Hepatic Dyrk1b impairs systemic glucose homeostasis by modulating Wbp2 expression in a kinase activity-dependent manner.

Patients with gain-of-function mutations of Dyrk1b have higher fasting blood glucose (FBG) levels. However, the role of Dyrk1b in glucose metabolism is not fully elucidated. Herein, we found that hepatic Dyrk1b overexpression in mice impaired systemic glucose tolerance and hepatic insulin signaling. Dyrk1b overexpression in vitro attenuated insulin signaling in a kinase activity-dependent manner, and its kinase activity was required for its effect on systemic glucose homeostasis and hepatic insulin signaling in vivo. Dyrk1b ablation improved systemic glucose tolerance and hepatic insulin signaling in mice. Quantitative proteomic analyses showed that Dyrk1b downregulated WW domain-binding protein 2 (Wbp2) protein abundance. Mechanistically, Dyrk1b enhanced Wbp2 ubiquitylation and proteasomal degradation. Restoration of hepatic Wbp2 partially rescued the impaired glucose homeostasis in Dyrk1b overexpression mice. In addition, Dyrk1b inhibition with AZ191 moderately improved systemic glucose homeostasis. Our study uncovers that hepatic Dyrk1b impairs systemic glucose homeostasis via its modulation of Wbp2 expression in a kinase activity-dependent manner.

Income insecurity and social protection: Examining the impact of the COVID-19 pandemic across income groups.

The COVID-19 pandemic has wrought unprecedented disruption on global economies, leading to widespread income insecurity among individuals and households. This study investigates the impact of the pandemic on income insecurity across different income groups and assesses the role of social protection measures in mitigating these effects. Using cross-country data, we analyze the prevalence of income reduction and the effectiveness of social assistance programs in high-income, upper middle-income, lower middle-income, and low-income countries. Our findings reveal significant variations in income insecurity and social protection responses across these groups. the pandemic had a significant impact on household incomes globally, with lower-middle-income countries experiencing the most significant income reductions. The average per capita transfer amounts show a general decrease over time, which could be due to the economic strain on governments and the need for more sustainable social protection programs. The correlation between transfer amounts and the proportion of households with reduced income indicates that countries with higher income reduction rates tended to have lower average per capita transfer amounts, suggesting a potential lack of adequate support for those in need. The study highlights the importance of robust social safety nets in cushioning the economic blow of the pandemic, particularly for vulnerable populations in lower-income countries.

Target Attainment and Population Pharmacokinetics of Nirmatrelvir/Ritonavir in Critically Ill Adult Patients.

Background: The population pharmacokinetics of nirmatrelvir/ritonavir (NIR/RIT) has not yet been described for critically ill adult patient. Purpose: This was a prospective observational population pharmacokinetic study of nirmatrelvir/ritonavir (NIR/RIT) in critically ill adult patients and identify optimal dosing regimens. Patients and Methods: The prescription of NIR/RIT is determined by the attending physician and ranges from 150mg/100mg to 300mg/100mg twice a day. Two to three serial blood samples were collected for each patient after the second doses. We developed and validated PK model for plasma NIR and plasma RIT. Monte Carlo dosing simulations were performed to assess target attainment. Results: We analyzed 89 plasma samples from 31 adult patients. The data were best described by a one-compartment model. Among the covariates tested on pharmacokinetic parameters, creatinine clearance (CrCL) and area under curve (AUC) of RIT had a significant effect on apparent clearance (CL/F) of NIR. Mean (SD) parameters estimates for the absorption rate constant (Ka), apparent distribution (V/F) and CL/F were 0.42 (0.10) h-1. 36.5 (8.5) L, 3.6 (0.26) L/h, respectively. Dosing simulations showed that the target in vitro 90% effective concentration (EC90) was more likely to be achieved twice a day than once a day at the same daily dose of NIR. High CrCL, low AUC of RIT were associated with a reduced likelihood of NIR reaching the target EC90. Conclusion: Based on our dosing simulations, the initial dosage of NIR/RIT was 300mg/100mg twice a day in critically ill patients with CrCL>45 mL/min; When CrCL in critically ill patients is between 15 and 45 mL/min, NIR/RIT is 150mg/100mg twice a day. The maintenance dose is adjusted according to CrCL and AUC of RIT, with the dosages varying between 75mg/100mg and 300mg/100mg.

