Assessing the interaction effects of mitochondrial DNA polymorphisms and lifestyle on heel bone mineral density.

BACKGROUND: Bone mineral density (BMD) is a major predictor of osteoporotic fractures, and previous studies have reported the effects of mitochondrial dysfunction and lifestyle on BMD, respectively. However, their interaction effects on BMD are still unclear. Therefore, we aimed to investigate the possible interaction of mitochondrial DNA (mtDNA) and common lifestyles contributing to osteoporosis. METHODS: Our analysis included 119,120 white participants (Nfemale=65,949 and Nmale=53,171) from the UK Biobank with heel BMD phenotype data. A generalized linear regression model of PLINK was performed to assess the interaction effects of mtDNA and five life environmental factors on heel BMD, including smoking, drinking, physical activity, dietary diversity score, and vitamin D. In addition, we also performed linear regression analysis for total body BMD. Finally, we assessed the potential causal relationships between mtDNA copy number (mtDNA-CN) and life environmental factors using Mendelian randomization (MR) analysis. RESULTS: Our study identified four mtDNA loci showing suggestive evidence of heel BMD, such as m.16356T>C (MT-DLOOP; P =1.50×10-3) in total samples. Multiple candidate mtDNA×lifetsyle interactions were also detected for heel BMD, such as MT-ND2×physical activity (P = 2.88×10-3) in total samples and MT-ND1×smoking (P = 8.54×10-4) in males. Notably, MT-CYB was a common candidate mtDNA loci for heel BMD to interact with five life environmental factors. Multivariable MR analysis indicated a causal effect of physical activity on heel BMD when mtDNA-CN was considered (P =1.13×10-3). CONCLUSIONS: Our study suggests the candidate interaction between mitochondria and lifestyles on heel BMD, providing novel clues for exploring the pathogenesis of osteoporosis.

Framework nucleic acids as promising reactive oxygen species scavengers for anti-inflammatory therapy.

Reactive oxygen species (ROS) are an array of derivatives of molecular oxygen that participate in multiple physiological processes under the control of redox homeostasis. However, under pathological conditions, the over-production of ROS often leads to oxidative stress and inflammatory reactions, indicating a potential therapeutic target. With the rapid development of nucleic acid nanotechnology, scientists have exploited various DNA nanostructures with remarkable biocompatibility, programmability, and structural stability. Among these novel organic nanomaterials, a group of skeleton-like framework nucleic acid (FNA) nanostructures attracts the most interest due to their outstanding self-assembly, cellular endocytosis, addressability, and functionality. Surprisingly, different FNAs manifest similarly satisfactory antioxidative and anti-inflammatory effects during their biomedical application process. First, they are intrinsically endowed with the ability to neutralize ROS due to their DNA nature. Therefore, they are extensively involved in the complicated inflammatory signaling network. Moreover, the outstanding editability of FNAs also allows for flexible modifications with nucleic acids, aptamers, peptides, antibodies, low-molecular-weight drugs, and so on, thus further strengthening the targeting and therapeutic ability. This review focuses on the ROS-scavenging potential of three representative FNAs, including tetrahedral framework nucleic acids (tFNAs), DNA origami, and DNA hydrogels, to summarize the recent advances in their anti-inflammatory therapy applications. Although FNAs exhibit great potential in treating inflammatory diseases as promising ROS scavengers, massive efforts still need to be made to overcome the emerging challenges in their clinical translation.

Identifying novel chemical-related susceptibility genes for five psychiatric disorders through integrating genome-wide association study and tissue-specific 3'aQTL annotation datasets.

