Pharmacokinetics, safety, and efficacy of Fuqi Guben Gao in the treatment of kidney-yang deficiency syndrome: a randomized, double-blind phase I trial.

Introduction: Fuqi Guben Gao (FQGBG) is a botanical drug formulation composed of FuZi (FZ; Aconitum carmichaelii Debeaux [Ranunculaceae; Aconiti radix cocta]), Wolfberry (Lycium barbarum L. [Solanaceae; Lycii fructus]), and Cinnamon (Neolitsea cassia (L.) Kosterm. [Lauraceae; Cinnamomi cortex]). It has been used to clinically treat nocturia caused by kidney-yang deficiency syndrome (KYDS) for over 30 years and warms kidney yang. However, the pharmacological mechanism and the safety of FQGBG in humans require further exploration and evaluation. Methods: We investigated the efficacy of FQGBG in reducing urination and improving immune organ damage in two kinds of KYDS model rats (hydrocortisone-induced model and natural aging model), and evaluated the safety of different oral FQGBG doses through pharmacokinetic (PK) parameters, metabonomics, and occurrence of adverse reactions in healthy Chinese participants in a randomized, double-blind, placebo-controlled, single ascending dose clinical trial. Forty-two participants were allocated to six cohorts with FQGBG doses of 12.5, 25, 50, 75, 100, and 125 g. The PKs of FQGBG in plasma were determined using a fully validated LC-MS/MS method. Results: FQGBG significantly and rapidly improved the symptoms of increased urination in both two KYDS model rats and significantly resisted the adrenal atrophy in hydrocortisone-induced KYDS model rats. No apparent increase in adverse events was observed with dose escalation. Major adverse drug reactions included toothache, thirst, heat sensation, gum pain, diarrhea, abdominal distension, T-wave changes, and elevated creatinine levels. The PK results showed a higher exposure level of benzoylhypaconine (BHA) than benzoylmesaconine (BMA) and a shorter half-life of BMA than BHA. Toxic diester alkaloids, aconitine, mesaconitine, and hypaconitine were below the lower quantitative limit. Drug-induced metabolite markers primarily included lysophosphatidylcholines, fatty acids, phenylalanine, and arginine metabolites; no safety-related metabolite changes were observed. Conclusion: Under the investigated dosing regimen, FQGBG was safe. The efficacy mechanism of FQGBG in treating nocturia caused by KYDS may be related to the improvement of the hypothalamus-pituitary-adrenal axis function and increased energy metabolism. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=26934, identifier ChiCTR1800015840.

Characterization of Pseudomonas spp. contamination and in situ spoilage potential in pasteurized milk production process.

To investigate the prevalence of Pseudomonas in the pasteurized milk production process and its effect on milk quality, 106 strains of Pseudomonas were isolated from the pasteurized milk production process of a milk production plant in Shaanxi Province, China. The protease, lipase and biofilm-producing capacities of the 106 Pseudomonas strains were evaluated, and the spoilage enzyme activities of their metabolites were assessed by simulating temperature incubation in the refrigerated (7 °C) and transport environment (25 °C) segments and thermal treatments of pasteurization (75 °C, 5 min) and ultra-high temperature sterilization (121 °C, 15 s). A phylogenetic tree was drawn based on 16S rDNA gene sequencing and the top 5 strains were selected as representative strains to identify their in situ spoilage potential by examining their growth potential and ability to hydrolyze proteins and lipids in milk using growth curves, pH, whiteness, Zeta-potential, lipid oxidation, SDS-PAGE and volatile flavor compounds. The results showed that half and more of the isolated Pseudomonas had spoilage enzyme production and biofilm capacity, and the spoilage enzyme activity of metabolites was affected by the culture temperature and sterilization method, but ultra-high temperature sterilization could not completely eliminate the enzyme activity. The growth of Pseudomonas lundensis and Pseudomonas qingdaonensis was less affected by temperature and time, and the hydrolytic capacity of extracellular protease and lipase secreted by Pseudomonas lurida was the strongest, which had the greatest effect on milk quality. Therefore, it is crucial to identify the key contamination links of Pseudomonas, the main bacteria responsible for milk spoilage, and the influence of environmental factors on its deterioration.

Enhancing the Inhibition of Breast Cancer Growth Through Synergistic Modulation of the Tumor Microenvironment Using Combined Nano-Delivery Systems.

