A novel dual mechanism-of-action bispecific PD-1-IL-2v armed by a "ßγ-only" interleukin-2 variant.

Introduction: Interleukin-2 (IL-2) is one of the first cytokines to be discovered as an immune agonist for cancer immunotherapy. Biased IL-2 variants had been discovered to eliminate Treg activation or enhance the tumor specific T cell cytotoxicity. However, all the biased IL-2 variants pose the risk to overstimulate immune response at a low-dose range. Here, we introduce a novel dual-MOA bispecific PD-1-IL-2v molecule with great anti-tumor efficacy in a high dosed manner. Methods: The novel IL-2 variant was designed by structural truncation and shuffling. The single armed bispecific PD-1-IL-2v molecule and IL-2v were studied by immune cell activations in vitro and in vivo and anti-tumor efficacy in mouse model. Results and discussion: The IL-2 variant in this bispecific antibody only binds to IL-2Rßγ complex in a fast-on/off manner without α, ß or γ single receptor binding. This IL-2v mildly activates T and NK cells without over stimulation, meanwhile it diminishes Treg activation compared to the wild type IL-2. This unique bispecific molecule with "ßγ-only" IL-2v can not only "in-cis" stimulate and expand CD8 T and NK cells moderately without Treg activation, but also block the PD-1/L1 interaction at a similar dose range with monoclonal antibody.

Elevating Low-Grade Heat Harvesting with Daytime Radiative Cooling and Solar Heating in Thermally Regenerative Electrochemical Cycles.

Thermal radiation control has garnered growing interest for its ability to provide localized cooling and heating without energy consumption. However, its direct application for energy harvesting remains largely underexplored. In this work, we demonstrate a novel system that leverages daytime radiative cooling and solar heating technologies to continuously power charging-free thermally regenerative electrochemical cycle (TREC) devices, turning ubiquitous low-grade ambient heat into electricity. Notably, by harnessing a substantial 35 °C temperature differential solely through passive cooling and heating effects, the integrated system exhibits a cell voltage of 50 mV and a specific capacity exceeding 20 mAh g-1 of PB. This work unlocks the potential of readily available low-grade ambient heat for sustainable electricity generation.

Efficacy and safety of Xiaoyao Pill combined with Western medicine in the treatment of schizophrenia: A Meta-analysis and Systematic review.

BACKGROUND: The efficacy and safety of Xiaoyao Pill combined with Western medicine in the treatment of schizophrenia are still inconclusive. This meta-analysis summarized relevant studies to compare the efficacy and safety of Xiaoyao Pill combined with Western medicine and Western medicine alone in the treatment of schizophrenia, aiming to provide guidance for clinical treatment. METHODS: In this meta-analysis, we searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, CQVIP, and CBM databases from the establishment of the databases to August 2023. The study proposed to include studies that reported combination of Xiaoyao Pill with Western medicine and Western medicine alone in the treatment of schizophrenia, excluding published literature, unpublished literature, literature with incomplete or inadequate information, animal experiments, literature reviews and systematic studies. Data were analyzed using Review manager 5.3. RESULTS: About 9 studies (6 RCTs and 3 case-control studies) were included in this meta-analysis. The sample size ranged from 60 to 128, with a total of 779 patients, including 395 in the combined treatment group and 384 in the control group. Pooled results showed that the total effective rate of combined treatment group was significantly higher than that of Western medicine alone (OR = 4.21, 95% CI: 1.50-11.83, P = .006). Positive and Negative Syndrome Scale (PANSS) (-) (MD = -2.30, 95% CI: -3.72 ~ -0.89, P = .001) and PANSS (+) (MD = -2.60, 95% CI: -3.34 ~ -1.86, P < .00001) of combined treatment group were all significantly lower than that of Western medicine alone. Additionally, PRL levels of combined treatment group was significantly lower than that of Western medicine alone (MD = -28.78, 95% CI: -42.20 ~ -15.35, P < .0001). However, there was no significant difference in BPRS and total PANSS between combined treatment group and Western medicine alone group. Notably, pooled results showed that there was no significant difference in incidence of adverse events between combined treatment group and Western medicine alone group. CONCLUSION: The effective rate of Xiaoyao Pill combined with Western medicine in the treatment of schizophrenia is higher than that of Western medicine alone, which can effectively relieve the positive and negative symptoms of schizophrenia, and can significantly reduce the level of PRL. In the treatment of schizophrenia, clinicians can give priority to Xiaoyao Pill combined with Western medicine therapy.

