Dual Starvations Induce Pyroptosis for Orthotopic Pancreatic Cancer Therapy through Simultaneous Deprivation of Glucose and Glutamine.

Pancreatic cancer is a highly fatal disease, and existing treatment methods are ineffective, so it is urgent to develop new effective treatment strategies. The high dependence of pancreatic cancer cells on glucose and glutamine suggests that disrupting this dependency could serve as an alternative strategy for pancreatic cancer therapy. We identified the vital genes glucose transporter 1 (GLUT1) and alanine-serine-cysteine transporter 2 (ASCT2) through bioinformatics analysis, which regulate glucose and glutamine metabolism in pancreatic cancer, respectively. Human serum albumin nanoparticles (HSA NPs) for delivery of GLUT1 and ASCT2 inhibitors, BAY-876/V-9302@HSA NPs, were prepared by a self-assembly process. This nanodrug inhibits glucose and glutamine uptake of pancreatic cancer cells through the released BAY-876 and V-9302, leading to nutrition deprivation and oxidative stress. The inhibition of glutamine leads to the inhibition of the synthesis of the glutathione, which further aggravates oxidative stress. Both of them lead to a significant increase in reactive oxygen species, activating caspase 1 and GSDMD and finally inducing pyroptosis. This study provides a new effective strategy for orthotopic pancreatic cancer treatment by dual starvation-induced pyroptosis. The study for screening metabolic targets using bioinformatics analysis followed by constructing nanodrugs loaded with inhibitors will inspire future targeted metabolic therapy for pancreatic cancer.

Insulin alleviates murine colitis through microbiome alterations and bile acid metabolism.

BACKGROUND: Insulin has been reported to exhibit anti-inflammatory activities in the context of bowel inflammation. However, the role of the interaction between insulin and the microbiota in gut health is unclear. Our goal was to investigate the mechanism of action of insulin in bowel inflammation and the relationship between insulin and the gut microbiota. METHODS: We used acute and chronic murine models of inflammatory bowel disease (IBD) to evaluate whether insulin influences the progression of colitis. Colonic tissues, the host metabolome and the gut microbiome were analyzed to investigate the relationship among insulin treatment, the microbiome, and disease. Experiments involving antibiotic (Abx) treatment and fecal microbiota transplantation (FMT) confirmed the association among the gut microbiota, insulin and IBD. In a series of experiments, we further defined the mechanisms underlying the anti-inflammatory effects of insulin. RESULTS: We found that low-dose insulin treatment alleviated intestinal inflammation but did not cause death. These effects were dependent on the gut microbiota, as confirmed by experiments involving Abx treatment and FMT. Using untargeted metabolomic profiling and 16S rRNA sequencing, we discovered that the level of the secondary bile acid lithocholic acid (LCA) was notably increased and the LCA levels were significantly associated with the abundance of Blautia, Enterorhadus and Rumi-NK4A214_group. Furthermore, LCA exerted anti-inflammatory effects by activating a G-protein-coupled bile acid receptor (TGR5), which inhibited the polarization of classically activated (M1) macrophages. CONCLUSION: Together, these data suggest that insulin alters the gut microbiota and affects LCA production, ultimately delaying the progression of IBD.

Homologous post-treatment strategy enabling phase-pureα-FAPbI3films.

Formamidinium lead triiodide (FAPbI3) is considered as the prospective light-absorbing layer on account of the close-to-ideal bandgap of theα-phase, wide optical absorption spectrum and good thermal stability. Therefore, how to realizeδtoα-phase transition to obtain phase-pureα-FAPbI3without additives is important for FAPbI3perovskite films. Herein, a homologous post-treatment strategy (HPTS) without additives is proposed to prepare FAPbI3films with pureα-phase. The strategy is processed along with dissolution and reconstruction process during the annealing. The FAPbI3film has tensile strain with the substrate, and the lattice keeps tensile, and the film maintains in anα/δhybrid phase. The HPTS process releases the tensile strain between the lattice and the substrate. The process of strain release realizes the phase transition fromδtoα-phase during this process. This strategy can accelerate the transformation from hexagonalδ-FAPbI3to cubicα-FAPbI3at 120 °C. As a result, the acquiredα-FAPbI3films exhibit better film quality in optical and electrical properties, accordingly achieving device efficiency of 19.34% and enhanced stability. This work explores an effective approach to obtain additive-free and phase-pureα-FAPbI3films through a HPTS to fabricate uniform high-performanceα-FAPbI3perovskite solar cells.

