For many years, polybrominated diphenyl ethers (PBDEs) were used as flame retardants in a large number of consumer products. Even though international law meanwhile prohibits the production and usage of PBDEs, these persistent and bioaccumulative chemicals still leak into the environment, and are frequently detected in wildlife and humans. Population-based studies reveal positive correlations between human PBDE exposure and various adverse health effects, emphasizing that a better understanding of the mode of action of these polybrominated chemicals is urgently needed. Therefore, we investigated the effect of two widespread PBDEs, namely BDE-47 and BDE-99, on epidermal growth factor receptor (EGFR) activity in human cells. Recent studies showed that the EGFR is not only orchestrating cellular functions, but also serves as a cell-surface receptor for dioxins, phenolic benzotriazoles and related organic pollutants. Results from in silico docking analyses, AlphaLISA-based receptor binding studies and SDS-PAGE/Western blot analyses revealed that BDE-47 and BDE-99 inhibit the growth factor-triggered activation of EGFR by binding to its extracellular domain. In keratinocytes, PBDEs also inhibit amphiregulin-induced and EGFR-mediated DNA synthesis as well as the EGFR-triggered trans-repression of the aryl hydrocarbon receptor signaling pathway. Our data identify EGFR as a cell-surface receptor for PBDEs and shed light on a novel mode of action of these ubiquitous and persistent chemicals. This finding may contribute to an improved hazard assessment of PBDEs and structurally related flame retardants.

Suppression of chimeric antigen receptor-modified T (CAR-T) cells by the immunosuppressive tumor microenvironment remains a major barrier to their efficacy against solid tumors. To address this, we develop an anti-PD-L1-expressing nanovesicle loaded with the STING agonist cGAMP (aPD-L1 NVs@cGAMP) to remodel the tumor microenvironment and thereby enhance CAR-T cell activity. Following pulmonary delivery, the nanovesicles rapidly accumulate in the lung and selectively deliver STING agonists to PD-L1-overexpressing cells via the PD-1/PD-L1 interaction. This targeted delivery effectively avoids the systemic inflammation and poor cellular uptake that plague free STING agonists. Internalized STING agonists trigger STING signaling and induce interferon responses, which diminish immunosuppressive cell populations such as myeloid-derived suppressor cells in the tumor microenvironment and promote CAR-T cell infiltration. Importantly, the anti-PD-L1 single chain variable fragment on the nanovesicle surface blocks PD-L1 upregulation induced by STING agonists and prevents CAR-T cell exhaustion. In both orthotopic lung cancer and lung metastasis model, combined therapy with CAR-T cells and aPD-L1 NVs@cGAMP potently inhibits tumor growth and prevents recurrence. Therefore, aPD-L1 NVs@cGAMP is expected to serve as an effective CAR-T cell enhancer to improve the efficacy of CAR-T cells against solid tumors.

Active biological molecules present a powerful, yet largely untapped, opportunity to impart autonomous regulation of materials. Because these systems can function robustly to regulate when and where chemical reactions occur, they have the ability to bring complex, life-like behavior to synthetic materials. Here, we achieve this design feat by using functionalized circadian clock proteins, KaiB and KaiC, to engineer time-dependent crosslinking of colloids. The resulting material self-assembles with programmable kinetics, producing macroscopic changes in material properties, via molecular assembly of KaiB-KaiC complexes. We show that colloid crosslinking depends strictly on the phosphorylation state of KaiC, with kinetics that are synced with KaiB-KaiC complexing. Our microscopic image analyses and computational models indicate that the stability of colloidal super-structures depends sensitively on the number of Kai complexes per colloid connection. Consistent with our model predictions, a high concentration stabilizes the material against dissolution after a robust self-assembly phase, while a low concentration allows for oscillatory material structure. This work introduces the concept of harnessing biological timers to control synthetic materials; and, more generally, opens the door to using protein-based reaction networks to endow synthetic systems with life-like functional properties.

Skin-like sensors capable of detecting multiple stimuli simultaneously have great potential in cutting-edge human-machine interaction. However, realizing multimodal tactile recognition beyond human tactile perception still faces significant challenges. Here, an extreme environments-adaptive multimodal triboelectric sensor was developed, capable of detecting pressure/temperatures beyond the range of human perception. Based on triboelectric nanogenerator technology, an asymmetric structure capable of independently outputting dual signals was designed to improve perception sensitivity. By converting the signals and the stimuli into feature matrices, parallel perception of complex objects (with a recognition rate of 94%) and temperature at high temperatures was achieved. The proposed multimodal triboelectric tactile sensor represents progress in maximum detection range and rapid response, realizing the upper limit of human skin's high-temperature sensing (60 °C) with a working temperature of 200 °C. The proposed self-powered multimodal sensing system offers a wider range of possibilities for human/robot/environment interaction applications.

