Identification and Root Cause Analysis of the Visible Particles Commonly Encountered in the Biopharmaceutical Industry.

Visible particle is an important issue in the biopharmaceutical industry, and it may occur across all the stages in the life cycle of biologics. Upon the occurrence of visible particles, it is often necessary to conduct chemical identification and root cause analysis to safeguard the safety and efficacy of the biotherapeutic products. In this article, we present a number of typical particles and relevant root cause analysis in the categories of extrinsic, intrinsic and inherent particles that are commonly encountered in the biopharma industry. In particular, the optical images of particles obtained both in situ and after isolation are provided, along with the spectral and elemental information. The particle identification was carried out with multiple microscopic and microspectroscopic techniques, including stereo optical microscopy, Fourier transform infrared microscopy, confocal Raman microscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy. Both commercial and in-house spectral databases were used for comparison and identification. In addition to particle identification, our significant efforts are placed on the root cause analysis of the addressed particles with the intention to provide a relatively whole picture of the particle related issues and practical references to particle mitigation for our peers in the biopharmaceutical industry.

Effects of Se-enriched yeast on the amelioration of atrazine-induced meat quality degradation.

Atrazine (ATR) is herbicide that causes serious harm to the environment and threatens human food safety. Se-enriched yeast is the best organic selenium source for protecting cells from damage caused by poisonous substances. To explore mechanism of ATR on meat quality degradation and potential protective effects of Se-enriched yeast on ATR-induced muscle injury, quails were treated with ATR and/or Se-enriched yeast for 28 days. The results found ATR disrupted muscle fiber structure and decreased pH, tenderness, water-holding capacity, essential amino acid content and polyunsaturated fatty acid content. ATR aggravated oxidative stress and inflammation by inhibiting Nrf2 pathway and activating NF-κB pathway, ultimately causing apoptosis. However, Se-enriched yeast alleviated ATR-induced alterations in muscle chemical and physical properties by inhibiting oxidative stress and inflammation. Taken together, these results revealed that ATR exposure caused meat quality degradation and Se-enriched yeast had the potential to counteract ATR-induced myotoxicity by inhibiting oxidative stress and inflammation.

Effectiveness of momentary intervention on influenza vaccination among the elderly in China: From willingness to action.

PURPOSE: To evaluate the impact of momentary intervention on the willingness and actual uptake of influenza vaccination among the elderly in China. METHODS: A cross-sectional study assessed the willingness of the elderly to receive influenza vaccination, and an momentary intervention aimed to increase vaccination willingness among those initially unwilling. The elderly reporting a willingness were offered free influenza vaccination through a community intervention program. RESULTS: A total of 3138 participants were recruited in this study, and 61.3 % (95 % CI 59.6 %-63.0 %) were willing to receive influenza vaccination at baseline. The willingness rate of influenza vaccination increased to 79.8 % (95 % CI 78.4 %-81.2 %), with an increase of 18.5 % (95 % CI 16.3 %-20.7 %) after momentary intervention. The influenza vaccination rate was 40.4 % (95 % CI 38.5 %-42.3 %) before and 53.9 % (95 % CI 52.0 %-55.8 %) after momentary intervention with an increase of 13.5 % (95 % CI 10.9 %-16.2 %). There was no significant difference in influenza vaccination rates between the initially willing people and those who changed to be willing to receive influenza vaccination after momentary intervention (vaccination rates: 78.0 % vs. 81.3 %). CONCLUSION: Momentary intervention has been shown to effectively enhance the willingness of the elderly to receive influenza vaccination, thereby facilitating the translation of this intention into actual behavior.

The impact of preanalytical variables on the analysis of cell-free DNA from blood and urine samples.