Wheat Height Estimation Using LiDAR in Comparison to Ultrasonic Sensor and UAS.

As one of the key crop traits, plant height is traditionally evaluated manually, which can be slow, laborious and prone to error. Rapid development of remote and proximal sensing technologies in recent years allows plant height to be estimated in more objective and efficient fashions, while research regarding direct comparisons between different height measurement methods seems to be lagging. In this study, a ground-based multi-sensor phenotyping system equipped with ultrasonic sensors and light detection and ranging (LiDAR) was developed. Canopy heights of 100 wheat plots were estimated five times during a season by the ground phenotyping system and an unmanned aircraft system (UAS), and the results were compared to manual measurements. Overall, LiDAR provided the best results, with a root-mean-square error (RMSE) of 0.05 m and an R² of 0.97. UAS obtained reasonable results with an RMSE of 0.09 m and an R² of 0.91. Ultrasonic sensors did not perform well due to our static measurement style. In conclusion, we suggest LiDAR and UAS are reliable alternative methods for wheat height evaluation.

Co-precipitation of Cd with struvite during phosphorus recovery.

During the struvite recovery process, Cd, a hazardous metal commonly found in waste streams, can be sequestered by struvite. This study investigated the influence of Cd2+ on the precipitation of struvite. Quantitative X-ray diffraction (QXRD) results showed that the purity of struvite decreased from 99.1% to 73.6% as Cd concentration increased from 1 to 500 µM. Scanning electron microscopy (SEM) revealed a roughened surface of struvite, and X-ray photoelectron spectroscopy (XPS) analysis indicated that the peak area ratio of Cd-OH increased from 19.4% to 51.3%, while the area ratio of Cd-PO4 decreased from 86.6% to 48.7% as Cd concentrations increased from 10 to 500 µM. The findings suggested that Cd2+ disrupted the crystal growth of struvite, and mainly combined with -OH and -PO4 to form amorphous Cd-bearing compounds co-precipitated with struvite. Additionally, Mg-containing amorphous phases were formed by incorporating Mg2+ with -OH and -PO4 during struvite formation.

Genetically Predicted Apolipoprotein E Levels with the Risk of Panvascular Diseases: A Mendelian Randomization Study.

The aim of this study was to comprehensively assess the causal relationship between the overall genetic effect of circulating ApoE levels and panvascular lesions using newer genome-wide association data and two-sample bidirectional Mendelian randomization (MR) analysis. Two-way MR using single-nucleotide polymorphisms of circulating ApoE as instrumental variables was performed using the highest-priority Genome-wide association study (GWAS) data, with factor-adjusted and data-corrected statistics, to estimate causal associations between circulating ApoE levels and 10 pan-vascular diseases in > 500,000 UK Biobank participants, > 400,000 participants of Finnish ancestry, and numerous participants in a consortium of predominantly European ancestry. Meta-analysis was conducted to assess positive results. After correcting for statistical results, elevated circulating ApoE levels were shown to have a significant protective effect against Cerebral ischemia (CI) [IVW odds ratio (OR) 0.888, 95% Confidence Interval (CI): 0.823-0.958, p = 2.3 × 10-3], Coronary heart disease [IVW OR 0.950,95% CI: 0.924-0.976, p = 2.0 × 10-4] had a significant protective effect and potentially suggestive protective causality against Angina pectoris [IVW odds ratio (OR) 0.961, 95%CI: 0.931-0.991, p = 1.1 × 10-2]. There was a potential causal effect for increased risk of Heart failure (HF) [IVW ratio (OR) 1.040, 95%CI: 1.006-1.060, p = 1.8 × 10-2]. (Bonferroni threshold p < 0.0026, PFDR < 0.05) Reverse MR analysis did not reveal significant evidence of a causal effect of PVD on changes in circulating ApoE levels. Meta-analysis increases reliability of results. Elevated circulating ApoE levels were particularly associated with an increased risk of heart failure. Elevated ApoE levels reduce the risk of cerebral ischemia, coronary heart disease, and angina pectoris, reflecting a protective effect. The possible pathophysiological role of circulating ApoE levels in the development of panvascular disease is emphasized.