As time progresses, the transmission pattern of a disease may change. To more precisely determine the spread behaviors of the disease, we develop non-autonomous topological and random spread models. In this article, we validate the survival characteristics of these spread models and elucidate their connection with mixing properties using the associated ξ-matrices or spread mean matrices. We also introduce the concept of spread rates for both periodic topological and random spread models and provide rigorous formulas for calculating these rates. Additionally, numerical examples and simulation results are provided as supporting evidence for the theory in both topological and random models.

The public, regulators, and domain experts alike seek to understand the effect of deployed SAE level 4 automated driving system (ADS) technologies on safety. The recent expansion of ADS technology deployments is paving the way for early stage safety impact evaluations, whereby the observational data from both an ADS and a representative benchmark fleet are compared to quantify safety performance.

Top-down proteomics, the characterization of intact proteoforms by tandem mass spectrometry, is the principal method for proteoform characterization in complex samples. Top-down proteomics relies on precursor isolation and subsequent gas-phase fragmentation to make proteoform identifications. While this strategy can produce highly detailed molecular information, the reliance on time-intensive tandem MS limits the speed with which proteoforms can be identified. We suggest that once proteoforms have been identified by top-down analysis in a system of interest, and archived in a system-specific Proteoform Atlas, subsequent analyses in that system can utilize the Atlas information to enable simpler and faster MS1-only identifications. We explore this idea here, using the ribosome as a model system of limited complexity. We used deep top-down analysis to construct an ribosomal Proteoform Atlas containing 2099 proteoforms from 52 of the 54 proteins that make up the ribosome. We show that using the Atlas enables confident MS1-only identifications of ribosomal proteoforms from that were perturbed by exposure to cold. Furthermore, this Atlas strategy identifies proteoforms up to 77% more rapidly compared to top-down identifications that require acquisition of both MS1 and MS2 spectra.

As a result of increased incidence of anterior cruciate ligament (ACL) injury in young athletes, there is a rise in the indications surgical ACL reconstruction procedures. The value of anterolateral ligament (ALL) reconstruction emerges as a proposed solution to prevent graft failures and improve stability in this high demanding category of patients. The purpose of this study is to present our experience with a novel hamstring auto-grafting technique, the single antegrade sling graft (SASG), for combined reconstruction of both ACL and ALL using autologous gracilis (GR) and semitendinosus (ST) grafts utilizing a single femoral tunnel and double tibial tunnels.

Trinucleotide repeats in DNA exhibit a dual nature due to their inherent instability. While their rapid expansion can diversify gene expression during evolution, exceeding a certain threshold can lead to diseases such as Huntington's disease (HD), a neurodegenerative condition, triggered by >36 C-A-G repeats in exon 1 of the Huntingtin gene. Notably, the discovery of somatic instability (SI) of the tract allows these mutations, inherited from an affected parent, to further expand throughout the patient's lifetime, resulting in a mosaic brain with specific neurons exhibiting variable and often extreme CAG lengths, ultimately leading to their death. Genome-wide association studies have identified genetic variants-both cis and trans, including mismatch repair modifiers-that modulate SI, as shown in blood cells, and influence HD's age of onset. This review will explore the evidence for SI in HD and its role in disease pathogenesis, as well as the therapeutic implications of these findings. We conclude by emphasizing the urgent need for reliable methods to quantify SI for diagnostic and prognostic purposes.