Cell-free DNA (cfDNA), a burgeoning class of molecular biomarkers, has been extensively studied across a variety of biomedical fields. As a key component of liquid biopsy, cfDNA testing is gaining prominence in disease detection and management due to the convenience of sample collection and the abundant wealth of genetic information it provides. However, the broader clinical application of cfDNA is currently impeded by a lack of standardization in the preanalytical procedures for cfDNA analysis. A number of fundamental challenges, including the selection of appropriate preanalytical procedures, prevention of short cfDNA fragment loss, and the validation of various cfDNA measurement methods, remain unaddressed. These existing hurdles lead to difficulties in comparing results and ensuring repeatability, thereby undermining the reliability of cfDNA analysis in clinical settings. This review discusses the crucial preanalytical factors that influence cfDNA analysis outcomes, including sample collection, transportation, temporary storage, processing, extraction, quality control, and long-term storage. The review provides clarification on achievable consensus and offers an analysis of the current issues with the goal of standardizing preanalytical procedures for cfDNA analysis.

Pd-Catalyzed Decarbonylative sp2 C-H Arylation: Construction of Five- and Six-Membered (Hetero)Cyclic Compounds.

The cyclic compounds have wide applications in the design and synthesis of drugs and materials; thus, their efficient construction attracts much attention from the synthetic community. In this letter, we report an efficient method for preparing cyclic compounds starting from the readily available carboxylic acids. This reaction takes place through intramolecular decarbonylative sp2 C-H arylation, enabling efficient synthesis of a wide range of five- and six-membered cyclic compounds. Both carbo- and heterocycles can be produced under the reaction conditions. Moreover, this reaction features a wide substrate scope with high functional group tolerance. The scale-up experiments also show its practicality in organic synthesis. Those experimental results indicate that this reaction would find wide applications in the synthetic community.

Drugs targeting CTGF in the treatment of pulmonary fibrosis.

Pulmonary fibrosis represents the final alteration seen in a wide variety of lung disorders characterized by increased fibroblast activity and the accumulation of substantial amounts of extracellular matrix, along with inflammatory damage and the breakdown of tissue architecture. This condition is marked by a significant mortality rate and a lack of effective treatments. The depositing of an excessive quantity of extracellular matrix protein follows the damage to lung capillaries and alveolar epithelial cells, leading to pulmonary fibrosis and irreversible damage to lung function. It has been proposed that the connective tissue growth factor (CTGF) plays a critical role in the advancement of pulmonary fibrosis by enhancing the accumulation of the extracellular matrix and exacerbating fibrosis. In this context, the significance of CTGF in pulmonary fibrosis is examined, and a summary of the development of drugs targeting CTGF for the treatment of pulmonary fibrosis is provided.

Polymer-based cascaded waveguide Bragg grating for blood glucose sensing.

Waveguide Bragg grating (WBG) blood glucose sensing, as a biological sensing technology with broad application prospects, plays an important role in the fields of health management and medical treatment. In this work, a polymer-based cascaded WBG is applied to glucose detection. We investigated photonic devices with two different grating structures cascaded-a crossed grating and a bilateral grating-and analyzed the effects of the crossed grating period, bilateral grating period, and number of grating periods on the sensing performance of the glucose sensor. Finally, the spectral reflectance characteristics, response time, and sensing specificity of the cascaded WBG were evaluated. The experimental results showed that the glucose sensor has a sensitivity of 175 nm/RIU in a glucose concentration range of 0-2 mg/ml and has the advantages of high integration, a narrow bandwidth, and low cost.

The Effects of Tremella fuciformis Polysaccharide on the Physicochemical, Multiscale Structure and Digestive Properties of Cyperus esculentus Starch.

In this study, we have investigated the effects of Tremella fuciformis polysaccharide (TP) on the pasting, rheological, structural and in vitro digestive properties of Cyperus esculentus starch (CS). The results showed that the addition of TP significantly changed the pasting characteristics of CS, increased the pasting temperature and pasting viscosity, inhibited pasting, reduced the exudation of straight-chain starch and was positively correlated with the amount of TP added. The addition of the appropriate amount of TP could increase its apparent viscosity and enhance its viscoelasticity. The composite system of CS/TP exhibited higher short-range ordered structure and solid dense structure, which protected the crystal structure of CS, but was related to the amount of TP added. In addition, the introduction of TP not only decreased the in vitro digestion rate of CS and increased the content of slow-digestible starch (SDS) and resistant starch (RS), but also reduced the degree of digestion. Correlation studies established that TP could improve the viscoelasticity, relative crystallinity and short-range order of the CS/TP composite gel, maintain the integrity of the starch granule and crystalline structure, reduce the degree of starch pasting and strengthen the gel network structure of CS, which could help to lower the digestibility of CS.

