A Triple-Responsive Polymeric Prodrug Nanoplatform with Extracellular ROS Consumption and Intracellular H2 O2 Self-Generation for Imaging-Guided Tumor Chemo-Ferroptosis-Immunotherapy.

High reactive oxygen species (ROS) levels in tumor microenvironment (TME) impair both immunogenic cell death (ICD) efficacy and T cell activity. Furthermore, tumor escapes immunosurveillance via programmed death-1/programmed death ligand-1 (PD-L1) signal, and the insufficient intracellular hydrogen peroxide weakens ferroptosis efficacy. To tackle the above issues, a glutathione (GSH)/ROS/pH triple-responsive prodrug nanomedicine that encapsulates Fe2 O3 nanoparticle via electrostatic interaction is constructed for magnetic resonance imaging (MRI)-guided multi-mode theranostics with chemotherapy/ferroptosis/immunotherapy. The diselenide bond consumes ROS in TME to increase T cells and ICD efficacy, the cleavage of which facilitates PD-L1 antagonist D peptide release to block immune checkpoint. After intracellular internalization, Fe2 O3 nanoparticle is released in the acidic endosome for MRI simultaneously with lipid peroxides generation for tumor ferroptosis. Doxorubicin is cleaved from polymers in the condition of high intracellular GSH level accompanied by tumor ICD, which simultaneously potentiates ferroptosis by NADPH oxidase mediated H2 O2 self-generation. In vivo results indicate that the nanoplatform strengthens tumor ICD, induces cytotoxic T lymphocytes proliferation, inhibits 4T1 tumor regression and metastasis, and prolongs survival median. In all, a new strategy is proposed in strengthening ICD and T cells activity cascade with ferroptosis as well as immune checkpoint blockade for effective tumor immunotherapy.

Short-term high temperature may increase the incidence risk of collective conflicts: A case-crossover study in the Greater Middle East.

BACKGROUND: Violent conflict is a formidable global challenge, with long-lasting impacts on individual health and society security. There has been compelling evidence that heat can increase aggression intention on the individual level. However, little is known about the short-term relationship between ambient temperature and collective violent conflicts, especially in less developed regions. METHOD: We conducted a time-stratified case-crossover study combined with the distributed lag nonlinear model (DLNM) among 247,773 violent conflicts from 29 countries or regions in the Greater Middle East, between 1997 and 2021. Potential modification effects of economic status and climate conditions were explored by stratified analyses. Negative control and sensitivity analyses were also performed to test the robustness of our model. RESULTS: We observed significant associations between higher temperature and the onset of five categories of violent conflicts. The effects generally occurred within the first several days after exposure. The incidence risks of battles, violence against civilians, explosions/remote violence, protests and riots were 1.60 [95 % confidence interval (CI): 1.31-1.95], 1.82 (95 % CI: 1.37-2.42), 1.24 (95 % CI: 1.08-1.41), 1.16 (95 % CI: 1.09-1.24) and 1.54 (95 % CI: 1.22-1.95) when comparing extreme high temperatures to minimum-risk temperatures. The associations were generally more prominent in areas with lower economic levels and associations in regions of the continental climate are also stronger. CONCLUSIONS: Our finding reveals novel and concrete evidence that short-term high temperature could increase the risk of multiple forms of violent conflict in the Greater Middle East and provides new insights into the potential short-term mechanisms under the heat-collective violence association.

Cell Death Pathway Regulation by Functional Nanomedicines for Robust Antitumor Immunity.

Cancer immunotherapy has become a mainstream cancer treatment over traditional therapeutic modes. Cancer cells can undergo programmed cell death including ferroptosis, pyroptosis, autophagy, necroptosis, apoptosis and cuproptosis which are find to have intrinsic relationships with host antitumor immune response. However, direct use of cell death inducers or regulators may bring about severe side effects that can also be rapidly excreted and degraded with low therapeutic efficacy. Nanomaterials are able to carry them for long circulation time, high tumor accumulation and controlled release to achieve satisfactory therapeutic effect. Nowadays, a large number of studies have focused on nanomedicines-based strategies through modulating cell death modalities to potentiate antitumor immunity. Herein, immune cell types and their function are first summarized, and state-of-the-art research progresses in nanomedicines mediated cell death pathways (e.g., ferroptosis, pyroptosis, autophagy, necroptosis, apoptosis and cuproptosis) with immune response provocation are highlighted. Subsequently, the conclusion and outlook of potential research focus are discussed.