We present experiments involving oscillating droplets in aqueous cyclodextrin-surfactant solutions. In these experiments, α-cyclodextrin (αCD) and anionic surfactants exhibit remarkable viscoelasticity at the liquid/air interface, with dilatational modulus varying across orders of magnitude. This rheological response depends on the concentrations of different complexes in the solution, particularly of the 2 : 1 inclusion complexes formed by two αCD molecules (αCD), and one surfactant (S). We propose a model that describes the distribution of these complexes on the droplet surface using a free energy approach, accounting for dipole-dipole interactions. The results of the model reproduce the interfacial behavior of the viscoelastic modulus and phase shift in excellent agreement with the data, clearly indicating that dipole-dipole interactions determine and control the viscoelastic properties of the drops.

spp. are known pathogens in fish, with their presence potentially resulting from the contamination of the aquatic environment or improper handling. Accurate bacterial identification is crucial across various fields, including medicine, microbiology, and the food industry, and thus a range of techniques are available for this purpose. In this study, spp. and other hydrogen sulphide-positive bacteria were investigated in the digestive contents of fish destined for consumption from the Atlantic area of Macaronesia. Two identification techniques were compared: the traditional API method and the MALDI-TOF MS technique. For the identification of spp. carriers, 59 samples were processed following ISO 6579-1:2017. A total of 47 strains of Gram-negative bacilli were obtained. No spp. isolates were detected. The most frequent genus was (76.50%), followed by (10.63%). The MALDI-TOF MS technique showed a high concordance with the API technique, with 72.34% concordance at the species level. Both techniques demonstrated a high degree of concordance in the identification of , with 87.23% genus-level concordance and 12.76% non-concordant identifications. This study highlights the limitations of the API technique and the speed and precision of MALDI-TOF MS. The identified bacteria could pose a health risk to humans.

Endometrial cancer (EC) presents a substantial health challenge, with increasing incidence and mortality rates. Despite advances in diagnosis and treatment, understanding the molecular underpinnings of EC progression remains unknown. In this study, we conducted a comprehensive investigation utilizing The Cancer Genome Atlas (TCGA-UCEC = 588) data to analyze gene co-expression patterns, elucidate biological process pathways, and identify potential prognostic and diagnostic biomarkers for EC, using weighted gene co-expression network analysis (WGCNA), differential gene expression, survival analysis, and functional analysis, respectively. We determined that the Green module (M5) was significantly correlated with patient survival. Functional analysis of the genes in module M5 indicates involvement in cell cycle regulation, mitotic spindle assembly, and intercellular signaling. , , and were among the top differentially expressed genes in the Green module, suggesting their involvement in critical pathways that contribute to disease progression and patient survival outcomes. The biological and clinical assessments of our findings provide an understanding of the molecular landscape of EC and identified several potential prognostic markers for patient risk stratification and treatment selection.

The increase in food production is accompanied by an increase in waste, particularly agricultural by-products from cultivation and processing. These residues are referred to as agricultural by-products. To address this issue, biotechnological processes can be used to create new applications for these by-products. This study explored the use of LAB strains (, subsp. , and ) on by-products such as white grape pomace, cocoa bean shells, apple pomace, and defatted roasted hazelnut to develop yoghurt-style fruit beverages. Microbial load and pH changes were monitored during a 24 h fermentation and 14-day shelf life at 5 °C. Concentrations of sugars, organic acids, and volatile organic compounds were also analyzed using HPLC and GC-qMS. The results showed that optimizing the matrix led to significant bacterial growth, with viable microbes remaining under refrigeration. In particular, the strain of tested on the cocoa bean shell yielded the most promising results. After 24 h of fermentation, the strain reached a charge of 9.3 Log CFU/mL, acidifying the substrate to 3.9 and producing 19.00 g/100 g of lactic acid. Aromatic compounds were produced in all trials, without off-flavours, and characteristic fermented food flavours developed. Additionally, secondary metabolites produced by lactic acid bacteria may enhance the health benefits of these beverages.

Mitochondrial dysfunction is closely linked to obesity and diabetes, with declining lung function in aging increasing diabetes risk, potentially due to elevated serum levels of dioxin-like mitochondria inhibitor substances (MIS) from prolonged exposure to environmental pollutants. However, the mechanisms connecting MIS, mitochondria, lung function, and metabolic disorder remain unclear. In this study, we analyzed data from 1371 adults aged 40-69 years in the 2008 Korean Genome Epidemiologic Study (KoGES) Ansung cohort. We indirectly estimated dioxin-like MIS levels by measuring intracellular ATP (MIS) and reactive oxygen species (MIS) in cultured cells treated with the serum of participants. Using correlation analysis and structural equation modeling (SEM), we explored the relationships among MIS, mitochondrial function, body mass index (BMI), and lung function (FEV1 and FVC). Our findings revealed that MIS was associated with BMI in females and with FVC in males, while MIS correlated with both BMI and FVC in males, not in females. Significant associations between BMI and FVC were found in the highest MIS subgroup in both sexes. SEM analyses demonstrated that MIS negatively influenced mitochondrial function, which in turn affected BMI and lung function. Age-related declines in lung function were also linked to mitochondrial dysfunction. This study underscores the potential of MIS assays as alternatives for assessing mitochondrial function and highlights the importance of mitochondrial health in metabolic disorders and lung function.