The establishment of 3'aQTLs comprehensive database provides an opportunity to help explore the functional interpretation from the genome-wide association study (GWAS) data of psychiatric disorders. In this study, we aim to search novel susceptibility genes, pathways, and related chemicals of five psychiatric disorders via GWAS and 3'aQTLs datasets. The GWAS datasets of five psychiatric disorders were collected from the open platform of Psychiatric Genomics Consortium (PGC, https://www.med.unc.edu/pgc/ ) and iPSYCH ( https://ipsych.dk/ ) (Demontis et al. in Nat Genet 51(1):63-75, 2019; Grove et al. in Nat Genet 51:431-444, 2019; Genomic Dissection of Bipolar Disorder and Schizophrenia in Cell 173: 1705-1715.e1716, 2018; Mullins et al. in Nat Genet 53: 817-829; Howard et al. in Nat Neurosci 22: 343-352, 2019). The 3'untranslated region (3'UTR) alternative polyadenylation (APA) quantitative trait loci (3'aQTLs) summary datasets of 12 brain regions were obtained from another public platform ( https://wlcb.oit.uci.edu/3aQTLatlas/ ) (Cui et al. in Nucleic Acids Res 50: D39-D45, 2022). First, we aligned the GWAS-associated SNPs of psychiatric disorders and datasets of 3'aQTLs, and then, the GWAS-associated 3'aQTLs were identified from the overlap. Second, gene ontology (GO) and pathway analysis was applied to investigate the potential biological functions of matching genes based on the methods provided by MAGMA. Finally, chemical-related gene-set analysis (GSA) was also conducted by MAGMA to explore the potential interaction of GWAS-associated 3'aQTLs and multiple chemicals in the mechanism of psychiatric disorders. A number of susceptibility genes with 3'aQTLs were found to be associated with psychiatric disorders and some of them had brain-region specificity. For schizophrenia (SCZ), HLA-A showed associated with psychiatric disorders in all 12 brain regions, such as cerebellar hemisphere (P = 1.58 × 10-36) and cortex (P = 1.58 × 10-36). GO and pathway analysis identified several associated pathways, such as Phenylpropanoid Metabolic Process (GO:0009698, P = 6.24 × 10-7 for SCZ). Chemical-related GSA detected several chemical-related gene sets associated with psychiatric disorders. For example, gene sets of Ferulic Acid (P = 6.24 × 10-7), Morin (P = 4.47 × 10-2) and Vanillic Acid (P = 6.24 × 10-7) were found to be associated with SCZ. By integrating the functional information from 3'aQTLs, we identified several susceptibility genes and associated pathways especially chemical-related gene sets for five psychiatric disorders. Our results provided new insights to understand the etiology and mechanism of psychiatric disorders.

A DNA nanostructure-Hif-1α inducer complex as novel nanotherapy against cisplatin-induced acute kidney injury.

Since its discovery in 1978, cisplatin-based chemotherapy regimens have served a pivotal role in human cancer treatment, saving millions of lives. However, its high risk still poses a significant challenge for cisplatin-induced acute kidney injury (AKI), which occurs in 30% of cisplatin-treated patients. Unfortunately, no effective solution for preventing or managing this severe complication, which greatly impacts its clinical administration. Kidney is the main organ injured by cisplatin, and the injury is related to cisplatin-induced cell apoptosis and DNA injury. Therefore, to achieve the safe use of cisplatin in tumour treatment, the key lies in identifying a kidney treatment that can effectively minimize cisplatin nephrotoxicity. Here, we successfully synthesized and applied a DNA-nanostructure complex, named TFG, which contains tetrahedral framework nucleic acids (tFNAs) and FG-4592, a novel Hif-1α inducer. As cargo, TFG is composed entirely of DNA strands. It possesses low nephrotoxicity and renal aggregation properties while FG-4592 is able to relieve renal injury by downregulating the apoptosis signal pathways. And it can relieve cisplatin-induced renal injury when taken cisplatin treatment. This work aims to enhance chemotherapy protection in tumour patients by using TFG, a DNA-based nanomedicines to kidney. This work has the potential to revolutionize the treatment of renal diseases, particularly drug-induced kidney injury, leading to improved clinical outcomes.

Assessing the association of coffee consumption on the relationship of chronic pain with depression and anxiety.

