Corticoamygdala Transfer of Socially Derived Information Gates Observational Learning.

Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC→BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC→BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC→BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this routing of information is critically instructive for observational fear conditioning. VIDEO ABSTRACT.

scKWARN: Kernel-weighted-average robust normalization for single-cell RNA-seq data.

MOTIVATION: Single-cell RNA-seq normalization is an essential step to correct unwanted biases caused by sequencing depth, capture efficiency, dropout, and other technical factors. Existing normalization methods primarily reduce biases arising from sequencing depth by modeling count-depth relationship and/or assuming a specific distribution for read counts. However, these methods may lead to over or under-correction due to presence of technical biases beyond sequencing depth and the restrictive assumption on models and distributions. RESULTS: We present scKWARN, a Kernel Weighted Average Robust Normalization designed to correct known or hidden technical confounders without assuming specific data distributions or count-depth relationships. scKWARN generates a pseudo expression profile for each cell by borrowing information from its fuzzy technical neighbors through a kernel smoother. It then compares this profile against the reference derived from cells with the same bimodality patterns to determine the normalization factor. As demonstrated in both simulated and real datasets, scKWARN outperforms existing methods in removing a variety of technical biases while preserving true biological heterogeneity. AVAILABILITY AND IMPLEMENTATION: scKWARN is freely available at https://github.com/cyhsuTN/scKWARN.

Stromal Rigidity Stress Accelerates Pancreatic Intraepithelial Neoplasia Progression and Chromosomal Instability via Nuclear Protein Tyrosine Kinase 2 Localization.

Because the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) foci linked to mechanotransduction pressure in vivo during serial orthotopic passages of mouse KrasLSL-G12D/+;Trp53flox/flox;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3-µm micropores. To search for pancreatic cancer cell-of-origin, analysis of single-cell data sets revealed that the extracellular matrix shaped an alternate route of acinar-ductal transdifferentiation of acinar cells into topoisomerase II α (TOP2A)-overexpressing cancer cells and derived subclusters with copy number amplifications in MYC-PTK2 (protein tyrosine kinase 2) locus and PIK3CA. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in The Cancer Genome Atlas-Pancreatic Adenocarcinoma cohort. Abolished RGD-integrin signaling by disintegrin KG blocked the PTK2 phosphorylation, increased cancer apoptosis, decreased vav guanine nucleotide exchange factor 1 (VAV1) expression, and prolonged overall survival in the KPC mice. Reduction of α-smooth muscle actin deposition in the CD248 knockout KPC mice remodeled the tissue stroma and down-regulated TOP2A expression in the epithelium. In summary, stromal stiffness induced the onset of cancer cells-of-origin by ectopic TOP2A expression, and the genomic amplification of MYC-PTK2 locus via alternative transdifferentiation of pancreatic progenitor cells is the vulnerability useful for disintegrin KG treatment.

Dopamine enhances signal-to-noise ratio in cortical-brainstem encoding of aversive stimuli.

Dopamine modulates medial prefrontal cortex (mPFC) activity to mediate diverse behavioural functions1,2; however, the precise circuit computations remain unknown. One potentially unifying model by which dopamine may underlie a diversity of functions is by modulating the signal-to-noise ratio in subpopulations of mPFC neurons3-6, where neural activity conveying sensory information (signal) is amplified relative to spontaneous firing (noise). Here we demonstrate that dopamine increases the signal-to-noise ratio of responses to aversive stimuli in mPFC neurons projecting to the dorsal periaqueductal grey (dPAG). Using an electrochemical approach, we reveal the precise time course of pinch-evoked dopamine release in the mPFC, and show that mPFC dopamine biases behavioural responses to aversive stimuli. Activation of mPFC-dPAG neurons is sufficient to drive place avoidance and defensive behaviours. mPFC-dPAG neurons display robust shock-induced excitations, as visualized by single-cell, projection-defined microendoscopic calcium imaging. Finally, photostimulation of dopamine terminals in the mPFC reveals an increase in the signal-to-noise ratio in mPFC-dPAG responses to aversive stimuli. Together, these data highlight how dopamine in the mPFC can selectively route sensory information to specific downstream circuits, representing a potential circuit mechanism for valence processing.

Mitochondrial Glutathione in Cellular Redox Homeostasis and Disease Manifestation.

