Shrimp Extract Exacerbates Allergic Immune Responses in Mice: Implications on Clinical Diagnosis of Shellfish Allergy.

Tropomyosin has been identified as the major cross-reactive shellfish allergen, but recent studies showed the presence of other clinically relevant allergens. This study aims at determining the allergic immune responses of mice sensitized with raw and boiled shrimp extracts in comparison to recombinant tropomyosin (rTM). Female Balb/c mice were intragastrically sensitized and challenged with raw, boiled shrimp or rTM. Systemic, cellular and humoral allergic responses were compared, while allergenicity of the extracts was also compared by skin prick test (SPT) and immunoblot on shrimp allergic subjects. We showed that rTM and shrimp extracts induced IgE- and Th2-mediated allergic responses in mice, distinguished by remarkable intestinal inflammation in small intestine across all regimens. Notably, boiled shrimp extract exhibited the highest sensitization rate (73.7% of mice developed positive TM-specific IgE response) when compared with raw extract (47.8%) and rTM (34.8%). Mice sensitized with boiled extract manifested the highest allergen-specific IgE and Th2 cytokine responses than the others. Immunoblot results indicated that tropomyosin remained the major allergen in extract-based sensitization and had stronger allergenicity in a heat-treated form comparing to untreated TM, which was in line with the SPT results that boiled extract induced larger wheal size in patients. Hemocyanin and glycogen phosphorylase were also identified as minor allergens associated with manifestation of shrimp allergy. This study shows that boiled extract enhanced sensitization and Th2 responses in agreement with the higher allergenicity of heat-treated TM. This study thus presents three shrimp allergy murine models suitable for mechanistic and intervention studies, and in vivo evidence implies higher effectiveness of boiled extract for the clinical diagnosis of shellfish allergy.

Contribution to pulmonary diseases diagnostic from X-ray images using innovative deep learning models.

Pulmonary disease identification and characterization are among the most intriguing research topics of recent years since they require an accurate and prompt diagnosis. Although pulmonary radiography has helped in lung disease diagnosis, the interpretation of the radiographic image has always been a major concern for doctors and radiologists to reduce diagnosis errors. Due to their success in image classification and segmentation tasks, cutting-edge artificial intelligence techniques like machine learning (ML) and deep learning (DL) are widely encouraged to be applied in the field of diagnosing lung disorders and identifying them using medical images, particularly radiographic ones. For this end, the researchers are concurring to build systems based on these techniques in particular deep learning ones. In this paper, we proposed three deep-learning models that were trained to identify the presence of certain lung diseases using thoracic radiography. The first model, named "CovCXR-Net", identifies the COVID-19 disease (two cases: COVID-19 or normal). The second model, named "MDCXR3-Net", identifies the COVID-19 and pneumonia diseases (three cases: COVID-19, pneumonia, or normal), and the last model, named "MDCXR4-Net", is destined to identify the COVID-19, pneumonia and the pulmonary opacity diseases (4 cases: COVID-19, pneumonia, pulmonary opacity or normal). These models have proven their superiority in comparison with the state-of-the-art models and reached an accuracy of 99,09 %, 97.74 %, and 90,37 % respectively with three benchmarks.

Implications of corporate social responsibility on the financial and non-financial performance of the banking sector: A moderated and mediated mechanism.

This study aims to investigate the influence of corporate social responsibility (CSR) on both financial and non-financial performance in the Pakistani banking sector by applying a quantitative research approach to the primary data from 405 branch managers in the Pakistani banking sector. Both financial and non-financial performance indicators are analyzed in relation to CSR practices. The CB-SEM findings of this study reveal a significant and positive correlation between CSR and both financial and non-financial performance. Our results demonstrate that CSR initiatives contribute to improved financial performance, reputation, and innovation within the sector. These findings confirm the importance of prioritizing social responsibility initiatives to enhance overall performance in the banking industry. This study provides valuable insights into the impact of CSR on performance in the context of the Pakistani banking sector. The research contributes to the existing literature by highlighting the positive relationship between CSR and financial/non-financial performance. The findings underscore the relevance of CSR practices for banks in Pakistan and emphasize the potential benefits of incorporating social responsibility initiatives into their operations. This study serves as a foundation for future research, encouraging further exploration of CSR's role in the banking industry and its implications for sustainable business practices.