Development and age estimation of the intrapuparial period of Phormia regina (Diptera: Calliphoridae) for postmortem interval estimation.

Phormia regina (Meigen, 1826; Diptera: Calliphoridae) is a Holarctic species that rapidly colonizes carcasses and has been used as an indicator for determining the minimum postmortem interval. However, studies using morphological methods to estimate the intrapuparial age of P. regina are lacking. In this study, morphological changes within the puparium were observed under a stereomicroscope at 7 constant temperatures ranging from 16 °C to 34 °C. The intrapuparial period was categorized into 12 substages. Morphological indicators, including compound eyes, mouthparts, antennae, thorax, legs, wings, and abdomen, were recorded in detail. The observed morphological changes were divided into 6-10 substages, and the duration of each substage was also recorded in detail. The results of this study provide primary data for using the intrapuparial morphology of P. regina when pupae are collected at a crime scene and estimating the minimum postmortem interval.

Insights into the Preparation of and Evaluation of the Bactericidal Effects of Phage-Based Hydrogels.

The rise of antibiotic-resistant strains demands new alternatives in antibacterial treatment. Bacteriophages, with their precise host specificity and ability to target and eliminate bacteria safely, present a valuable option. Meanwhile, hydrogels, known for their excellent biodegradability and biocompatibility, serve as ideal carriers for bacteriophages. The combination of bacteriophages and hydrogels ensures heightened phage activity, concentration, controlled release, and strong antibacterial properties, making it a promising avenue for antibacterial treatment. This article provides a comprehensive review of different crosslinking methods for phage hydrogels, focusing on their application in treating infections caused by various drug-resistant bacteria and highlighting their effective antibacterial properties and controlled release capabilities.

Toxic effects of avermectin on liver function, gut microbiota, and colon barrier in the rat model.

Avermectin (AVM), a compound derived from the fermentation of Avermectin Streptomyces, has insecticidal, acaricidal, and nematicidal properties. Widely employed in agriculture, it serves as an effective and broad-spectrum insecticide for pest control. Although the toxicity of AVM at low doses may not be readily apparent, prolonged and extensive exposure can result in poisoning. To investigate the toxic effects of AVM on the body, this study established rat models of AVM poisoning with both low and high concentrations of the compound. Fifteen male rats were randomly assigned to one of three groups (n=5 per group): a control group, a low-concentration group, and a high-concentration group. The low-concentration group was administered an oral dose of 2 mg/kg AVM once daily for a duration of seven days, while the high-concentration group received an oral dose of 10 mg/kg AVM once daily for the same period. This study examined the impact of AVM on liver function and gut microbiota in rats using weight monitoring, liver function indicator detection, liver metabolomics sequencing, colon barrier function testing, and gut microbiota sequencing. The findings of this study demonstrated that exposure to 2 or 10 mg/kg AVM for seven days can lead to a notable decrease in rat weight, as well as induce liver dysfunction and metabolic disturbances. Additionally, AVM exposure can disrupt the composition of the intestinal microbiota and impair the integrity of the colon mucosal barrier, causing downregulation of Occludin expression and upregulation of inflammation-related protein expression levels such as IL-1ß, Myd88, and TLR4. Furthermore, bioinformatics analysis revealed a significant association between liver dysfunction and dysbiosis of the gut microbiota. These findings have implications for the agricultural use of AVM and its potential contribution to environmental pollution. Consequently, individuals involved in AVM usage should prioritize safety precautions and monitor liver function.

People with higher systemizing traits have wider right hands.

