CAR-Macrophage Therapy Alleviates Myocardial Ischemia-Reperfusion Injury.

BACKGROUND: Given the growing acknowledgment of the detrimental effects of excessive myocardial fibrosis on pathological remodeling after myocardial ischemia-reperfusion injury (I/R), targeting the modulation of myocardial fibrosis may offer protective and therapeutic advantages. However, effective clinical interventions and therapies that target myocardial fibrosis remain limited. As a promising chimeric antigen receptor (CAR) cell therapy, whether CAR macrophages (CAR-Ms) can be used to treat I/R remains unclear. METHODS: The expression of FAP (fibroblast activation protein) was studied in mouse hearts after I/R. FAP CAR-Ms were generated to target FAP-expressing cardiac fibroblasts in mouse hearts after I/R. The phagocytosis activity of FAP CAR-Ms was tested in vitro. The efficacy and safety of FAP CAR-Ms in treating I/R were evaluated in vivo. RESULTS: FAP was significantly upregulated in activated cardiac fibroblasts as early as 3 days after I/R. Upon demonstrating their ability to engulf FAP-overexpressing fibroblasts, we intravenously administered FAP CAR-Ms to mice at 3 days after I/R and found that FAP CAR-Ms significantly improved cardiac function and reduced myocardial fibrosis in mice after I/R. No toxicities associated with FAP CAR-Ms were detected in the heart or other organs at 2 weeks after I/R. Finally, we found that FAP CAR-Ms conferred long-term cardioprotection against I/R. CONCLUSIONS: Our proof-of-concept study demonstrates the therapeutic potential of FAP CAR-Ms in alleviating myocardial I/R and potentially opens new avenues for the treatment of a range of heart diseases that include a fibrotic phenotype.

Dysbiosis of gut microbiota inhibits NMNAT2 to promote neurobehavioral deficits and oxidative stress response in the 6-OHDA-lesioned rat model of Parkinson's disease.

BACKGROUND: New data are accumulating on gut microbial dysbiosis in Parkinson's disease (PD), while the specific mechanism remains uncharacterized. This study aims to investigate the potential role and pathophysiological mechanism of dysbiosis of gut microbiota in 6-hydroxydopamine (6-OHDA)-induced PD rat models. METHODS: The shotgun metagenome sequencing data of fecal samples from PD patients and healthy individuals were obtained from the Sequence Read Archive (SRA) database. The diversity, abundance, and functional composition of gut microbiota were further analyzed in these data. After the exploration of the functional pathway-related genes, KEGG and GEO databases were used to obtain PD-related microarray datasets for differential expression analysis. Finally, in vivo experiments were performed to confirm the roles of fecal microbiota transplantation (FMT) and upregulated NMNAT2 in neurobehavioral symptoms and oxidative stress response in 6-OHDA-lesioned rats. RESULTS: Significant differences were found in the diversity, abundance, and functional composition of gut microbiota between PD patients and healthy individuals. Dysbiosis of gut microbiota could regulate NAD+ anabolic pathway to affect the occurrence and development of PD. As a NAD+ anabolic pathway-related gene, NMNAT2 was poorly expressed in the brain tissues of PD patients. More importantly, FMT or overexpression of NMNAT2 alleviated neurobehavioral deficits and reduced oxidative stress in 6-OHDA-lesioned rats. CONCLUSIONS: Taken together, we demonstrated that dysbiosis of gut microbiota suppressed NMNAT2 expression, thus exacerbating neurobehavioral deficits and oxidative stress response in 6-OHDA-lesioned rats, which could be rescued by FMT or NMNAT2 restoration.

Prevalence, Clinical Features, and Psychological Characteristics of Dissociative Subtype of Posttraumatic Stress Disorder in Chinese Prisoners.