Monomolecular Membrane-Assisted Growth of Antimony Halide Perovskite/MoS2 Van der Waals Epitaxial Heterojunctions with Long-Lived Interlayer Exciton.

Epitaxial growth stands as a key method for integrating semiconductors into heterostructures, offering a potent avenue to explore the electronic and optoelectronic characteristics of cutting-edge materials, such as transition metal dichalcogenide (TMD) and perovskites. Nevertheless, the layer-by-layer growth atop TMD materials confronts a substantial energy barrier, impeding the adsorption and nucleation of perovskite atoms on the 2D surface. Here, we epitaxially grown an inorganic lead-free perovskite on TMD and formed van der Waals (vdW) heterojunctions. Our work employs a monomolecular membrane-assisted growth strategy that reduces the contact angle and simultaneously diminishing the energy barrier for Cs3Sb2Br9 surface nucleation. By controlling the nucleation temperature, we achieved a reduction in the thickness of the Cs3Sb2Br9 epitaxial layer from 30 to approximately 4 nm. In the realm of inorganic lead-free perovskite and TMD heterojunctions, we observed long-lived interlayer exciton of 9.9 ns, approximately 36 times longer than the intralayer exciton lifetime, which benefited from the excellent interlayer coupling brought by direct epitaxial growth. Our research introduces a monomolecular membrane-assisted growth strategy that expands the diversity of materials attainable through vdW epitaxial growth, potentially contributing to future applications in optoelectronics involving heterojunctions.

Modulation of miR-146b by N6-methyladenosine modification remodels tumor-associated macrophages and enhances anti-PD-1 therapy in colorectal cancer.

PURPOSE: MicroRNA-146b (miR-146b) alleviates experimental colitis in mice by mediating macrophage polarization and the release of inflammatory factors. Our goals were to evaluate the antitumor efficacy of miR-146b in colorectal cancer (CRC) and to investigate the underlying mechanisms. METHODS: We used murine models of CRC to evaluate whether miR-146b influenced the progression of tumors independent of tumor-associated macrophages (TAMs). RNA immunoprecipitation, N6-methyladenosine (m6A) RNA immunoprecipitation and in vitro pri-miRNA processing assays were conducted to examine whether m6A mediates the maturation of pri-miR-146b/miR-146b. In a series of in vitro and in vivo experiments, we further defined the molecular mechanisms of methyltransferase-like 3 (METTL3)/miR-146b-mediated antitumor immunity and its efficacy in combination with anti-PD-1 immunotherapy. RESULTS: We found that miR-146b deletion supported tumor progression by increasing the number of alternatively activated (M2) TAMs. Mechanistically, the m6A-related "writer" protein METTL3 and "reader" protein HNRNPA2B1 controlled miR-146b maturation by regulating the m6A modification region of pri-miR-146b. Furthermore, miR-146b deletion promoted the polarization of M2-TAMs by enhancing phosphoinositide 3-kinase (PI3K)/AKT signaling, and this effect was mediated by the class IA PI3K catalytic subunit p110ß, which reduced T cell infiltration, aggravated immunosuppression and ultimately promoted tumor progression. METTL3 knockdown or miR-146b deletion induced programmed death ligand 1 (PD-L1) production via the p110ß/PI3K/AKT pathway in TAMs and consequently augmented the antitumor activity of anti-PD-1 immunotherapy. CONCLUSIONS: The maturation of pri-miR-146b is m6A-dependent, and miR-146b deletion-mediated TAM differentiation promotes the development of CRC by activating the PI3K/AKT pathway, which induces upregulation of PD-L1 expression, inhibits T cell infiltration into the TME and enhances the antitumor activity of anti-PD-1 immunotherapy. The findings reveal that targeting miR-146b can serve as an adjuvant to anti-PD-1 immunotherapy.

D-Optimal Design and Development of a Koumine-Loaded Microemulsion for Rheumatoid Arthritis Treatment: In vivo and in vitro Evaluation.