Introduction: Various genetic mutations have been implicated in autism spectrum disorder (ASD). Some candidate genes for ASD are known to be related to signal transduction and may be involved in hand development as well as neurodevelopment. Therefore, although subtle, anatomical variations in hand configurations may be observed in individuals with ASD. However, except for research on the finger ratio, which has been suggested to be related to prenatal sex hormone exposure, only few studies have been conducted. Given the spectrum characteristics of ASD, we explored whether hand configurations are associated with ASD-related traits in the general population. Methods: Photographs of the dorsal surface of each hand were obtained, and the distances between the metacarpophalangeal joints and finger lengths were measured. The Autism Spectrum Quotient, Empathy Quotient, and Systemizing Quotient were used to evaluate ASD-related traits. Results: We found a significant positive correlation between the aspect ratio of the right hand and the Systemizing Quotient score: individuals with a larger width relative to the finger length showed more systemizing traits. Discussion: These findings suggest that gene polymorphisms or prenatal sex hormone exposure may underlie the relationship between systemizing traits and hand configurations.

Molecular characteristic, evolution, and pathogenicity analysis of avian infectious bronchitis virus isolates associated with QX type in China.

Infectious bronchitis virus (IBV) is one of the major avian pathogens plaguing the global poultry industry. Although vaccination is the primary preventive measure for IBV infection, the emergence of virus variants with mutations and recombination has resulted in IBV circulating globally, presenting a challenge for IB control. Here, we isolated 3 IBV strains (CZ200515, CZ210840, and CZ211063) from suspected sick chickens vaccinated with IBV live attenuated vaccines (H120, 4/91, or QXL87). Phylogenetic analysis of the S1 gene sequence of the spike (S) revealed that the 3 isolates belonged to the QX-type (GI-19 lineage). Whole genome sequencing and recombination analysis indicated that CZ200515 and CZ210840 contained genetic material from 4/91 and Scyz3 (QX-type), possibly due to recombination between the circulating strain and the 4/91 vaccine strain, while no evidence of recombination was found in CZ211063. Pathogenicity analysis in 1-day-old specific pathogen-free (SPF) chickens demonstrated that all 3 isolates caused severe tissue damage and varying degrees of mortality. Virus cross-neutralization assay revealed decreased antigen relatedness between the isolates and the QX-type vaccine strain (QXL87). Amino acid sequence homology analysis of S1 revealed 5%-6.5% variances between the isolates and QXL87. Analysis of the S1 subunit structure revealed that mutations of amino acid residues in the hypervariable region (HVR) and the neutralizing epitope region resulted in antigenic variation in isolates by changing the antigen conformation. Our data indicate antigenicity variances between QX isolates and QXL87 vaccine strains, potentially resulting in immune evasion occurrences. Overall, these results offer crucial insights into the epidemiology and pathogenicity of QX-type IBV, facilitating improved selection and formulation of vaccines for disease management.

Beidou Navigation Satellite System metaverse resource sharing and commons sustainable development framework.

The metaverse represents a transformative landscape for human interaction, promising an immersive digital ecosystem where users can create, share, and experience resources in novel ways. Within this context, the establishment of Beidou Navigation Satellite System (BDS) commons in the metaverse is an exciting prospect that could revolutionize knowledge sharing, governance, and sustainability. This paper explores the potential of the metaverse as a platform for building BDS commons, focusing on three key dimensions: resource sharing, collaborative governance, and sustainable development. We examine the current state of research, identify existing gaps, and propose directions for future inquiries to fully harness the potential of the metaverse for global resource sharing and collective action.

Insights into the assembly of the neovaginal microbiota in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome patients.

Neovaginas are surgically constructed to correct uterovaginal agenesis in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome or as part of gender-affirming surgery for transfeminine individuals. Understanding the assembly of the neovaginal microbiota is crucial for guiding its management. To address this, we conducted a longitudinal study on MRKH patients following laparoscopic peritoneal vaginoplasty. Our findings reveal that the early microbial assemblage exhibited stochastic characteristics, accompanied with a notable bloom of Enterococcus faecalis and genital Mycoplasmas. While both the pre-surgery dimple microbiota and the fecal microbiota constituted the primary species pool, the neovaginal microbiota developed into a microbiota that resembled that of a normal vagina at 6-12 months post-surgery, albeit with a bacterial vaginosis (BV)-like structure. By 2-4 years post-surgery, the neovaginal microbiota had further evolved into a structure closely resembling with the homeostatic pre-surgery dimple microbiota. This concords with the development of the squamous epithelium in the neovagina and highlights the pivotal roles of progressive selective forces imposed by the evolving neovaginal environment and the colonization tropism of vaginal species. Notably, we observed that strains of Lactobacillus crispatus colonizing the neovagina primarily originated from the dimple. Since L. crispatus is generally associated with vaginal health, this finding suggests potential avenues for future research to promote its colonization.

