Halide Perovskite Inducing Anomalous Nonvolatile Polarization in Poly(vinylidene fluoride)-based Flexible Nanocomposites.

Ferroelectric materials have important applications in transduction, data storage, and nonlinear optics. Inorganic ferroelectrics such as lead zirconate titanate possess large polarization, though they are rigid and brittle. Ferroelectric polymers are light weight and flexible, yet their polarization is low, bottlenecked at 10 µC cm-2. Here we show poly(vinylidene fluoride) nanocomposite with only 0.94% of self-nucleated CH3NH3PbBr3 nanocrystals exhibits anomalously large polarization (~19.6 µC cm-2) while retaining superior stretchability and photoluminance, resulting in unprecedented electromechanical figures of merit among ferroelectrics. Comprehensive analysis suggests the enhancement is accomplished via delicate defect engineering, with field-induced Frenkel pairs in halide perovskite stabilized by the poled ferroelectric polymer through interfacial coupling. The strategy is general, working in poly(vinylidene fluoride-co-hexafluoropropylene) as well, and the nanocomposite is stable. The study thus presents a solution for overcoming the electromechanical dilemma of ferroelectrics while enabling additional optic-activity, ideal for multifunctional flexible electronics applications.

Predicting future vaccination habits: The link between influenza vaccination patterns and future vaccination decisions among old aged adults in China.

BACKGROUND: Annual influenza vaccination is crucially recommended for the elderly to maintain humoral immunity. Insufficient coverage requires us to understand the determinants of their influenza behaviors and how these patterns impact vaccination choices. METHODS: Data from 540 Beijing residents aged over 65 were collected through interviews, capturing vaccination history and sociodemographic details. Individual influenza vaccination records from 2016 to 2020 were obtained from China's Immunization Information Systems. A latent class model identified three vaccination patterns. Multinomial logistic regression assessed relative risk ratios (RRRs) for vaccination based on sociodemographic factors. Vaccination patterns were used to predict future vaccination likelihood. RESULTS: The analysis revealed three groups: sporadically vaccinated (63.33%), occasionally vaccinated (18.71%), and frequently vaccinated (17.96%). Factors associated with frequent vaccination included age over 70 (RRR = 2.81), lower income (RRR = 0.39), higher vaccine hesitancy (RRR = 3.10), multiple chronic conditions (RRR = 2.72), and rural residence (RRR = 2.48). The frequently vaccinated group was more likely to sustain regular vaccination habits in subsequent years compared to the occasionally vaccinated group. CONCLUSIONS: Only 17.96% of Beijing's older population exhibited a consistent influenza vaccination pattern. Older age, rural residency, and chronic diseases correlated with repeated influenza vaccination. Segmenting the population based on past vaccination behavior can aid in designing targeted interventions to improve vaccination rates.

Mechanistic insights into cardiovascular effects of ultrafine particle exposure: A longitudinal panel study.

BACKGROUND: Ultrafine particle (UFP) has been linked with higher risks of cardiovascular diseases; however, the biological mechanisms remain to be fully elucidated. OBJECTIVES: This study aims to investigate the cardiovascular responses to short-term UFP exposure and the biological pathways involved. METHODS: A longitudinal panel study was conducted among 32 healthy, non-smoking young adults in Shanghai, China, who were engaged in five rounds of follow-ups between December 2020 and November 2021. Individual exposures were calculated based on the indoor and outdoor real-time measurements. Blood pressure, arterial stiffness, targeted biomarkers, and untargeted proteomics and metabolomics were examined during each follow-up. Linear mixed-effect models were applied to analyze the exposure and health data. The differential proteins and metabolites were used for pathway enrichment analyses. RESULTS: Short-term UFP exposure was associated with significant increases in blood pressure and arterial stiffness. For example, systolic blood pressure increased by 2.10 % (95 % confidence interval: 0.63 %, 3.59 %) corresponding to each interquartile increase in UFP concentrations at lag 0-3 h, while pulse wave velocity increased by 2.26 % (95 % confidence interval: 0.52 %, 4.04 %) at lag 7-12 h. In addition, dozens of molecular biomarkers altered significantly. These effects were generally present within 24 h after UFP exposure, and were robust to the adjustment of co-pollutants. Molecular changes detected in proteomics and metabolomics analyses were mainly involved in systemic inflammation, oxidative stress, endothelial dysfunction, coagulation, and disturbance in lipid transport and metabolism. DISCUSSION: This study provides novel and compelling evidence on the detrimental subclinical cardiovascular effects in response to short-term UFP exposure. The multi-omics profiling further offers holistic insights into the underlying biological pathways.

