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Retraction: An Indole Alkaloid from a Tribal Folklore Inhibits Immediate Early Event in HSV-2 Infected Cells with Therapeutic Efficacy in Vaginally Infected Mice
Evolutionary game and simulation analysis of tripartite subjects in public health emergencies under government reward and punishment mechanisms
Neutralizing antibody immune correlates in COVAIL trial recipients of an mRNA second COVID-19 vaccine boost
Abstract Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic’s evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate’s contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.4/5] in the COVAIL trial (NCT05289037), titers against 5 strains were assessed as correlates of risk of symptomatic COVID-19 (“COVID-19”) and as correlates of relative (Pfizer-BioNTech Omicron vs. Prototype) booster protection against COVID-19 over 6 months of follow-up during the BA.2-BA.5 Omicron-dominant period. Consistently across the Moderna and Pfizer-BioNTech vaccine platforms and across all variant Spike inserts assessed, both peak and exposure-proximal (“predicted-at-exposure”) titers correlated with lower Omicron COVID-19 risk in individuals previously infected with SARS-CoV-2, albeit significantly less so in naïve individuals [e.g., exposure-proximal hazard ratio per 10-fold increase in BA.1 titer 0.74 (95% CI 0.59, 0.94) for naïve vs. 0.41 (95% CI 0.23, 0.64) for non-naïve; interaction p = 0.013]. Neutralizing antibody titer was a strong inverse correlate of Omicron COVID-19 in non-naïve individuals and a weaker correlate in naïve individuals, posing questions about how prior infection alters the neutralization correlate.
Convolutional neural network (CNN) configuration using a learning automaton model for neonatal brain image segmentation
CNN is considered an efficient tool in brain image segmentation. However, neonatal brain images require specific methods due to their nature and structural differences from adult brain images. Hence, it is necessary to determine the optimal structure and parameters for these models to achieve the desired results. In this article, an adaptive method for CNN automatic configuration for neonatal brain image segmentation is presented based on the encoder-decoder structure, in which the hyperparameters of this network, i.e., size, length, and width of the filter in each layer along with the type of pooling functions with a reinforcement learning approach and an LA model are determined. These LA models determine the optimal configuration for the CNN model by using DICE and ASD segmentation quality evaluation criteria, so that the segmentation quality can be maximized based on the goal criteria. The effectiveness of the proposed method has been evaluated using a database of infant MRI images and the results have been compared with previous methods. The results show that by using the proposed method, it is possible to segment NBI with higher quality and accuracy.
Prognostic value of adjuvant chemotherapy for hormone receptor-negative T1a and T1bN0M0 breast cancer patients
Tracking solid electrolyte interphase dynamics using operando fibre-optic infra-red spectroscopy and multivariate curve regression
Investigation of the trends and associated factors of ovarian cancer in Indonesia: A systematic analysis of the Global Burden of Disease study 1990–2021
Introduction Ovarian cancer is one of the most lethal gynecological cancers. Despite diagnosis and treatment advances, survival rates have not increased over the past 32 years. This study estimated and reported the global burden of ovarian cancer during the past 32 years to inform preventative and control strategies. Methods We examined ovarian cancer incidence, mortality, and disability-adjusted life years (DALYs) using age-standardized rates from the Global Burden of Disease, Injuries, and Risk Factors Study 2021. high body mass index and occupational asbestos exposure were linked with death and DALYs. Data are presented as averages with 95% uncertainty intervals (UIs). Results Indonesia had 13 250 (8 574–21 565) ovarian cancer cases in 2021, with 5 296 (3 520–8958) deaths and 186 917 (121 866–309 820) DALYs. The burden increased by 233.53% for new cases, 221.95% for mortalities, and 206.65% for DALYs. The age-standardized rate also increased from 1990 to 2021. Ovarian cancer burden increased with age but declined in the 50+ year age group. According to the sociodemographic index, the gross domestic product per capita and number of obstetricians and oncologic gynecologists in provinces showed different trends. Conclusions Indonesian ovarian cancer rates are rising despite gynecologic oncologists in 24 of 34 provinces. These findings will help policymakers and healthcare providers identify ovarian cancer prevention and control gaps.