BACKGROUND: A bidirectional relationship between chronic pain (CP) and mental disorders has been reported, and coffee was believed to be associated with both. However, the association of coffee in this bidirectional relationship remains unclear. We aim to analyze the association of coffee consumption on the relationship of CP with depression and anxiety. METHODS: A total of 376,813 participants from UK Biobank were included. We collected data on anxiety, depression and CP from objects of our study population. The association of coffee consumption on the relationship of CP with depression and anxiety was assessed through logistic/linear regression models. Moreover, seemingly unrelated estimation test (SUEST) was used to compare whether the coefficients differed in two different groups. RESULTS: We observed significant associations of coffee consumption in the interaction of CP with depression and anxiety, such as the association of multisite chronic pain (MCP) on self-reported depression (ßcoffee = 0.421, ßnon-coffee = 0.488, PSUEST = 0.001), and the association of MCP on generalized anxiety disorder-7 (GAD-7) scores (ßcoffee = 0.561, ßnon-coffee = 0.678, PSUEST = 0.004) were significantly different between coffee drinking and non-coffee drinking groups. Furthermore, in analysis stratified by gender, we found headache (ßmale = 0.392, ßfemale = 0.214, PSUEST = 0.022) and hip pain (ßmale = 0.480, ßfemale = 0.191, PSUEST = 0.021) had significant associations with self-reported depression between males and females groups in coffee drinkers. CONCLUSIONS: Our results suggested that coffee consumption has a significant association on the relationship of CP with depression and anxiety.

A Metabolomics Study of Feces Revealed That a Disturbance of Selenium-Centered Metabolic Bioprocess Was Involved in Kashin-Beck Disease, an Osteoarthropathy Endemic to China.

Background: Kashin-Beck disease (KBD) is a distinct osteoarthropathy in China with an unclear pathogenesis. This study aims to explore whether perturbations in the intestine metabolome could be linked to KBD individuals. Methods: An investigation was conducted in KBD endemic villages and fecal samples were collected. After applying inclusion and exclusion criteria, a total of 75 subjects were enrolled for this study, including 46 KBD (including 19 Grade I KBD and 27 Grade II KBD) and 29 controls. Untargeted metabolomics analysis was performed on the platform of UHPLC-MS. PLS-DA and OPLS-DA were conducted to compare the groups and identify the differential metabolites (DMs). Pathway analysis was conducted on MPaLA platform to explore the functional implication of the DMs. Results: Metabolomics analysis showed that compared with the control group, KBD individuals have a total of 584 differential metabolites with dysregulated levels such as adrenic acid (log2FC = -1.87, VIP = 4.84, p = 7.63 × 10-7), hydrogen phosphate (log2FC = -2.57, VIP = 1.27, p = 1.02 × 10-3), taurochenodeoxycholic acid (VIP = 1.16, log2FC = -3.24, p = 0.03), prostaglandin E3 (VIP = 1.17, log2FC = 2.67, p = 5.61 × 10-4), etc. Pathway analysis revealed several significantly perturbed pathways associated with KBD such as selenium micronutrient network (Q value = 3.11 × 10-3, Wikipathways), metabolism of lipids (Q value = 8.43 × 10-4, Reactome), free fatty acid receptors (Q value = 3.99 × 10-3, Reactome), and recycling of bile acids and salts (Q value = 2.98 × 10-3, Reactome). Subgroup comparisons found a total of 267 differential metabolites were shared by KBD vs. control, KBD II vs. control, and KBD I vs. control, while little difference was found between KBD II and KBD I (only one differential metabolite detected). Conclusions: KBD individuals showed distinct metabolic features characterized by perturbations in lipid metabolism and selenium-related bioprocesses. Our findings suggest that the loss of nutrients metabolism balance in intestine was involved in KBD pathogenesis. Linking the nutrients metabolism (especially selenium and lipid) to KBD cartilage damage should be a future direction of KBD study.

A Mitochondrial Nanoguard Modulates Redox Homeostasis and Bioenergy Metabolism in Diabetic Peripheral Neuropathy.