This study aimed to examine prevalence, clinical symptoms, and psychological characteristics of D-PTSD in a sample of Chinese prisoners with probable PTSD. A total of 1458 male prisoners were recruited from a large prison in Guangdong, China. Participants completed self-administrated questionnaires that assessed PTSD and dissociative symptoms, psychopathology, emotion regulation, emotional expressivity, social pleasure, traumatic events, and social support. According to DSM-5 criteria, participants were classified into four groups: D-PTSD, PTSD only, derealization/depersonalization (DD) only, and neither. The proportions of D-PTSD, PTSD only, DD only and neither were 2.5%, 4.7%, 2.4%, and 92.2%, respectively. PTSD symptoms and emotion regulation difficulties were distinguishing for the four groups: PTSD symptoms declined gradually in the order of D-PTSD, PTSD only, DD only, and neither, while emotion regulation difficulties declined in an order from D-PTSD, DD only, and PTSD only to neither, all ps < .001. D-PTSD and DD only had higher depressive and dissociative symptoms than PTSD only and the neither groups, all ps < .001. D-PTSD also had more borderline personality symptoms, emotion regulation difficulties, and more negative emotional expressivity than PTSD only and DD only, all ps < .05. Logistic regressions indicated that D-PTSD reported lower social support compared to PTSD only (OR = 0.95, p < .01), DD only (OR = 0.96, p < .05) and neither (OR = 0.93, p < .001). D-PTSD is common in probable PTSD in prisoners and is associated with complex clinical presentations as well as emotional processing. Social support is an important protective factor of D-PTSD.

A Prospective Study of Psychiatric Symptoms Among Adolescents After the Wenchuan Earthquake.

Natural disaster exposure is associated with increased risk of mental health problems. This study aimed to investigate the prevalence, course, and risk factors of probable psychiatric disorders among 1,573 adolescents following the May 2008 Wenchuan earthquake in China. Symptoms of posttraumatic stress disorder (PTSD), depression, panic disorder (PD), generalized anxiety disorder (GAD), separation anxiety disorder (SAD), social phobia (SP), conduct disorder (CD), and attention deficit hyperactivity disorder (ADHD) were assessed at 6 and 18 months postearthquake using a battery of standardized measures. Approximately 62.9% and 56.1% of the sample, respectively, had at least one probable psychiatric disorder at 6 and 18 months postearthquake. The most common disorders were PTSD, depression, PD, GAD, and ADHD. With regard to the course of disorders, PTSD, GAD, PD, SAD. and ADHD decreased; SP and CD remained stable; and depression increased. Generalized estimating equations models showed that female sex, older age, having experienced the death or injury of family members, being a direct witness of tragic scenes, low social support, and a high level of negative life events were risk factors for most disorders, odds ratios (ORs) = 1.3-20.8. However, logistic regressions indicated that earthquake exposure variables were specifically related to persistent PTSD, ORs = 2.0-2.5, and negative life events were associated with persistent depression, ORs = 2.4-5.3. Various psychiatric symptoms are pervasive, intense, and persistent among adolescent survivors. Systematic and periodic screening are needed to closely monitor the onset, course, and risk factors of mental health problems after disasters.

Ultra-low-noise transimpedance amplifier with a single HEMT in pre-amplifier for measuring shot noise in cryogenic STM.

In this work, a design of transimpedance amplifier (TIA) for cryogenic scanning tunneling microscope (CryoSTM) is proposed. TIA with the tip-sample component in CryoSTM is called as CryoSTM-TIA. With transimpedance gain of 1 GΩ, the bandwidth of the CryoSTM-TIA is larger than 200 kHz. The distinctive feature of the proposed CryoSTM-TIA is that its pre-amplifier is made of a single cryogenic high electron mobility transistor (HEMT), so the apparatus equivalent input noise current power spectral density at 100 kHz is lower than 6 (fA)2/Hz. In addition, "bias-cooling method" can be used to in-situ control the density of the frozen DX- centers in the HEMT doping area, changing its structure to reduce the device noises. With this apparatus, fast scanning tunneling spectra measurements with high-energy-resolution are capable to be performed. And, it is capable to measure scanning tunneling shot noise spectra (STSNS) at the atomic scale for various quantum systems, even if the shot noise is very low. It provides a powerful tool to investigate novel quantum states by measuring STSNS, such as detecting the existence of Majorana bound states in the topological quantum systems.

Revisiting the factor structure of the insomnia severity index among survivors of the 2013 Super Typhoon Haiyan.