Molecular mechanisms of noncoding RNA and epigenetic regulation in obesity with consequent diabetes mellitus development.

Diabetes mellitus (DM) and obesity have become two of the most prevalent and challenging diseases worldwide, with increasing incidence and serious complications. Recent studies have shown that noncoding RNA (ncRNA) and epigenetic regulation play crucial roles in the pathogenesis of DM complicated by obesity. Identification of the involvement of ncRNA and epigenetic regulation in the pathogenesis of diabetes with obesity has opened new avenues of investigation. Targeting these mechanisms with small molecules or RNA-based therapies may provide a more precise and effective approach to diabetes treatment than traditional therapies. In this review, we discuss the molecular mechanisms of ncRNA and epigenetic regulation and their potential therapeutic targets, and the research prospects for DM complicated with obesity.

Nanotechnology-Assisted Immunogenic Cell Death for Effective Cancer Immunotherapy.

Tumor vaccines have been used to treat cancer. How to efficiently induce tumor-associated antigens (TAAs) secretion with host immune system activation is a key issue in achieving high antitumor immunity. Immunogenic cell death (ICD) is a process in which tumor cells upon an external stimulus change from non-immunogenic to immunogenic, leading to enhanced antitumor immune responses. The immune properties of ICD are damage-associated molecular patterns and TAA secretion, which can further promote dendritic cell maturation and antigen presentation to T cells for adaptive immune response provocation. In this review, we mainly summarize the latest studies focusing on nanotechnology-mediated ICD for effective cancer immunotherapy as well as point out the challenges.

Relationships between urban expansion and socioenvironmental indicators across multiple scales of watersheds: a case study among watersheds running through China.

Understanding the relationships between urban expansion and social/environmental features is fundamental to managing watershed and urban expansion. However, such relationships remain unclear, especially across multiple scales of watersheds. Here, we quantified the correlation between urban expansion measures and 255 socioenvironmental indicators across three scales of watersheds running through China (20, 103, and 349 watersheds) during 1992-2016 and analyzed their scaling relations. The results showed that the number of indicators showing a significant correlation with the area and speed of urban expansion increased from 132 and 153 to 234 and 237, respectively, from level 1 to level 3 watersheds. Among these indicators, urban expansion was significantly correlated with indicators of climate and anthropogenic impact. From a large scale (level 1 watershed) to a small scale (level 3 watershed), 104 and 84 socioenvironmental indicators shifted from uncorrelated to significantly correlated with urban expansion area and speed. The constraint line analysis further confirmed that some relationships were nonlinear, which suggested that the drivers and impacts of urban expansion have scaling effects. We argue that it is crucial to consider the scaling effects of urban expansion when we formulate urban or watershed management plans.

Transformable prodrug nanoplatform via tumor microenvironment modulation and immune checkpoint blockade potentiates immunogenic cell death mediated cancer immunotherapy.

Rationale: Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) as well as immune checkpoints for escaping immunosurveillance. Methods: Herein, a new type of TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was constructed when the D-peptide antagonist (DPPA-1) of programmed death ligand-1 was conjugated onto the surface, and talabostat mesylate (Tab, a fibroblast activation protein inhibitor) was encapsulated in the watery core (DPPA-TRPP/Tab). Doxorubicin (DOX) conjugation in the chain served as an immunogenic cell death (ICD) inducer and hydrophobic part. Results: DPPA-TRPP/Tab reassembled into a micellar structure in vivo with TME modulation by Tab, ROS consumption by 2, 2'-diselanediylbis(ethan-1-ol), immune checkpoint blockade by DPPA-1 and ICD generation by DOX. This resolved the dilemma between a hydrophilic Tab release in the TME for CAF inhibition and intracellular hydrophobic DOX release for ICD via re-assembly in weakly acidic TME with polymersome-micelle transformation. In vivo results indicated that DPPA-TRPP/Tab could improve tumor accumulation, suppress CAF formation, downregulate regulatory T cells and promote T lymphocyte infiltration. In mice, it gave a 60% complete tumor regression ratio and a long-term immune memory response. Conclusion: The study offers potential in tumor eradication via exploiting an "all-in-one" smart polymeric nanoplatform.