As a major late complication of diabetes, diabetic peripheral neuropathy (DPN) is the primary reason for amputation. Nevertheless, there are no wonder drugs available. Regulating dysfunctional mitochondria is a key therapeutic target for DPN. Resveratrol (RSV) is widely proven to guard mitochondria, yet the unsatisfactory bioavailability restricts its clinical application. Tetrahedral framework nucleic acids (tFNAs) are promising carriers due to their excellent cell entrance efficiency, biological safety, and structure editability. Here, RSV was intercalated into tFNAs to form the tFNAs-RSV complexes. tFNAs-RSV achieved enhanced stability, bioavailability, and biocompatibility compared with tFNAs and RSV alone. With its treatment, reactive oxygen species (ROS) production was minimized and reductases were activated in an in vitro model of DPN. Besides, respiratory function and adenosine triphosphate (ATP) production were enhanced. tFNAs-RSV also exhibited favorable therapeutic effects on sensory dysfunction, neurovascular deterioration, demyelination, and neuroapoptosis in DPN mice. Metabolomics analysis revealed that redox regulation and energy metabolism were two principal mechanisms that were impacted during the process. Comprehensive inspections indicated that tFNAs-RSV inhibited nitrosation and oxidation and activated reductase and respiratory chain. In sum, tFNAs-RSV served as a mitochondrial nanoguard (mito-guard), representing a viable drilling target for clinical drug development of DPN.

Tetrahedral framework nucleic acids enhance the chondrogenic potential of human umbilical cord mesenchymal stem cells via the PI3K/AKT axis.

The field of regenerative medicine faces a notable challenge in terms of the regeneration of articular cartilage. Without proper treatment, it can lead to osteoarthritis. Based on the research findings, human umbilical cord mesenchymal stem cells (hUMSCs) are considered an excellent choice for regenerating cartilage. However, there is still a lack of suitable biomaterials to control their ability to self-renew and differentiate. To address this issue, in this study using tetrahedral framework nucleic acids (tFNAs) as a new method in an in vitro culture setting to manage the behaviour of hUMSCs was proposed. Then, the influence of tFNAs on hUMSC proliferation, migration and chondrogenic differentiation was explored by combining bioinformatics methods. In addition, a variety of molecular biology techniques have been used to investigate deep molecular mechanisms. Relevant results demonstrated that tFNAs can affect the transcriptome and multiple signalling pathways of hUMSCs, among which the PI3K/Akt pathway is significantly activated. Furthermore, tFNAs can regulate the expression levels of multiple proteins (GSK3ß, RhoA and mTOR) downstream of the PI3K-Akt axis to further enhance cell proliferation, migration and hUMSC chondrogenic differentiation. tFNAs provide new insight into enhancing the chondrogenic potential of hUMSCs, which exhibits promising potential for future utilization within the domains of AC regeneration and clinical treatment.

Recent progress and application of the tetrahedral framework nucleic acid materials on drug delivery.

INTRODUCTION: The application of DNA framework nucleic acid materials in the biomedical field has witnessed continual expansion. Among them, tetrahedral framework nucleic acids (tFNAs) have gained significant traction as the foremost biological vectors due to their superior attributes of editability, low immunogenicity, biocompatibility, and biodegradability. tFNAs have demonstrated promising results in numerous in vitro and in vivo applications. AREAS COVERED: This review summarizes the latest research on tFNAs in drug delivery, including a discussion of the advantages of tFNAs in regulating biological behaviors, and highlights the updated development and advantageous applications of tFNAs-based nanostructures from static design to dynamically responsive design. EXPERT OPINION: tFNAs possess distinct biological regulatory attributes and can be taken up by cells without the requirement of transfection, differentiating them from other biological vectors. tFNAs can be easily physically/chemically modified and seamlessly incorporated with other functional systems. The static design of the tFNAs-based drug delivery system makes it versatile, reproducible, and predictable. Further use of the dynamic response mechanism of DNA to external stimuli makes tFNAs-based drug delivery more effective and specific, improving the uptake and utilization of the payload by the intended target. Dynamic targeting is poised to become the future primary approach for drug delivery.

Application and prospects of nucleic acid nanomaterials in tumor therapy.

Cancer poses a great threat to human life, and current cancer treatments, such as radiotherapy, chemotherapy, and surgery, have significant side effects and limitations that hinder their application. Nucleic acid nanomaterials have specific spatial configurations and can be used as nanocarriers to deliver different therapeutic drugs, thereby enabling various biomedical applications, such as biosensors and cancer therapy. In recent decades, a variety of DNA nanostructures have been synthesized, and they have demonstrated remarkable potential in cancer therapy related applications, such as DNA origami structures, tetrahedral framework nucleic acids, and dynamic DNA nanostructures. Importantly, more attention is also being paid to RNA nanostructures, which play an important role in gene therapy. Therefore, this review introduces the developmental history of nucleic acid nanotechnology, summarizes the applications of DNA and RNA nanostructures for tumor treatment, and discusses the development opportunities for nucleic acid nanomaterials in the future.