Association of cardiovascular health metrics with all-cause and cardiovascular disease mortality in chronic kidney disease: A cohort study.

BACKGROUND AND AIMS: Since the global burden of chronic kidney disease (CKD) is rising rapidly, the study aimed to assess the association of cardiovascular health (CVH) metrics with all-cause and cardiovascular disease (CVD) mortality among individuals with CKD. METHODS AND RESULTS: The cohort study included 5834 participants with CKD from the National Health and Nutrition Examination Survey 1999-2018. A composite CVH score was calculated based on smoking status, physical activity, body mass index, blood pressure, total cholesterol, diet quality, and glucose control. Primary outcomes were all-cause and CVD mortality as of December 31, 2019. Multivariable-adjusted Cox proportional hazards models were used to estimate the association between CVH metrics and deaths in CKD patients. During a median follow-up of 7.2 years, 2178 all-cause deaths and 779 CVD deaths were documented. Compared to participants with ideal CVH, individuals with intermediate CVH exhibited a 46.0% increase in all-cause mortality (hazard ratio, 1.46; 95% confidence interval: 1.17, 1.83), while those with poor CVH demonstrated a 101.0% increase (2.01; 1.54, 2.62). For CVD mortality, individuals with intermediate CVH experienced a 56.0% increase (1.56; 1.02, 2.39), and those with poor CVH demonstrated a 143.0% increase (2.43; 1.51, 3.91). Linear trends were noted for the associations of CVH with both all-cause mortality (P for trend <0.001) and CVD mortality (P for trend = 0.02). CONCLUSIONS: Lower CVH levels were associated with higher all-cause and CVD mortality in individuals with CKD, which highlights the importance of maintaining good CVH in CKD patients.

Lipidome is a valuable tool for the severity prediction of coronavirus disease 2019.

Objective: To describe the lipid metabolic profile of different patients with coronavirus disease 2019 (COVID-19) and contribute new evidence on the progression and severity prediction of COVID-19. Methods: This case-control study was conducted in Peking University Third Hospital, China. The laboratory-confirmed COVID-19 patients aged ≥18 years old and diagnosed as pneumonia from December 2022 to January 2023 were included. Serum lipids were detected. The discrimination ability was calculated with the area under the curve (AUC). A random forest (RF) model was conducted to determine the significance of different lipids. Results: Totally, 44 COVID-19 patients were enrolled with 16 mild and 28 severe patients. The top 5 super classes were triacylglycerols (TAG, 55.9%), phosphatidylethanolamines (PE, 10.9%), phosphatidylcholines (PC, 6.8%), diacylglycerols (DAG, 5.9%) and free fatty acids (FFA, 3.6%) among the 778 detected lipids from the serum of COVID-19 patients. Certain lipids, especially lysophosphatidylcholines (LPCs), turned to have significant correlations with certain immune/cytokine indexes. Reduced level of LPC 20:0 was observed in severe patients particularly in acute stage. The AUC of LPC 20:0 reached 0.940 in discriminating mild and severe patients and 0.807 in discriminating acute and recovery stages in the severe patients. The results of RF models also suggested the significance of LPCs in predicting the severity and progression of COVID-19. Conclusion: Lipids probably have the potential to differentiate and forecast the severity, progression, and clinical outcomes of COVID-19 patients, with implications for immune/inflammatory responses. LPC 20:0 might be a potential target in predicting the progression and outcome and the treatment of COVID-19.

Dynamics of respiratory infectious diseases under rapid urbanization and COVID-19 pandemic in the subcenter of Beijing during 2014-2022.