Introduction: Koumine (KME) is the most abundant active ingredient separated from Gelsemium elegans Benth and exhibits a significant therapeutic effect on rheumatoid arthritis (RA). It is a lipophilic compound with poor aqueous solubility, and there is an urgent need to develop novel dosage forms of KME and promote its clinical application for the treatment of RA. The aim of this study was to design and develop KME-loaded microemulsions (KME-MEs) for the effective management of RA. Methods: The composition of the microemulsion was selected by carrying out a solubility study and generating pseudoternary phase diagrams, and further optimized by D-Optimal design. The optimized KME-MEs was evaluated for particle size, viscosity, drug release, storage stability, cytotoxicity, cellular uptake, Caco-2 cell transport and everted gut sac investigations. In vivo fluorescence imaging and the therapeutic effects of KME and KME-MEs on collagen-induced arthritis (CIA) rats were also evaluated. Results: The optimized microemulsion contained 8% oil, 32% Smix (surfactant/cosurfactant) and 60% water and was used for in vivo and in vitro studies. The optimal KME-MEs exhibited a small globule size of 18.5 ± 0.14 nm and good stability over 3 months, and the release kinetics followed a first-order model. These KME-MEs had no toxic effect on Caco-2 cells but were efficiently internalized into the cytoplasm. Compared to KME, the KME-MEs displayed significantly increased permeability and absorption in Caco-2 cell monolayer assay and ex vivo everted gut sac experiment. As expected, the KME-MEs attenuated the progression of RA in CIA rats and were more effective than free KME with a reduced frequency of administration. Conclusion: The KME-MEs improved the solubility and therapeutic efficacy of KME by employing formulation technology. These results provide a promising vehicle for the oral delivery of KME to treat RA and have attractive potential for clinical translation.

Non-suicidal self-injury in adolescents with mood disorders and the roles of self-compassion and emotional regulation.

Objective: We aimed to investigate the characteristics and psychological mechanism of non-suicidal self-injury (NSSI) in adolescents with mood disorders. We examined how self-compassion and emotional regulation affected NSSI and tested the mediating role of self-compassion in the link between emotional regulation and NSSI. Method: We recruited outpatient and inpatient adolescent patients with bipolar and related disorders or depressive disorders (DSM-5), with a focus on NSSI. We also recruited healthy controls from the community. We collected demographic and clinical data. The Adolescent Self-injury Questionnaire, Self-compassion Scale (SCS), and Emotion Regulation Questionnaire (ERQ) were used to assess the frequency and severity of NSSI, level of self-compassion, and emotional regulation. Results: In total, we recruited 248 adolescent patients with mood disorders (N = 196 with NSSI, and 52 without NSSI) and 212 healthy controls. NSSI was significantly associated with the female sex, lower levels of education and less use of cognitive reappraisal strategies, lower levels of self-warmth, and higher levels of self-coldness. Multivariate analysis of variance showed that there were significant differences in the scores of ERQ, cognitive reassessment score, and the scores of SCS among the three groups, but no statistical differences in expressive suppression score among the three groups. Self-warmth had a mediating effect between cognitive reappraisal and NSSI behavior. Conclusion: NSSI is prevalent among adolescent patients with mood disorders in clinical settings, especially among girls and those with lower levels of education and less cognitive reappraisal strategies. More clinical attention is needed. Self-compassion and its factors may mediate the association between emotional regulation and NSSI. Clinical implications and future research directions were discussed.

Colloid driven low supersaturation crystallization for atomically thin Bismuth halide perovskite.

It is challenging to grow atomically thin non-van der Waals perovskite due to the strong electronic coupling between adjacent layers. Here, we present a colloid-driven low supersaturation crystallization strategy to grow atomically thin Cs3Bi2Br9. The colloid solution drives low-concentration solute in a supersaturation state, contributing to initial heterogeneous nucleation. Simultaneously, the colloids provide a stable precursor source in the low-concentration solute. The surfactant is absorbed in specific crystal nucleation facet resulting in the anisotropic growth of planar dominance. Ionic perovskite Cs3Bi2Br9 is readily grown from monolayered to six-layered Cs3Bi2Br9 corresponding to thicknesses of 0.7, 1.6, 2.7, 3.6, 4.6 and 5.7 nm. The atomically thin Cs3Bi2Br9 presents layer-dependent nonlinear optical performance and stacking-induced second harmonic generation. This work provides a concept for growing atomically thin halide perovskite with non-van der Waal structures and demonstrates potential application for atomically thin single crystals' growth with strong electronic coupling between adjacent layers.