Ascorbic acid-induced warfarin resistance after breast cancer surgery: a case report and literature review.

Warfarin is an anticoagulant that requires INR-based dosage adjustment. Ascorbic acid may impair warfarin effectiveness according to limited literature. We report a rare case of a 63-year-old woman with an aortic valve replacement history who developed warfarin resistance after taking ascorbic acid for anemia following breast cancer surgery. Despite increasing the warfarin dose from 6 mg to 10 mg daily, her INR remained below the therapeutic range. After ruling out other causes of warfarin resistance, we discontinued ascorbic acid and observed a rapid increase in INR to target values. The temporal relationship and the absence of other confounding factors confirmed the causality of ascorbic acid in this case. We recommend that patients concomitantly taking vitamin C and warfarin should monitor their INR values closely and discontinue ascorbic acid as soon as possible if they exhibit signs of warfarin resistance.

China's Fossil Fuel CO2 Emissions Estimated Using Surface Observations of Coemitted NO2.

Accurate estimates of fossil fuel CO2 (FFCO2) emissions are of great importance for climate prediction and mitigation regulations but remain a significant challenge for accounting methods relying on economic statistics and emission factors. In this study, we employed a regional data assimilation framework to assimilate in situ NO2 observations, allowing us to combine observation-constrained NOx emissions coemitted with FFCO2 and grid-specific CO2-to-NOx emission ratios to infer the daily FFCO2 emissions over China. The estimated national total for 2016 was 11.4 PgCO2·yr-1, with an uncertainty (1σ) of 1.5 PgCO2·yr-1 that accounted for errors associated with atmospheric transport, inversion framework parameters, and CO2-to-NOx emission ratios. Our findings indicated that widely used "bottom-up" emission inventories generally ignore numerous activity level statistics of FFCO2 related to energy industries and power plants in western China, whereas the inventories are significantly overestimated in developed regions and key urban areas owing to exaggerated emission factors and inexact spatial disaggregation. The optimized FFCO2 estimate exhibited more distinct seasonality with a significant increase in emissions in winter. These findings advance our understanding of the spatiotemporal regime of FFCO2 emissions in China.

Mechanistic and Kinetic Insights into Cellular Uptake of Biomimetic Dinitrosyl Iron Complexes and Intracellular Delivery of NO for Activation of Cytoprotective HO-1.

Dinitrosyl iron unit (DNIU), [Fe(NO)2], is a natural metallocofactor for biological storage, delivery, and metabolism of nitric oxide (NO). In the attempt to gain a biomimetic insight into the natural DNIU under biological system, in this study, synthetic dinitrosyl iron complexes (DNICs) [(NO)2Fe(µ-SCH2CH2COOH)2Fe(NO)2] (DNIC-COOH) and [(NO)2Fe(µ-SCH2CH2COOCH3)2Fe(NO)2] (DNIC-COOMe) were employed to investigate the structure-reactivity relationship of mechanism and kinetics for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective heme oxygenase (HO)-1. After rapid cellular uptake of dinuclear DNIC-COOMe through a thiol-mediated pathway (tmax = 0.5 h), intracellular assembly of mononuclear DNIC [(NO)2Fe(SR)(SCys)]n-/[(NO)2Fe(SR)(SCys-protein)]n- occurred, followed by O2-induced release of free NO (tmax = 1-2 h) or direct transfer of NO to soluble guanylate cyclase, which triggered the downstream HO-1. In contrast, steady kinetics for cellular uptake of DNIC-COOH via endocytosis (tmax = 2-8 h) and for intracellular release of NO (tmax = 4-6 h) reflected on the elevated activation of cytoprotective HO-1 (∼50-150-fold change at t = 3-10 h) and on the improved survival of DNIC-COOH-primed mesenchymal stem cell (MSC)/human corneal endothelial cell (HCEC) under stressed conditions. Consequently, this study unravels the bridging thiolate ligands in dinuclear DNIC-COOH/DNIC-COOMe as a switch to control the mechanism, kinetics, and efficacy for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective HO-1, which poses an implication on enhanced survival of postengrafted MSC for advancing the MSC-based regenerative medicine.