Purpose: Breast cancer is a prevalent malignancy among women worldwide, and malignancy is closely linked to the tumor microenvironment (TME). Here, we prepared mixed nano-sized formulations composed of pH-sensitive liposomes (Ber/Ru486@CLPs) and small-sized nano-micelles (Dox@CLGs). These liposomes and nano-micelles were modified by chondroitin sulfate (CS) to selectively target breast cancer cells. Methods: Ber/Ru486@CLPs and Dox@CLGs were prepared by thin-film dispersion and ethanol injection, respectively. To mimic actual TME, the in vitro "condition medium of fibroblasts + MCF-7" cell model and in vivo "4T1/NIH-3T3" co-implantation mice model were established to evaluate the anti-tumor effect of drugs. Results: The physicochemical properties showed that Dox@CLGs and Ber/Ru486@CLPs were 28 nm and 100 nm in particle size, respectively. In vitro experiments showed that the mixed formulations significantly improved drug uptake and inhibited cell proliferation and migration. The in vivo anti-tumor studies further confirmed the enhanced anti-tumor capabilities of Dox@CLGs + Ber/Ru486@CLPs, including smaller tumor volumes, weak collagen deposition, and low expression levels of α-SMA and CD31 proteins, leading to a superior anti-tumor effect. Conclusion: In brief, this combination therapy based on Dox@CLGs and Ber/Ru486@CLPs could effectively inhibit tumor development, which provides a promising approach for the treatment of breast cancer.

Can a cup a day keep cancer away? A systematic review exploring the potential of coffee constituents in preventing oral squamous cell carcinoma.

BACKGROUND: Coffee is one of the most consumed beverages in the world. Containing an abundance of bioactive molecules including polyphenols and flavonoids, the constituents of this beverage may exert antiproliferative, antioxidant and anti-inflammatory effects. METHODS: We conducted a systematic review to summarise the available evidence on the anticancer effects of coffee constituents and their potential therapeutic use for oral squamous cell carcinoma (OSCC). Studies were identified through a comprehensive search of OVID MEDLINE, OVID EMBASE and Web of Science, including articles from any year up to 15 May 2023. RESULTS: Of the 60 reviewed papers, 45 were in vitro, 1 was in silico and 8 were in vivo exclusively. The remaining studies combined elements of more than one study type. A total of 55 studies demonstrated anti-proliferative effects, whilst 12 studies also investigated migration and invasion of neoplastic cells. The constituents studied most frequently were quercetin and epigallocatechin gallate (EGCG), demonstrating various cytotoxic effects whilst also influencing apoptotic mechanisms in cancer cell lines. Dose-dependent responses were consistently found amongst the studied constituents. CONCLUSION: Whilst there was heterogeneity of study models and methods, consistent use of specific models such as SCC25 for in vitro studies and golden hamsters for in vivo studies enabled relative comparability. The constituents of coffee have gained significant interest over the last 30 years, particularly in the last decade, and present an area of interest with significant public health implications. Currently, there is a paucity of literature on utilization of active coffee constituents for the therapeutic treatment of oral cancers.

Disparities in preconception health indicators in U.S. women: a cross-sectional analysis of the behavioral risk factor surveillance system 2019.

OBJECTIVES: Optimized preconception care improves birth outcomes and women's health. Yet, little research exists identifying inequities impacting preconception health. This study identifies age, race/ethnicity, education, urbanicity, and income inequities in preconception health. METHODS: We performed a cross-sectional analysis of the Center for Disease Control and Prevention's (CDC) 2019 Behavioral Risk Factor Surveillance System (BRFSS). This study included women aged 18-49 years who (1) reported they were not using any type of contraceptive measure during their last sexual encounter (usage of condoms, birth control, etc.) and (2) reported wanting to become pregnant from the BRFSS Family Planning module. Sociodemographic variables included age, race/ethnicity, education, urbanicity, and annual household income. Preconception health indicators were subdivided into three categories of Physical/Mental Health, Healthcare Access, and Behavioral Health. Chi-squared statistical analysis was utilized to identify sociodemographic inequities in preconception health indicators. RESULTS: Within the Physical/Mental Health category, we found statistically significant differences among depressive disorder, obesity, high blood pressure, and diabetes. In the Healthcare Access category, we found statistically significant differences in health insurance status, having a primary care doctor, and being able to afford a medical visit. Within the Behavioral Health category, we found statistically significant differences in smoking tobacco, consuming alcohol, exercising in the past 30 days, and fruit and vegetable consumption. CONCLUSIONS: Maternal mortality and poor maternal health outcomes are influenced by many factors. Further research efforts to identify contributing factors will improve the implementation of targeted preventative measures in directly affected populations to alleviate the current maternal health crisis.

