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Exploring potential drug targets for SLE through Mendelian randomization and network pharmacology

Background Systemic lupus erythematosus (SLE) is a complex and incurable autoimmune disease, so several drug remission for SLE symptoms have been developed and used at present. However, treatment varies by patient and disease activity, and existing medications for SLE were far from satisfactory. Novel drug targets to be found for SLE therapy are still needed. Methods Mendelian randomization (MR), an observational study way, was performed to explore potential drug targets for SLE using protein quantitative trait loci (pQTL) from recently published genome-wide association studies (GWAS) of cerebrospinal fluid (CSF) and plasma proteins, which obtained genetic instruments for 154 CSF proteins of 971 participants, and 734 plasma proteins of 23591 participants. Bidirectional Mendelian randomization analysis, colocalization analysis, and phenotype scanning were performed to find key proteins for SLE. In addition, external data verification was implemented to further consolidate the Mendelian randomization findings. Candidate proteins as targets to find drugs and discuss the druggability. Finally, Network pharmacology and molecular docking methods were used to verify the effects of Voclosporin and Cyclosporine on SLE targets. Protein-protein interaction (PPI) and core target analysis of candidate drugs and SLE overlapping targets were performed to identify potential hub targets and interactions. The affinity between drug targets and SLE targets was confirmed by molecular docking. Results In the preliminary analysis, we identified four key proteins as possible drug targets in CSF and plasma proteins, included ICAM-1(P = 4.62E-05, OR = 0.90(0.86, 0.95)), sICAM-1(P = 4.62E-05, OR = 0.49(0.35, 0.69)), FCG2B (P = 7.63E-11, OR = 0.57(0.48, 0.67)), PPP3CA; PPP3R1 (P = 5.47E-07, OR = 0.66(0.57, 0.78)). Among them, ICAM1 was detected in both CSF and plasma proteins. By excluding reverse causality, confounding factors, and linkage disequilibrium (LD), we identified PPP3CA; PPP3R1 as novel drug targets for SLE, including Voclosporin and Cyclosporine. Finally, the Drugbank database shows that novel drugs contain 33 targets for treating SLE. PPI suggested that SIRT1, ACE, PTGS2, and BACE1 were pivotal targets for SLE treatment. In addition, the molecular docking showed that the bioactive molecules of Voclosporin and Cyclosporine had a good affinity with the target of SLE. Conclusions Our integrative analysis suggested that levels of circulating PPP3CA; PPP3R1 had causal effects on SLE risk and served as potential treatment targets. Moreover, this study provides new evidence for Voclosporin as an SLE treatment through Mendelian randomization and Network pharmacology, and warrants further clinical investigation.

The impact and transformation evaluation of art intervention in public space on ancient villages: a case study of Tengchong, Yunnan Province

Preference for and resistance to a toxic sulfur volatile opens up a unique niche in Drosophila busckii

Abstract The ability to tolerate otherwise toxic compounds can open up unique niches in nature. Among drosophilid flies, few examples of such adaptations are known and those which are known are typically from highly host-specific species. Here we show that the human commensal species Drosophila busckii uses dimethyldisulfide (DMDS) as a key mediator in its host selection. Despite DMDS’s neurotoxic properties, D. busckii has evolved tolerance towards high concentrations and uses the compound as an olfactory cue to pinpoint food and oviposition sites. This adaptability is likely linked to insensitivity of the enzyme complex cytochrome c oxidase (COX), which is a DMDS target in other insects. Our findings position D. busckii as a potential model for studying resistance to toxic gases affecting COX and offers insight into evolutionary adaptations within specific ecological contexts.

Effect of family support and work resources in the relationship of economic constraints and work volition: Evidence from China

