Harnessing nanomedicine for modulating microglial states in the central nervous system disorders: Challenges and opportunities.

Microglia are essential for maintaining homeostasis and responding to pathological events in the central nervous system (CNS). Their dynamic and multidimensional states in different environments are pivotal factors in various CNS disorders. However, therapeutic modulation of microglial states is challenging due to the intricate balance these cells maintain in the CNS environment and the blood-brain barrier's restriction of drug delivery. Nanomedicine presents a promising avenue for addressing these challenges, offering a method for the targeted and efficient modulation of microglial states. This review covers the challenges faced in microglial therapeutic modulation and potential use of nanoparticle-based drug delivery systems. We provide an in-depth examination of nanoparticle applications for modulating microglial states in a range of CNS disorders, encompassing neurodegenerative and autoimmune diseases, infections, traumatic injuries, stroke, tumors, chronic pain, and psychiatric conditions. This review highlights the recent advancements and future prospects in nanomedicine for microglial modulation, paving the way for future research and clinical applications of therapeutic interventions in CNS disorders.

Responses of Soil Carbon and Microbial Residues to Degradation in Moso Bamboo Forest.

Moso bamboo (Phyllostachys heterocycla cv. Pubescens) is known for its high capacity to sequester atmospheric carbon (C), which has a unique role to play in the fight against global warming. However, due to rising labor costs and falling bamboo prices, many Moso bamboo forests are shifting to an extensive management model without fertilization, resulting in gradual degradation of Moso bamboo forests. However, many Moso bamboo forests are being degraded due to rising labor costs and declining bamboo timber prices. To delineate the effect of degradation on soil microbial carbon sequestration, we instituted a rigorous analysis of Moso bamboo forests subjected to different degradation durations, namely: continuous management (CK), 5 years of degradation (D-5), and 10 years of degradation (D-10). Our inquiry encompassed soil strata at 0-20 cm and 20-40 cm, scrutinizing alterations in soil organic carbon(SOC), water-soluble carbon(WSOC), microbial carbon(MBC)and microbial residues. We discerned a positive correlation between degradation and augmented levels of SOC, WSOC, and MBC across both strata. Furthermore, degradation escalated concentrations of specific soil amino sugars and microbial residues. Intriguingly, extended degradation diminished the proportional contribution of microbial residuals to SOC, implying a possible decline in microbial activity longitudinally. These findings offer a detailed insight into microbial C processes within degraded bamboo ecosystems.

Metabolomics efficiently discriminates monozygotic twins in peripheral blood.

Monozygotic (MZ) twins cannot be distinguished using conventional forensic STR typing because they present identical STR genotypings. However, MZ twins do not always live in the same environment and often have different dietary and other lifestyle habits. Metabolic profiles are deyermined by individual characteristics and are also influenced by the environment in which they live. Therefore, they are potential markers capable of identifying MZ twins. Moreover, the production of proteins varies from organism to organism and is influenced by both the physiological state of the body and the external environment. Hence, we used metabolomics and proteomics to identify metabolites and proteins in peripheral blood to discriminate MZ twins. We identified 1749 known metabolites and 622 proteins in proteomic analysis. The metabolic profiles of four pairs of MZ twins revealed minor differences in intra-MZ twins and major differences in inter-MZ twins. Each pair of MZ twins exhibited distinct characteristics, and four metabolites-methyl picolinate, acesulfame, paraxanthine, and phenylbenzimidazole sulfonic acid-were observed in all four MZ twin pairs. These four differential exogenous metabolites conincidently show that the different external environments and life styles can be well distinguished by metabolites, considering that twins do not all have the same eating habits and living environments. Moreover, MZ twins showed different protein profiles in serum but not in whole blood. Thus, our results indicate that differential metabolites provide potential biomarkers for the personal identification of MZ twins in forensic medicine.

3D printing of highly conductive and strongly adhesive PEDOT:PSS hydrogel-based bioelectronic interface for accurate electromyography monitoring.