Longitudinal Changes in the Retinal Nerve Fiber Layer Thickness in Amyotrophic Lateral Sclerosis and Parkinson's Disease.

BACKGROUND AND PURPOSE: There is increasing evidence that the anterior visual pathways are involved in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). This study investigated longitudinal changes in retinal nerve fiber layer (RNFL) thickness in patients with ALS and PD with the aim of better understanding their roles as biomarkers of disease progression. METHODS: This study recruited 21 ALS patients, 19 age-matched PD patients, and 21 agematched healthy controls. Patient demographics and clinical scores relating to the respective diseases were documented. The RNFL thickness was measured using optical coherence tomography at baseline and after 6 months. RESULTS: At baseline, the RNFL in the superior quadrant was significantly thinner in the patients with ALS than in healthy controls (109.90±22.41 µm vs. 127.81±17.05 µm [mean±standard deviation], p=0.008). The RNFL thickness did not differ significantly between the ALS and PD patients or between the PD patients and healthy controls. At 6 months, there was further significant RNFL thinning in patients with ALS, for both the overall thickness (baseline: median=94.5 µm, range=83.0-106.0 µm; follow-up: median=93.5 µm, range=82.5-104.5 µm, p=0.043) and the thickness in the inferior quadrant (median=126 µm, range=109.5-142.5 µm; and median=117.5 µm, range=98.5-136.5 µm; respectively, p=0.032). However, these changes were not correlated with the ALS functional scores. In contrast, the patients with PD did not demonstrate a significant change in RNFL thickness between the two time points. CONCLUSIONS: The RNFL thickness is a promising biomarker of disease progression in patients with ALS but not in those with PD, which has a slower disease progression.

Investigating the Cell Origin and Liver Metastasis Factors of Colorectal Cancer by Single-Cell Transcriptome Analysis.

Background: Colorectal cancer (CRC) is one of the deadliest causes of death by cancer worldwide. Liver metastasis (LM) is the main cause of death in patients with CRC. Therefore, identification of patients with the greatest risk of liver metastasis is critical for early treatment and reduces the mortality of patients with colorectal cancer liver metastases. Methods: Initially, we characterized cell composition through single-cell transcriptome analysis. Subsequently, we employed copy number variation (CNV) and pseudotime analysis to delineate the cellular origins of LM and identify LM-related epithelial cells (LMECs). The LM-index was constructed using machine learning algorithms to forecast the relative abundance of LMECs, reflecting the risk of LM. Furthermore, we analyzed drug sensitivity and drug targeted gene expression in LMECs and patients with a high risk of LM. Finally, functional experiments were conducted to determine the biological roles of metastasis-related gene in vitro. Results: Single-cell RNA sequencing analysis revealed different immune landscapes between primary CRC and LM tumor. LM originated from chromosomal variants with copy number loss of chr1 and chr6p and copy number gain of chr7 and chr20q. We identified the LMECs cluster and found LM-associated pathways such as Wnt/beta-catenin signaling and KRAS signaling. Subsequently, we identified ten metastasis-associated genes, including SOX4, and established the LM-index, which correlates with poorer prognosis, higher stage, and advanced age. Furthermore, we screened two drugs as potential candidates for treating LM, including Linsitinib_1510, Lapatinib_1558. Immunohistochemistry results demonstrated significantly elevated SOX4 expression in tumor samples compared to normal samples. Finally, in vitro experiments verified that silencing SOX4 significantly inhibited tumor cell migration and invasion. Conclusion: This study reveals the possible cellular origin and driving factors of LM in CRC at the single cell level, and provides a reference for early detection of CRC patients with a high risk of LM.