Hyperspectral measurement of dispersion in aqueous solution and its effect on ultra-sensitive interferometer.

Since the reported Sellmeier equation of water is fitted with sparse sampling points in the near-infrared region, the simulated refractive index sensitivity of dispersion enhanced interferometers deviates from the true value. Here, we measure the refractive index of aqueous sample based on hyperspectra, and research the effect of dispersion on ultra-sensitive interferometer. A piece of quartz plate is used to generate hyperspectra in the near-infrared region by building a wavefront splitting fiber Mach-Zehnder interferometer (WFSF-MZIs). The refractive index of saline water is tested after measuring the thickness of the quartz plate. By taking the wavelength of 1450 nm as break-point, the empirical dispersion equations of saline water are piecewise fitted. When the normal and abnormal dispersion are taken into account, the theoretical sensitivity of phase compensated WFSF-MZI is in good agreement with the experimental results. Our methodology provides a good reference in designing dispersion sensitized optical refractive index sensor for detecting aqueous samples.

Comparative analysis of single cell lung atlas of bat, cat, tiger, and pangolin.

Horseshoe bats (Rhinolophus sinicus) might help maintain coronaviruses severely affecting human health, such as severe acute respiratory syndrome coronavirus (SARS-CoV). Bats may be more tolerant of viral infection than other mammals due to their unique immune system, but the exact mechanism remains to be fully explored. During the coronavirus disease 2019 (COVID-19) pandemic, multiple animal species were diseased by coronavirus infection, especially in the respiratory system. Herein, a comparative analysis with single nucleus transcriptomic data of the lungs across four species, including horseshoe bat, cat, tiger, and pangolin, were conducted. The distribution of entry factors for twenty-eight respiratory viruses was characterized for the four species. Our findings might increase our understanding of the immune background of horseshoe bats.

Optimization design and performance analysis of quaternion spatial pseudo-depolarizer.

In this study, to improve the uniformity of transmission light intensity of depolarizer, we present an optimal design of the quaternion space pseudo-depolarizer consisting of four wedge crystals. By designing the optical axis and wedge angle of each crystals, the square distribution of the output spot is realized. The mathematical expression of the degree of depolarization is obtained using the light wave superposition method. Theoretical analysis shows that the new type of depolarizer can optimize the intensity distribution of the emergent light field when the depolarizer wedge angle is sufficiently large, and it can realize the perfect depolarization of monochromatic linear polarized light. A samples of the quartz crystal material are developed and tested using lasers of 405 nm and 670 nm wavelengths. The degree of depolarization is observed to be 99% for any azimuth angle, whereas the angle of field of view is -10°-10°.

Screening of cell-virus, cell-cell, gene-gene crosstalk among animal kingdom at single cell resolution.

BACKGROUND: The exact animal origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains obscure and understanding its host range is vital for preventing interspecies transmission. METHODS: Herein, we applied single-cell sequencing to multiple tissues of 20 species (30 data sets) and integrated them with public resources (45 data sets covering 26 species) to expand the virus receptor distribution investigation. While the binding affinity between virus and receptor is essential for viral infectivity, understanding the receptor distribution could predict the permissive organs and tissues when infection occurs. RESULTS: Based on the transcriptomic data, the expression profiles of receptor or associated entry factors for viruses capable of causing respiratory, blood, and brain diseases were described in detail. Conserved cellular connectomes and regulomes were also identified, revealing fundamental cell-cell and gene-gene cross-talks from reptiles to humans. CONCLUSIONS: Overall, our study provides a resource of the single-cell atlas of the animal kingdom which could help to identify the potential host range and tissue tropism of viruses and reveal the host-virus co-evolution.

Joint profiling of gene expression and chromatin accessibility during amphioxus development at single-cell resolution.