PEDOT: PSS hydrogel-based bioelectronic interfaces have gained significant attention in various fields including biomedical devices, wearable devices, and epidermal electronics. However, the development of high-performance bioelectronic interfaces that integrate excellent conductivity, strong adhesion, and advanced processing compatibility remains a challenge. Herein, we develop a high-performance bioelectronic interface by 3D printing of a novel poly(vinyl alcohol-formaldehyde) (PVAF)-PEDOT:PSS composite ink. Such a PEDOT:PSS-PVAF ink exhibits favorable rheological properties for direct-ink-writing 3D printing, enabling the fabrication of high-resolution patterns and three-dimensional structures with high aspect ratios. Hydrogel bioelectronic interface printed by such PEDOT:PSS-PVAF ink simultaneously achieves high conductivity (over 100 S m-1), strong adhesion (31.44 ± 7.07 kPa), as well as stable electrochemical performance (charge injection capacity of 13.72 mC cm-2 and charge storage capacity of 18.80 mC cm-2). We further integrate PEDOT:PSS-PVAF hydrogel bioelectronic interface to fabricate adhesive skin electrodes for electromyography (EMG) signal recording. The resultant EMG skin electrodes demonstrate superior performance and stability compared to commercial products, maintaining high signal-to-noise ratio of > 10 dB under varying weights and repetitive motions. These advantageous performance of PEDOT:PSS-PVAF based hydrogel bioelectronic interfaces may be helpful for diverse bioelectronic applications like healthcare monitoring and epidermal bioelectronics.

Relation-driven Query of Multiple Time Series.

Querying time series based on their relations is a crucial part of multiple time series analysis. By retrieving and understanding time series relations, analysts can easily detect anomalies and validate hypotheses in complex time series datasets. However, current relation extraction approaches, including knowledge- and data-driven ones, tend to be laborious and do not support heterogeneous relations. By conducting a formative study with 11 experts, we concluded six time series relations, including correlation, causality, similarity, lag, arithmetic, and meta, and summarized three pain points in querying time series involving these relations. We proposed RelaQ, an interactive system that supports the time series query via relation specifications. RelaQ allows users to intuitively specify heterogeneous relations when querying multiple time series, understand the query results based on a scalable, multi-level visualization, and explore possible relations beyond the existing queries. RelaQ is evaluated with two cases and a user study with 12 participants, showing promising effectiveness and usability.

Risk Factors of Chemotherapy-Induced Thrombocytopenia After Oxaliplatin-Containing Chemotherapy for Gastrointestinal Malignancies.

PURPOSE: Thrombocytopenia is among the most common chemotherapy-related hematologic toxicities. We aim to determine the predictors of oxaliplatin chemotherapy-induced thrombocytopenia in patients with gastrointestinal tumors to guide the clinic. METHODS: Clinical data of 750 patients with a malignant gastrointestinal tumor were included as the primary cohort. Basic clinical data, serological indices, and anthropometric indices of these patients were collected. According to the presence or absence of CIT, univariate analysis was performed to identify significant factors for multivariate analysis. In R language software, nomogram was constructed based on the results of multi-factor analysis, and the calibration curve and ROC curve were drawn. RESULTS: Univariate analysis identified 17 factors as closely related to CIT occurrence, namely age, lymph node metastasis (N) stage, metastasis (M) stage, lung metastasis, other site metastasis, chemotherapy regimen, course of treatment, total dose of oxaliplatin, AST, albumin, neutrophils, monocytes, baseline platelets, transferrin, natural killer (NK) cell, phase angle, and SMI (P < 0.10). The binary logistic multivariate regression analysis revealed five independent risk factors for developing CIT (P < 0.05), including the M stage, total dose of oxaliplatin, albumin, baseline thrombocyte count, and NK cell. Based on the results of multivariate logistic regression analysis, R software was used to establish a nomogram model. The calibration curve shows that the combined predictor has good consistency. The area under the ROC curve was 0.877 and the best cut-off value was 0.3579613 (sensitivity, 78.9%; specificity, 81.8%), which showed the better prediction efficiency. CONCLUSION: The total dose of oxaliplatin, M stage, albumin, baseline platelet count, and NK cell was independent risk factors for CIT. The sequentially constructed histogram model had a good predictive effect on the risk of thrombocytopenia caused by oxaliplatin chemotherapy in patients with gastrointestinal malignancies.

Exploring the use of metabarcoding to reveal eukaryotic associations with mononchids nematodes.