A longitudinal genome-wide association study of bone mineral density mean and variability in the UK Biobank.

Bone mineral density (BMD) is an essential predictor of osteoporosis and fracture. We conducted a genome-wide trajectory analysis of BMD and analyzed the BMD change. PURPOSE: This study aimed to identify the genetic architecture and potential biomarkers of BMD. METHODS: Our analysis included 141,261 white participants from the UK Biobank with heel BMD phenotype data. We used a genome-wide trajectory analysis tool, TrajGWAS, to conduct a genome-wide association study (GWAS) of BMD. Then, we validated our findings in previously reported BMD genetic associations and performed replication analysis in the Asian participants. Finally, gene-set enrichment analysis (GSEA) of the identified candidate genes was conducted using the FUMA platform. RESULTS: A total of 52 genes associated with BMD trajectory mean were identified, of which the top three significant genes were WNT16 (P = 1.31 × 10-126), FAM3C (P = 4.18 × 10-108), and CPED1 (P = 8.48 × 10-106). In addition, 114 genes associated with BMD within-subject variability were also identified, such as AC092079.1 (P = 2.72 × 10-13) and RGS7 (P = 4.72 × 10-10). The associations for these candidate genes were confirmed in the previous GWASs and replicated successfully in the Asian participants. GSEA results of BMD change identified multiple GO terms related to skeletal development, such as SKELETAL SYSTEM DEVELOPMENT (Padjusted = 2.45 × 10-3) and REGULATION OF OSSIFICATION (Padjusted = 2.45 × 10-3). KEGG enrichment analysis showed that these genes were mainly enriched in WNT SIGNALING PATHWAY. CONCLUSIONS: Our findings indicated that the CPED1-WNT16-FAM3C locus plays a significant role in BMD mean trajectories and identified several novel candidate genes contributing to BMD within-subject variability, facilitating the understanding of the genetic architecture of BMD.

Functional micro-RNA drugs acting as a fate manipulator in the regulation of osteoblastic death.

Bone loss is prevalent in clinical pathological phenomena such as osteoporosis, which is characterized by decreased osteoblast function and number, increased osteoclast activity, and imbalanced bone homeostasis. However, current treatment strategies for bone diseases are limited. Regulated cell death (RCD) is a programmed cell death pattern activated by the expression of specific genes in response to environmental changes. Various studies have shown that RCD is closely associated with bone diseases, and manipulating the death fate of osteoblasts could contribute to effective bone treatment. Recently, microRNA-targeting therapy drugs have emerged as a potential solution because of their precise targeting, powerful curative effect, and limited side effects. Nevertheless, their clinical application is limited by their inherent instability, easy enzymatic degradation, and poor membrane penetrability. To address this challenge, a self-assembling tetrahedral DNA nanostructure (TDN)-based microRNA (Tmi) delivery system has been proposed. TDN features excellent biocompatibility, cell membrane penetrability, serum stability, and modification versatility, making it an ideal nucleic acid carrier for miRNA protection and intracellular transport. Once inside cells, Tmi can dissociate and release miRNAs to manipulate key molecules in the RCD signaling pathway, thereby regulating bone homeostasis and curing diseases caused by abnormal RCD activation. In this paper, we discuss the impact of the miRNA network on the initiation and termination of four critical RCD programs in bone tissues: apoptosis, autophagy, pyroptosis, and ferroptosis. Furthermore, we present the Tmi delivery system as a miRNA drug vector. This provides insight into the clinical translation of miRNA nucleic acid drugs and the application of miRNA drugs in bone diseases.

A systematical association analysis of 25 common virus infection and genetic susceptibility of COVID-19 infection.