OBJECTIVE: The insomnia severity index (ISI) is often used as a screening tool used with its recommended clinical cutoff scores. However, this practice presumes a single-factor structure, which has received little theoretical or empirical support. This study examined the factor structure of the ISI with the aim to validate its clinical application in postdisaster contexts. METHOD: One hundred sixty-eight Filipino adult survivors of the 2013 Super Typhoon Haiyan completed two waves of questionnaires that were 7 months apart. Confirmatory factor analyses were first conducted to compare models with different factor structures, followed by a test of longitudinal measurement invariance. The longitudinal interrelations among factors of the ISI as well as between insomnia and symptoms of psychological distress were then examined with path analysis. RESULTS: Results supported a two-factor model, composed of severity and impact of insomnia, which achieved strong longitudinal invariance. The change in impact of insomnia at T2 was predicted by severity of insomnia at T1. Impact of insomnia was significantly associated with symptoms of stress but not depression and anxiety. CONCLUSION: We preliminarily propose a model in which the impact of insomnia mediates the influence of severity of insomnia on subsequent stress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Low-noise large-bandwidth transimpedance amplifier for measuring scanning tunneling shot noise spectra in cryogenic STM and its applications.

Shot noise is a powerful tool to study quantum systems. In this work, a design of transimpedance amplifier (TIA) for a cryogenic scanning tunneling microscope (CryoSTM) is proposed to meet the requirements of the shot noise measurements for quantum systems. In the TIA, the preamplifier is made of the low-noise low-power cryogenic high electron mobility transistors. With the high transimpedance gain of 1 GΩ, the bandwidth of the proposed TIA is larger than 300 kHz. In the CryoSTM, the TIA with the tip-sample component is called as CryoSTM-TIA. The bandwidth of the proposed CryoSTM-TIA is still larger than 300 kHz. Its equivalent input noise current power spectral density is less than 30(fA)2/Hz at 100 kHz. It is detailed, for quantum systems, by using the CryoSTM-TIA, how to measure scanning tunneling current spectra, scanning tunneling differential conductance spectra, and scanning tunneling noise current power spectra, in atomic scale, and then extract their scanning tunneling shot noise spectra. Thus, it is possible to study novel quantum phenomena in various quantum systems by measuring shot noise with the CryoSTM-TIA, such as the Andreev reflection in atomic scale, the Kondo effect in a single molecular magnet, and the existence of Majorana bound states, etc.

Pharmacological properties of total flavonoids in Scutellaria baicalensis for the treatment of cardiovascular diseases.

BACKGROUND: Scutellaria baicalensis, a medicinal herb belonging to the Lamiaceae family, has been recorded in the Chinese, European, and British Pharmacopoeias. The medicinal properties of this plant are attributed to the total flavonoids of Scutellaria baicalensis (TFSB), particularly the main component, baicalin. This study provides a systematic and comprehensive list of the identified TFSB components and their chemical structures. The quality control process, pharmacokinetics, clinical application, and safety of Scutellaria baicalensis are discussed, and its pharmacological effect on cardiovascular diseases (CVDs) is detailed. Finally, the future research trends and prospects of this medicinal plant are provided. METHODS: The Chinese and English papers related to TFSB were collected from the PubMed and CNKI databases using the relevant keywords. To highlight the pharmacological mechanism, clinical application, and safety of TFSB, the collected articles were screened and classified based on their research content. RESULTS: TFSB contains at least 100 different kinds of flavonoids, of which baicalin, baicalein, wogonin, wogonoside, scutellarin, and scutellarein are the main active ingredients. The preparation process of TFSB is relatively well established, and the extraction rate can be significantly increased by enzymatic pretreatment and ultrasonication. The low oral availability of TFSB may be effectively enhanced using nanoformulations. The available pharmacokinetic data show that flavonoid glycosides and aglycones with the same parent nucleus may be converted to structures that are conducive to absorption in vivo. Moreover, TFSB can protect against CVDs by inhibiting apoptosis, regulating oxidative stress response, participating in inflammatory response, protecting against myocardial fibrosis, inhibiting myocardial hypertrophy, and regulating blood vessels. In terms of clinical application and animal safety, the available studies show that TFSB can be applied in a wide range of clinical treatments and is safe to use is animals. CONCLUSION: This article systematically reviews the therapeutic effect and underlying pharmacological mechanism of TFSB against CVDs. The available studies clearly suggest that TFSB has great potential for the treatment of CVDs and is worthy of in-depth research and development.