Zinc/carbon nanomaterials inhibit antibiotic resistance genes by affecting quorum sensing and microbial community in cattle manure production.

This study used metagenomic sequencing to examine the effects of carbon-based zinc oxide nanoparticles (CZnONPs) and graphene-based zinc oxide nanoparticles (GZnONPs) on quorum sensing (QS), antibiotic resistance genes (ARGs) and microbial community changes during cattle manure production. The manure zinc content was significantly reduced in GZnONPs group. In the QS pathway, the autoinducer gene increases significantly in Control group, while the transporter and repressor genes experience a substantial increase in CZnONPs group. These results contributed to the significantly decreased the abundance of ARGs in GZnONPs group. The co-occurrence network analysis revealed a correlation between core ARGs and QS-related KEGG Orthology or ARGs' hosts, indicating that the selective pressure of zinc influences microbial QS, forming a unique ARG pattern in in vivo anaerobic fermentation. These findings suggest that implementing nutritional regulation in farming practices can serve as a preventive measure to mitigate the potential transmission of ARGs resulting from livestock waste.

Exploring the links between alexithymia and cognitive emotion regulation strategies in internet addiction: A network analysis model.

Alexithymia and emotion regulation are closely related to internet addiction. However, no research has examined how the different components of alexithymia are associated with cognitive emotion regulation in the context of multi-strategy use in internet addiction. The current study aimed to investigate the relation between alexithymia and cognitive emotion regulation in individuals with internet addiction via network analysis. Participants included 560 students with Young's Internet Addiction Test scores greater than 50 points; they were also asked to complete the Toronto Alexithymia Scale (TAS-20) and the Cognitive Emotion Regulation Questionnaire (CERQ). The results revealed two bridge nodes emerging within the combined alexithymia and cognitive emotion regulation network model: "catastrophizing" and "externally oriented thoughts." These findings indicate a more specific relation between alexithymia and cognitive emotion regulation and provide empirical evidence for targeted prevention and targeted interventions for internet addiction.

Overexpression of KLF5 is associated with poor survival and G1/S progression in pancreatic cancer.

Despite improvements in surgical procedures and comprehensive therapies, pancreatic cancer remains one of the most aggressive and deadly human malignancies. It is therefore necessary to determine which cellular mediators associate with prognosis in pancreatic cancer so as to improve the treatment of this disease. In the present study, mRNA array and immunohistochemical analyses showed that KLF5 is highly expressed in tissue samples from three short-surviving patients with pancreatic cancer. Survival analysis using data from The Cancer Genome Atlas showed that patients highly expressing KLF5 exhibited shorter overall and tumor-free survival times. Mechanistically, KLF5 promoted expression of E2F1, cyclin D1 and Rad51, while inhibiting expression of p16 in pancreatic cancer cells. Finally, flow cytometric analyses verified that KLF5 promotes G1/S progression of the cell cycle in pancreatic cancer cells. Collectively, these findings demonstrate that KLF5 is an important prognostic biomarker in pancreatic cancer patients, and they shed light on the molecular mechanism by which KLF5 stimulates cell cycle progression in pancreatic cancer.

Principal variable selection to explain grain yield variation in winter wheat from features extracted from UAV imagery.