Nematodes play a vital ecological role in soil and marine ecosystems, but there is limited information about their dietary diversity and feeding habits. Due to methodological challenges, the available information is based on inference rather than confirmed observations. The lack of correct dietary requirements also hampers rearing experiments. To achieve insight into the prey of mononchid nematodes, this study employed high-throughput Illumina paired-end sequencing using universal eukaryotic species 18S primers on 10 pooled mononchid nematode species, namely Mylonchulus brachyuris, M. brevicaudatus, Mylonchulus sp., Clarkus parvus, Prionchulus sp. M. hawaiiensis, M. sigmaturellus, M. vulvapapillatus, Anatonchus sp. and Miconchus sp. The results indicate that mononchids are associated with a remarkable diversity of eukaryotes, including fungi, algae, and protists. While the metabarcoding approach, first introduced here for mononchids, proved to be a simple and rapid method, it has several limitations and crucial methodological challenges that should be addressed in future studies. Ultimately, such methods should be able to evaluate the dietary complexity of nematodes and provide a valuable avenue for unraveling the dietary requirements of previously unculturable nematodes. This can contribute to the methodology of understanding their feeding habits and contributions to ecosystem dynamics.

BR regulates wheat root salt tolerance by maintaining ROS homeostasis.

MAIN CONCLUSION: Trace amounts of epibrassinolide (EpiBL) could partially rescue wheat root length inhibition in salt-stressed situation by scavenging ROS, and ectopic expression of TaDWF4 or TaBAK1 enhances root salt tolerance in Arabidopsis by balancing ROS level. Salt stress often leads to ion toxicity and oxidative stress, causing cell structure damage and root development inhibition in plants. While prior research indicated the involvement of exogenous brassinosteroid (BR) in plant responses to salt stress, the precise cytological role and the function of BR in wheat root development under salt stress remain elusive. Our study demonstrates that 100 mM NaCl solution inhibits wheat root development, but 5 nM EpiBL partially rescues root length inhibition by decreasing H2O2 content, oxygen free radical (OFR) content, along with increasing the peroxidase (POD) and catalase (CAT) activities in salt-stressed roots. The qRT-PCR experiment also shows that expression of the ROS-scavenging genes (GPX2 and CAT2) increased in roots after applying BR, especially during salt stress situation. Transcriptional analysis reveals decreased expression of BR synthesis and root meristem development genes under salt stress in wheat roots. Differential expression gene (DEG) enrichment analysis highlights the significant impact of salt stress on various biological processes, particularly "hydrogen peroxide catabolic process" and "response to oxidative stress". Additionally, the BR biosynthesis pathway is enriched under salt stress conditions. Therefore, we investigated the involvement of wheat BR synthesis gene TaDWF4 and BR signaling gene TaBAK1 in salt stress responses in roots. Our results demonstrate that ectopic expression of TaDWF4 or TaBAK1 enhances salt tolerance in Arabidopsis by balancing ROS (Reactive oxygen species) levels in roots.

MulTFBS: A Spatial-Temporal Network with Multichannels for Predicting Transcription Factor Binding Sites.

Revealing the mechanisms that influence transcription factor binding specificity is the key to understanding gene regulation. In previous studies, DNA double helix structure and one-hot embedding have been used successfully to design computational methods for predicting transcription factor binding sites (TFBSs). However, DNA sequence as a kind of biological language, the method of word embedding representation in natural language processing, has not been considered properly in TFBS prediction models. In our work, we integrate different types of features of DNA sequence to design a multichanneled deep learning framework, namely MulTFBS, in which independent one-hot encoding, word embedding encoding, which can incorporate contextual information and extract the global features of the sequences, and double helix three-dimensional structural features have been trained in different channels. To extract sequence high-level information effectively, in our deep learning framework, we select the spatial-temporal network by combining convolutional neural networks and bidirectional long short-term memory networks with attention mechanism. Compared with six state-of-the-art methods on 66 universal protein-binding microarray data sets of different transcription factors, MulTFBS performs best on all data sets in the regression tasks, with the average R2 of 0.698 and the average PCC of 0.833, which are 5.4% and 3.2% higher, respectively, than the suboptimal method CRPTS. In addition, we evaluate the classification performance of MulTFBS for distinguishing bound or unbound regions on TF ChIP-seq data. The results show that our framework also performs well in the TFBS classification tasks.

Association between sugar-sweetened beverages and pure fruit juice with risk of six cardiovascular diseases: a Mendelian randomization study.