Mitochondria are critical for providing energy to maintain cell viability. Oxidative phosphorylation involves the transfer of electrons from energy substrates to oxygen to produce adenosine triphosphate. Mitochondria also regulate cell proliferation, metastasis, and deterioration. The flow of electrons in the mitochondrial respiratory chain generates reactive oxygen species (ROS), which are harmful to cells at high levels. Oxidative stress caused by ROS accumulation has been associated with an increased risk of cancer, and cardiovascular and liver diseases. Glutathione (GSH) is an abundant cellular antioxidant that is primarily synthesized in the cytoplasm and delivered to the mitochondria. Mitochondrial glutathione (mGSH) metabolizes hydrogen peroxide within the mitochondria. A long-term imbalance in the ratio of mitochondrial ROS to mGSH can cause cell dysfunction, apoptosis, necroptosis, and ferroptosis, which may lead to disease. This study aimed to review the physiological functions, anabolism, variations in organ tissue accumulation, and delivery of GSH to the mitochondria and the relationships between mGSH levels, the GSH/GSH disulfide (GSSG) ratio, programmed cell death, and ferroptosis. We also discuss diseases caused by mGSH deficiency and related therapeutics.

Neonatal mortality risk of large-for-gestational-age and macrosomic live births in 15 countries, including 115.6 million nationwide linked records, 2000-2020.

OBJECTIVE: We aimed to compare the prevalence and neonatal mortality associated with large for gestational age (LGA) and macrosomia among 115.6 million live births in 15 countries, between 2000 and 2020. DESIGN: Population-based, multi-country study. SETTING: National healthcare systems. POPULATION: Liveborn infants. METHODS: We used individual-level data identified for the Vulnerable Newborn Measurement Collaboration. We calculated the prevalence and relative risk (RR) of neonatal mortality among live births born at term + LGA (>90th centile, and also >95th and >97th centiles when the data were available) versus term + appropriate for gestational age (AGA, 10th-90th centiles) and macrosomic (≥4000, ≥4500 and ≥5000 g, regardless of gestational age) versus 2500-3999 g. INTERGROWTH 21st served as the reference population. MAIN OUTCOME MEASURES: Prevalence and neonatal mortality risks. RESULTS: Large for gestational age was common (median prevalence 18.2%; interquartile range, IQR, 13.5%-22.0%), and overall was associated with a lower neonatal mortality risk compared with AGA (RR 0.83, 95% CI 0.77-0.89). Around one in ten babies were ≥4000 g (median prevalence 9.6% (IQR 6.4%-13.3%), with 1.2% (IQR 0.7%-2.0%) ≥4500 g and with 0.2% (IQR 0.1%-0.2%) ≥5000 g). Overall, macrosomia of ≥4000 g was not associated with increased neonatal mortality risk (RR 0.80, 95% CI 0.69-0.94); however, a higher risk was observed for birthweights of ≥4500 g (RR 1.52, 95% CI 1.10-2.11) and ≥5000 g (RR 4.54, 95% CI 2.58-7.99), compared with birthweights of 2500-3999 g, with the highest risk observed in the first 7 days of life. CONCLUSIONS: In this population, birthweight of ≥4500 g was the most useful marker for early mortality risk in big babies and could be used to guide clinical management decisions.

Using Transfer Learning of Convolutional Neural Network on Neck Radiographs to Identify Acute Epiglottitis.

Acute epiglottitis (AE) is a life-threatening condition and needs to be recognized timely. Diagnosis of AE with a lateral neck radiograph yields poor reliability and sensitivity. Convolutional neural networks (CNN) are powerful tools to assist the analysis of medical images. This study aimed to develop an artificial intelligence model using CNN-based transfer learning to identify AE in lateral neck radiographs. All cases in this study are from two hospitals, a medical center, and a local teaching hospital in Taiwan. In this retrospective study, we collected 251 lateral neck radiographs of patients with AE and 936 individuals without AE. Neck radiographs obtained from patients without and with AE were used as the input for model transfer learning in a pre-trained CNN including Inception V3, Densenet201, Resnet101, VGG19, and Inception V2 to select the optimal model. We used five-fold cross-validation to estimate the performance of the selected model. The confusion matrix of the final model was analyzed. We found that Inception V3 yielded the best results as the optimal model among all pre-train models. Based on the average value of the fivefold cross-validation, the confusion metrics were obtained: accuracy = 0.92, precision = 0.94, recall = 0.90, and area under the curve (AUC) = 0.96. Using the Inception V3-based model can provide an excellent performance to identify AE based on radiographic images. We suggest using the CNN-based model which can offer a non-invasive, accurate, and fast diagnostic method for AE in the future.