Objective: The study analyzed the impact of urbanization on epidemiological characteristics of respiratory infectious disease in Tongzhou District, Beijing during 2014-2022 to provide reference for prevention and control priorities of respiratory infectious diseases during the innovative urbanization process in China. Methods: The incidence data of notifiable respiratory infectious diseases (NRIDs) in Tongzhou Beijing during 2014-2022 were summarized. The trend of incidence rate was analyzed by Joinpoint regression model, and entropy method was performed to construct the comprehensive index of urbanization (CIU) and generalized linear model was used to analyze the influence of CIU on the incidence rate of respiratory infectious diseases. Results: Totally 72616 NRIDs cases were reported in Tongzhou District during 2014-2022, and the incidence rate of NRIDs was higher during 2017-2019 (153/100 000) than during 2014-2016 (930/100 000) and during 2020-2022 (371/100 000), respectively (both P < 0.001). The CIU constantly increased with slight fluctuation in 2016 and 2018, respectively. The incidence rate of NRIDs showed an increase along with the CIU during 2014-2019 (r = 0.95, P = 0.004), while the incidence rate's tendency was interrupted by COVID-19 during 2020 with slight decrease in 2020-2021 and rebounded in 2022. For the patients aged <15 years, the incidence rate of NRIDs revealed a very sharp rise at the urbanization period without COVID-19 pandemic compared with that under pre-urbanization period (RR = 7.93, 95 % CI 7.63-8.24), and dropped off to the similar level as of pre-urbanization period when COVID-19 pandemic spread. Conclusions: Urbanization process may increase the incidence of NRIDs but constrained by COVID-19. Certain measures should be taken to prevent and control the effects by urbanization process, such as good natural environment with less population density, ecological environment with good air quality, promoted hand hygiene, mask wearing, keeping interpersonal distance, vaccination, media publicity for NRIDs' prevention and control.

1-Methyltryptophan treatment ameliorates high-fat diet-induced depression in mice through reversing changes in perineuronal nets.

Depression and obesity are prevalent disorders with significant public health implications. In this study, we used a high-fat diet (HFD)-induced obese mouse model to investigate the mechanism underlying HFD-induced depression-like behaviors. HFD-induced obese mice exhibited depression-like behaviors and a reduction in hippocampus volume, which were reversed by treatment with an indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan (1-MT). Interestingly, no changes in IDO levels were observed post-1-MT treatment, suggesting that other mechanisms may be involved in the anti-depressive effect of 1-MT. We further conducted RNA sequencing analysis to clarify the potential underlying mechanism of the anti-depressive effect of 1-MT in HFD-induced depressive mice and found a significant enrichment of shared differential genes in the extracellular matrix (ECM) organization pathway between the 1-MT-treated and untreated HFD-induced depressive mice. Therefore, we hypothesized that changes in ECM play a crucial role in the anti-depressive effect of 1-MT. To this end, we investigated perineuronal nets (PNNs), which are ECM assemblies that preferentially ensheath parvalbumin (PV)-positive interneurons and are involved in many abnormalities. We found that HFD is associated with excessive accumulation of PV-positive neurons and upregulation of PNNs, affecting synaptic transmission in PV-positive neurons and leading to glutamate-gamma-aminobutyric acid imbalances in the hippocampus. The 1-MT effectively reversed these changes, highlighting a PNN-related mechanism by which 1-MT exerts its anti-depressive effect.

Characteristics and degradation mechanisms of polychlorinated naphthalenes in surface soil in Yangtze River Delta, China.

Both thermal and environmental processes are significant factors influencing the existing characteristics, e.g., congener distributions, and existing levels, of polychlorinated naphthalenes (PCNs) in the environment. Soil plays an important role in the life cycle of PCNs, but degradation of PCNs in soils has never been reported. In this study, we collected surface soil samples from 13 cities in the Yangtze River Delta, which is one of the most crowded areas of China and analyzed the samples for 75 PCNs. The long-range transportation from polluted areas was the major source for PCNs in remote areas, but the PCN profiles in remote areas reported in our previous studies were different from those in human settlement in this study, indicating there is a transformation of PCNs after emissions from anthropogenic activities. Two experiments were then designed to reveal the degradation mechanisms, including influencing factors, products, and pathways, of PCNs in surface soils. Based on the experiments, we found that the major factor driving the losses of PCNs in surface soils was volatilization, followed by photo irradiation and microbial metabolism. Under photo-irradiation, the PCN structures would be destroyed through a process of dechlorination followed by oxidation. In addition, the dechlorination pathways of PCNs have been established and found to be significantly influenced by the structure-related parameters.