BACKGROUND: In observational and prospective cohort studies, intake of sugar-sweetened beverages (SSBs) and pure fruit juice (PFJ) has been associated with cardiovascular disease (CVD). Still, the causality of the connection has not yet been determined. Our objective was to uncover the relationship between SSBs/PFJ and CVD. METHODS: Genetically predicted causal associations between SSBs/PFJ (obtained in a published genome-wide association study) and six common CVDs (atrial fibrillation (AF), angina, heart failure (HF), acute myocardial infarction, hypertension, and coronary atherosclerosis) were assessed using MR analytic modeling. The primary analysis method utilized was the inverse variance weighted (IVW) method, complemented by additional methods such as the weighted median method, MR Egger regression, Cochran's Q test, MR pleiotropy residual, funnel plot, Bonferroni correction, and others for MR analysis. To ensure the robustness of the findings, F-values were calculated as a complementary test to set looser thresholds for exposing genetic instrumental variables (P < 1e-5). RESULTS: The results of MR analysis suggested genetically causal associations between SSBs and AF (odds ratio (OR): 1.023; 95% confidence interval (CI) 1.007-1.038; P = 0.0039) as well as between PFJ and angina (OR: 0.968; 95% CI, 0.943-0.993; P = 0.0138) there was genetic causality. However, MR analysis showed no causal association between SSBs/PFJ and other CVD risks. CONCLUSION: This study suggests that there may be a potential causal relationship between SSBs intake and AF and a causal negative association between PFJ intake and angina.

Chemokine systems in oncology: From microenvironment modulation to nanocarrier innovations.

Over the past few decades, significant strides have been made in understanding the pivotal roles that chemokine networks play in tumor biology. These networks, comprising chemokines and their receptors, wield substantial influence over cancer immune regulation and therapeutic outcomes. As a result, targeting these chemokine systems has emerged as a promising avenue for cancer immunotherapy. However, therapies targeting chemokines face significant challenges in solid tumor treatment, due to the complex and fragile of the chemokine networks. A nuanced comprehension of the complicacy and functions of chemokine networks, and their impact on the tumor microenvironment, is essential for optimizing their therapeutic utility in oncology. This review elucidates the ways in which chemokine networks interact with cancer immunity and tumorigenesis. We particularly elaborate on recent innovations in manipulating these networks for cancer treatment. The review also highlights future challenges and explores potential biomaterial strategies for clinical applications.

Development and validation of HPV-associated and HPV-independent penile squamous cell carcinoma prognostic nomogram.

OBJECTIVE: The aim of this study was to introduce HPV-associated and HPV-independent histologic classifications to analyze prognostic factors and develop a prognostic nomogram for patients with penile squamous cell carcinoma (PSCC). METHODS: Data of 1502 PSCC patients between 2010 and 2020 were accessed from the SEER database, and the patients were randomly divided into a training set and a validation set. Independent risk factors for PSCC patients prognosis were analyzed by using univariate and multivariate COX proportional hazards regression, and was used for the construction of the nomogram, and the predictive performance of the model was evaluated by C-index, calibration curve and ROC curve. Kaplan-Meier analysis was applied to explore the impact of HPV-related factors on patient survival, while propensity score matching (PSM) and inverse probability treatment weighting (IPTW) techniques were used to balance other confounding factors like individual clinical and pathological factors, and to evaluate the differences in overall survival (OS) and cause-specific survival (CSS) between subgroups. RESULT: The results indicated that histologic type, Grade classification, T/M stage, surgical methods and chemotherapy were independent risk factors affecting OS and CSS in PSCC patients. In addition, age and marital status were significantly associated with OS, while lymph node metastasis was an independent prognostic factor for CSS, the validation results of the model showed that the nomogram had a superior predictive performance compared with the American Joint Committee on Cancer staging system. In addition, subgroup analyses prior to and after IPTW and PSM adjustments showed that HPV-associated group had better OS and CSS than HPV-independent group. CONCLUSION: Our study developed and validated a nomogram using a novel histologic classification and achieved satisfactory results, which can better help clinicians to predict the prognosis of penile squamous cell carcinoma patients.

Deciphering Estrus Expression in Gilts: The Role of Alternative Polyadenylation and LincRNAs in Reproductive Transcriptomics.