Effects of Cage Implantation Depth on Sagittal Parameters and Functional Outcomes in Posterior Lumbar Interbody Fusion for the Treatment of L4-L5 Lumbar Degenerative Spondylolisthesis.

OBJECTIVE: In the treatment of lumbar degenerative spondylolisthesis (LDS) with Posterior lumbar interbody fusion (PLIF) surgery, interbody fusion implants play a key role in supporting the vertebral body and facilitating fusion. The objective of this study was to assess the impact of implantation depth on sagittal parameters and functional outcomes in patients undergoing PLIF surgery. METHODS: This study reviewed 128 patients with L4-L5 LDS between January 2016 and August 2019. All patients underwent an open PLIF surgery that included intravertebral decompression, implantation of pedicle screws and cage. We grouped according to the position of the center of the cage relative to the L5 vertebral endplate. Patients with the center of the cage located at the anterior 1/2 of the upper end plate of the L5 vertebral body were divided into Anterior group, and located at the posterior 1/2 of the upper end plate of the L5 vertebral body were divided into Posterior group. The lumbar lordosis (LL), segmental lordosis (SL), sacral slope (SS), pelvic incidence (PI), pelvic tilt (PT) and slope degree (SD) was measured for radiographic outcomes. We used the visual analog scale (VAS) and the oswestry disability index (ODI) score to assess functional outcomes. Paired t-test was used to compare imaging and bedside data before and after surgery between the two groups, and independent sample t-test, χ2 test and Fisher exact test were used to compare the data between the two groups. RESULT: The mean follow-up of Anterior group was 44.13 ± 9.23 months, and Posterior group was 45.62 ± 10.29 months (P > 0.05). The LL, SL, PT, SS, SD and PI-LL after operation showed great improvements, relative to the corresponding preoperative values in both groups (P < 0.05). Compared to Posterior group, Anterior group exhibited far enhanced SL (15.49 ± 3.28 vs. 13.67 ± 2.53, P < 0.05), LL (53.47 ± 3.21 vs. 52.08 ± 3.15, P < 0.05) outcomes and showed depressed PI-LL (8.87 ± 5.05 vs. 10.73 ± 5.39, P < 0.05) outcomes at the final follow-up. Meanwhile, the SL in Anterior group (16.18 ± 3.99) 1 months after operation were also higher than in Posterior group (14.12 ± 3.57) (P < 0.05). We found that VAS and ODI at the final follow-up in Anterior group (3.62 ± 0.96, 25.19 ± 5.25) were significantly lower than those in Posterior group (4.12 ± 0.98, 27.68 ± 5.13) (P < 0.05). CONCLUSIONS: For patients with LDS, the anteriorly placed cage may provide better improvement of SL after PLIF surgery. Meanwhile, the anteriorly placed cage may achieve better sagittal parameters of LL and PI-LL and functional outcomes at the final follow-up.

Orthostatic hypotension in Parkinson's disease: Sit-to-stand vs. supine-to-stand protocol and clinical correlates.