Associations of positive and adverse childhood experiences and adulthood insomnia in a community sample of Chinese adults.

STUDY OBJECTIVES: Research has documented that adverse childhood experiences (ACEs) are associated with increased adult sleep disturbances, little is known about whether positive childhood experiences (PCEs) influence sleep health in adulthood. This study aimed to examine the associations of ACEs and PCEs with adulthood insomnia, as well as the extent to which PTSD and depressive symptoms mediated these associations. METHODS: A sample of 7245 adults in China (male 32.7%; mean age 38.09 years, SD = 7.84, range from 18 to 81) completed self-report questionnaires to assess ACEs, PCEs, PTSD and depressive symptoms. Multiple linear regressions were used to examine the independent and interaction effects of ACEs and PCEs on insomnia. Path analyses were performed to examine the direct and indirect effects of ACEs and PCEs on insomnia. RESULTS: After adjustment of demographics, ACEs (ß = 0.11, p < 0.001) and PCEs (ß = -0.09, p < 0.001) were both independently associated with adulthood insomnia, while the relationship between PCEs and insomnia was weakened but still significant among participants with high levels of ACEs. After controlling for demographics, PTSD and depressive symptoms partially mediated the overall effect of PCEs on insomnia, and fully mediated the relationship between ACEs and insomnia. CONCLUSIONS: These data demonstrate that both positive and adverse childhood experiences influence adulthood insomnia. The findings highlight the importance of joint assessment of PCEs and ACEs to prevent and intervene insomnia. Optimizing the early childhood environment may help to foster healthy sleep throughout the life course.

The inactivated vaccine of reassortant H3N2 canine influenza virus based on internal gene cassette from PR8 is safe and effective.

Canine influenza (CI) is a contagious respiratory disease in dogs, which poses a threat to canine health. A safe, high-yield vaccine seed virus is critical for CI vaccine development. We developed a PR8-based reassortant H3N2 canine influenza virus (RT CIV) using the reverse genetic method and evaluated its yield in canine kidney epithelial (MDCK) cells, Vero cells, and specific pathogen-free (SPF) chicken embryos. Mice and dogs were infected with RT CIV, and the pathogenicity was evaluated. The viral titers of RT CIV increased in MDCK cells, Vero cells, and SPF chicken embryos; the HA yield in SPF chicken embryos increased 4-fold. However, RT CIV was not lethal to mice, and it showed similar virulence as wild-type CIV. RT CIV also showed minimal pathogenicity in dogs, which manifested as mild fever and rhinorrhea for the first two days post-infection. Thus, RT CIV carrying the internal gene cassette from PR8 showed almost no pathogenicity in dogs. And the reassortant virus inactivated vaccine could provide complete protection against H3N2 CIV. To our knowledge, this is the first report on the pathogenicity of PR8-based reassortant H3N2 CIV in dogs. These studies are relevant for developing a high-yield and safe CI vaccine.

Phosphoproteomics to Characterize Host Response During H3N2 Canine Influenza Virus Infection of Dog Lung.

Avian-origin H3N2 canine influenza viruses (CIVs) cause severe contagious respiratory disease in dogs, and quickly adapt to new environments. To further understand the mechanism of virus infection and host-virus interactions, we characterized the complete phosphoproteome of dogs infected with H3N2 CIV. Nine-week-old Beagle dogs were inoculated intranasally with 106 EID50 of A/canine/Guangdong/04/2014 (H3N2) virus. Lung sections were harvested at 5 days post-inoculation (dpi) and processed for global and quantitative analysis of differentially expressed phosphoproteins. A total of 1,235 differentially expressed phosphorylated proteins were identified in the dog lung after H3N2 CIV infection, and 3,016 modification sites were identified among all differentially expressed proteins. We then performed an enrichment analysis of functional annotations using Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) database analyses to predict the functions of the identified differential phosphoproteins. Our data indicate that H3N2 CIV infection causes dramatic changes in the host protein phosphorylation of dog lungs. To our knowledge, this is the first study to assess the effect of H3N2 CIV infection on the phosphoproteome of beagles. These data provide novel insights into H3N2-CIV-triggered regulatory phosphorylation circuits and signaling networks and may improve our understanding of the mechanisms underlying CIV pathogenesis in dogs.