Prioritizing disease-related rare variants by integrating gene expression data.

Rare variants, comprising a vast majority of human genetic variations, are likely to have more deleterious impact on human diseases compared to common variants. Here we present carrier statistic, a statistical framework to prioritize disease-related rare variants by integrating gene expression data. By quantifying the impact of rare variants on gene expression, carrier statistic can prioritize those rare variants that have large functional consequence in the diseased patients. Through simulation studies and analyzing real multi-omics dataset, we demonstrated that carrier statistic is applicable in studies with limited sample size (a few hundreds) and achieves substantially higher sensitivity than existing rare variants association methods. Application to Alzheimer's disease reveals 16 rare variants within 15 genes with extreme carrier statistics. We also found strong excess of rare variants among the top prioritized genes in diseased patients compared to that in healthy individuals. The carrier statistic method can be applied to various rare variant types and is adaptable to other omics data modalities, offering a powerful tool for investigating the molecular mechanisms underlying complex diseases.

Prioritizing disease-related rare variants by integrating gene expression data.

Rare variants, comprising a vast majority of human genetic variations, are likely to have more deleterious impact on human diseases compared to common variants. Here we present carrier statistic, a statistical framework to prioritize disease-related rare variants by integrating gene expression data. By quantifying the impact of rare variants on gene expression, carrier statistic can prioritize those rare variants that have large functional consequence in the diseased patients. Through simulation studies and analyzing real multi-omics dataset, we demonstrated that carrier statistic is applicable in studies with limited sample size (a few hundreds) and achieves substantially higher sensitivity than existing rare variants association methods. Application to Alzheimer's disease reveals 16 rare variants within 15 genes with extreme carrier statistics. The carrier statistic method can be applied to various rare variant types and is adaptable to other omics data modalities, offering a powerful tool for investigating the molecular mechanisms underlying complex diseases.

Physical fitness levels and trends of kindergarteners in Hong Kong during the COVID-19 pandemic.

Background/objectives: The study aimed to examine the physical fitness and activity levels of kindergarteners in Hong Kong during the coronavirus disease 2019 pandemic. Methods: A total of 2052 kindergarteners (48% girls; 32.9% Grade 1, 34% Grade 2, and 33.1% Grade 3) were recruited from July 2020 to November 2021. Participants completed the physical fitness tests, including body composition, flexibility, lower-limb muscle strength, upper-limb muscle strength, lower-limb muscle endurance, and agility. Children's physical activity and overall well-being were examined using parental proxy reports. Parents also reported their physical activity and parental support to children's physical activity engagement, as well as their perception of children's kindergarten physical activity environment. Fitness differences by age and gender were analyzed using one-way ANOVA and ANCOVA measuring effect size with partial eta-squared. Additionally, correlations assessed the relationship between children's fitness and parents' proxy reports. Results: The results of the physical fitness tests were higher than those in previous studies conducted by the Physical Fitness Association of Hong Kong in 2015-2018. Gender-based differences were observed in most tests for children aged 4 years and older, with boys showing higher scores in the standing long jump, shot put, and balance tests, while girls had higher scores in the sit-and-reach test. Parents' proxy questionnaire answers indicated that children's continuous jump test performances were significantly related to their frequency of physical activity per week (r = 0.19, p < 0.001), and that children's health was significantly and positively correlated with their fitness level (r = 0.179, p < 0.009). Inadequate school physical activity was associated with poor upper-limb strength (r = 0.078, p < 0.005). Moreover, a high level of parental support for their children's participation in physical activity was correlated with a high level of parental participation in vigorous-intensity physical activities (r = 0.167, p < 0.005). Conclusion: The physical fitness of children in Hong Kong was less affected by the epidemic. Parents' healthy behaviors and support were related to children's participation in PA. Efforts to improve children's physical fitness and motor development should include parent education and physical activity involvement.