PreTP-2L: identification of therapeutic peptides and their types using two-layer ensemble learning framework.

MOTIVATION: Therapeutic peptides play an important role in immune regulation. Recently various therapeutic peptides have been used in the field of medical research, and have great potential in the design of therapeutic schedules. Therefore, it is essential to utilize the computational methods to predict the therapeutic peptides. However, the therapeutic peptides cannot be accurately predicted by the existing predictors. Furthermore, chaotic datasets are also an important obstacle of the development of this important field. Therefore, it is still challenging to develop a multi-classification model for identification of therapeutic peptides and their types. RESULTS: In this work, we constructed a general therapeutic peptide dataset. An ensemble-learning method named PreTP-2L was developed for predicting various therapeutic peptide types. PreTP-2L consists of two layers. The first layer predicts whether a peptide sequence belongs to therapeutic peptide, and the second layer predicts if a therapeutic peptide belongs to a particular species. AVAILABILITY AND IMPLEMENTATION: A user-friendly webserver PreTP-2L can be accessed at http://bliulab.net/PreTP-2L.

DAQE: Enhancing the Quality of Compressed Images by Exploiting the Inherent Characteristic of Defocus.

Image defocus is inherent in the physics of image formation caused by the optical aberration of lenses, providing plentiful information on image quality. Unfortunately, existing quality enhancement approaches for compressed images neglect the inherent characteristic of defocus, resulting in inferior performance. This paper finds that in compressed images, significantly defocused regions have better compression quality, and two regions with different defocus values possess diverse texture patterns. These observations motivate our defocus-aware quality enhancement (DAQE) approach. Specifically, we propose a novel dynamic region-based deep learning architecture of the DAQE approach, which considers the regionwise defocus difference of compressed images in two aspects. (1) The DAQE approach employs fewer computational resources to enhance the quality of significantly defocused regions and more resources to enhance the quality of other regions; (2) The DAQE approach learns to separately enhance diverse texture patterns for regions with different defocus values, such that texture-specific enhancement can be achieved. Extensive experiments validate the superiority of our DAQE approach over state-of-the-art approaches in terms of quality enhancement and resource savings.

Protocol for indirect and direct co-culture between human cancer cells and endothelial cells.

The cross talk between cancer cells and endothelial cells (ECs) within the tumor microenvironment plays a critical role in tumor progression, recurrence, and cancer stemness. Here, we present a protocol containing two in vitro approaches to study such interactions. We first describe an indirect co-culture system to study the regulation of stemness markers in cancer cells by secreted factors from ECs. We then detail a direct co-culture system to study juxtracrine communications between the cell types. For complete details on the use and execution of this protocol, please refer to Sewell-Loftin et al.1 and Guo et al.2.

Anti-HER2 scFv-nCytc-Modified Lipid-Encapsulated Oxygen Nanobubbles Prepared with Bulk Nanobubble Water for Inducing Apoptosis and Improving Photodynamic Therapy.

Bulk nanobubbles fascinate scientists because of their stability over long periods of time and their ability to carry gases, leading to numerous potential applications. Considering the hypoxic tumor microenvironment and the advantages of bulk nanobubbles, lipid-encapsulated oxygen nanobubbles are prepared from free bulk oxygen nanobubbles in this study. The obtained carrier is then modified with a protein fused with the single-chain antibody of human epidermal growth factor receptor 2 (anti-HER2 scFv) and tandem-repeat cytochrome c (anti-HER2 scFv-nCytc) to enhance tumor targeting and induce tumor apoptosis. Copper phthalocyanine is used as the photosensitizer to demonstrate how the oxygen in the nanobubbles affects the efficiency of photodynamic therapy (PDT). The combination of anti-HER2 scFv-nCytc and PDT synergistically improves the therapeutic effect and alleviates hypoxia in tumors in vivo while causing little inflammatory response. Based on the findings, bulk nanobubble water shows promise in the targeted delivery of oxygen and can be combined with antibody therapy to enhance the efficiency of PDT.