OBJECTIVES: Previous studies identified a number of diseases were associated with 2019 coronavirus disease (COVID-19). However, the associations between these diseases related viral infections and COVID-19 remains unknown now. METHODS: In this study, we utilized single nucleotide polymorphisms (SNPs) related to COVID-19 from genome-wide association study (GWAS) and individual-level genotype data from the UK biobank to calculate polygenic risk scores (PRS) of 487,409 subjects for eight COVID-19 clinical phenotypes. Then, multiple logistic regression models were established to assess the correlation between serological measurements (positive/negative) of 25 viruses and the PRS of eight COVID-19 clinical phenotypes. And we performed stratified analyses by age and gender. RESULTS: In whole population, we identified 12 viruses associated with the PRS of COVID-19 clinical phenotypes, such as VZV seropositivity for Varicella Zoster Virus (Unscreened/Exposed_Negative: ß = 0.1361, P = 0.0142; Hospitalized/Unscreened: ß = 0.1167, P = 0.0385) and MCV seropositivity for Merkel Cell Polyomavirus (Unscreened/Exposed_Negative: ß = -0.0614, P = 0.0478). After age stratification, we identified seven viruses associated with the PRS of eight COVID-19 clinical phenotypes in the age < 65 years group. After gender stratification, we identified five viruses associated with the PRS of eight COVID-19 clinical phenotypes in the women group. CONCLUSION: Our study findings suggest that the genetic susceptibility to different COVID-19 clinical phenotypes is associated with the infection status of various common viruses.

Evaluating the interaction between 3'aQTL and alcohol consumption/smoking on anxiety and depression: 3'aQTL-by-environment interaction study in UK Biobank cohort.

BACKGROUND: Smoking and alcohol consumption were associated with the development of depression and anxiety. 3'UTR APA quantitative trait loci (3'aQTLs) have been associated with multiple health states and conditions. Our aim is to evaluate the interactive effects of 3'aQTLs-alcohol consumption/tobacco smoking on the risk of anxiety and depression. METHODS: The 3'aQTL data of 13 brain regions were extracted from the large-scale 3'aQTL atlas. The phenotype data (frequency of cigarette smoking and alcohol drinking, anxiety score, self-reported anxiety, depression score and self-reported depression) of 90,399-103,011 adults aged 40-69 years living in the UK and contributing to the UK Biobank during 2006-2010, were obtained from the UK Biobank cohort. The frequency of cigarette smoking and alcohol drinking of each subject were defined by the amount of smoking and alcohol drinking of self-reported, respectively. The continuous alcohol consumption/smoking terms were further categorized in tertiles. 3'aQTL-by-environmental interaction analysis was then performed to evaluate the associations of gene-smoking/alcohol consumption interactions with anxiety and depression using generalized linear model (GLM) of PLINK 2.0 with an additive mode of inheritance. Furthermore, GLM was also used to explore the relationship between alcohol consumption/smoking with hazard of anxiety/depression stratified by allele for the significant genotyped SNPs that modified the alcohol consumption/smoking-anxiety/depression association. RESULTS: The interaction analysis identified several candidate 3'aQTLs-alcohol consumption interactions, such as rs7602638 located in PPP3R1 (ß = 0.08, P = 6.50 × 10-6) for anxiety score; rs10925518 located in RYR2 (OR = 0.95, P = 3.06 × 10-5) for self-reported depression. Interestingly, we also observed that the interactions between TMOD1 (ß = 0.18, P = 3.30 × 10-8 for anxiety score; ß = 0.17, P = 1.42 × 10-6 for depression score), ZNF407 (ß = 0.17, P = 2.11 × 10-6 for anxiety score; ß = 0.15, P = 4.26 × 10-5 for depression score) and alcohol consumption was not only associated with anxiety, but related to depression. Besides, we found that relationship between alcohol consumption and hazard of anxiety/depression was significantly different for different SNPs genotypes, such as rs34505550 in TMOD1 (AA: OR = 1.03, P = 1.79 × 10-6; AG: OR = 1.00, P = 0.94; GG: OR = 1.00, P = 0.21) for self-reported anxiety. LIMITATIONS: The identified 3'aQTLs-alcohol consumption/smoking interactions were associated with depression and anxiety, and its potential biological mechanisms need to be further revealed. CONCLUSIONS: Our study identified important interactions between candidate 3'aQTL and alcohol consumption/smoking on depression and anxiety, and found that the 3'aQTL may modify the associations between consumption/smoking with depression and anxiety. These findings may help to further explore the pathogenesis of depression and anxiety.