Possible Pathogenesis and Prevention of Long COVID: SARS-CoV-2-Induced Mitochondrial Disorder.

Patients who have recovered from coronavirus disease 2019 (COVID-19) infection may experience chronic fatigue when exercising, despite no obvious heart or lung abnormalities. The present lack of effective treatments makes managing long COVID a major challenge. One of the underlying mechanisms of long COVID may be mitochondrial dysfunction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can alter the mitochondria responsible for energy production in cells. This alteration leads to mitochondrial dysfunction which, in turn, increases oxidative stress. Ultimately, this results in a loss of mitochondrial integrity and cell death. Moreover, viral proteins can bind to mitochondrial complexes, disrupting mitochondrial function and causing the immune cells to over-react. This over-reaction leads to inflammation and potentially long COVID symptoms. It is important to note that the roles of mitochondrial damage and inflammatory responses caused by SARS-CoV-2 in the development of long COVID are still being elucidated. Targeting mitochondrial function may provide promising new clinical approaches for long-COVID patients; however, further studies are needed to evaluate the safety and efficacy of such approaches.

SiO2 Fibers of Two Lengths and Their Effect on Cellular Responses of Macrophage-like Cells.

The immunoreactivity or/and stress response can be induced by nanomaterials' different properties, such as size, shape, etc. These effects are, however, not yet fully understood. This study aimed to clarify the effects of SiO2 nanofibers (SiO2NFs) on the cellular responses of THP-1-derived macrophage-like cells. The effects of SiO2NFs with different lengths on reactive oxygen species (ROS) and pro-inflammatory cytokines TNF-α and IL-1ß in THP-1 cells were evaluated. From the two tested lengths, it was only the L-SiO2NFs with a length ≈ 44 ± 22 µm that could induce ROS. Compared to this, only S-SiO2NFs with a length ≈ 14 ± 17 µm could enhance TNF-α and IL-1ß expression. Our results suggested that L-SiO2NFs disassembled by THP-1 cells produced ROS and that the inflammatory reaction was induced by the uptake of S-SiO2NFs by THP-1 cells. The F-actin staining results indicated that SiO2NFs induced cell motility and phagocytosis. There was no difference in cytotoxicity between L- and S-SiO2NFs. However, our results suggested that the lengths of SiO2NFs induced different cellular responses.

Integration of speed and time for estimating time to contact.

To coordinate movements with events in a dynamic environment the brain has to anticipate when those events occur. A classic example is the estimation of time to contact (TTC), that is, when an object reaches a target. It is thought that TTC is estimated from kinematic variables. For example, a tennis player might use an estimate of distance (d) and speed (v) to estimate TTC (TTC = d/v). However, the tennis player may instead estimate TTC as twice the time it takes for the ball to move from the serve line to the net line. This latter strategy does not rely on kinematics and instead computes TTC solely from temporal cues. Which of these two strategies do humans use to estimate TTC? Considering that both speed and time estimates are inherently uncertain and the ability of the human brain to combine different sources of information, we hypothesized that humans estimate TTC by integrating speed information with temporal cues. We evaluated this hypothesis systematically using psychophysics and Bayesian modeling. Results indicated that humans rely on both speed information and temporal cues and integrate them to optimize their TTC estimates when both cues are present. These findings suggest that the brain's timing mechanisms are actively engaged when interacting with dynamic stimuli.

Unmasking the Actual COVID-19 Case Count.

This report presents a novel approach to estimate the total number of COVID-19 cases in the United States, including undocumented infections, by combining the Centers for Disease Control and Prevention's influenza-like illness surveillance data with aggregated prescription data. We estimated that the cumulative number of COVID-19 cases in the United States by 4 April 2020 was > 2.5 million.

Immune sensing of DNA and strategies for fish DNA vaccine development.