Posttraumatic Stress Disorder and Psychiatric Comorbidity among Adolescent Earthquake Survivors: a Longitudinal Cohort Study.

Although posttraumatic stress disorder (PTSD) is highly comorbid with psychiatric disorders, little longitudinal research has been conducted to determine the potentially causal links. This study aimed to investigate the prevalence and comorbidity patterns of posttraumatic stress disorder symptoms and psychiatric symptoms among adolescents exposed to the 2008 Wenchuan earthquake in China and to examine the bidirectional prospective associations between PTSD symptoms and other psychiatric symptoms. A sample of 1573 adolescent survivors (45.8% male; mean age at initial survey was 15.0 years, SD = 1.3) completed a battery of standardized measures assessing symptoms of PTSD, depression, panic disorder, generalized anxiety disorder (GAD), separation anxiety disorder (SAD), social phobia, conduct disorder, and attention deficit hyperactivity disorder at 6 and 18 months post-earthquake. Among participants with PTSD symptoms, 91.9 and 94.0% had at least one comorbid psychiatric disorder at 6 and 18 months post-earthquake, respectively; however, among those without PTSD symptoms, 54.3 and 50.4% had at least one psychiatric disorder. PTSD symptoms were more likely to co-occur with subtypes of anxiety or depression symptoms than with behavior problems. Participants who were screened as having PTSD comorbid with depression or SAD at 6 months were less likely to recover from PTSD over time. Longitudinal analyses showed that symptoms of depression, GAD and SAD predicted increases in PTSD symptoms. In turn, PTSD symptoms predicted increases in GAD and panic disorder symptoms. Overall, our results support causal hypotheses of PTSD comorbidity. Specific multi-modal assessments and treatments targeting to both PTSD and its comorbidity disorders are warranted.

Bidirectional associations between insomnia, posttraumatic stress disorder, and depressive symptoms among adolescent earthquake survivors: a longitudinal multiwave cohort study.

STUDY OBJECTIVES: To assess insomnia symptoms in adolescents with probable posttraumatic stress disorder (PTSD) and to determine whether there are longitudinal and reciprocal associations between insomnia, PTSD, and depressive symptoms. METHODS: Participants were 1,492 adolescent survivors who had been exposed to the 2008 Wenchuan earthquake in China. Insomnia, PTSD, and depressive symptoms were measured at 12 months (T1, n = 1407), 18 months (T2, n = 1335), and 24 months (T3, n = 1361) postearthquake by self-report questionnaires. Generalized estimating equation (GEE) models were used to examine the cross-sectional and longitudinal associations of insomnia with PTSD and depression. RESULTS: Insomnia, PTSD, and depressive symptoms were common among adolescent survivors. Among participants with probable PTSD, approximately 47% (48.5%, T1; 48.1%, T2; and 44.2%, T3) reported difficulty falling asleep or difficulty maintaining sleep. Cross-sectional analyses showed that insomnia co-occurred with PTSD (odds ratio [OR] = 2.04) and depressive symptoms (OR = 2.10). Longitudinal analyses revealed that probable PTSD (OR = 1.50) and depression (OR = 1.42) predicted the incidence of insomnia; in turn, insomnia predicted the incidence of depression (OR = 1.65) over time. Furthermore, PTSD predicted (OR = 3.11) and was predicted (OR = 3.25) by depressive symptoms. CONCLUSIONS: There is a bidirectional relationship between insomnia, PTSD, and depressive symptoms. This suggests that insomnia, PTSD, and depression are intertwined over time.

A Longitudinal Study of Recurrent Experience of Earthquake and Mental Health Problems Among Chinese Adolescents.