Association between electronic device use and health status among a middle-aged and elderly population: a cross-sectional analysis in the UK Biobank.

Aim: Few previous studies have investigated the impact of multiple types of electronic devices on health status, and the moderating effects of gender, age, and BMI. Our aim is to examine the relationships between the use of four types of electronics and three health status indicators in a middle-aged and elderly population, and how these relationships varied by gender, age, and BMI. Subject and methods: Using data from 376,806 participants aged 40-69 years in the UK Biobank, we conducted a multivariate linear regression to estimate the association between electronic device use and health status. Electronics use was categorized as TV watching, computer use, computer gaming, and mobile phone use, and health status included self-rated health (SRH), multisite chronic pain (MCP), and total physical activity (TPA). Interaction terms were utilized to assess whether the above associations were modified by BMI, gender, and age. Further stratified analysis was performed to explore the role of gender, age, and BMI. Results: Higher levels of TV watching (BSRH = 0.056, BMCP = 0.044, BTPA= -1.795), computer use (BSRH = 0.007, BTPA= -3.469), and computer gaming (BSRH = 0.055, BMCP = 0.058, BTPA= -6.076) were consistently associated with poorer health status (all P < 0.05). Contrastingly, earlier exposure to mobile phones (BSRH = -0.048, BTPA= 0.933, BMCP = 0.056) was inconsistent with health (all P < 0.05). Additionally, BMI (Bcomputer use-SRH= 0.0026, Bphone-SRH= 0.0049, BTV-MCP= 0.0031, and BTV-TPA= -0.0584) exacerbated the negative effects of electronics use, and male (Bphone-SRH = -0.0414, Bphone-MCP = -0.0537, Bphone-TPA= 2.8873) were healthier with earlier exposure to mobile phones (all P < 0.05). Conclusion: Our findings suggest that the adverse health effects associated with watching TV, computer use, and computer gaming were consistent and were moderated by BMI, gender, and age, which advances a comprehensive understanding of the association between multiple types of electronic devices and health status, and provides new perspectives for future research. Supplementary Information: The online version contains supplementary material available at 10.1007/s10389-023-01886-5.

Combined effects of inflammation and coronavirus disease 2019 (COVID-19) on the risks of anxiety and depression: A cross-sectional study based on UK Biobank.

Infection-induced perturbation of immune homeostasis could promote psychopathology. Psychiatric sequelae have been observed after previous coronavirus outbreaks. However, limited studies were conducted to explore the potential interaction effects of inflammation and coronavirus disease 2019 (COVID-19) on the risks of anxiety and depression. In this study, first, polygenic risk scores (PRS) were calculated for eight COVID-19 clinical phenotypes using individual-level genotype data from the UK Biobank. Then, linear regression models were developed to assess the effects of COVID-19 PRS, C-reactive protein (CRP), systemic immune inflammation index (SII), and their interaction effects on the Generalized Anxiety Disorder-7 (GAD-7, 104 783 individuals) score and the Patient Health Questionnaire-9 (PHQ-9, 104 346 individuals) score. Several suggestive interactions between inflammation factors and COVID-19 clinical phenotypes were detected for PHQ-9 score, such as CRP/SII × Hospitalized/Not_Hospitalized in women group and CRP × Hospitalized/Unscreened in age >65 years group. For GAD-7 score, we also found several suggestive interactions, such as CRP × Positive/Unscreened in the age ≤65 years group. Our results suggest that not only COVID-19 and inflammation have important effects on anxiety and depression but also the interactions of COVID-19 and inflammation have serious risks for anxiety and depression.

Evaluating the role of anxiety on the association between irritable bowel syndrome and brain volumes: a mediation analysis in the UK Biobank cohort.