The predictive utility of atherosclerosis-related risk factors as predictors of the prognosis of idiopathic sudden sensorineural hearing loss in older adults.

BACKGROUND: There have been few studies to date exploring prognostic outcomes associated with idiopathic sudden sensorineural hearing loss (ISSNHL) in order adults. OBJECTIVE: This investigation was designed to explore the relationship between atherosclerosis-related risk factors and ISSNHL outcomes among older individuals. MATERIAL AND METHODS: In total, 172 older adults diagnosed ISSNHL from 2016 to 2021 were retrospectively evaluated to compare demographic and clinical test results. RESULTS: Relative to healthy controls, ISSNHL patients exhibited significant differences in hypertension incidence and factors related to coagulation. With respect to prognosis, age, onset days, hypertension, the degree of hearing loss, type of hearing curve, fibrinogen and D-dimer levels were significant univariate prognostic factors, whereas multivariate logistic analysis showed that hypertension (p = .005) and D-dimer concentration (p = .000) were related to the treatment outcome of older ISSNHL patients. The area under the curve (AUC) for D-dimer levels was 0.795 (95% CI: 0.724-0.866). When using a D-dimer cut-off threshold value of 107.5 ng/mL, the sensitivity and specificity values of 77.0% and 76.7%. CONCLUSIONS: The present results indicate that hypertension incidence and D-dimer levels may be presented as an important prognostic indicator in older affected ISSNHL individuals.

The patent foramen ovale may alter migraine brain activity: A pilot study of electroencephalography spectrum and functional connectivity analysis.

Background: A link has been shown between patent foramen ovale (PFO) and migraine, particularly migraine with aura. However, it is unknown if PFO might cause migraine by altering cortical excitability and neural network, which may lower the threshold of cortical spreading depression (CSD). This study aims to compare the spectrum power and functional connectivity of the alpha and beta bands of electroencephalography (EEG) across migraine patients with and without PFO. Methods: Thirty-five migraine patients with PFO (PFO +), 35 migraine patients without PFO (PFO -) and 20 PFO patients without migraine (control) were enrolled in this cross-sectional analysis. 19-channel EEG was recorded for all patients under resting state and intermittent photic stimulation. Power spectrum density (PSD) and phase lag index (PLI) of alpha and beta bands were then calculated and compared between the three groups. Results: During photic stimulation, the beta band PSD at the occipital area was substantially higher in PFO + migraine patients compared to PFO-migraine patients (p < 0.05, Bonferroni corrected). Subgroup analysis showed that both migraine with and without aura patients with PFO had increased PSD in the alpha and beta bands at the occipital region during photic stimulation (p < 0.05, Bonferroni corrected). Meanwhile, the beta band PLI during photic stimulation was significantly elevated (adjusted p = 0.008, utilizing the network-based statistic technique) in PFO + group compared to PFO-group. Furthermore, although failed to pass the correction, the beta band power in the occipital area during photic stimulation at 20 Hz on O1 (R = 0.392, p = 0.024) and O2 channel (R = 0.348, p = 0.047) was prone to positively correlated with MIDAS score, and during photic stimulation at 12 Hz on O2 channel (R = 0.396, p = 0.022) and 20 Hz (R = 0.365, p = 0.037) on O1 channel was prone to positively correlated to HIT-6 score in PFO+ migraineurs, whereas no similar correlation was found in the PFO-group patients. Conclusion: The outcomes of this investigation suggested that PFO may change the cortical excitability in the occipital lobe of both migraineurs with and without aura. Meanwhile, the beta band PSD on the occipital area during photic stimulation might be an objective measure of severity in migraineurs with PFO.