Background As the pace of economic development slows, college students are facing an increasingly challenging employment landscape. For instance, the expansion of higher education has led to a swell in the number of job seekers, which has in turn intensified competition. Given the limited job opportunities, it’s understandable that many college students are developing a pessimistic employment mindset. Therefore, it’s crucial to explore how objective factors influence their work aspirations. But few studies have explored the role of mediating factors between the two, such as family and resource factors. Thus, this study examines the effects of family support and work resources between the relationship between economic constraints and work volition. Methods The study examined 1249 Chinese undergraduate students as participants ((714 men and 535 women; Mage = 19.32, SD = 1.50), using the questionnaire with the Wenjuanxing online survey tool. The questionnaire were collected between August, 2022 and December, 2022. SPSS 21.0 and AMOS 24.0 were used to conducted a comprehensive analysis of the collected data, and investigate the relationships among latent variables and assess the goodness of fit of the observed indicators on their associated latent constructs. Additionally, we evaluated all the hypothesized direct and indirect effects. Results The results showed the direct and indirect relationships among economic constraints, family support, work resources and work volition. Economic constraints can directly predict work volition. Moreover, economic constraints have a significant negative impact on work volition via two mediators: family support and work resources. On the one hand, economic constraints negatively affect work volition through family support and work resource separately. On the other hand, economic constraints negatively predict family support and work resource, thus negatively impact work volition. Contribution The current study has established the independent mediating and chain-mediated effects of family support and work resources on the relationship between economic constraints and work volition. This deeper understanding of internal mechanisms provides valuable insights that can inform strategies for enhancing individual’s work volition, particularly from the perspectives of economic constraints, family support, and work volition.

Structure and quantification of Ce3+/Ce4+ and stability analysis of basaltic glasses for the immobilization of simulated tetravalent amines

Abstract Basaltic glass was prepared via the solid-state melt method, using Ce4+ to simulate tetravalent actinides. The structure, thermal stability and leaching characteristics of basaltic glass with different contents of CeO2 were investigated. The XRD/SEM-EDX/Raman results showed that the simulated waste loading of CeO2 in basaltic glass reached ~ 18 wt%, and CeO2 crystals precipitated when the CeO2 content reached 20 wt%. XPS analysis revealed that approximately half of the Ce4+ ions in the basaltic glass doped with CeO2 were reduced to Ce3+ ions. The DSC results showed that the thermal stability increased with increasing CeO2 content. The ASTM product consistency test (PCT) results indicated that all the samples had good leaching resistance. Among them, the standard mass loss of Ce was the greatest after 28 days: The NL Ce was 2 orders of magnitude lower than those of the other elements.

Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease

Abstract Animal models that accurately reflect COVID-19 are vital for understanding mechanisms of disease and advancing development of improved vaccines and therapeutics. Pigs are increasingly recognized as valuable models for human disease due to their genetic, anatomical, physiological, and immunological similarities to humans, and they present a more ethically viable alternative to non-human primates. However, pigs are not susceptible to SARS-CoV-2 infection which limits their utility as a model. To address this, we have developed transgenic pigs expressing human ACE2 that are susceptible to SARS-CoV-2 infection. Following challenge, clinical signs consistent with COVID-19, including fever, coughing and respiratory distress were observed, with virus replication detected in the nasal turbinates, trachea and lungs up to the study endpoint, seven days post-infection. Notably, examination of tissues revealed immunopathology in the lungs consistent with histological changes observed in fatal human COVID-19 cases. This study establishes human ACE2 transgenic pigs as a large animal model that accurately reflects many aspects of COVID-19 disease.

Development of a rapid antigen-based lateral flow assay for tick-borne spotted fever rickettsioses

Tick-borne spotted fever rickettsioses (SFRs) continue to cause severe illness and death in otherwise-healthy individuals due to lack of a timely and reliable diagnostic laboratory test. We recently identified a diagnostic biomarker for SFRs, the putative N-acetylmuramoyl-l-alanine amidase RC0497. Here, we developed a prototype laboratory test that targets RC0497 for diagnosis of SFRs. The concentrations of RC0497 in sera of Rickettsia rickettsii-infected guinea pigs and R. conorii-infected mice were determined by stable isotope dilution–parallel reaction monitoring mass spectrometry (SID-PRM-MS), ranging from 0.1 to 1.1 ng/ml. Using europium chelate nanoparticle reporters, we developed a lateral flow assay (LFA) and evaluated the test with a panel of serum samples of mock and experimentally infected animals. Interestingly, 21 of 22 (95.5%) serum samples from R. rickettsii-infected guinea pigs and R. conorii-infected mice yielded positive results with a ratio of test line / control line greater than the cutoff value determined for non-infected animals. All uninfected samples were in agreement with the intended results, suggesting that the initially assessed specificity of the test is 100%, among these samples. Mice infected with a lethal dose of R. conorii and treated with doxycycline on day 3 post-infection (p.i.), upon RC0497 detection by LFA, displayed significantly decreased rickettsial loads, comparable to the sublethal infection group on day 5 p.i.. A panel of human serum samples spiked with various concentrations of recombinant RC0497 were analyzed by LFA, suggesting that the limit of detection of the LFA was 0.64 ng/mL. These findings suggest that the timely detection of RC0497 by a europium LFA offers guidance for treatment, leading to a significant improvement in infection outcomes. This work, for the first time, shows significant promise for a rapid and easy-to-use platform offering a timely diagnostic assay for severe SFRs.