Background An artificial intelligence (AI)-based method for measuring intraprostatic tumor volume based on data from MRI may provide prognostic information. Purpose To evaluate whether the total volume of intraprostatic tumor from AI-generated segmentations (V) provides independent prognostic information in patients with localized prostate cancer treated with radiation therapy (RT) or radical prostatectomy (RP). Materials and Methods For this retrospective, single-center study (January 2021 to August 2023), patients with cT1-3N0M0 prostate cancer who underwent MRI and were treated with RT or RP were identified. Patients who underwent RT were randomly divided into cross-validation and test RT groups. An AI segmentation algorithm was trained to delineate Prostate Imaging Reporting and Data System (PI-RADS) 3-5 lesions in the cross-validation RT group before providing segmentations for the test RT and RP groups. Cox regression models were used to evaluate the association between V and time to metastasis and adjusted for clinical and radiologic factors for combined RT (ie, cross-validation RT and test RT) and RP groups. Areas under the receiver operating characteristic curve (AUCs) were calculated for V and National Comprehensive Cancer Network (NCCN) risk categorization for prediction of 5-year metastasis (RP group) and 7-year metastasis (combined RT group). Results Overall, 732 patients were included (combined RT group, 438 patients; RP group, 294 patients). Median ages were 68 years (IQR, 62-73 years) and 61 years (IQR, 56-66 years) for the combined RT group and the RP group, respectively. V was associated with metastasis in the combined RT group (median follow-up, 6.9 years; adjusted hazard ratio [AHR], 1.09 per milliliter increase; 95% CI: 1.04, 1.15; = .001) and the RP group (median follow-up, 5.5 years; AHR, 1.22; 95% CI: 1.08, 1.39; = .001). AUCs for 7-year metastasis for the combined RT group for V and NCCN risk category were 0.84 (95% CI: 0.74, 0.94) and 0.74 (95% CI: 0.80, 0.98), respectively ( = .02). Five-year AUCs for the RP group for V and NCCN risk category were 0.89 (95% CI: 0.80, 0.98) and 0.79 (95% CI: 0.64, 0.94), respectively ( = .25). Conclusion The volume of AI-segmented lesions was an independent, prognostic factor for localized prostate cancer. © RSNA, 2024

Calcium channel blockers (CCBs) are frequently co-administered with clopidogrel in cardiovascular disease. Although an inhibitory drug interaction exists between them, comprehensive large-scale studies for its validation are lacking. We investigated interactions between CCBs and clopidogrel using a large-scale national registry of patients who underwent percutaneous coronary intervention (PCI). The Platelet function and genoType-Related long-term Prognosis-Platelet Function Test consortium investigates the association between platelet function test and long-term prognosis during dual antiplatelet therapy including clopidogrel in patients using drug-eluting stents. We compared the platelet reactivity using the VerifyNow P2Y12 test and clinical outcomes between CCB users and non-users. Between 2003 and 2018, 11 714 patients were enrolled and categorized into two groups according to CCB usage. A composite endpoint encompassing all-cause mortality, myocardial infarction, stent thrombosis, or stroke was defined as a major adverse cardiac and cerebrovascular event (MACCE). During the 5-year follow-up period, no significant differences were observed in P2Y12 reaction units (215.8 ± 84.7 vs 218.4 ± 76.7,  = .156), MACCEs, major bleeding, or high platelet reactivity rates, even after adjusting for propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). When limited to the high platelet reactivity cohort (≥252 PRU), the results remained consistent for MACCE [PSM-adjusted, HR: 0.923 (0.644-1.323), -value .663; IPTW-adjusted, HR: 1.300 (0.822-2.056), -value .262]. CCB and clopidogrel co-administration does not appear to significantly impact clopidogrel responsiveness or clinical outcomes. Despite these promising results, further investigation may be warranted. Platelet Function and genoType-Related Long-term progGosis in DES-treated Patients: A Consortium From Multi-centered Registries [PTRG-DES]; NCT04734028.