Background: The effects of recurrent exposure to disasters on adolescents' mental health have rarely been studied. We examined the effects of two earthquake experiences 5 years apart in a longitudinal cohort of Chinese adolescents. Methods: A total of 858 adolescents were assessed in September, 2011 (3.5 years after the Wenchuan earthquake, 1.5 years before Ya'an earthquake, T1) and April, 2013 (1 week after the Ya'an earthquake, T2). Participants' Wenchuan earthquake experiences and symptoms of post-traumatic stress disorder (PTSD) and depression were assessed at T1, and their Ya'an earthquake experiences, Acute Stress Disorder (ASD), PTSD, and depression were assessed at T2. Results: Structural equation models showed a positive relationship between Ya'an earthquake experiences and symptoms of ASD, PTSD, and depression at T2. T1 PTSD symptoms significantly increased T2 ASD, PTSD, and depression symptoms, and also mediated the relationships between Wenchuan earthquake experiences and T2 ASD, PTSD, and depression symptoms. T1 Depression symptoms also significantly increased T2 ASD, PTSD, and depression symptoms, but only mediated the association between Wenchuan earthquake experiences and T2 depression symptoms. In addition, Wenchuan earthquake experiences moderated the effects of Ya'an earthquake experiences on ASD symptoms and PTSD symptoms but not depression. Conclusion: Repeated to exposure to disasters have adverse additive effects on adolescents' mental health. Adolescents who experience one disaster may be sensitive to the negative impact of subsequent ones.

Prospective associations between sleep problems and subtypes of anxiety symptoms among disaster-exposed adolescents.

OBJECTIVE: This study aimed to investigate longitudinal relationships between sleep problems and subtypes of anxiety symptoms among adolescent earthquake survivors. METHODS: Participants were 1573 adolescents (male, 45.8%; mean age at baseline 15.01 years, standard deviation (SD) = 1.26) in the Wenchuan Earthquake Adolescent Health Cohort. The Pittsburgh Sleep Quality Index and the Screen for Child Anxiety Related Emotional Disorders were used to assess participants' sleep problems and anxiety symptoms four times during 2.5 years after the earthquake. Anxiety symptoms included subtypes of panic disorder (PD), generalized anxiety disorder (GAD), separation anxiety disorder (SeAD), social phobia (SP), school phobia (ScP). Longitudinal lagged generalized estimating equations (GEE) models were used to determine the prospective associations. RESULTS: Overall, there was a bidirectional relationship between sleep problems and anxiety symptoms. For the specific sleep problems and anxiety subtypes, short sleep duration predicted symptoms of PD, GAD, and ScP, and was predicted by GAD; difficulty falling asleep predicted GAD symptoms, whereas PD symptoms increased difficulty falling asleep; poor sleep quality predicted ScP symptoms and was predicted by symptoms of GAD and ScP; difficulty maintaining sleep was not associated with any subtype of anxiety symptoms in any direction; SeAD and SP were not associated with any specific sleep problems in any direction. CONCLUSION: While sleep problems and anxiety symptoms are bidirectional, the associations vary by subtypes of sleep problems and anxiety symptoms. The potential biological mechanisms for the specific associations between dimensional sleep and anxiety symptoms and their clinical implications should be further investigated.

ActO, a positive cluster-situated regulator for actinomycins biosynthesis in Streptomyces antibioticus ZS.

Actinomycins are a class of cyclic lipopeptide antibiotics produced by Streptomyces, which have rich biological activities and demonstrate great potential value. Among them, actinomycin D is currently the effective drug for some malignant tumor diseases. Although the chemical properties, biological activities and biosynthesis of actinomycins have been extensively studied, the regulation of their biosynthesis remains poorly understood. Streptomyces antibioticus ZS isolated from deep-sea corals is a producer of actinomycin D and actinomycin V. Here, we reported the characterization of a cluster-situated regulator ActO in actinomycins biosynthetic gene cluster (act cluster) of S. antibioticus ZS, which belongs to LmbU family. Deletion of actO completely blocked the synthesis of actinomycins. Overexpression of actO increased the yields of actinomycin D and actinomycin V by 4.4 fold and 2.6 fold, respectively. The result of RT-qPCR showed that ActO activates the transcription of all genes in act cluster. However, no specific binding of His6-ActO to the promoters of target genes was observed after electrophoretic mobility shift assay (EMSA). These results proved that ActO serves as a positive regulator involved in the biosynthesis of actinomycins, affecting the transcription of all genes related to the synthesis of intermediates, skeleton modification and extracellular transportation of final products. Moreover, we demonstrated that overexpression of actO is a novel strategy to increase the yields of actinomycins.