Sequential Regulation of Local Reactive Oxygen Species by Ir@Cu/Zn-MOF Nanoparticles for Promoting Infected Wound Healing.

Most antimicrobials treat wound infections by an oxidation effect, which is induced by the generation of reactive oxygen species (ROS). However, the potential harm of the prolonged high level of ROS should not be ignored. In this study, we presented a novel cascade-reaction nanoparticle, Ir@Cu/Zn-MOF, to effectively regulate the ROS level throughout the healing progress of the infected wound. The nanoparticles consisted of a copper/zinc-modified metal-organic framework (Cu/Zn-MOF) serving as the external structure and an inner core composed of Ir-PVP NPs, which were achieved through a process known as "bionic mineralization". The released Cu2+ and Zn2+ from the shell structure contributed to the production of ROS, which acted as antimicrobial agents during the initial stage. With the disintegration of the shell, the Ir-PVP NP core was gradually released, exhibiting the property of multiple antioxidant enzyme activities, thereby playing an important role in clearing excessive ROS and alleviating oxidative stress. In a full-layer infected rat wound model, Ir@Cu/Zn-MOF nanoparticles presented exciting performance in promoting wound healing by clearing the bacteria and accelerating neovascularization as well as collagen deposition. This study provided a promising alternative for the repair of infected wounds.

Dietary choline intake and health outcomes in U.S. adults: exploring the impact on cardiovascular disease, cancer prevalence, and all-cause mortality.

BACKGROUND: Choline, an indispensable nutrient, plays a pivotal role in various physiological processes. The available evidence regarding the nexus between dietary choline intake and health outcomes, encompassing cardiovascular disease (CVD), cancer, and all-cause mortality, is limited and inconclusive. This study aimed to comprehensively explore the relationship between dietary choline intake and the aforementioned health outcomes in adults aged > 20 years in the U.S. METHODS: This study utilized data from the National Health and Nutrition Examination Survey between 2011 and 2018. Dietary choline intake was evaluated using two 24-h dietary recall interviews. CVD and cancer status were determined through a combination of standardized medical status questionnaires and self-reported physician diagnoses. Mortality data were gathered from publicly available longitudinal Medicare and mortality records. The study utilized survey-weighted logistic and Cox regression analyses to explore the associations between choline consumption and health outcomes. Restricted cubic spline (RCS) analysis was used for dose‒response estimation and for testing for nonlinear associations. RESULTS: In our study of 14,289 participants (mean age 48.08 years, 47.71% male), compared with those in the lowest quintile (Q1), the adjusted odds ratios (ORs) of CVD risk in the fourth (Q4) and fifth (Q5) quintiles of choline intake were 0.70 (95% CI 0.52, 0.95) and 0.65 (95% CI 0.47, 0.90), respectively (p for trend = 0.017). Each 100 mg increase in choline intake was associated with a 9% reduced risk of CVD. RCS analysis revealed a linear correlation between choline intake and CVD risk. Moderate choline intake (Q3) was associated with a reduced risk of mortality, with an HR of 0.75 (95% CI 0.60-0.94) compared with Q1. RCS analysis demonstrated a significant nonlinear association between choline intake and all-cause mortality (P for nonlinearity = 0.025). The overall cancer prevalence association was nonsignificant, except for colon cancer, where each 100 mg increase in choline intake indicated a 23% reduced risk. CONCLUSION: Elevated choline intake demonstrates an inverse association with CVD and colon cancer, while moderate consumption exhibits a correlated reduction in mortality. Additional comprehensive investigations are warranted to elucidate the broader health implications of choline.

Targeting reprogrammed metabolism as a therapeutic approach for respiratory diseases.