The fertility rate and litter size of female pigs are critically affected by the expression of estrus. The objective of this study was to elucidate the regulatory mechanisms of estrus expression by analyzing the differential expression of genes and long intergenic non-coding RNAs (lincRNA), as well as the utilization of alternative polyadenylation (APA) sites, in the vulva and vagina during the estrus and diestrus stages of Large White and indigenous Chinese Mi gilts. Our study revealed that the number of differentially expressed genes (DEG) in the vulva was less than that in the vagina, and the DEGs in the vulva were enriched in pathways such as "neural" pathways and steroid hormone responses, including the "Calcium signaling pathway" and "Oxytocin signaling pathway". The DEGs in the vagina were enriched in the "Metabolic pathways" and "VEGF signaling pathway". Furthermore, 27 and 21 differentially expressed lincRNAs (DEL), whose target genes were enriched in the "Endocrine resistance" pathway, were identified in the vulva and vagina, respectively. Additionally, we observed that 63 and 618 transcripts of the 3'-untranslated region (3'-UTR) were lengthened during estrus in the vulva and vagina, respectively. Interestingly, the genes undergoing APA events in the vulva exhibited species-specific enrichment in neural or steroid-related pathways, whereas those in the vagina were enriched in apoptosis or autophagy-related pathways. Further bioinformatic analysis of these lengthened 3'-UTRs revealed the presence of multiple miRNAs binding sites and cytoplasmic polyadenylation element (CPE) regulatory aspects. In particular, we identified more than 10 CPEs in the validated lengthened 3'-UTRs of the NFIX, PCNX4, CEP162 and ABHD2 genes using RT-qPCR. These findings demonstrated the involvement of APA and lincRNAs in the regulation of estrus expression in female pigs, providing new insights into the molecular mechanisms underlying estrus expression in pigs.

Ginseng fermentation solution affects the gut microbiota in zebrafish with alcoholic liver disease via PI3K/Akt pathway.

BACKGROUND: Ginsenosides have received increased amounts of attention due to their ability to modulate the intestinal flora, which may subsequently alleviate alcoholic liver disease (ALD). The effects of ginseng fermentation solution (GFS) on the gut microbiota and metabolism in ALD patients have not been explored. PURPOSE: This research aimed to explore the regulatory effect of GFS on ALD both in vitro and in vivo. METHOD: This study assessed the anti-ALD efficacy of GFS using an LO2 cell model and a zebrafish model. Untargeted metabolomics was used for differentially abundant metabolite analysis, and high-throughput 16S rRNA sequencing was used to examine the effect of GFS on ALD. RESULTS: The LO2 cell line experiments demonstrated that GFS effectively mitigated alcohol-induced oxidative stress and reduced apoptosis by upregulating PI3K and Bcl-2 expression and decreasing the levels of malondialdehyde, total cholesterol, and triglycerides. In zebrafish, GFS improved morphological and physiological parameters and diminished oxidative stress-induced ALD. Meanwhile, the results from Western blotting indicated that GFS enhanced the expression of PI3K, Akt, and Bcl-2 proteins while reducing Bax protein expression, thereby ameliorating the ALD model in zebrafish. Metabolomics data revealed significant changes in a total of 46 potential biomarkers. Among them, metabolites such as prostaglandin F2 alpha belong to arachidonic acid metabolism. In addition, GFS also partly reversed the imbalance of gut microbiota composition caused by alcohol. At the genus level, alcohol consumption elevated the presence of Flectobacillus, Curvibacter, among others, and diminished Elizabethkingia within the intestinal microbes of zebrafish. Conversely, GFS reversed these effects, notably enhancing the abundance of Proteobacteria and Archaea. Correlation analyses further indicated a significant negative correlation between prostaglandin F2 alpha, 11,14,15-THETA, Taurocholic acid and Curvibacter. CONCLUSION: This study highlights a novel mechanism by which GFS modulates anti-ALD activity through the PI3K/Akt signalling pathway by influencing the intestinal flora-metabolite axis. These results indicate the potential of GFS as a functional food for ALD treatment via modulation of the gut flora.

High-speed and large-scale intrinsically stretchable integrated circuits.