Association of TyG index with mortality at 28 days in sepsis patients in intensive care from MIMIC IV database
Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin
Abstract Toxic protein aggregates are associated with various neurodegenerative diseases, including Huntington’s disease (HD). Since no current treatment delays the progression of HD, we develop a mechanistic approach to prevent mutant huntingtin (mHttex1) aggregation. Here, we engineer the ATP-independent cytosolic chaperone PEX19, which targets peroxisomal membrane proteins to peroxisomes, to remove mHttex1 aggregates. Using yeast toxicity-based screening with a random mutant library, we identify two yeast PEX19 variants and engineer equivalent mutations into human PEX19 ( hs PEX19). These variants effectively delay mHttex1 aggregation in vitro and in cellular HD models. The mutated hydrophobic residue in the α4 helix of hs PEX19 variants binds to the N17 domain of mHttex1, thereby inhibiting the initial aggregation process. Overexpression of the hs PEX19-FV variant rescues HD-associated phenotypes in primary striatal neurons and in Drosophila . Overall, our data reveal that engineering ATP-independent membrane protein chaperones is a promising therapeutic approach for rational targeting of mHttex1 aggregation in HD.
MRI noise and auditory health: Can one hundred scans be linked to hearing loss? The case of the Courtois NeuroMod project
Magnetic resonance imaging (MRI) is one of the most commonly used tools in neuroscience. However, it implies exposure to high noise levels. Exposure to noise can lead to temporary or permanent hearing loss, especially when the exposure is long and/or repeated. Little is known about the hearing risks for people undergoing several MRI examinations, especially in the context of longitudinal studies. The goal of this study was to assess the potential impact of repeated exposure to MRI noise on hearing in research participants undergoing dozens of MRI scans. This investigation was made possible thanks to an unprecedented intensive MRI research data collection effort (the Courtois NeuroMod project) where participants have been scanned weekly (up to twice a week), with the use of hearing protection, since 2018. Their hearing was tested periodically, over a period of 1.5 years. First, baseline pure-tone thresholds and distortion product otoacoustic emission (DPOAE) amplitudes were acquired before the beginning of this study. Hearing tests were then scheduled immediately before/immediately after a scan and with a delay of two to seven days after a scan. Pure-tone thresholds and DPOAE amplitudes showed no scanner noise impact right after the scan session when compared to the values acquired right before the scan session. Pure-tone thresholds and DPOAE amplitudes acquired in the delayed condition and compared to the baseline showed similar results. These results suggest an absence of impact from MRI noise exposure. Overall, our results show that an intensive longitudinal MRI study like the Courtois NeuroMod project likely does not cause hearing damage to participants when they properly utilize adequate hearing protection.
Improved feature reduction framework for sign language recognition using autoencoders and adaptive Grey Wolf Optimization
MethylBERT enables read-level DNA methylation pattern identification and tumour deconvolution using a Transformer-based model
Abstract DNA methylation (DNAm) is a key epigenetic mark that shows profound alterations in cancer. Read-level methylomes enable more in-depth analyses, due to their broad genomic coverage and preservation of rare cell-type signals, compared to summarized data such as 450K/EPIC microarrays. Here, we propose MethylBERT, a Transformer-based model for read-level methylation pattern classification. MethylBERT identifies tumour-derived sequence reads based on their methylation patterns and local genomic sequence, and estimates tumour cell fractions within bulk samples. In our evaluation, MethylBERT outperforms existing deconvolution methods and demonstrates high accuracy regardless of methylation pattern complexity, read length and read coverage. Moreover, we show its applicability to cell-type deconvolution as well as non-invasive early cancer diagnostics using liquid biopsy samples. MethylBERT represents a significant advancement in read-level methylome analysis and enables accurate tumour purity estimation. The broad applicability of MethylBERT will enhance studies on both tumour and non-cancerous bulk methylomes.
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.