Evaluation of the therapeutic efficacy of high-intensity focused ultrasound ablation combined with different drugs in the treatment of adenomyosis.

OBJECTIVES: To observe the therapeutic efficacy of high-intensity focused ultrasound (HIFU) combined with different pharmacological treatments for adenomyosis. MATERIALS AND METHODS: A total of 126 patients with adenomyosis who underwent HIFU combined with pharmacological treatment were retrospectively reviewed. Patients were treated with either dienogest (DNG) (Group A, N = 38) or GnRH-a (Group B, N = 88) for three months after HIFU, and received levonorgestrel-releasing intrauterine systems (LNG-IUS) at the end of the third month. Visual Analog Scale (VAS) and Pictorial Blood Loss Assessment Chart (PBAC) scores were used for evaluating symptom improvement. RESULTS: After propensity score matching (1:2), 38 patients were included in Group A and 76 in Group B. All patients showed significant improvement in VAS and PBAC scores after HIFU, but the PBAC score of Group A was significantly higher than that of patients in Group B at 18 months [11.50 (1.00, 29.50) vs. 0.00 (0.00, 16.50), p < 0.01] and 24 months [4.00 (0.25, 27.75) vs. 0.00 (0.00, 12.75), p = 0.04] after HIFU. Furthermore, patients in Group B had a greater uterine volume reduction at 24 months after HIFU than that of patients in Group A [51.00 (27.00, 62.00) vs. 30.00 (17.00, 42.75, p = 0.02)]. However, the adverse effects in Group A were lower than those in Group B [7 (15.79) vs. 35 (46.05), p < 0.01]. No significant difference was observed in the recurrence rate between the two groups. CONCLUSIONS: HIFU combined with DNG and LNG-IUS is a safe and effective treatment for patients with adenomyosis.

Co-production of plant- and microbial- proteins from waste tobacco leaves by optimizing alkaline extraction and strengthening pectin bioconversion.

The production of alternative proteins is of great significance in the mitigation of food problems. This study proposes an integrated approach including protein extraction, enzymatic hydrolysis, and fermentation to produce both plant proteins and single-cell proteins as alternative proteins from tobacco leaves, a highly-abundant and protein-rich agricultural waste. Alkaline extraction of proteins before polysaccharide hydrolysis was found to be preferable for increasing the yields of plant proteins and mono-sugars. The combined use of pectinase-rich enzymes from Aspergillus brunneoviolaceus and hemicellulase-rich enzymes from Penicillium oxalicum achieved the release of 80.7 % of the sugars after 72 h. Cutaneotrichosporon cutaneum could simultaneously utilize multiple sugars, including galacturonic acid, in the enzymatic hydrolysate to produce single-cell proteins. Via this approach, 43.54 g crude proteins of high protein contents and rich in essential amino acids can be produced from 100.00 g waste tobacco leaves, providing a promising strategy for its valorization.

Peimine promotes microglial polarization to the M2 phenotype to attenuate drug-resistant epilepsy through suppressing the TLR4/NF-κB/HIF-1α signaling pathway in a rat model and in BV-2 microglia.