BACKGROUND: Screening for orthostatic hypotension (OH) is integral in Parkinson's disease (PD) management, yet evidence-based guidelines on best practice methods for diagnosing OH in PD are lacking. METHODS: We investigated the frequency and correlates of OH, symptomatic OH, and neurogenic OH, in a large consecutively recruited PD cohort (n = 318), and compared the diagnostic performance of the sit-to-stand vs. the supine-to-stand blood pressure (BP) test. We evaluated the utility of continuous BP monitoring and tilt table testing in patients with postural symptoms or falls who were undetected to have OH with clinic-based BP measurements. Disease severity, fluid intake, orthostatic and overactive bladder symptoms, falls, comorbidities and medication history were evaluated. RESULTS: Patients' mean age was 66.1 ± 9.5years, with mean disease duration 7.8 ± 5.5years. OH frequency was 35.8 % based on the supine-to-stand test. OH in PD was significantly associated with older age, lower body mass index, longer disease duration, worse motor, cognitive and overactive bladder symptoms and functional disabilities, falls, and lower fluid intake. A similar profile was seen with asymptomatic OH. Three quarters of OH were neurogenic, with the majority also having supine hypertension. The sit-to-stand test had a sensitivity of only 0.39. One quarter of patients were additionally diagnosed with OH during continuous BP monitoring. CONCLUSIONS: The sit-to-stand test substantially underdiagnoses OH in PD, with the important practice implication that supine-to-stand measurements may be preferred. Screening for OH is warranted even in asymptomatic patients. Adequate fluid intake, treatment of urinary dysfunction and falls prevention are important strategies in managing PD patients with OH.

AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility.

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.

Intercellular Signaling Pathways as Therapeutic Targets for Vascular Dementia Repair.

Vascular dementia (VaD) is a white matter ischemic disease and the second-leading cause of dementia, with no direct therapy. Within the lesion site, cell-cell interactions dictate the trajectory towards disease progression or repair. To elucidate the underlying intercellular signaling pathways, a VaD mouse model was developed for transcriptomic and functional studies. The mouse VaD transcriptome was integrated with a human VaD snRNA-Seq dataset. A custom-made database encompassing 4053 human and 2032 mouse ligand-receptor (L-R) interactions identified significantly altered pathways shared between human and mouse VaD. Two intercellular L-R systems, Serpine2-Lrp1 and CD39-A3AR, were selected for mechanistic study as both the ligand and receptor were dysregulated in VaD. Decreased Seprine2 expression enhances OPC differentiation in VaD repair. A clinically relevant drug that reverses the loss of CD39-A3AR function promotes tissue and behavioral recovery in the VaD model. This study presents novel intercellular signaling targets and may open new avenues for VaD therapies.

Achieving High-Performance Lithium-Sulfur Batteries by Modulating Li+ Desolvation Barrier with Liquid Crystal Polymers.

Lithium-sulfur (Li-S) batteries offer high theoretical capacity but are hindered by poor rate capability and cycling stability due to sluggish Li2S precipitation kinetics. Here a sulfonate-group-rich liquid crystal polymer (poly-2,2'-disulfonyl-4,4'-benzidine terephthalamide, PBDT) is designed and fabricated to accelerate Li2S precipitation by promoting the desolvation of Li+ from electrolyte. PBDT-modified separators are employed to assemble Li-S batteries, which deliver a remarkable rate capacity (761 mAh g-1 at 4 C) and cycling stability (500 cycles with an average decay rate of 0.088% per cycle at 0.5 C). A PBDT-based pouch cell even delivers an exceptional capacity of ≈1400 mAh g-1 and an areal capacity of ≈11 mAh cm-2 under lean-electrolyte and high-sulfur-loading condition, demonstrating promise for practical applications. Results of Raman spectra, molecular dynamic (MD) and density functional theory (DFT) calculations reveal that the abundant anionic sulfonate groups of PBDT aid in Li+ desolvation by attenuating Li+-solvent interactions and lowering the desolvation energy barrier. Plus, the polysulfide adsorption/catalysis is also excluded via electrostatic repulsion. This work elucidates the critical impact of Li+ desolvation on Li-S batteries and provides a new design direction for advanced Li-S batteries.

Algorithmic and sensor-based research on Chinese children's and adolescents' screen use behavior and light environment.

