimulated genes (ISGs), thereby impairing innate antiviral immune responses against RNA viruses. These findings reveal a previously unknown function of eIF4A3 in host innate immunity and establish a mechanistic link between eIF4A3 and IRF3 activation that expands potential therapeutic strategies for viral infectious diseases. IMPORTANCE Production of type I IFN is pivotal for the cellular antiviral immunity. Virus infection leads to the activation of transcription factor IRF3 and subsequent production of type I IFN to eliminate viral infection. Thus, the regulation of IRF3 activity is an important way to affect type I IFN production. IRF3 activation requires phosphorylation, dimerization, and nuclear translocation. Here, we first reported that eIF4A3, a member of DEAD box family, served as a negative regulator of antiviral innate immune responses by inhibiting IRF3 activation. Mechanistically, eIF4A3 binds to IRF3 to impair the recruitment of IRF3 by TBK1, which is independent of eIF4A3 ATP binding, ATPase, and RNA helicase activities. Our study delineates a common mechanism of eIF4A3 promoting replication of different RNA viruses and provides important insights into the negative regulation of host antiviral innate immune responses against virus infections.

Transportin-3 Facilitates Uncoating of Influenza A Virus.

Influenza A viruses (IAVs) are a major global health threat and in the future, may cause the next pandemic. Although studies have partly uncovered the molecular mechanism of IAV-host interaction, it requires further research. In this study, we explored the roles of transportin-3 (TNPO3) in IAV infection. We found that TNPO3-deficient cells inhibited infection with four different IAV strains, whereas restoration of TNPO3 expression in knockout (KO) cells restored IAV infection. TNPO3 overexpression in wild-type (WT) cells promoted IAV infection, suggesting that TNPO3 is involved in the IAV replication. Furthermore, we found that TNPO3 depletion restrained the uncoating in the IAV life cycle, thereby inhibiting the process of viral ribonucleoprotein (vRNP) entry into the nucleus. However, KO of TNPO3 did not affect the virus attachment, endocytosis, or endosomal acidification processes. Subsequently, we found that TNPO3 can colocalize and interact with viral proteins M1 and M2. Taken together, the depletion of TNPO3 inhibits IAV uncoating, thereby inhibiting IAV replication. Our study provides new insights and potential therapeutic targets for unraveling the mechanism of IAV replication and treating influenza disease.

LncRNA RP5-998N21.4 promotes immune defense through upregulation of IFIT2 and IFIT3 in schizophrenia.

Schizophrenia is a complex polygenic disease that is affected by genetic, developmental, and environmental factors. Accumulating evidence indicates that environmental factors such as maternal infection and excessive prenatal neuroinflammation may contribute to the onset of schizophrenia by affecting epigenetic modification. We recently identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA) RP5-998N21.4 by transcriptomic analysis of monozygotic twins discordant for schizophrenia. Importantly, we found that genes coexpressed with RP5-998N21.4 were enriched in immune defense-related biological processes in twin subjects and in RP5-998N21.4-overexpressing (OE) SK-N-SH cell lines. We then identified two genes encoding an interferon-induced protein with tetratricopeptide repeat (IFIT) 2 and 3, which play an important role in immune defense, as potential targets of RP5-998N21.4 by integrative analysis of RP5-998N21.4OE-induced differentially expressed genes (DEGs) in SK-N-SH cells and RP5-998N21.4-coexpressed schizophrenia-associated DEGs from twin subjects. We further demonstrated that RP5-998N21.4 positively regulates the transcription of IFIT2 and IFIT3 by binding to their promoter regions and affecting their histone modifications. In addition, as a general nuclear coactivator, RMB14 (encoding RNA binding motif protein 14) was identified to facilitate the regulatory role of RP5-998N21.4 in IFIT2 and IFIT3 transcription. Finally, we observed that RP5-998N21.4OE can enhance IFIT2- and IFIT3-mediated immune defense responses through activation of signal transducer and activator of transcription 1 (STAT1) signaling pathway in U251 astrocytoma cells under treatment with the viral mimetic polyinosinic: polycytidylic acid (poly I:C). Taken together, our findings suggest that lncRNA RP5-998N21.4 is a critical regulator of immune defense, providing etiological and therapeutic implications for schizophrenia.