Discovery of a novel class of rosmarinic acid derivatives as antibacterial agents: Synthesis, structure-activity relationship and mechanism of action.

Twenty-seven rosmarinic acid derivatives were synthesized, among which compound RA-N8 exhibited the most potent antibacterial ability. The minimum inhibition concentration of RA-N8 against both S. aureus (ATCC 29213) and MRSA (ATCC BAA41 and ATCC 43300) was found to be 6 µg/mL, and RA-N8 killed E. coli (ATCC 25922) at 3 µg/mL in the presence of polymyxin B nonapeptide (PMBN) which increased the permeability of E. coli. RA-N8 exhibited a weak hemolytic effect at the minimum inhibitory concentration. SYTOX Green assay, SEM, and LIVE/DEAD fluorescence staining assay proved that the mode of action of RA-N8 is targeting bacterial cell membranes. Furthermore, no resistance in wildtype S. aureus developed after incubation with RA-N8 for 20 passages. Cytotoxicity studies further demonstrated that RA-N8 is non-toxic to the human normal cell line (HFF1). RA-N8 also exerted potent inhibitory ability against biofilm formation of S. aureus and even collapsed the shaped biofilm.

Mitochondria-Selective Dicationic Small-Molecule Ligand Targeting G-Quadruplex Structures for Human Colorectal Cancer Therapy.

Mitochondria are important drug targets for anticancer and other disease therapies. Certain human mitochondrial DNA sequences capable of forming G-quadruplex structures (G4s) are emerging drug targets of small molecules. Despite some mitochondria-selective ligands being reported for drug delivery against cancers, the ligand design is mostly limited to the triphenylphosphonium scaffold. The ligand designed with lipophilic small-sized scaffolds bearing multipositive charges targeting the unique feature of high mitochondrial membrane potential (MMP) is lacking and most mitochondria-selective ligands are not G4-targeting. Herein, we report a new small-sized dicationic lipophilic ligand to target MMP and mitochondrial DNA G4s to enhance drug delivery for anticancer. The ligand showed marked alteration of mitochondrial gene expression and substantial induction of ROS production, mitochondrial dysfunction, DNA damage, cellular senescence, and apoptosis. The ligand also exhibited high anticancer activity against HCT116 cancer cells (IC50, 3.4 µM) and high antitumor efficacy in the HCT116 tumor xenograft mouse model (∼70% tumor weight reduction).

Gene Doping Control Analysis of Human Erythropoietin Transgene in Equine Plasma by PCR-Liquid Chromatography High-Resolution Tandem Mass Spectrometry.

Gene doping involves the misuse of genetic materials to alter an athlete's performance, which is banned at all times in both human and equine sports. Quantitative polymerase chain reaction (qPCR) assays have been used to control the misuse of transgenes in equine sports. Our laboratory recently developed and implemented duplex as well as multiplex qPCR assays for transgenes detection. To further advance gene doping control, we have developed for the first time a sensitive and definitive PCR-liquid chromatography high-resolution tandem mass spectrometry (PCR-LC-HRMS/MS) method for transgene detection with an estimated limit of detection of below 100 copies/mL for the human erythropoietin (hEPO) transgene in equine plasma. The method involved magnetic-glass-particle-based extraction of DNA from equine plasma prior to PCR amplification with 2'-deoxyuridine 5'-triphosphate (dUTP) followed by treatments with uracil DNA glycosylase and hot piperidine for selective cleavage to give small oligonucleotide fragments. The resulting DNA fragments were then analyzed by LC-HRMS/MS. The applicability of this method has been demonstrated by the successful detection of hEPO transgene in a blood sample collected from a gelding (castrated male horse) that had been administered the transgene. This novel approach not only serves as a complementary method for transgene detection but also paves the way for developing a generic PCR-LC-HRMS/MS method for the detection of multiple transgenes.

Impacts of income inequality and the mediation role of reporting delays on COVID-19 deaths during 2020 and 2021 in Hong Kong: an observational study.