Characterization and mitigation of artifacts derived from NGS library preparation due to structure-specific sequences in the human genome.

BACKGROUND: Hybridization capture-based targeted next generation sequencing (NGS) is gaining importance in routine cancer clinical practice. DNA library preparation is a fundamental step to produce high-quality sequencing data. Numerous unexpected, low variant allele frequency calls were observed in libraries using sonication fragmentation and enzymatic fragmentation. In this study, we investigated the characteristics of the artifact reads induced by sonication and enzymatic fragmentation. We also developed a bioinformatic algorithm to filter these sequencing errors. RESULTS: We used pairwise comparisons of somatic single nucleotide variants (SNVs) and insertions and deletions (indels) of the same tumor DNA samples prepared using both ultrasonic and enzymatic fragmentation protocols. Our analysis revealed that the number of artifact variants was significantly greater in the samples generated using enzymatic fragmentation than using sonication. Most of the artifacts derived from the sonication-treated libraries were chimeric artifact reads containing both cis- and trans-inverted repeat sequences of the genomic DNA. In contrast, chimeric artifact reads of endonuclease-treated libraries contained palindromic sequences with mismatched bases. Based on these distinctive features, we proposed a mechanistic hypothesis model, PDSM (pairing of partial single strands derived from a similar molecule), by which these sequencing errors derive from ultrasonication and enzymatic fragmentation library preparation. We developed a bioinformatic algorithm to generate a custom mutation "blacklist" in the BED region to reduce errors in downstream analyses. CONCLUSIONS: We first proposed a mechanistic hypothesis model (PDSM) of sequencing errors caused by specific structures of inverted repeat sequences and palindromic sequences in the natural genome. This new hypothesis predicts the existence of chimeric reads that could not be explained by previous models, and provides a new direction for further improving NGS analysis accuracy. A bioinformatic algorithm, ArtifactsFinder, was developed and used to reduce the sequencing errors in libraries produced using sonication and enzymatic fragmentation.

A comprehensive performance evaluation, comparison, and integration of computational methods for detecting and estimating cross-contamination of human samples in cancer next-generation sequencing analysis.

Cross-sample contamination is one of the major issues in next-generation sequencing (NGS)-based molecular assays. This type of contamination, even at very low levels, can significantly impact the results of an analysis, especially in the detection of somatic alterations in tumor samples. Several contamination identification tools have been developed and implemented as a crucial quality-control step in the routine NGS bioinformatic pipeline. However, no study has been published to comprehensively and systematically investigate, evaluate, and compare these computational methods in the cancer NGS analysis. In this study, we comprehensively investigated nine state-of-the-art computational methods for detecting cross-sample contamination. To explore their application in cancer NGS analysis, we further compared the performance of five representative tools by qualitative and quantitative analyses using in silico and simulated experimental NGS data. The results showed that Conpair achieved the best performance for identifying contamination and predicting the level of contamination in solid tumors NGS analysis. Moreover, based on Conpair, we developed a Python script, Contamination Source Predictor (ConSPr), to identify the source of contamination. We anticipate that this comprehensive survey and the proposed tool for predicting the source of contamination will assist researchers in selecting appropriate cross-contamination detection tools in cancer NGS analysis and inspire the development of computational methods for detecting sample cross-contamination and identifying its source in the future.

Irritable bowel syndrome in children: the placebo response rate and influencing factors a meta-analysis.