Vertebrate evolution was accompanied by two rounds of whole-genome duplication followed by functional divergence in terms of regulatory circuits and gene expression patterns. As a basal and slow-evolving chordate species, amphioxus is an ideal paradigm for exploring the origin and evolution of vertebrates. Single-cell sequencing has been widely used to construct the developmental cell atlas of several representative species of vertebrates (human, mouse, zebrafish, and frog) and tunicates (sea squirts). Here, we perform single-nucleus RNA sequencing (snRNA-seq) and single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) for different stages of amphioxus (covering embryogenesis and adult tissues). With the datasets generated, we constructed a developmental tree for amphioxus cell fate commitment and lineage specification and characterize the underlying key regulators and genetic regulatory networks. The data are publicly available on the online platform AmphioxusAtlas.

Endothelial cell heterogeneity and microglia regulons revealed by a pig cell landscape at single-cell level.

Pigs are valuable large animal models for biomedical and genetic research, but insights into the tissue- and cell-type-specific transcriptome and heterogeneity remain limited. By leveraging single-cell RNA sequencing, we generate a multiple-organ single-cell transcriptomic map containing over 200,000 pig cells from 20 tissues/organs. We comprehensively characterize the heterogeneity of cells in tissues and identify 234 cell clusters, representing 58 major cell types. In-depth integrative analysis of endothelial cells reveals a high degree of heterogeneity. We identify several functionally distinct endothelial cell phenotypes, including an endothelial to mesenchymal transition subtype in adipose tissues. Intercellular communication analysis predicts tissue- and cell type-specific crosstalk between endothelial cells and other cell types through the VEGF, PDGF, TGF-ß, and BMP pathways. Regulon analysis of single-cell transcriptome of microglia in pig and 12 other species further identifies MEF2C as an evolutionally conserved regulon in the microglia. Our work describes the landscape of single-cell transcriptomes within diverse pig organs and identifies the heterogeneity of endothelial cells and evolutionally conserved regulon in microglia.

VThunter: a database for single-cell screening of virus target cells in the animal kingdom.

Viral infectious diseases are a devastating and continuing threat to human and animal health. Receptor binding is the key step for viral entry into host cells. Therefore, recognizing viral receptors is fundamental for understanding the potential tissue tropism or host range of these pathogens. The rapid advancement of single-cell RNA sequencing (scRNA-seq) technology has paved the way for studying the expression of viral receptors in different tissues of animal species at single-cell resolution, resulting in huge scRNA-seq datasets. However, effectively integrating or sharing these datasets among the research community is challenging, especially for laboratory scientists. In this study, we manually curated up-to-date datasets generated in animal scRNA-seq studies, analyzed them using a unified processing pipeline, and comprehensively annotated 107 viral receptors in 142 viruses and obtained accurate expression signatures in 2 100 962 cells from 47 animal species. Thus, the VThunter database provides a user-friendly interface for the research community to explore the expression signatures of viral receptors. VThunter offers an informative and convenient resource for scientists to better understand the interactions between viral receptors and animal viruses and to assess viral pathogenesis and transmission in species. Database URL: https://db.cngb.org/VThunter/.

Single cell atlas for 11 non-model mammals, reptiles and birds.

The availability of viral entry factors is a prerequisite for the cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Large-scale single-cell screening of animal cells could reveal the expression patterns of viral entry genes in different hosts. However, such exploration for SARS-CoV-2 remains limited. Here, we perform single-nucleus RNA sequencing for 11 non-model species, including pets (cat, dog, hamster, and lizard), livestock (goat and rabbit), poultry (duck and pigeon), and wildlife (pangolin, tiger, and deer), and investigated the co-expression of ACE2 and TMPRSS2. Furthermore, cross-species analysis of the lung cell atlas of the studied mammals, reptiles, and birds reveals core developmental programs, critical connectomes, and conserved regulatory circuits among these evolutionarily distant species. Overall, our work provides a compendium of gene expression profiles for non-model animals, which could be employed to identify potential SARS-CoV-2 target cells and putative zoonotic reservoirs.

Refractive index modulation in magnetophoresis of bioreaction induced self-assembled magnetic fluid.

We explore the refractive index (RI) modulation of bioreaction induced self-assembled magnetic fluid (SAMF) so as to facilitate the design of sensitive biosensors. Bovine serum albumin (BSA) is taken as a model protein to induce self-assembly of carboxylated magnetic nanoparticles (MNPs). A bidirectional magnetophoresis (BDMP) system is designed to generate uniform and large RI modulation to SAMF. A robust Mach-Zehnder interferometer compatible to the BDMP system is used for the RI detection. It is found that BDMP has greater ability in modulating the RI of magnetic fluid than the alignment of MNPs in a uniform magnetic field. The modulation depth of the RI increases with the increase of BSA concentration when applying a certain external magnetic field for a period of time. A larger magnetic field has greater ability to modulate the RI of SAMF. However, it may generate an over-modulation.