OBJECTIVE: To estimate the impacts of demographic factors and income disparities on the case fatality rate (CFR) of COVID-19 in Hong Kong, taking into account the influence of reporting delays (ie, the duration between symptom onset and case confirmation). DESIGN: Retrospective observational longitudinal study. PARTICIPANTS: A total of 7406 symptomatic patients with residence information reported between 23 January 2020 and 2 October 2021. MAIN OUTCOME MEASURES: The study examined the disparity in COVID-19 deaths associated with the factors such as age (≥65 vs 0-64 years old groups), gender and the income level of districts (low income vs non-low income). The severe reporting delay (>10 days) was considered as the mediator for mediation analysis. A Cox proportional hazards regression model was constructed. RESULTS: We found that CFR was 3.07% in the low-income region, twofold higher than 1.34% in the other regions. Although the severe reporting delay was associated with a hazard ratio (HR) of about 1.9, its mediation effect was only weakly present for age, but not for gender or income level. Hence, high CFR in Hong Kong was largely attributed to the direct effects of the elderly (HR 25.967; 95% CI 14.254 to 47.306) and low income (HR 1.558; 95% CI 1.122 to 2.164). CONCLUSION: The disparity in COVID-19 deaths between income regions is not due to reporting delays, but rather to health inequities in Hong Kong. These risks may persist after the discontinuation of test-and-trace measures and extend to other high-threat respiratory pathogens. Urgent actions are required to identify vulnerable groups in low-income regions and understand the underlying causes of health inequities.

Endogenous nature of estra-4,9-diene-3,17-dione in entire male horses.

Estra-4,9-diene-3,17-dione (dienedione) is an anabolic androgenic steroid (AAS) sold as a bodybuilding supplement. It is prohibited in both human and equine sports. With no report of 4,9-diene configuration in endogenous steroids, dienedione has long been considered a synthetic AAS. Nevertheless, the reoccurring detection of dienedione in colt (entire male horse) urine samples lead to the investigation of its possible endogenous nature in horses. This paper describes (i) the detection of naturally occurring dienedione in colts, (ii) the conjugation study of dienedione and (iii) the population study of free and glucuronide-conjugated dienedione in colt urine. Qualitative and quantitative analyses of dienedione content in colt urine were performed, employing liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Qualitative analyses showed that dienedione was endogenous in colt urine and mainly in the form of glucuronide conjugates. Glucuronidation of dienedione was believed to happen at 3-enol leading to dienedione-3-glucuronide. Upon the population study of free and glucuronide-conjugated dienedione in colt urine samples (n = 175), the mean ± SD was determined to be 2.5 ± 3.5 ng/ml. The population data fitted a normal distribution after a fifth root transformation with the exclusion of one outlier by Grubb's test. A possible in-house threshold was proposed at 30 ng/ml of free and glucuronide-conjugated dienedione in colt urine associated with a risk factor of 1 in 14,269 (with a degree of freedom of 173). This is the first report of endogenous dienedione in entire male horses and the approach for controlling its potential misuse by using a threshold is also presented.

Live Cell Imaging and Real-Time Monitoring of Nucleolus Morphology and Mitophagy with a Red Fluorescent and Photostable rRNA-Specific Probe in Human Cancer Cells.

rRNAs are prevalent in living organisms. They are produced in nucleolus and mitochondria and play essential cellular functions. In addition to the primary biofunction in protein synthesis, rRNAs have been recognized as the emerging signaling molecule and drug target for studies on nucleolus morphology, mitochondrial autophagy, and tumor cell malignancy. Currently, only a few rRNA-selective probes have been developed, and most of them encounter the drawbacks of low water solubility, poor nuclear membrane permeability, short emission wavelength, low stability against photobleaching, and high cytotoxicity. These unfavorable properties of rRNA probes limit their potential applications. In the present study, we reported a new rRNA-selective and near-infrared fluorescent turn-on probe, 4MPS-TO, capable of tracking rRNA in live human cancer cells. The real-time monitoring performance in nucleolus morphology and mitochondrial autophagy is demonstrated in HeLa cells. The probe shows great application potential for being used as a rRNA-selective, sensitive, and photostable imaging tool in chemical biology study and drug screening.