Studies of DNA vaccines have shown that understanding the mechanism of DNA vaccine-mediated action is the key for vaccine development. Current knowledge has shown the presence of antigen presenting cells (APCs) involving in B and T cells at the muscle injection site and the upregulation of type I interferon (IFN-I) that initiates antiviral response and benefits adaptive immunity in fish DNA vaccines. IFN-I may be triggered by expressed antigen such as the rhabdovirus G protein encoded DNA vaccine or by plasmid DNA itself through cytosolic DNA sensing. The investigating of Toll-like receptor 9, and 21 are the CpG-motif sensors in many fish species, and the cytosolic DNA receptors DDX41 and downstream STING signaling revealed the mechanisms for IFN-I production. This review article describes the recent finding of receptors for cytosolic DNA, the STING-TBK1-IRF signaling, and the possibility of turning these findings into strategies for the future development of DNA vaccines.

Role of an additional third screw in the fixation of transverse patellar fracture with two parallel cannulated screw and anterior wire.

BACKGROUND: Two parallel cannulated screws along with an anterior wire to construct a tension band is a popular approach in transverse patellar fractures. However, the optimal screw proximity, either deep or superficial screw placements, remains controversial. Hence, a new concept of the addition of a third screw to form a triangular configuration along with the original two parallel screws was proposed in this study. Therefore, the biomechanical effect of the additional third screw on the stability of the fractured patella was investigated with finite element (FE) simulation. METHODS: An FE knee model including the distal femur, proximal tibia, and fractured patella (type AT/OTA 34-C) was developed in this study. Four different screw configurations, including two parallel cannulated screws with superficial (5-mm proximity) and deep (10-mm proximity) placements and two parallel superficial screws plus a third deep screw, and two parallel deep screws plus a third superficial screw, with or without the anterior wire, were considered for the simulation. RESULTS: Results indicated that the addition of a third screw increased stability by reducing the dorsal gap opening when two parallel screws were deeply placed, particularly on the fractured patella without an anterior wire. However, the third screw was of little value when two parallel screws were superficially placed. In the existence of two deep parallel screws and the anterior wire, the third screw reduced the gap opening by 23.5% (from 1.15 mm to 0.88 mm) and 53.6% (from 1.21 mm to 0.61 mm) in knee flexion 45° and full extension, respectively. Furthermore, in the absence of the anterior wire, the third screw reduced the gap opening by 73.5% (from 2 mm to 0.53 mm) and 72.2% (from 1.33 mm to 0.37 mm) in knee flexion 45° and full extension, respectively. CONCLUSION: Based on the results, a third cannulated screw superficially placed (5-mm proximity) is recommended to increase stability and maintain contact of the fractured patella, fixed with two parallel cannulated screws deeply placed (10-mm proximity), particularly when an anterior wire was not used. Furthermore, the third screw deeply placed is not recommended in a fractured patella with two parallel superficial screws.

EGF Conjugation Improves Safety and Uptake Efficacy of Titanium Dioxide Nanoparticles.

Titanium dioxide nanoparticles (TiO2 NPs) have a strong potential for cancer therapeutic and bioimaging applications such as photodynamic therapy (PDT) and photodynamic diagnosis (PDD). Our previous results have shown that TiO2 NPs have a low cellular uptake and can induce cell proliferation. This suggests that TiO2 NPs could increase the risk of tumor overgrowth while being used for PDD and PDT. To solve this problem, we constructed epidermal growth factor-ligated polyethylene glycol-coated TiO2 NPs (EGF-TiO2 PEG NPs). In this work, we studied the effect of EGF conjugation on the cellular uptake of TiO2 PEG NPs. Then, we investigated the effect of both non-conjugated and EGF-TiO2 PEG NPs on the A431 epidermal cancer cell line, proliferation and growth via the investigation of EGFR localization and expression. Our results indicated that TiO2 PEG NPs induced EGFRs aggregation on the A431 cells surface and induced cell proliferation. In addition, EGF-TiO2 PEG NPs induced the internalization of EGFRs inside of cells with increased cellular NPs uptake and decreased cellular proliferation compared to TiO2 PEG NPs-treated cells. These findings suggest that EGF conjugation can increase the efficacy of TiO2 PEG NPs for biomedical applications such as PDD and PDT with decreased risk of tumor overgrowth.

[Associations of Personality, Distress, Social Support With Self-Care Behaviors in Patients With Type 2 Diabetes].