BACKGROUND: Irritable bowel syndrome is common in children and exhibits a high placebo response. This study was to explore the placebo response rate and its influencing factors in children with irritable bowel syndrome. METHODS: A systematic search was performed on Pubmed, Embase, MEDLINE, Cochrane Library, CNKI, Wanfang, and CBM from database inception to March 2022. Randomized controlled trials of irritable bowel syndrome in children were included in the study. The primary outcome was the placebo response rate of improvement. RESULTS: Thirteen studies were included, with 445 patients in the placebo group. The rate of improvement and abdominal pain disappearance were 28.2% (95% CI, 16.6-39.9%) and 5% (95% CI, 0-18.4%). The placebo response based on the abdominal pain score was 0.675 (95% CI, 0.203-1.147). The mode of administration (P < 0.01), dosing schedule (P < 0.01), and clinical outcome assessor (P = 0.04) have a significant impact on the magnitude of placebo effect. CONCLUSIONS: The placebo response rate for pediatric irritable bowel syndrome was 28.2%. In clinical trials, reducing dosing frequency, selecting appropriate dosage forms, and using patient-reported outcomes can help mitigate the placebo effect. IMPACT: This is the first meta-analysis to assess the placebo response rates for improvement and disappearance in children with IBS. The finding suggested that the mode of administration, dosing schedule, and clinical outcome assessor could potentially influence the magnitude of the placebo effect in children with IBS. This study would provide a basis for estimating sample size in clinical trial design with a placebo control.

Silibinin, a potential fasting mimetic, inhibits hepatocellular carcinoma by triggering extrinsic apoptosis.

Fasting, without inducing malnutrition, has been shown to have various beneficial effects, including the inhibition of tumor initiation and progression. However, prolonged fasting poses challenges for many cancer patients, particularly those in intermediate and terminal stages. Thus, there is an urgent need for the development of fasting mimetics which harness the protective effects of fasting but more suitable for patients. In this study, we first highlighted the pivotal role of silibinin in AMP-activated protein kinase (AMPK) pathway and may serve, as a potential fasting mimetic via screening hepatoprotective drugs. Further metabolic analysis showed that silibinin inhibited the adenosine triphosphate (ATP) levels, glucose uptake and diminished glycolysis process, which further confirmed that silibinin served as a fasting mimetic. In addition, fasting synergized with silibinin, or used independently, to suppress the growth of hepatocellular carcinoma (HCC) in vivo. Mechanistically, silibinin upregulated death receptor 5 (DR5) through AMPK activation, and thus promoting extrinsic apoptosis and inhibiting HCC growth both in vitro and in vivo. Inhibition of AMPK using small interfering RNA (siRNA) or compound C, an AMPK inhibitor, significantly attenuated the upregulation of DR5 and the apoptotic response induced by silibinin. These findings suggest that silibinin holds promise as a fasting mimetic and may serve as an adjuvant drug for HCC treatment.

Ultrahigh Passive Cooling Power in Hydrogel with Rationally Designed Optofluidic Properties.

The cooling power of a radiative cooler is more than halved in the tropics, e.g., Singapore, because of its harsh weather conditions including high humidity (84% on average), strong downward atmospheric radiation (∼40% higher than elsewhere), abundant rainfall, and intense solar radiation (up to 1200 W/m2 with ∼58% higher UV irradiation). So far, there has been no report of daytime radiative cooling that well achieves effective subambient cooling. Herein, through integrated passive cooling strategies in a hydrogel with desirable optofluidic properties, we demonstrate stable subambient (4-8 °C) cooling even under the strongest solar radiation in Singapore. The integrated passive cooler achieves an ultrahigh cooling power of ∼350 W/m2, 6-10 times higher than a radiative cooler in a tropical climate. An in situ study of radiative cooling with various hydration levels and ambient humidity is conducted to understand the interaction between radiation and evaporative cooling. This work provides insights for the design of an integrated cooler for various climates.

Defect Engineering of WO3 by Rapid Flame Reduction for Efficient Photoelectrochemical Conversion of Methane into Liquid Oxygenates.

Photoelectrochemical (PEC) conversion is a promising way to use methane (CH4) as a chemical building block without harsh conditions. However, the PEC conversion of CH4 to value-added chemicals remains challenging due to the thermodynamically favorable overoxidation of CH4. Here, we report WO3 nanotube (NT) photoelectrocatalysts for PEC CH4 conversion with high liquid product selectivity through defect engineering. By tuning the flame reduction treatment, we carefully controlled the oxygen vacancies of WO3 NTs. The optimally reduced WO3 NTs suppressed overoxidation of CH4 showing a high total C1 liquid selectivity of 69.4% and a production rate of 0.174 µmol cm-2 h-1. Scanning electrochemical microscopy revealed that oxygen vacancies can restrain the production of hydroxyl radicals, which, in excess, could further oxidize C1 intermediates to CO2. Additionally, band diagram analysis and computational studies elucidated that oxygen vacancies thermodynamically suppress overoxidation. This work introduces a strategy for understanding and controlling the selectivity of photoelectrocatalysts for direct conversion of CH4 to liquids.

Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer's disease.

Cognitive deterioration and memory decline associated with the progression of Alzheimer's disease (AD) primarily results from synaptic failure. However, current understanding of the upstream regulatory mechanisms controlling synaptic plasticity remains limited. Salt-inducible kinase 3 (SIK3) is central to the signal pathway and is involved in neuronal regulation of sleep duration in mice. We speculated that the SIK3 cascade signaling pathway might contribute to the pathogenesis of AD. Thus, the present study employed AD transgenic mouse models, Morris Water Maze, virus-mediated gene transfer, electrophysiology, co-immunoprecipitation, western blotting, quantitative polymerase chain reaction, immunofluorescence, ChIP-qPCR, Golgi-Cox staining and dendritic spine analysis to investigate this connection. Our results revealed that SIK3 mRNA/protein expression was significantly reduced in middle-aged AD transgenic mouse models and AD patients. Conditional deletion of SIK3 gene in dorsal hippocampal neurons of 5×FAD mice further accelerated cognitive deterioration and impaired synaptic plasticity. In hippocampal neuronal cultures, SIK3 formed a complex with HDAC4, directly phosphorylated HDAC4 and regulated its nuclear cytoplasmic shuttle. Overexpression of SIK3 could facilitate the expression of synaptic plasticity-related genes by directly repressing mef2c or involving the recruitment of histone deacetylase to promoter regions of target genes through regulation of p-HDAC4, and vice versa. Moreover, up-regulation of SLP-S, the truncated fragment of SIK3, in dorsal hippocampal neurons, restored the synaptic plasticity and alleviates the cognitive impairment in 5×FAD mice. Collectively, these findings revealed a novel and important role of SIK3-HDAC4 regulation of synaptic plasticity and propose a new target for therapeutic approaches of cognitive deficits associated with AD.

High excess-free-fructose beverage consumption is not associated with prevalent allergy in US adults: a population-based analysis of NHANES 2005-2006.

BACKGROUND: A strong association exists between high-excess free fructose (EFF) beverage consumption and prevalent allergy in children and adolescents; however, whether this association exists in the adult population is unclear. Therefore, this study aimed to investigate the relationship between high-EFF beverage intake and prevalent allergy. METHODS: This cross-sectional study extracted data from the National Health and Nutrition Examination Survey 2005-2006. Adults aged ≥ 20 were eligible for inclusion, excluding those without complete information on beverage intake, allergic symptom survey, and allergen-specific immunoglobulin E test results. A total of 2077 adults were included. Univariate and multivariable logistic regression analyses determined the associations between high-EFF beverage consumption, prevalent allergic symptoms, and allergic sensitization. RESULTS: After adjusting for confounders, there were no significant associations between high intake (vs. low) of sum of high-EFF beverage (adjusted odds ratio [aOR] = 1.10, 95% confidence interval [CI] 0.77, 1.57), apple juice (aOR = 0.95, 95% 0.55, 1.65), fruit drinks (aOR = 0.95, 95%CI 0.70, 1.29), soft drinks (aOR = 1.17, 95%CI 0.89, 1.55) and presence of allergic sensitization, or allergic symptoms. Stratified analyses also revealed no associations between high intake of high-EFF beverage in sum, presence of allergic symptoms or sensitization among individuals aged 20-39y, 40-59y, and ≥ 60y. CONCLUSIONS: Our findings indicate no independent association between frequent intake of high-EFF beverage and increased likelihood of allergy in US adults.

Effects of health concept model-based detailed behavioral care on mood and quality of life in elderly patients with chronic heart failure.