Metabolic reprogramming underlies the etiology and pathophysiology of respiratory diseases such as asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD). The dysregulated cellular activities driving airway inflammation and remodelling in these diseases have reportedly been linked to aberrant shifts in energy-producing metabolic pathways: glycolysis and oxidative phosphorylation (OXPHOS). The rewiring of glycolysis and OXPHOS accompanying the therapeutic effects of many clinical compounds and natural products in asthma, IPF, and COPD, supports targeting metabolism as a therapeutic approach for respiratory diseases. Correspondingly, inhibiting glycolysis has largely attested effective against experimental asthma, IPF, and COPD. However, modulating OXPHOS and its supporting catabolic pathways like mitochondrial pyruvate catabolism, fatty acid ß-oxidation (FAO), and glutaminolysis for these respiratory diseases remain inconclusive. An emerging repertoire of metabolic enzymes are also interconnected to these canonical metabolic pathways that similarly possess therapeutic potential for respiratory diseases. Taken together, this review highlights the urgent demand for future studies to ascertain the role of OXPHOS in different respiratory diseases, under different stimulatory conditions, and in different cell types. While this review provides strong experimental evidence in support of the inhibition of glycolysis for asthma, IPF, and COPD, further verification by clinical trials is definitely required.

TIM3 activates the ERK1/2 pathway to promote invasion and migration of thyroid tumors.

BACKGROUND: This study aims to study the possible action mechanism of T-cell immunoglobulin and mucin domain 3 (TIM3) on the migratory and invasive abilities of thyroid carcinoma (TC) cells. METHODS: GSE104005 and GSE138198 datasets were downloaded from the GEO database for identifying differentially expressed genes (DEGs). Functional enrichment analysis and protein-protein interaction (PPI) analysis were performed on the common DEGs in GSE104005 and GSE138198 datasets. Subsequently, in order to understand the effect of a common DEG (TIM3) on TC cells, we performed in vitro experiments using FRO cells. The migratory and invasive abilities of FRO cells were detected by wound scratch assay and Transwell assay. Proteins expression levels of the phosphorylated (p)-extracellular signal-regulated kinase (ERK)1/2, matrix metalloproteinase-2 (MMP-2) and MMP-9 were determined via Western blotting after ERK1/2 inhibition in TIM3-NC group and TIM3-mimic group. RESULTS: 316 common DEGs were identified in GSE104005 and GSE138198 datasets. These DEGs were involved in the biological process of ERK1 and ERK2 cascade. TIM3 was significantly up-regulated in TC. In vitro cell experiments showed that TIM3 could promote migration and invasion of TC cells. Moreover, TIM3 may affect the migration, invasive abilities of TC cells by activating the ERK1/2 pathway. CONCLUSION: The above results indicate that TIM3 may affect the migratory and invasive of TC cells by activating the ERK1/2 pathway.

The role of molecular chaperone CCT/TRiC in translation elongation: A literature review.

Protein synthesis from mRNA is an energy-intensive and strictly controlled biological process. Translation elongation is a well-coordinated and multifactorial step in translation that ensures the accurate and efficient addition of amino acids to a growing nascent-peptide chain encoded in the sequence of messenger RNA (mRNA). Which undergoes dynamic regulation due to cellular state and environmental determinants. An expanding body of research points to translational elongation as a crucial process that controls the translation of an mRNA through multiple feedback mechanisms. Molecular chaperones are key players in protein homeostasis to keep the balance between protein synthesis, folding, assembly, and degradation. Chaperonin-containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC) is an essential eukaryotic molecular chaperone that plays an essential role in assisting cellular protein folding and suppressing protein aggregation. In this review, we give an overview of the factors that influence translation elongation, focusing on different functions of molecular chaperones in translation elongation, including how they affect translation rates and post-translational modifications. We also provide an understanding of the mechanisms by which the molecular chaperone CCT plays multiple roles in the elongation phase of eukaryotic protein synthesis.

Marine-Fungus-Derived Natural Compound 4-Hydroxyphenylacetic Acid Induces Autophagy to Exert Antithrombotic Effects in Zebrafish.

Marine natural products are important sources of novel drugs. In this study, we isolated 4-hydroxyphenylacetic acid (HPA) from the marine-derived fungus Emericellopsis maritima Y39-2. The antithrombotic activity and mechanism of HPA were reported for the first time. Using a zebrafish model, we found that HPA had a strong antithrombotic activity because it can significantly increase cardiac erythrocytes, blood flow velocity, and heart rate, reduce caudal thrombus, and reverse the inflammatory response caused by Arachidonic Acid (AA). Further transcriptome analysis and qRT-PCR validation demonstrated that HPA may regulate autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway to exert antithrombotic effects.