Unveiling cellular changes in leukaemia cell lines after cannabidiol treatment through lipidomics

Aggregation control of anionic pentamethine cyanine enabling excitation wavelength selective NIR-II fluorescence imaging-guided photodynamic therapy

Effectiveness of couple-based violence prevention education in reducing intimate partner violence during pregnancy in rural Ethiopia: A cluster randomized controlled trial

Background Pregnancy is often seen as a joyful and fulfilling time for many women. However, a significant number of women in Ethiopia experience intimate partner violence (IPV) during this period. Despite this, there is limited evidence on interventions aimed at preventing violence during pregnancy. The purpose of this trial was to examine the effectiveness of Couple-Based Violence Prevention Education (CBVPE) in reducing IPV during pregnancy in rural Ethiopia. Method A cluster randomized controlled trial was conducted using a two-arm parallel group design. The 16 clusters were randomly allocated into 8 intervention groups and 8 control groups. A total of 432 pregnant women (216 in the intervention group and 216 in the control group) participated in the trial. Couple-based violence prevention education was provided to the participants in the intervention group, while the control group received routine or standard care. We used difference-in-difference analysis and the Generalized Estimating Equation (GEE) model to assess the effectiveness of the intervention. Result At the endline, 94.9% of women in the intervention group and 95.3% of women in the control group were available for intention-to-treat analysis. There was a substantial drop in the proportion of any IPV during pregnancy from 39.4% at baseline to 13.0% at endline (p<0.001). Women in the intervention group were 74.1% less likely to report any IPV during pregnancy compared to the control group (AOR = 0.259; 95% CI 0.161–0.417). Specifically, the intervention also reduced psychological, physical, and sexual violence during pregnancy. Conclusion The study found that CBVPE is effective in reducing IPV during pregnancy in the study setting. Scale-up and adaptation to similar settings are recommended. Trial registration The trial is registered on ClinicalTrials.gov under the identifier NCT05856214 on May 4, 2023.

A two-tier optimization strategy for feature selection in robust adversarial attack mitigation on internet of things network security

Author Correction: Classification of distinct tendinopathy subtypes for precision therapeutics

Effects of antioxidant nutrients on muscle mass, strength and function in COPD patients: A meta-analysis of randomized controlled trials

Aim To comprehensively investigate the effects of antioxidant nutrients on muscle mass, strength and function in chronic obstructive pulmonary disease (COPD) patients. Methods PubMed, Embase, Cochrane Library, and Web of Science were comprehensively searched from the inception to January 3, 2024. The quality of randomized controlled trials (RCTs) was measured using the Jadad scale. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were used as the effect size for measurement data. Further, subgroup analysis was conducted based on whether patients participated in lung rehabilitation plans while receiving nutritional interventions. Sensitivity analysis was performed on all outcomes. Results A total of 12 studies involving 595 patients with COPD were included, with 11 studies had high quality, and one study had low quality. For muscle mass, patients receiving antioxidant nutrients had a significantly increased lean body mass index compared with those not receiving antioxidant nutrients (pooled WMD: 0.903, 95% CI: 0.264, 1.541, P = 0.006). For patients who did not participate in lung rehabilitation plan while receiving nutritional interventions, antioxidant nutrients brought about a significantly higher lean body mass index (pooled WMD: 1.360, 95% CI: 0.560, 2.160, P = 0.001). For muscle strength, patients in the antioxidant nutrient intervention group had significantly higher hand grip strength (HGS) than those in the non-antioxidant nutrient intervention group (pooled WMD: 1.976, 95% CI: 1.337, 2.615, P < 0.001). Patients receiving antioxidant nutrients had significantly greater inspiratory muscle strength (MIP) than those not receiving antioxidant nutrients (pooled WMD: 8.127, 95% CI: 2.677, 13.577, P = 0.003). Conclusion Antioxidant nutrient intervention significantly improved HGS, MIP and lean body mass index in COPD. Clinicians should consider increasing food intake or supplementation rich in antioxidants in the treatment plan of patients with COPD.