BACKGROUND: Automated phenotyping technologies are continually advancing the breeding process. However, collecting various secondary traits throughout the growing season and processing massive amounts of data still take great efforts and time. Selecting a minimum number of secondary traits that have the maximum predictive power has the potential to reduce phenotyping efforts. The objective of this study was to select principal features extracted from UAV imagery and critical growth stages that contributed the most in explaining winter wheat grain yield. Five dates of multispectral images and seven dates of RGB images were collected by a UAV system during the spring growing season in 2018. Two classes of features (variables), totaling to 172 variables, were extracted for each plot from the vegetation index and plant height maps, including pixel statistics and dynamic growth rates. A parametric algorithm, LASSO regression (the least angle and shrinkage selection operator), and a non-parametric algorithm, random forest, were applied for variable selection. The regression coefficients estimated by LASSO and the permutation importance scores provided by random forest were used to determine the ten most important variables influencing grain yield from each algorithm. RESULTS: Both selection algorithms assigned the highest importance score to the variables related with plant height around the grain filling stage. Some vegetation indices related variables were also selected by the algorithms mainly at earlier to mid growth stages and during the senescence. Compared with the yield prediction using all 172 variables derived from measured phenotypes, using the selected variables performed comparable or even better. We also noticed that the prediction accuracy on the adapted NE lines (r = 0.58-0.81) was higher than the other lines (r = 0.21-0.59) included in this study with different genetic backgrounds. CONCLUSIONS: With the ultra-high resolution plot imagery obtained by the UAS-based phenotyping we are now able to derive more features, such as the variation of plant height or vegetation indices within a plot other than just an averaged number, that are potentially very useful for the breeding purpose. However, too many features or variables can be derived in this way. The promising results from this study suggests that the selected set from those variables can have comparable prediction accuracies on the grain yield prediction than the full set of them but possibly resulting in a better allocation of efforts and resources on phenotypic data collection and processing.

Cell-in-Cell Phenomenon and Its Relationship With Tumor Microenvironment and Tumor Progression: A Review.

The term cell-in-cell, morphologically, refers to the presence of one cell within another. This phenomenon can occur in tumors but also among non-tumor cells. The cell-in-cell phenomenon was first observed 100 years ago, and it has since been found in a variety of tumor types. Recently, increasing attention has been paid to this phenomenon and the underlying mechanism has gradually been elucidated. There are three main related process: cannibalism, emperipolesis, and entosis. These processes are affected by many factors, including the tumor microenvironment, mitosis, and genetic factors. There is considerable evidence to suggest that the cell-in-cell phenomenon is associated with the prognosis of cancers, and it promotes tumor progression in most situations. Notably, in pancreatic cancer, the cell-in-cell phenomenon is associated with reduced metastasis, which is the opposite of what happens in other tumor types. Thus, it can also inhibit tumor progression. Studies show that cell-in-cell structure formation is affected by the tumor microenvironment, and that it may lead to changes in cellular characteristics. In this review, we summarize the different cell-in-cell processes and discuss their role in tumor progression and how they are regulated by different mechanisms.

Elucidating Sorghum Biomass, Nitrogen and Chlorophyll Contents With Spectral and Morphological Traits Derived From Unmanned Aircraft System.

Unmanned aircraft systems (UAS) provide an efficient way to phenotype crop morphology with spectral traits such as plant height, canopy cover and various vegetation indices (VIs) providing information to elucidate genotypic responses to the environment. In this study, we investigated the potential use of UAS-derived traits to elucidate biomass, nitrogen and chlorophyll content in sorghum under nitrogen stress treatments. A nitrogen stress trial located in Nebraska, USA, contained 24 different sorghum lines, 2 nitrogen treatments and 8 replications, for a total of 384 plots. Morphological and spectral traits including plant height, canopy cover and various VIs were derived from UAS flights with a true-color RGB camera and a 5-band multispectral camera at early, mid and late growth stages across the sorghum growing season in 2017. Simple and multiple regression models were investigated for sorghum biomass, nitrogen and chlorophyll content estimations using the derived morphological and spectral traits along with manual ground truthed measurements. Results showed that, the UAS-derived plant height was strongly correlated with manually measured plant height (r = 0.85); and the UAS-derived biomass using plant height, canopy cover and VIs had strong exponential correlations with the sampled biomass of fresh stalks and leaves (maximum r = 0.85) and the biomass of dry stalks and leaves (maximum r = 0.88). The UAS-derived VIs were moderately correlated with the laboratory measured leaf nitrogen content (r = 0.52) and the measured leaf chlorophyll content (r = 0.69) in each plot. The methods developed in this study will facilitate genetic improvement and agronomic studies that require assessment of stress responses in large-scale field trials.