BACKGROUND: With the intensification of social aging, the susceptibility of the elderly population to diseases has attracted increasing attention, especially chronic heart failure (CHF) that accounts for a large proportion of the elderly. AIM: To evaluate the application value of health concept model-based detailed behavioral care in elderly patients with CHF. METHODS: This study recruited 116 elderly CHF patients admitted from October 2018 to October 2020 and grouped them according to the nursing care that they received. The elderly patients who underwent health concept model-based detailed behavioral care were included in a study group (SG; n = 62), and those who underwent routine detailed behavioral nursing intervention were included as a control group (CG; n = 54). Patients' negative emotions (NEs), quality of life (QoL), and nutritional status were assessed using the self-rating anxiety/ depression scale (SAS/SDS), the Minnesota Living with Heart Failure Ques-tionnaire (MLHFQ), and the Modified Quantitative Subjective Global Assessment (MQSGA) of nutrition, respectively. Differences in rehabilitation efficiency, NEs, cardiac function (CF) indexes, nutritional status, QoL, and nursing satisfaction were comparatively analyzed. RESULTS: A higher response rate was recorded in the SG vs the CG after intervention (P < 0.05). After care, the left ventricular ejection fraction was higher while the left ventricular end-diastolic dimension and left ventricular end systolic diameter were lower in the SG compared with the CG (P < 0.05). The post-intervention SAS and SDS scores, as well as MQSGA and MLHFQ scores, were also lower in the SG (P < 0.05). The SG was also superior to the CG in the overall nursing satisfaction rate (P < 0.05). CONCLUSION: Health concept model-based detailed behavioral care has high application value in the nursing care of elderly CHF patients, and it can not only effectively enhance rehabilitation efficiency, but also mitigate patients' NEs and improve their CF and QoL.

ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer's disease.

BACKGROUND: Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer's disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood. METHODS: We detected ACSS2 expression and histone acetylation levels in the brains of AD patients and 5 × FAD mice. When we altered ACSS2 expression by injecting adeno-associated virus into the dorsal hippocampus of 5 × FAD mice and replenished ACSS2 substrate (acetate), we observed changes in cognitive function by Morris water maze. We next performed RNA-seq, ChIP-qPCR, and electrophysiology to study molecular mechanism underlying ACSS2-mediated spatial learning and memory in 5 × FAD mice. RESULTS: We reported that ACSS2 expression and histone acetylation (H3K9, H4K12) were reduced in the hippocampus and prefrontal cortex of 5 × FAD mice. Reduced ACSS2 levels were also observed in the temporal cortex of AD patients. 5 × FAD mice exhibited a low enrichment of acetylated histones on the promoters of NMDARs and AMPARs, together with impaired basal and activity-dependent synaptic plasticity, all of which were rescued by ACSS2 upregulation. Moreover, acetate replenishment enhanced ac-H3K9 and ac-H4K12 in 5 × FAD mice, leading to an increase of NMDARs and AMPARs and a restoration of synaptic plasticity and cognitive function in an ACSS2-dependent manner. CONCLUSION: ACSS2 is a key molecular switch of cognitive impairment and that targeting ACSS2 or acetate administration may serve as a novel therapeutic strategy for the treatment of intermediate or advanced AD. Nuclear acetyl-CoA pools are generated partly from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). Model depicts that ACSS2 expression is downregulated in the brains of 5×FAD model mice and AD patients. Of note, ACSS2 downregulation mediates a reduction in ionotropic glutamate receptor expression through histone acetylation, which exacerbates synaptic plasticity impairment in AD. These deficits can be rescued by ACSS2 upregulation or acetate supplementation (GTA, an FDA-approved food additive), which may serve as a promising therapeutic strategy for AD treatment.

Effectiveness of non-pharmacological traditional Chinese medicine combined with conventional therapy in treating fibromyalgia: a systematic review and meta-analysis.

Objective: Fibromyalgia is a chronic musculoskeletal disorder characterized by generalized pain, which is also known as "muscular rheumatism" in Chinese medicine. We undertook this systematic review to evaluate the effectiveness of non-pharmacological traditional Chinese medicine (TCM) combined with conventional therapy on pain, health status, depression, and the quality of life of fibromyalgia patients. Methods: Studies were retrieved from five electronic databases (PubMed, the Cumulative Index to Nursing and Allied Health, Cochrane Library, Embase, and Web of Science) with publication date up to August 2022. We included randomized controlled trials examining the effects of a combination of non-pharmacological TCM and conventional therapy on pain intensity, health status, depression, and quality of life. Results: Four randomized controlled trials with 384 fibromyalgia patients met the inclusion criteria. Results of the meta-analysis showed that non-pharmacological TCM combined with conventional therapy exerted significant positive effects on alleviating pain at the post-intervention time point than conventional therapy only (visual analog scale WMD1 = -1.410, P < 0.01; pressure pain threshold WMD2 = 0.830, P < 0.001, respectively). Significant differences in pain assessment were also observed between the two groups after a long-term follow-up (12 months) (WMD1 = -1.040 and WMD2= 0.380, all P < 0.05). The combination therapy group also showed a greater reduction in fibromyalgia impact questionnaire than the control group after a long-term follow-up (WMD = -6.690, P < 0.05). Depression and pain-related quality of life showed no difference between groups (all P > 0.05). Conclusion: Non-pharmacological TCM combined with conventional therapy may be more effective in alleviating pain and improving health status than conventional therapy only. However, it remains some concerns over the safety and clinic application. Systematic review registration: Identifier: CRD42022352991.