Laboratory investigation on added-value application of the COVID-19 disposable mask in hot mix asphalt (HMA).

The outbreak of the COVID-19 pandemic has stimulated the demand for disposable masks to an unprecedented level, which also poses a significant risk to the natural environment from the improper treatment or disposal of waste masks. To lower such an environmental risk and maximize the added value of the waste masks, this paper proposed to recycle the waste mask fiber (MF) in combination with the waste cooking oil (WCO) for hot mix asphalt (HMA) application. A series of MF + WCO modified asphalt binders were first designed and fabricated. Their performance properties were then systematically measured. The physical-rheological test results showed that the incorporation of MF can significantly improve the high-temperature rutting resistance performance of asphalt binder. However, it may also lower the asphalt's low-temperature anti-cracking performance. The addition of WCO was found to compensate for this low-temperature performance loss effectively, and the MF5% + WCO3% was identified as the best combination. The Fourier transform infrared (FTIR) spectroscopy test results revealed that the asphalt modified by the MF + WCO involved only a physical modification. The performance test results indicated that the high-temperature permanent deformation resistance and low-temperature anti-cracking of MF5% + WCO3% modified HMA was greatly enhanced, while its moisture stability was slightly reduced but still met the specification requirement. The environmental benefit assessments proved that recycling the waste masks for asphalt paving can provide an enormous added value to pavement engineering in terms of carbon emission reduction and land resource saving.

sAMPpred-GAT: prediction of antimicrobial peptide by graph attention network and predicted peptide structure.

MOTIVATION: Antimicrobial peptides (AMPs) are essential components of therapeutic peptides for innate immunity. Researchers have developed several computational methods to predict the potential AMPs from many candidate peptides. With the development of artificial intelligent techniques, the protein structures can be accurately predicted, which are useful for protein sequence and function analysis. Unfortunately, the predicted peptide structure information has not been applied to the field of AMP prediction so as to improve the predictive performance. RESULTS: In this study, we proposed a computational predictor called sAMPpred-GAT for AMP identification. To the best of our knowledge, sAMPpred-GAT is the first approach based on the predicted peptide structures for AMP prediction. The sAMPpred-GAT predictor constructs the graphs based on the predicted peptide structures, sequence information and evolutionary information. The Graph Attention Network (GAT) is then performed on the graphs to learn the discriminative features. Finally, the full connection networks are utilized as the output module to predict whether the peptides are AMP or not. Experimental results show that sAMPpred-GAT outperforms the other state-of-the-art methods in terms of AUC, and achieves better or highly comparable performance in terms of the other metrics on the eight independent test datasets, demonstrating that the predicted peptide structure information is important for AMP prediction. AVAILABILITY AND IMPLEMENTATION: A user-friendly webserver of sAMPpred-GAT can be accessed at http://bliulab.net/sAMPpred-GAT and the source code is available at https://github.com/HongWuL/sAMPpred-GAT/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PreTP-Stack: Prediction of Therapeutic Peptides Based on the Stacked Ensemble Learing.

Therapeutic peptide prediction is critical for drug development and therapeutic therapy. Researchers have developed several computational methods to identify different therapeutic peptide types. However, most computational methods focus on identifying the specific type of therapeutic peptides and fail to accurately predict all types of therapeutic peptides. Moreover, it is still challenging to utilize different properties features to predict the therapeutic peptides. In this study, a novel stacking framework PreTP-Stack is proposed for predicting different types of therapeutic peptide. PreTP-Stack is constructed based on ten different features and four predictors (Random Forest, Linear Discriminant Analysis, XGBoost and Support Vector Machine). Then the proposed method constructs an auto-weighted multi-view learning model as a final meta-classifier to enhance the performance of the basic models. Experimental results showed that the proposed method achieved better or highly comparable performance with the state-of-the-art methods for predicting eight types of therapeutic peptides A user-friendly web-server predictor is available at http://bliulab.net/PreTP-Stack.

Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity.