Unravelling the nexus between energy prices and exchange rate in Malaysia: Fresh insights from a non-linear perspective using threshold cointegration analysis.

This paper proposes a nonlinear threshold cointegration framework to study how energy prices affect Malaysia's nominal exchange rate, considering the money supply, income, and interest rate. The study employs a threshold cointegration approach utilizing threshold autoregressive and momentum threshold autoregressive models. The momentum threshold vector error correction model determines the short-run adjustment of exchange rate deviation from the long-run equilibrium level. The findings reveal that the nonlinear adjustment process to capture the short-run deviation in the long-run equilibrium path is primarily influenced by energy prices, money supply, and interest rates. These results highlight the importance of considering the impact of energy prices on exchange rate policies when formulating and implementing economic policies in Malaysia. The findings can also be valuable for decision-makers to comprehend the future dynamics of exchange rates and make well-informed decisions.

Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post-treatment.

INTRODUCTION: Valoctocogene roxaparvovec uses an adeno-associated virus serotype 5 (AAV5) vector to transfer a factor VIII (FVIII) coding sequence to individuals with severe haemophilia A, providing bleeding protection. AIM: To assess safety and efficacy of valoctocogene roxaparvovec 5-6 years post-treatment. METHODS: In a phase 1/2 trial, adult male participants with severe haemophilia A (FVIII ≤1 IU/dL) without FVIII inhibitors or anti-AAV5 antibodies received valoctocogene roxaparvovec and were followed for 6 (6 × 1013 vg/kg; n = 7) and 5 (4 × 1013 vg/kg; n = 6) years. Safety, including investigation of potential associations between a malignancy and gene therapy, and efficacy are reported. RESULTS: No new treatment-related safety signals emerged. During year 6, a participant in the 6 × 1013  vg/kg cohort was diagnosed with grade 2 parotid gland acinar cell carcinoma; definitive treatment was uncomplicated parotidectomy with lymph node dissection. Target enrichment sequencing of tumour and adjacent healthy tissue revealed low vector integration (8.25 × 10-5 per diploid cell). Integrations were not elevated in tumour samples, no insertions appeared to drive tumorigenesis, and no clonal expansion of integration-containing cells occurred. During all follow-ups, >90% decreases from baseline in annualised treated bleeds and FVIII infusion rates were maintained. At the end of years 6 and 5, mean FVIII activity (chromogenic assay) was 9.8 IU/dL (median, 5.6 IU/dL) and 7.6 IU/dL (median, 7.1 IU/dL) for the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, representing proportionally smaller year-over-year declines than earlier timepoints. CONCLUSIONS: Valoctocogene roxaparvovec safety and efficacy profiles remain largely unchanged; genomic investigations showed no association with a parotid tumour.

A smart cysteine-activated and heavy-atom-free nano-photosensitizer for photodynamic therapy to treat cancers.

A smart and heavy-atom-free photoinactive nano-photosensitizer capable of being activated by cysteine at the tumor site to generate highly photoactive nano-photosensitizers that show strong NIR absorption and fluorescence with a good singlet oxygen quantum yield (16.8%) for photodynamic therapy is reported.

Multi-targeting oligopyridiniums: Rational design for biofilm dispersion and bacterial persister eradication.

The development of effective antibacterial drugs to combat bacterial infections, particularly the biofilm-related infections, remains a challenge. There are two important features of bacterial biofilms, which are well-known critical factors causing biofilms hard-to-treat in clinical, including the dense and impermeable extracellular polymeric substances (EPS) and the metabolically repressed dormant and persistent bacterial population embedded. These characteristics largely increase the difficulty for regular antibiotic treatment due to insufficient penetration into EPS. In addition, the dormant bacteria are insensitive to the growth-inhibiting mechanism of traditional antibiotics. Herein, we explore the potential of a series of new oligopyridinium-based oligomers bearing a multi-biomacromolecule targeting function as the potent bacterial biofilm eradication agent. These oligomers were rationally designed to be "charge-on-backbone" that can offer a special alternating amphiphilicity. This novel and unique feature endows high affinity to bacterial membrane lipids, DNAs as well as proteins. Such a broad multi-targeting nature of molecules not only enables its penetration into EPS, but also plays vital roles in the bactericidal mechanism of action that is highly effective against dormant and persistent bacteria. Our in vitro, ex vivo, and in vivo studies demonstrated that OPc3, one of the most effective derivatives, was able to offer excellent antibacterial potency against a variety of bacteria and effectively eliminate biofilms in zebrafish models and mouse wound biofilm infection models.