There is a strong link between irritable bowel syndrome and brain volumes, yet, to date, research examining the mediators of this association has been little. Based on the phenotypic data of 15 248 participants from the UK Biobank, a two-stage mediation analysis was performed to assess the association among brain volumes, anxiety, and irritable bowel syndrome. In the first stage, we identified the candidate mediating role of anxiety for irritable bowel syndrome associated with brain volumes using regression models. Then, we quantified the magnitude of the mediation effects by evaluating the average causal-mediated effect and proportion of mediation through performing mediation analyses in the R package in the second stage. In the first stage, we identified the partly mediating role of anxiety in the association between irritable bowel syndrome and the volume of thalamus (P left = 1.16 × 10-4, P right = 2.41 × 10-4), and grey matter (P left = 3.22 × 10-2, P right = 1.18 × 10-2) in the VIIIa cerebellum. In the second stage, we observed that the proportion of the total effect of irritable bowel syndrome on volume of thalamus mediated by anxiety was 14.3% for the left region (ß Average causal-mediated effect = -0.008, P Average causal-mediated effect = 0.004) and 14.6% for the right region (ß Average causal-mediated effect = -0.007, P Average causal-mediated effect = 0.006). Anxiety mediated 30.8% for the left region (ß Average causal-mediated effect = -0.013, P Average causal-mediated effect = 0.002) and 21.6% for the right region (ß Average causal-mediated effect = -0.010, P Average causal-mediated effect x= 0.018) of the total effect of irritable bowel syndrome on the volume of grey matter in the VIIIa cerebellum. Our study revealed the indirect mediating role of anxiety in the association between irritable bowel syndrome and brain volumes, promoting our understanding of the functional mechanisms of irritable bowel syndrome and its related psychosocial factors.

Identification of novel functional brain proteins for treatment-resistant schizophrenia: Based on a proteome-wide association study.

OBJECTIVE: Genetic approaches are increasingly advantageous in characterizing treatment-resistant schizophrenia (TRS). We aimed to identify TRS-associated functional brain proteins, providing a potential pathway for improving psychiatric classification and developing better-tailored therapeutic targets. METHODS: TRS-related proteome-wide association studies (PWAS) were conducted on genome-wide association studies (GWAS) from CLOZUK and the Psychiatric Genomics Consortium (PGC), which provided TRS individuals (n = 10,501) and non-TRS individuals (n = 20,325), respectively. The reference datasets for the human brain proteome were obtained from ROS/MAP and Banner, with 8,356 and 11,518 proteins collected, respectively. We then performed colocalization analysis and functional enrichment analysis to further explore the biological functions of the proteins identified by PWAS. RESULTS: In PWAS, two statistically significant proteins were identified using the ROS/MAP and then replicated using the Banner reference dataset, including CPT2 (PPWAS-ROS/MAP = 4.15 × 10-2 and PPWAS-Banner = 3.38 × 10-3) and APOL2 (PPWAS-ROS/MAP = 4.49 × 10-3 and PPWAS-Banner = 8.26 × 10-3). Colocalization analysis identified three variants that were causally related to protein expression in the human brain, including CCDC91 (PP4 = 0.981), PRDX1 (PP4 = 0.894), and WARS2 (PP4 = 0.757). We extended PWAS results from gene-based analysis to pathway-based analysis, identifying 14 gene ontology (GO) terms and the only candidate pathway for TRS, metabolic pathways (all P < 0.05). CONCLUSIONS: Our results identified two protein biomarkers, and cautiously support that the pathological mechanism of TRS is linked to lipid oxidation and inflammation, where mitochondria-related functions may play a role.

Tetrahedral Framework Nucleic Acids: A Novel Strategy for Antibiotic Treating Drug-Resistant Infections.

Antibiotic multiresistance (AMR) has emerged as a major threat to human health as millions of people die from AMR-related problems every year. As has been witnessed during the global COVID-19 pandemic, the significantly increased demand for antibiotics has aggravated the issue of AMR. Therefore, there is an urgent need to find ways to alleviate it. Tetrahedral framework nucleic acids (tFNAs) are novel nanomaterials that are often used as drug delivery platforms because of their structural diversity. This study formed a tFNAs-antibiotic compound (TAC) which has a strong growth inhibitory effect on Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA) in vitro owing to the increased absorption of antibiotics by bacteria and improved drug movement across cell membranes. We established a mouse model of systemic peritonitis and local wound infections. The TAC exhibited good biosafety and improved the survival rate of severely infected mice, promoting the healing of local infections. In addition to the better transport of antibiotics to the target, the TAC may also enhance immunity by regulating the differentiation of M1 and M2 macrophages, providing a new option for the treatment of infections.