The relationship between interpersonal trust, family capital, and physical activity behavior among university students: a cross-lagged study

Author Correction: Noninvasive rejuvenation strategy of nickel-rich layered positive electrode for Li-ion battery through magneto-electrochemical synergistic activation

Psilocybin-assisted massed cognitive processing therapy for chronic posttraumatic stress disorder: Protocol for an open-label pilot feasibility trial

Background Posttraumatic stress disorder (PTSD) affects 3.9% of the general population. While massed cognitive processing therapy (CPT) has demonstrated efficacy in treating chronic PTSD, a substantial proportion of patients still continue to meet PTSD criteria after treatment, highlighting the need for novel therapeutic approaches. Preliminary evidence supports the potential therapeutic action of psilocybin to alleviate PTSD symptoms. This open-label pilot study aims to evaluate the feasibility, tolerability, and preliminary efficacy of a single dose 25 mg psilocybin in combination with one week of massed CPT in patients with chronic PTSD. Method Fifteen participants with chronic PTSD will undergo 12 CPT sessions, two psilocybin-related psychotherapy sessions, and one psilocybin dosing session over a 7-days period. The primary outcomes are feasibility and tolerability, which will be measured by recruitment rates, withdrawal, data completion, adherence, number and nature of adverse events. Secondary objectives include assessing the preliminary efficacy of psilocybin-assisted CPT in reducing PTSD severity, self-reported treatment outcomes and exploring putative mechanisms of change. Participants will be monitored weekly for 12 weeks post-treatment and passive data relevant to mental health and well-being will be collected using a wearable device. Discussion This trial will generate important preliminary data on the use of psilocybin-assisted CPT for treating PTSD. The findings will guide the design of a multi-site, large-scale randomized control trial to more rigorously assess the efficacy of this intervention. De-identified data from this study will be available upon request after publication of the results. This study represents a promising and innovative approach to PTSD treatment, potentially offering an alternative therapeutic option for individuals unresponsive to conventional therapies. Trial registration ClinicalTrials.gov NCT06386003.

Evolution of the umbilical cord blood proteome across gestational development

Rationally designed universal passivator for high-performance single-junction and tandem perovskite solar cells

Optimization of HIV drugs through MCDM technique Analytic Hierarchy Process(AHP)

Topological indices are crucial tools for predicting the physicochemical and biological features of different drugs. They are numerical values obtained from the structure of chemical molecules. These indices, particularly the degree-based TIs are a useful tools for evaluating the connection between a compound’s structure and its attributes. This study addresses the research problemof how to optimize drug design for HIV treatment using degree-based topological indices. The need for safer and more effective medicines for HIV is further emphasized by the advent of drug resistance and severe negative effects from current therapies. Employing degree-based graph invariants, the study investigates 13 HIV drugs by applying a quantitative structure-property relationship (QSPR) technique to associate their molecular structures with their physical properties. HIV drugs are ranked using the Analytic Hierarchy Process (AHP) according to specific parameters. The findings of the study demonstrate how well these approaches can determine the most effective possible drug combinations and designs, offering insightful information in developing improved HIV treatments.

Mini-open transosseous repair with bursal augmentation improves outcomes in massive rotator cuff tears

Abstract Treatment of Massive rotator cuff tears (MRCT) is difficult, with high rates of retears. Using biological augmentation in the form of the highly vascular subacromial bursa, was used to improve tendon healing. This work aimed to evaluate the results of arthroscopic guided mini-open transosseous repair with bursal augmentation in the treatment of MRCTs in a five-step approach. Forty-eight patients, with a mean age of 63.15 years, were treated with this technique. The patients were evaluated with the constant, UCLA and VAS scores. Plain X-rays were performed to evaluate the CSA and MRI was done to confirm the diagnosis of MRCT and determine the degree of fatty degeneration. Ultrasound was done at 1 year post-operative to determine any retears. The mean follow-up period was 29 months ± 4.95. The Constant and UCLA mean scores improved from (52.52) to (89) and (13.2) to (30.5) respectively (p < 0.0001). The post-operative active flexion and abduction improved from a mean of (112° to 170°) and (136.2° to 167°) respectively, while ER improved from (62.8° to 70°) with their p values (p < 0.0001). Pain improved from a mean VAS of (5.85) to (0.5) (p < 0.0001). No deterioration of function was noted throughout the follow-up period, and no retears occurred on post-operative ultrasound evaluation. Mini-open transosseous repair with bursal augmentation in the treatment of MRCT is an effective and low-cost method that achieves satisfactory results with no retears.