BACKGROUND: The findings of recent studies indicate that self-care behaviors are significantly associated with diabetes-related distress and social support in patients with type 2 diabetes. Moreover, Big-Five personality traits are also considered to be associated with self-care behaviors and should be considered. PURPOSE: This study was designed to investigate the associations between Big-Five personality traits, diabetes-related distress, and social support and diabetes self-care behaviors in patients with type 2 diabetes. METHODS: A cross-sectional study design was conducted with 200 participants recruited by convenience sampling. A self-reported questionnaire was used to collect data on demographic and disease characteristics, Big Five personality indicators, diabetes-related distress, social support, and self-care behavior. Data were analyzed using percentage, mean and standard deviation, independent t-test, one-way ANOVA, Pearson's correlation test, and enter method multiple regression analysis. RESULTS: Social support was found to relate positively and significantly with self-care behavior, while no significant relationship was found between diabetes-related distress and self-care behaviors. Participants with high scores for extroversion, agreeableness, and conscientiousness tended to have better self-care behavior, while those with a high score for neuroticism tended to have poor self-care behaviors. The results of the enter method multiple regression analysis showed age and social support to be significant factors associated with self-care behaviors, explaining 19.5% of the variance. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Priority concern should be given to patient age and social support status when working to improve the self-care behaviors of patients with type 2 diabetes. As personality traits were found to be significantly associated with self-care behaviors, these should be included in the individual health education program.

Spike-Based Winner-Take-All Computation: Fundamental Limits and Order-Optimal Circuits.

Winner-take-all (WTA) refers to the neural operation that selects a (typically small) group of neurons from a large neuron pool. It is conjectured to underlie many of the brain's fundamental computational abilities. However, not much is known about the robustness of a spike-based WTA network to the inherent randomness of the input spike trains. In this work, we consider a spike-based k-WTA model wherein n randomly generated input spike trains compete with each other based on their underlying firing rates and k winners are supposed to be selected. We slot the time evenly with each time slot of length 1 ms and model the n input spike trains as n independent Bernoulli processes. We analytically characterize the minimum waiting time needed so that a target minimax decision accuracy (success probability) can be reached. We first derive an information-theoretic lower bound on the waiting time. We show that to guarantee a (minimax) decision error ≤δ (where δ∈(0,1)), the waiting time of any WTA circuit is at least [Formula: see text]where R⊆(0,1) is a finite set of rates and TR is a difficulty parameter of a WTA task with respect to set R for independent input spike trains. Additionally, TR is independent of δ, n, and k. We then design a simple WTA circuit whose waiting time is [Formula: see text]provided that the local memory of each output neuron is sufficiently long. It turns out that for any fixed δ, this decision time is order-optimal (i.e., it matches the above lower bound up to a multiplicative constant factor) in terms of its scaling in n, k, and TR.

Nitrogen-Doped Carbon Dots from Averrhoa carambola Fruit Extract as a Fluorescent Probe for Methyl Orange.

In this study, a simple and green hydrothermal treatment was performed to prepare nitrogen-doped carbon dots (NCDs) from Averrhoa carambola (AC) fruit extract as a carbon precursor and L-arginine (Arg) as a nitrogen dopant. The AC-NCDs were characterized by UV light, fluorescence spectroscopy, transmission electron microscopy, FTIR spectroscopy, Raman spectroscopy, UV-vis spectroscopy, and zeta potential analyzer. The AC-NCDs were spherical and the average diameter was estimated to be 6.67 nm. The AC-NCDs exhibited the maximum emission intensity at 446 nm with 360 nm excitation wavelength. The fluorescence quenching behavior of AC-NCDs after interacting with methyl orange (MO) dye was studied. The interaction of AC-NCDs and MO was achieved within 3 min and the fluorescence quenching was maintained to a fixed value even after 30 min. The linearity was obtained in the range of 1 to 25 µM MO with a 0.30 µM detection limit. Furthermore, the pH values affected the quenching behavior of the AC-NCDs/MO system where the interaction mechanisms were driven by the electrostatic interaction, π-π interaction, inner filter effect, and energy transfer. The pH 5 maintained higher quenching efficiency while other pH values slightly decreased the quenching efficiency. Incoming applications, the AC-NCDs can be used in various important fields, especially for environmental protection.

Change in Renal Glomerular Collagens and Glomerular Filtration Barrier-Related Proteins in a Dextran Sulfate Sodium-Induced Colitis Mouse Model.