Intrinsically stretchable electronics with skin-like mechanical properties have been identified as a promising platform for emerging applications ranging from continuous physiological monitoring to real-time analysis of health conditions, to closed-loop delivery of autonomous medical treatment1-7. However, current technologies could only reach electrical performance at amorphous-silicon level (that is, charge-carrier mobility of about 1 cm2 V-1 s-1), low integration scale (for example, 54 transistors per circuit) and limited functionalities8-11. Here we report high-density, intrinsically stretchable transistors and integrated circuits with high driving ability, high operation speed and large-scale integration. They were enabled by a combination of innovations in materials, fabrication process design, device engineering and circuit design. Our intrinsically stretchable transistors exhibit an average field-effect mobility of more than 20 cm2 V-1 s-1 under 100% strain, a device density of 100,000 transistors per cm2, including interconnects and a high drive current of around 2 µA µm-1 at a supply voltage of 5 V. Notably, these achieved parameters are on par with state-of-the-art flexible transistors based on metal-oxide, carbon nanotube and polycrystalline silicon materials on plastic substrates12-14. Furthermore, we realize a large-scale integrated circuit with more than 1,000 transistors and a stage-switching frequency greater than 1 MHz, for the first time, to our knowledge, in intrinsically stretchable electronics. Moreover, we demonstrate a high-throughput braille recognition system that surpasses human skin sensing ability, enabled by an active-matrix tactile sensor array with a record-high density of 2,500 units per cm2, and a light-emitting diode display with a high refreshing speed of 60 Hz and excellent mechanical robustness. The above advancements in device performance have substantially enhanced the abilities of skin-like electronics.

Revolutionizing Daptomycin Dosing: A Single 7-11 Hour Sample for Pragmatic Application.

Precision daptomycin dosing faces clinical implementation barriers despite known exposure-safety concerns with the use of twice the regulatory-approved doses. We propose achieving a single 7-11 hour post-dose plasma target concentration of 30 mg/L to 43 mg/L to be a practical starting point to facilitate precision daptomycin dosing.

Air quality and health benefits for different heating decarbonization pathways in China.

The urgent need for decarbonization in China's heating system, comprised of approximately one hundred thousand boilers, is imperative to meet climate and clean air objectives. To formulate national and regional strategies, we developed an integrated model framework that combines a facility-level emission inventory, the Community Multiscale Air Quality (CMAQ) model, and the Global Exposure Mortality Model (GEMM). We then explore the air quality and health benefits of alternative heating decarbonization pathways, including the retirement of coal-fired industrial boilers (CFIBs) for replacement with grid-bound heat supply systems, coal-to-gas conversion, and coal-to-biomass conversion. The gas replacement pathway shows the greatest potential for reducing PM2.5 concentration by 2.8 (2.3-3.4) µg/m3 by 2060, avoiding 23,100 (19,600-26,500) premature deaths. In comparison, the biomass replacement pathway offers slightly lower environmental and health benefits, but is likely to reduce costs by approximately two-thirds. Provincially, optimal pathways vary - Xinjiang, Sichuan, and Chongqing favor coal-to-gas conversion, while Shandong, Henan, Hebei, Inner Mongolia, and Shanxi show promise in CFIBs retirement. Henan leads in environmental and health benefits. Liaoning, Heilongjiang, and Jilin, rich in biomass resources, present opportunities for coal-to-biomass conversion.

Assessment of Secondary Sulfate Aqueous-Phase Formation Pathways in the Tropical Island City of Haikou: A Chemical Kinetic Perspective.

Sulfate (SO42-) is an essential chemical species in atmospheric aerosols and plays an influential role in their physical-chemical characteristics. The mechanisms of secondary SO42- aerosol have been intensively studied in air-polluted cities. However, few studies have focused on cities with good air quality. One-year PM2.5 samples were collected in the tropical island city of Haikou, and water-soluble inorganic ions, as well as water-soluble Fe and Mn, were analyzed. The results showed that non-sea-salt SO42- (nss-SO42-) was the dominant species of water-soluble inorganic ions, accounting for 40-57% of the total water-soluble inorganic ions in PM2.5 in Haikou. The S(IV)+H2O2 pathway was the main formation pathway for secondary SO42- in wintertime in Haikou, contributing to 57% of secondary SO42- formation. By contrast, 54% of secondary SO42- was produced by the S(IV)+Fe×Mn pathway in summer. In spring and autumn, the S(IV)+H2O2, S(IV)+Fe×Mn, and S(IV)+NO2 pathways contributed equally to secondary SO42- formation. The ionic strength was the controlling parameter for the S(IV)+NO2 pathway, while pH was identified as a key factor that mediates the S(IV)+H2O2 and S(IV)+Fe×Mn pathways to produce secondary SO42-. This study contributes to our understanding of secondary SO42- production under low PM2.5 concentrations but high SO42- percentages.