Pancreatic neuroendocrine tumors (pNETs) are extremely diverse and highly vascularized neoplasms that arise from endocrine cells in the pancreas. The pNETs harbor a subpopulation of stem cell-like malignant cells, known as cancer stem cells (CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study, we demonstrate that CSCs in human pNETs co-express protein kinase PKD1 and CD44. We further identify PKD1 signaling as a critical pathway in the control of CSC maintenance in pNET cells. PKD1 signaling regulates the expression of a CSC- and EMT-related gene signature and promotes CSC self-renewal, likely leading to the preservation of a subpopulation of CSCs at an intermediate EMT state. This suggests that the PKD1 signaling pathway may be required for the development of a unique CSC phenotype with plasticity and partial EMT. Given that the signaling networks connected with CSC maintenance and EMT are complex, and extend through multiple levels of regulation, this study provides insight into signaling regulation of CSC plasticity and partial EMT in determining the fate of CSCs. Inhibition of the PKD1 pathway may facilitate the elimination of specific CSC subsets, thereby curbing tumor progression and metastasis.

Albumins as Extracellular Protein Nanoparticles Collaborate with Plasma Ions to Control Biological Osmotic Pressure.

Introduction: Plasma albumins as protein nanoparticles (PNs) exert essential functions in the control of biological osmotic pressure (OP), being involved in regulating water metabolism, cell morphology and cell tension. Understanding how plasma albumins and different electrolytes co-determine biological OP effects is crucial for correct interpretation of hemodynamic disorders, and practical treatment of hypo/hyper-proteinemia. Methods: Optical measurement based on intermediate filament (IF) tension probe was used for real-time evaluation of transmembrane osmotic effects in live cells. Ion fluorescent probes were employed to evaluate intracellular ion levels, and a current clamp was used to measure membrane potential, thus exploring association of electrochemical and osmotic effects. Results: Albumins are involved in regulation of intracellular osmolarity by a quantitative relationship. Extracellular PNs can alter membrane potentials by adsorbing counterions, induce production of intracellular PNs and further control the opening of ion channels and ion flow, contributing to electrochemical and osmotic re-equilibrium. Furthermore, various ions interplay with extracellular PNs, showing different osmotic effects: increased levels of calcium ions result in a hypotonic effect, whereas potassium ions induce hyper-osmolarity. Conclusion: Extracellular PNs and Ca2+/K+ display antagonistic or synergetic effects in regulating biological OP. Live cells can spontaneously regulate osmotic effects through changing membrane potential and controlling intracellular ion content. Various plasma components need to be comprehensively analyzed, further developing a diagnostic index that considers the biological OP effects of various blood components and improves the evaluation of symptoms and diseases, such as calcium/potassium-hemodynamic disorders and edema.

Why it is Unfortunate that Linear Machine Learning "Works" so well in Electromechanical Switching of Ferroelectric Thin Films.

Machine learning (ML) is relied on for materials spectroscopy. It is challenging to make ML models fail because statistical correlations can mimic the physics without causality. Here, using a benchmark band-excitation piezoresponse force microscopy polarization spectroscopy (BEPS) dataset the pitfalls of the so-called "better", "faster", and "less-biased" ML of electromechanical switching are demonstrated and overcome. Using a toy and real experimental dataset, it is demonstrated how linear nontemporal ML methods result in physically reasonable embedding (eigenvalues) while producing nonsensical eigenvectors and generated spectra, promoting misleading interpretations. A new method of unsupervised multimodal hyperspectral analysis of BEPS is demonstrated using long-short-term memory (LSTM) ß-variational autoencoders (ß-VAEs) . By including LSTM neurons, the ordinal nature of ferroelectric switching is considered. To improve the interpretability of the latent space, a variational Kullback-Leibler-divergency regularization is imposed . Finally, regularization scheduling of ß as a disentanglement metric is leveraged to reduce user bias. Combining these experiment-inspired modifications enables the automated detection of ferroelectric switching mechanisms, including a complex two-step, three-state one. Ultimately, this work provides a robust ML method for the rapid discovery of electromechanical switching mechanisms in ferroelectrics and is applicable to other multimodal hyperspectral materials spectroscopies.