Renal disease is not rare among patients with inflammatory bowel disease (IBD) and is gaining interest as a target of research. However, related changes in glomerular structural have rarely been investigated. This study was aimed at clarifying the changes in collagens and glomerular filtration barrier (GFB)-related proteins of glomeruli in a dextran sulfate sodium (DSS)-induced colitis mouse model. Acute colitis was induced by administering 3.5% DSS in Slc:ICR strain mice for eight days. Histological changes to glomeruli were examined by periodic acid-Schiff (PAS) and Masson's trichrome staining. Expressions of glomerular collagens and GFB-related proteins were analyzed by immunofluorescent staining and Western blot analysis. DSS-colitis mice showed an elevated disease activity index (DAI), colon shortening, massive cellular infiltration and colon damage, confirming that DSS-colitis mice can be used as an IBD animal model. DSS-colitis mice showed increased glycoprotein and collagen deposition in glomeruli. Interestingly, we observed significant changes in glomerular collagens, including a decrease in type IV collagen, and an increment in type I and type V collagens. Moreover, declined GFB-related proteins expressions were detected, including synaptopodin, podocalyxin, nephrin and VE-cadherin. These results suggest that renal disease in DSS-colitis mice might be associated with changes in glomerular collagens and GFB-related proteins. These findings are important for further elucidation of the clinical pathological mechanisms underlying IBD-associated renal disease.

The Influence of a Nanopatterned Scaffold that Mimics Abnormal Renal Mesangial Matrix on Mesangial Cell Behavior.

The alteration of mesangial matrix (MM) components in mesangium, such as type IV collagen (COL4) and type I collagen (COL1), is commonly found in progressive glomerular disease. Mesangial cells (MCs) responding to altered MM, show critical changes in cell function. This suggests that the diseased MM structure could play an important role in MC behavior. To investigate how MC behavior is influenced by the diseased MM 3D nanostructure, we fabricated the titanium dioxide (TiO2)-based nanopatterns that mimic diseased MM nanostructures. Immortalized mouse MCs were used to assess the influence of disease-mimic nanopatterns on cell functions, and were compared with a normal-mimic nanopattern. The results showed that the disease-mimic nanopattern induced disease-like behavior, including increased proliferation, excessive production of abnormal MM components (COL1 and fibronectin) and decreased normal MM components (COL4 and laminin α1). In contrast, the normal-mimic nanopattern actually resulted in cells displaying normal proliferation and the production of normal MM components. In addition, increased expressions of α-smooth muscle actin (α-SMA), transforming growth factor ß1 (TGF-ß1) and integrin α5ß1 were detected in cells grown on the disease-mimic nanopattern. These results indicated that the disease-mimic nanopattern induced disease-like cell behavior. These findings will help further establish a disease model that mimics abnormal MM nanostructures and also to elucidate the molecular mechanisms underlying glomerular disease.

Measurement of Pre-Existing IgG and IgM Antibodies against Polyethylene Glycol in Healthy Individuals.

Polyethylene glycol (PEG) is a biocompatible polymer that is often attached to therapeutic molecules to improve bioavailability and therapeutic efficacy. Although antibodies with specificity for PEG may compromise the safety and effectiveness of PEGylated medicines, the prevalence of pre-existing anti-PEG antibodies in healthy individuals is unclear. Chimeric human anti-PEG antibody standards were created to accurately measure anti-PEG IgM and IgG antibodies by direct ELISA with confirmation by a competition assay in the plasma of 1504 healthy Han Chinese donors residing in Taiwan. Anti-PEG antibodies were detected in 44.3% of healthy donors with a high prevalence of both anti-PEG IgM (27.1%) and anti-PEG IgG (25.7%). Anti-PEG IgM and IgG antibodies were significantly more common in females as compared to males (32.0% vs 22.2% for IgM, p < 0.0001 and 28.3% vs 23.0% for IgG, p = 0.018). The prevalence of anti-PEG IgG antibodies was higher in younger (up to 60% for 20 year olds) as opposed to older (20% for >50 years) male and female donors. Anti-PEG IgG concentrations were negatively associated with donor age in both females (p = 0.0073) and males (p = 0.026). Both anti-PEG IgM and IgG strongly bound PEGylated medicines. The described assay can assist in the elucidation of the impact of anti-PEG antibodies on the safety and therapeutic efficacy of PEGylated medicines.