Epilepsy is a chronic neurological disorder. Drug-resistant epilepsy (DRE) accounts for about one-third of epilepsy patients worldwide. Peimine, a main active component of Fritillaria, has been reported to show anti-inflammatory effects. However, its potential therapeutic role in DRE is not yet fully understood. In this work, a DRE rat model was established by injecting 1 µg kainic acid (KA), followed by a 250 mg/kg administration of valproic acid (VPA) from day 4-31. Rats were treated with different doses of peimine (2.5 mg/kg, 5 mg/kg and 10 mg/kg) daily from day 32-62. In vitro, BV-2 microglia were exposed to different doses of peimine (7.5 µg/ml, 15 µg/ml, and 30 µg/ml) in presence of LPS. The aim of this study was to investigate the potential therapeutic effects of peimine on DRE. The results showed that peimine efficiently suppressed the KA-induced epileptic behaviors of rats in a dose-dependent manner, as recorded by electroencephalography. Furthermore, peimine ameliorated hippocampal neuron injury in DRE rats, and promoted an M1-to-M2 microglial phenotype shift in a dose-dependent manner. Mechanistically, peimine inhibited the TLR4/NF-κB/HIF-1α signaling pathway both in vivo and in vitro. Additionally, peimine suppressed the apoptosis of primary neurons induced by LPS-treated microglia. In conclusion, peimine augments the microglial polarization towards an M2 phenotype by inhibiting the TLR4/NF-κB/HIF-1α signaling pathway, thereby attenuating DRE.

The effects of sleep quality on loneliness among older adults: cohort analysis from the life course perspective.

BACKGROUND: Using cohort analysis to examine the effects of sleep quality on loneliness among older adults from the life course perspective. METHODS: The hierarchical age-period-cohort growth curve model was used to analyze the data from the 2005-2018 Chinese Longitudinal Healthy Longevity Survey (CLHLS). RESULTS: (1) Loneliness has a 'U' curve relationship with age, but with the rate of increase gradually slowing down. (2) There were significant differences in loneliness across birth cohorts, with younger cohorts having higher predicted loneliness than older cohorts at the same age. (3) The influence of different sleep quality on loneliness showed a trend of increasing with age. (4) There were no significant differences in the impact of sleep quality on loneliness in different cohorts. CONCLUSIONS: This study has identified heterogeneity in loneliness, emphasising the need for a diversified intervention approach. Sleep quality has a protective effect on loneliness and is easy to assess, making it an important intervention tool. In addition, it is imperative to account for the influences of age and cohort effects when formulating intervention strategies.

Advances in the synthesis and applications of macrocyclic polyamines.

Macrocyclic polyamines constitute a significant class of macrocyclic compounds that play a pivotal role in the realm of supramolecular chemistry. They find extensive applications across diverse domains including industrial and agricultural production, clinical diagnostics, environmental protection and other multidisciplinary fields. Macrocyclic polyamines possess a distinctive cavity structure with varying sizes, depths, electron-richness degrees and flexibilities. This unique feature enables them to form specific supramolecular structures through complexation with diverse objects, thereby attracting considerable attention from chemists, biologists and materials scientists alike. However, there is currently a lack of comprehensive summaries on the synthesis methods for macrocyclic polyamines. In this review article, we provide an in-depth introduction to the synthesis of macrocyclic polyamines while analysing their respective advantages and disadvantages. Furthermore, we also present an overview of the recent 5-year advancements in using macrocyclic polyamines as non-viral gene vectors, fluorescent probes, diagnostic and therapeutic reagents as well as catalysts. Looking ahead to future research directions on the synthesis and application of macrocyclic polyamines across various fields will hopefully inspire new ideas for their synthesis and use.

Pharmacological Inhibition of TXNRD1 by a Small Molecule Flavonoid Butein Overcomes Cisplatin Resistance in Lung Cancer Cells.

Mammalian cytosolic selenoprotein thioredoxin reductase (TXNRD1) is crucial for maintaining the reduced state of cellular thioredoxin 1 (TXN1) and is commonly up-regulated in cancer cells. TXNRD1 has been identified as an effective target in cancer chemotherapy. Discovering novel TXNRD1 inhibitors and elucidating the cellular effects of TXNRD1 inhibition are valuable for developing targeted therapies based on redox regulation strategies. In this study, we demonstrated that butein, a plant-derived small molecule flavonoid, is a novel TXNRD1 inhibitor. We found that butein irreversibly inhibited recombinant TXNRD1 activity in a time-dependent manner. Using TXNRD1 mutant variants and LC-MS, we identified that butein modifies the catalytic cysteine (Cys) residues of TXNRD1. In cellular contexts, butein promoted the accumulation of reactive oxygen species (ROS) and exhibited cytotoxic effects in HeLa cells. Notably, we found that pharmacological inhibition of TXNRD1 by butein overcame the cisplatin resistance of A549 cisplatin-resistant cells, accompanied by increased cellular ROS levels and enhanced expression of p53. Taken together, the results of this study demonstrate that butein is an effective small molecule inhibitor of TXNRD1, highlighting the therapeutic potential of inhibiting TXNRD1 in platinum-resistant cancer cells.