Metabolic scaling: individual versus intraspecific scaling of Nile tilapia (Oreochromis niloticus).

We examined intraspecific scaling of the resting metabolic rate (RMR) of Nile tilapia (Oreochromis niloticus) under different culture conditions and further explored the allometric relationships between organ mass (heart, liver, brain, gills, viscera, and red muscles) and blood parameters (erythrocyte size and red blood cell counts) and body mass. Oreochromis niloticus were bred in individual and group cultures. The scaling exponent of the RMR in the individual cultures was b = 0.620-0.821 (n = 30) and that in the group culture was b = 0.770 [natural logarithm (ln) RMR = 0.770 ln M - 1.107 (n = 76)]. The results of the two experimental methods were similar and were not significantly different from 0.75 (3/4), as predicted by the metabolic theory of ecology. The active and inactive organs were scaled with body mass by an exponent of 0.940 and 1.012, respectively. There was no significant relationship between the blood parameters and body mass. These results suggest that the differences in the culture methods may not have affected the allometric scaling of O. niloticus metabolism. The proportion of active and inactive organs contributed to allometric changes in the metabolic rate with body mass. Red blood cells in fish are not generally representative, and cell size can only partially explain the allometric scaling of metabolism.

Suppression of circDcbld1 Alleviates Intimal Hyperplasia in Rat Carotid Artery by Targeting miR-145-3p/Neuropilin-1.

We replicated the rat common carotid artery (CCA) intima hyperplasia model and found the expression of a circular RNA, circRNA_009723 (circDcbld1), was markedly increased in the CCA with intimal hyperplasia. In vitro, the suppression of circDcbld1 in rat vascular smooth muscle cells (VSMCs) led the increase of contractile smooth muscle cell markers and the decrease of cell migration. In vivo, the injection of chemically modified circDcbld1 small interfering RNA (siRNA) lessened the formation of neointima in rat CCA after balloon injury. Further experiments proved that circDcbld1, as a competing endogenous RNA, interacted with miR-145-3p and upregulated the level of neuropilin-1 (Nrp1), thereby regulating the migration of VSMCs. In this study, we demonstrated a new mechanism by which circular RNA promotes intimal hyperplasia. We deem that intervention in the circDcbld1-miR-145-3p/Nrp1 pathway might be a feasible approach to alleviate the post-injury intimal hyperplasia.

[Repair of electrical burns on hands with flaps].

OBJECTIVE: To summarize the experiences and shortcomings of repair of wounds on hands due to electrical burns with flaps, aiming at further improvement. METHODS: Clinical data of 425 patients with electrical burn of hands admitted to Burn Institute of Wuhan, City Hospital NO. 3 & Tongren Hospital of Wuhan University from January 2000 to December 2006 were collected and summarized. Therapeutic methods and outcomes of all patients were statistically analyzed. Flap types, complications after surgery and problems existed in patients having undergone flap transplantation were summarized. Patients were divided into surgery within 7days post burn (PBD) group (SW) and surgery after PBD 7 group (SA) according to the timing of surgery. Survival rate of flaps and incidence of complications in patients of two groups were compared. RESULTS: Out of the 425 patients, 348 (90.2%) patients underwent surgery, among which 248 flaps of different types were transplanted in 209 patients, including 202 (81.5%) distant pedicle flaps, 19 (7.7%) local flaps, 12 (4.8%) free flaps, and 15 (6.0%) other kinds of tissue flaps. Five flaps failed because of necrosis of torn off, and the resulting wounds were treated with other methods. Eight flaps showed necrosis of distal margin, and the wound healed with dressing changing or skin grafting. All the remaining flaps survived with satisfactory cosmetic and functional results. In SW group (n = 170) and SA group (n = 78), survival rate of flaps was respectively 98.8% (168/170) and 96.2% (75/78), incidence of complications was respectively 10.6% (18/170) and 12.8% (10/78). There was no statistical difference between above two sets of data (with chi(2) value respectively 0.81 and 0.27, and P values both above 0.05). CONCLUSIONS: There are many types of flaps that can be used to repair electric burn wounds on hands. Appropriate choice and design of flaps, skillful operation, and careful post-operation observation and treatment are key points for good therapeutic effect.