High-power synchronous multi-wavelength solitons from a multimode mode-locked fiber laser system.

In this Letter, we implement a multimode fiber (MMF) laser system mode-locked by a nonlinear polarization rotation technique for controllable synchronous multi-wavelength soliton generation. The synchronization of the repetition rates for different wavelengths is realized by the special mode transmission in MMF. For dual-wavelength mode-locking at 1566.7 nm and 1617.2 nm, each of the synchronously mode-locked solitons consists of a train of quasi-periodic beat pulses with a pulse width of 84 fs and period of 162 fs. The total output power reaches 532 mW with optimally balanced two-color intensities. Furthermore, switchable dual- and tri-wavelength synchronized femtosecond pulses are also obtained. In contrast to previous reports, this synchronously mode-locked multi-wavelength is output directly from a laser oscillator, which provides a simpler candidate to achieve pulse synchronization.

Immunization information system status in China, 2017.

Immunization Information Systems (IIS) are computerized population-based systems with individual-level vaccination-related information used to help ensure protection from vaccine preventable diseases. The Chinese Center for Diseases Control and Prevention (China CDC) conducted a survey of the 32 mainland China provincial CDCs to determine IIS coverage and implementation of key functions: individual vaccination records, vaccine management, cold-chain management, and school entry vaccination status verification. Twenty-seven IISs collectively managed 252 million immunization records, 43.8% for children under 6 years; 20 could exchange records with other IISs. The within-province duplicate-record rate varied from 0.3% to 4.0%, but compared with National Statistical Bureau's census estimates, 138.0% of births from 2012 to 2017 were represented in the IISs, implying significant across-province record duplication. China CDC should consider developing a national-level IIS center for data exchange and analysis.

Design and performance analysis of a single-unit polarizing beam-splitting prism based on negative refraction in a uniaxial crystal.

A new type of single-unit polarizing beam-splitting prism is proposed based on negative refraction and total internal reflection in uniaxial crystals. The performance of the proposed design is studied theoretically and experimentally using a calcite prism. The results indicate that the single-unit negative refraction polarization-splitting prism can yield a maximum splitting angle of 19.5° (for an incident light wavelength of 633 nm), whereby the splitting angle is insensitive to changes in the incidence angle. The proposed structure exhibits good stability and reliability. The design is beneficial to application in special working environments involving intense vibration and increased radiation.

Deaths reported to national surveillance for adverse events following immunization in China, 2010-2015.

BACKGROUND: The national Adverse Events Following Immunization (AEFI) surveillance system in China (CNAEFIS) has collected AEFI reports -including deaths following all vaccines used in China since 2008. AIMS: To review reports of AEFI-associated death cases from 2010 to 2015 to assess potential vaccine safety issues. METHODS: Descriptive analysis of epidemiologic characteristic of AEFI-associated death cases and standard causality assessment for reported causes of deaths. To estimate the risk of death after vaccination, we used population data, administered doses and live births to calculate denominators. RESULTS: During 2010-2015, 753 deaths were reported to CNAEFIS from mainland China. Highest numbers were reported in 2013 and 2014 when reporting peak of AEFI-associated deaths occurred after media reports concerning "death following Hepatitis B vaccination" in China. About 95% of deaths were in children <5 years of age and males accounted for 60%. Most common vaccines associated with reports of fatal AEFIs were vaccines in national immunization schedule. In causality assessment, 120 (16.0%) deaths were classified as vaccine-associated reactions such as anaphylactic reactions and disseminated BCG infections; 594 (78.9%) deaths were identified as coincidental events. The main causes of death were asphyxia, and Sudden Infant Death Syndrome. The overall estimated AEFI-associated death rates were: 0.26 per million vaccination doses administered and 0.09 per million population. The neonatal AEFI death rate was 0.77 per million live births. CONCLUSIONS: These data provide reassuring information about the small risk of death following immunization. They also illustrate sensitivity of passive reporting to public information and that peaks in serious AEFI reports should be interpreted with caution. Continuous monitoring and scientific causality assessment for serious AEFIs, including AEFI-associated deaths is imperative to ensure public confidence in the immunization program.