Intraoperative hypotension is associated with decreased long-term survival in older patients after major noncardiac surgery: Secondary analysis of three randomized trials.

STUDY OBJECTIVE: To assess the association of intraoperative hypotension with long-term survivals in older patients after major noncardiac surgery mainly for cancer. DESIGN: A secondary analysis of databases from three randomized trials with long-term follow-up. SETTING: The underlying trials were conducted in 17 tertiary hospitals in China. PATIENTS: Patients aged 60 to 90 years who underwent major noncardiac thoracic or abdominal surgeries (≥ 2 h) in a single center were included in this analysis. EXPOSURES: Restricted cubic spline models were employed to determine the lowest mean arterial pressure (MAP) threshold that was potentially harmful for long-term survivals. Patients were arbitrarily divided into three groups according to the cumulative duration or area under the MAP threshold. The association between intraoperative hypotension exposure and long-term survivals were analyzed with the Cox proportional hazard regression models. MEASUREMENTS: Our primary endpoint was overall survival. Secondary endpoints included recurrence-free and event-free survivals. MAIN RESULTS: A total of 2664 patients (mean age 69.0 years, 34.9% female sex, 92.5% cancer surgery) were included in the final analysis. MAP < 60 mmHg was adopted as the threshold of intraoperative hypotension. Patients were divided into three groups according to duration under MAP < 60 mmHg (<1 min, 1-10 min, and > 10 min) or area under MAP <60 mmHg (< 1 mmHg⋅min, 1-30 mmHg⋅min, and > 30 mmHg⋅min). After adjusting confounders, duration under MAP < 60 mmHg for > 10 min was associated with a shortened overall survival when compared with the < 1 min patients (adjusted hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.09 to 1.57, P = 0.004); area under MAP < 60 mmHg for > 30 mmHg⋅min was associated with a shortened overall survival when compared with the < 1 mmHg⋅min patients (adjusted HR 1.40, 95% CI 1.16 to 1.68, P < 0.001). Similar associations exist between duration under MAP < 60 mmHg for > 10 min or area under MAP < 60 mmHg for > 30 mmHg⋅min and recurrence-free or event-free survivals. CONCLUSIONS: In older patients who underwent major noncardiac surgery mainly for cancer, intraoperative hypotension was associated with worse overall, recurrence-free, and event-free survivals.

Enhanced Coexistence of Quantum Key Distribution and Classical Communication over Hollow-Core and Multi-Core Fibers.

In this paper, we investigate the impact of classical optical communications in quantum key distribution (QKD) over hollow-core fiber (HCF), multi-core fiber (MCF) and single-core fiber (SCF) and propose wavelength allocation schemes to enhance QKD performance. Firstly, we theoretically analyze noise interference in QKD over HCF, MCF and SCF, such as spontaneous Raman scattering (SpRS) and four-wave mixing (FWM). To mitigate these noise types and optimize QKD performance, we propose a joint noise suppression wavelength allocation (JSWA) scheme. FWM noise suppression wavelength allocation and Raman noise suppression wavelength allocation are also proposed for comparison. The JSWA scheme indicates a significant enhancement in extending the simultaneous transmission distance of classical signals and QKD, reaching approximately 100 km in HCF and 165 km in MCF under a classical power per channel of 10 dBm. Therefore, MCF offers a longer secure transmission distance compared with HCF when classical signals and QKD coexist in the C-band. However, when classical signals are in the C-band and QKD operates in the O-band, the performance of QKD in HCF surpasses that in MCF. This research establishes technical foundations for the design and deployment of QKD optical networks.