Data integration and inference of gene regulation using single-cell temporal multimodal data with scTIE.

Single-cell technologies offer unprecedented opportunities to dissect gene regulatory mechanisms in context-specific ways. Although there are computational methods for extracting gene regulatory relationships from scRNA-seq and scATAC-seq data, the data integration problem, essential for accurate cell type identification, has been mostly treated as a standalone challenge. Here we present scTIE, a unified method that integrates temporal multimodal data and infers regulatory relationships predictive of cellular state changes. scTIE uses an autoencoder to embed cells from all time points into a common space by using iterative optimal transport, followed by extracting interpretable information to predict cell trajectories. Using a variety of synthetic and real temporal multimodal data sets, we show scTIE achieves effective data integration while preserving more biological signals than existing methods, particularly in the presence of batch effects and noise. Furthermore, on the exemplar multiome data set we generated from differentiating mouse embryonic stem cells over time, we show scTIE captures regulatory elements highly predictive of cell transition probabilities, providing new potentials to understand the regulatory landscape driving developmental processes.

Genetic effects of sequence-conserved enhancer-like elements on human complex traits.

BACKGROUND: The vast majority of findings from human genome-wide association studies (GWAS) map to non-coding sequences, complicating their mechanistic interpretations and clinical translations. Non-coding sequences that are evolutionarily conserved and biochemically active could offer clues to the mechanisms underpinning GWAS discoveries. However, genetic effects of such sequences have not been systematically examined across a wide range of human tissues and traits, hampering progress to fully understand regulatory causes of human complex traits. RESULTS: Here we develop a simple yet effective strategy to identify functional elements exhibiting high levels of human-mouse sequence conservation and enhancer-like biochemical activity, which scales well to 313 epigenomic datasets across 106 human tissues and cell types. Combined with 468 GWAS of European (EUR) and East Asian (EAS) ancestries, these elements show tissue-specific enrichments of heritability and causal variants for many traits, which are significantly stronger than enrichments based on enhancers without sequence conservation. These elements also help prioritize candidate genes that are functionally relevant to body mass index (BMI) and schizophrenia but were not reported in previous GWAS with large sample sizes. CONCLUSIONS: Our findings provide a comprehensive assessment of how sequence-conserved enhancer-like elements affect complex traits in diverse tissues and demonstrate a generalizable strategy of integrating evolutionary and biochemical data to elucidate human disease genetics.

Seeing through a robot's eyes: A cross-sectional exploratory study in developing a robotic screening technology for autism.

The present exploratory cross-sectional case-control study sought to develop a reliable and scalable screening tool for autism using a social robot. The robot HUMANE, installed with computer vision and linked with recognition technology, detected the direction of eye gaze of children. Children aged 3-8 (M = 5.52; N = 199) participated, 87 of whom had been confirmed with autism, 55 of whom were suspected to have autism, and 57 of whom were not considered to cause any concern for having autism. Before a session, a human experimenter instructed HUMANE to narrate a story to a child. HUMANE prompted the child to return his/her eye gaze to the robot if the child looked away, and praised the child when it re-established its eye gaze quickly after a prompt. The reliability of eye gaze detection was checked across all pairs of human raters and HUMANE and reached 0.90, indicating excellent interrater agreement. Using the pre-specified reference standard (Autism Spectrum Quotient), the sensitivity and specificity of the index tests (i.e., the number of robot prompts and duration of inattentiveness) reached 0.88 or above and the Diagnostic Odds Ratios were beyond 190. These results show that social robots may detect atypical eye patterns, suggesting a potential future for screening autism using social robots.