Hierarchically Patterned Self-Cleaning Polymer Composites for Daytime Radiative Cooling.

Passive daytime radiative cooling (PDRC) has the potential to reduce energy demand and mitigate global warming. However, surface contamination from dust and bacterial buildup limits practical PDRC applications. Here, we develop a hierarchically patterned nanoporous composite (HPNC) using a facile template-molding fabrication method to integrate PDRC materials with self-cleaning and antibacterial functions. The HPNC design decouples multifunctional control into different characteristic length scales that can be optimized simultaneously. The nanoporous polymer matrix embedded with tunable fillers enables 7.8 and 4.4 °C temperature reduction for outdoor personal and building cooling, respectively, under intense solar irradiance. Meanwhile, a microscale pillar array pattern integrated into the HPNC enables superhydrophobicity with self-cleaning and antisoiling functions to mitigate surface contamination. Moreover, the surface coating of photocatalytic agents can generate photoinduced antibacterial effects. The scalable fabrication and multifunctional capabilities of our HPNC design offer a promising solution for practical PDRC applications with minimal maintenance needs.

Comparison of different ratios of cefoperazone/sulbactam in patients with pyelonephritis.

Objective: To compare the clinical efficacy of different ratios of cefoperazone/sulbactam in the treatment of patients with pyelonephritis. Methods: In this retrospective study clinical records of patients with pyelonephritis treated in Huzhou Traditional Chinese Medicine Hospital from July 2020 to July 2021 were collected,. It included 55 patients who received cefoperazone/sulbactam 2:1 treatment (Control group) and 57 patients who received 1 cefoperazone/sulbactam 1:1 treatment (Observation group). Clinical response, inflammatory reaction and bacterial clearance were compared between the two groups. Results: The levels of C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8) and leukocyte count (WBC) in the observation group were lower than those in the control group (P<0.05). The total efficacy of the Observation-group was 92.98%, higher than 80.00% of the control group (P<0.05). Fifty-eight strains of bacteria were isolated from the Control-group and 59 strains from the Observation-group. The bacterial clearance rates were 65.52% (38/58) and 83.05% (49/59), respectively. The differences were statistically significant (P<0.05). Conclusions: The clinical efficacy of 1:1 ratio of cefoperazone/sulbactam in the treatment of patients with pyelonephritis was superior that of 2:1 ratio. This ratio allows to fully utilize the antibacterial effect of cefoperazone, with a significant decrease in inflammation markers and an improvement in bacterial clearance.

Discrete Element Modeling of the Meso-Mechanical Response of Asphalt Pavement under Vehicle Load.

Numerical simulation is an effective way to study the mechanical response of asphalt pavement, which is very important for the pavement structural design. In this study, a three-dimensional meso-structure discrete element model of asphalt pavement was generated with the FISH programming language and its meso-mechanical response under vehicle load was analyzed. The contact forces within the asphalt pavement, in asphalt mastic, in coarse aggregates and between asphalt mastic and coarse aggregates were studied. The results of the study show that the contact forces within the asphalt mixture are highly uneven. The number of contact points in coarse aggregates account only for about 10% of all contact points while the sum of the contact forces in coarse aggregates contributes to over 50% of all contact forces. This demonstrates that the coarse aggregates bear most of the vehicle load. The average normal contact force in coarse aggregates is about 5 N and the average tangential contact force in coarse aggregates is about 2 N. The modeling results provide a quantitative understanding of the distribution of loading in asphalt pavement.