Background: Myopia poses a global health concern and is influenced by both genetic and environmental factors. The incidence of myopia tends to increase during infectious outbreaks, such as the COVID-19 pandemic. This study examined the screen-time behaviors among Chinese children and adolescents and investigated the efficacy of artificial intelligence (AI)-based alerts in modifying screen-time practices. Methods: A cross-sectional analysis was performed using data from 6,716 children and adolescents with AI-enhanced tablets that monitored and recorded their behavior and environmental light during screen time. Results: The median daily screen time of all participants was 58.82 min. Among all age groups, elementary-school students had the longest median daily screen time, which was 87.25 min and exceeded 4 h per week. Children younger than 2 years engaged with tablets for a median of 41.84 min per day. Learning accounted for 54.88% of participants' screen time, and 51.03% (3,390/6,643) of the participants used tablets for 1 h at an average distance <50 cm. The distance and posture alarms were triggered 807,355 and 509,199 times, respectively. In the study, 70.65% of the participants used the tablet under an illuminance of <300 lux during the day and 61.11% under an illuminance of <100 lux at night. The ambient light of 85.19% of the participants exceeded 4,000 K color temperature during night. Most incorrect viewing habits (65.49% in viewing distance; 86.48% in viewing posture) were rectified swiftly following AI notifications (all p < 0.05). Conclusion: Young children are increasingly using digital screens, with school-age children and adolescents showing longer screen time than preschoolers. The study highlighted inadequate lighting conditions during screen use. AI alerts proved effective in prompting users to correct their screen-related behavior promptly.

Parkinson's Disease is Predominantly a Genetic Disease.

The discovery of a pathogenic variant in the alpha-synuclein (SNCA) gene in the Contursi kindred in 1997 indisputably confirmed a genetic cause in a subset of Parkinson's disease (PD) patients. Currently, pathogenic variants in one of the seven established PD genes or the strongest known risk factor gene, GBA1, are identified in ∼15% of PD patients unselected for age at onset and family history. In this Debate article, we highlight multiple avenues of research that suggest an important - and in some cases even predominant - role for genetics in PD aetiology, including familial clustering, high rates of monogenic PD in selected populations, and complete penetrance with certain forms. At first sight, the steep increase in PD prevalence exceeding that of other neurodegenerative diseases may argue against a predominant genetic etiology. Notably, the principal genetic contribution in PD is conferred by pathogenic variants in LRRK2 and GBA1 and, in both cases, characterized by an overall late age of onset and age-related penetrance. In addition, polygenic risk plays a considerable role in PD. However, it is likely that, in the majority of PD patients, a complex interplay of aging, genetic, environmental, and epigenetic factors leads to disease development.

Physics-driven structural docking and protein language models accelerate antibody screening and design for broad-spectrum antiviral therapy.

Therapeutic antibodies have become one of the most influential therapeutics in modern medicine to fight against infectious pathogens, cancer, and many other diseases. However, experimental screening for highly efficacious targeting antibodies is labor-intensive and of high cost, which is exacerbated by evolving antigen targets under selective pressure such as fast-mutating viral variants. As a proof-of-concept, we developed a machine learning-assisted antibody generation pipeline that greatly accelerates the screening and re-design of immunoglobulins G (IgGs) against a broad spectrum of SARS-CoV-2 coronavirus variant strains. These viruses infect human host cells via the viral spike protein binding to the host cell receptor angiotensin-converting enzyme 2 (ACE2). Using over 1300 IgG sequences derived from convalescent patient B cells that bind with spike's receptor binding domain (RBD), we first established protein structural docking models in assessing the RBD-IgG-ACE2 interaction interfaces and predicting the virus-neutralizing activity of each IgG with a confidence score. Additionally, employing Gaussian process regression (also known as Kriging) in a latent space of an antibody language model, we predicted the landscape of IgGs' activity profiles against individual coronaviral variants of concern. With functional analyses and experimental validations, we efficiently prioritized IgG candidates for neutralizing a broad spectrum of viral variants (wildtype, Delta, and Omicron) to prevent the infection of host cells in vitro and hACE2 transgenic mice in vivo. Furthermore, the computational analyses enabled rational redesigns of selective IgG clones with single amino acid substitutions at the RBD-binding interface to improve the IgG blockade efficacy for one of the severe, therapy-resistant strains - Delta (B.1.617). Our work expedites applications of artificial intelligence in antibody screening and re-design even in low-data regimes combining protein language models and Kriging for antibody sequence analysis, activity prediction, and efficacy improvement, in synergy with physics-driven protein docking models for antibody-antigen interface structure analyses and functional optimization.

Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node.

Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a CD8+ PD-1+ Tcf-1+ stem-like T cell subset in the tumor-draining lymph node (TdLN). Using murine melanoma models, we found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. Our data indicate that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor.

CD39hi identifies an exhausted tumor-reactive CD8+ T cell population associated with tumor progression in human gastric cancer.

The ectonucleotidase CD39 has been regarded as a promising immune checkpoint in solid tumors. However, the expression of CD39 by tumor-infiltrating CD8+ T cells as well as their potential roles and clinical implications in human gastric cancer (GC) remain largely unknown. Here, we found that GC-infiltrating CD8+ T cells contained a fraction of CD39hi cells that constituted about 6.6% of total CD8+ T cells in tumors. These CD39hi cells enriched for GC-infiltrating CD8+ T cells with features of exhaustion in transcriptional, phenotypic, metabolic and functional profiles. Additionally, GC-infiltrating CD39hiCD8+ T cells were also identified for tumor-reactive T cells, as these cells expanded in vitro were able to recognize autologous tumor organoids and induced more tumor cell apoptosis than those of expanded their CD39int and CD39-CD8+ counterparts. Furthermore, CD39 enzymatic activity controlled GC-infiltrating CD39hiCD8+ T cell effector function, and blockade of CD39 efficiently enhanced their production of cytokines IFN-γ and TNF-α. Finally, high percentages of GC-infiltrating CD39hiCD8+ T cells correlated with tumor progression and independently predicted patients' poor overall survival. These findings provide novel insights into the association of CD39 expression level on CD8+ T cells with their features and potential clinical implications in GC, and empowering those exhausted tumor-reactive CD39hiCD8+ T cells through CD39 inhibition to circumvent the suppressor program may be an attractive therapeutic strategy against GC.

Macrophage AHR-TLR4 cross-talk drives p-STAT3 (Ser727)-mediated mitochondrial oxidative stress and upregulates IDO/ICAM-1 in the steatohepatitis induced by aflatoxin B1.

Aflatoxin B1 (AFB1) is a major mycotoxin contaminant showing in the environment and foods. In this study, the molecular initiating events (MIEs) of AFB1-induced steatohepatitis were explored in mice and human cell model. We observed dose-dependent steatohepatitis in the AFB1-treated mice, including triglyceride accumulation, fibrotic collagen secretion, enrichment of CD11b + and F4/80+ macrophages/Kupffer cells, cell death, lymphocytes clusters and remarkable atrophy areas. The gut barrier and gut-microbiota were also severely damaged after the AFB1 treatment and pre-conditioned colitis in the experimental mice aggravated the steatohepatitis phenotypes. We found that macrophages cells can be pro-inflammatorily activated to M1-like phenotype by AFB1 through an AHR/TLR4/p-STAT3 (Ser727)-mediated mitochondrial oxidative stress. The phenotypes can be rescued by AHR inhibitors in the mice model and human cell model. We further showed that this signaling axis is based on the cross-talk interaction between AHR and TLR4. Gene knock-up experiment found that the signaling is dependent on AFB1 ligand-binding with AHR, but not protein expressions of TLR4. The signaling elevated NLRP3 and two immune metabolic enzymes ICAM-1 and IDO that are associated with macrophage polarization. Results from intervention experiments with natural anti-oxidant and AHR inhibitor CH223191 suggest that the macrophage polarization may rely on AHR and ROS. Our study provides novel and critical references to the food safety and public health regulation of AFB1.