Construction and validation of a novel immunological model to predict prognosis in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer, with limited treatment options. In this study, we investigated the role of immune cell infiltration in PDAC progression and constructed an immune-related predictive model for patients with PDAC based on the International Cancer Genome Consortium (ICGC) cohort. Related algorithms have been used to assess the immune microenvironment. Least Absolute Shrinkage and Selection Operator (LASSO) Cox analysis was used to construct the model, and receiver operating characteristic and decision curve analysis analyses were conducted to evaluate its diagnostic and prognostic efficacy. The results demonstrated a correlation between high immune infiltration and better prognosis in PDAC. The immune-related prognostic model (IPM) identified four genes through LASSO Cox analysis, with the high IPM group being associated with a worse prognosis. Cox regression analysis confirmed that IPM is an independent risk factor for PDAC. Validation through analysis of The Cancer Genome Atlas cohort and our own individual tumor samples revealed a similar trend to that observed in the ICGC cohort. Finally, a nomogram incorporating age and IPM demonstrated efficacy in the prognostic evaluation of patients with PDAC. In conclusion, we developed a novel immune-related prognosis prediction model for PDAC that offers new possibilities for the measurement of immunotherapy and prognostic assessment of patients.

Squaraine Dyes Exhibit Spontaneous Fluorescence Blinking That Enables Live-Cell Nanoscopy.

Hampered by their susceptibility to nucleophilic attack and chemical bleaching, electron-deficient squaraine dyes have long been considered unsuitable for biological imaging. This study unveils a surprising twist: in aqueous environments, bleaching is not irreversible but rather a reversible spontaneous quenching process. Leveraging this new discovery, we introduce a novel deep-red squaraine probe tailored for live-cell super-resolution imaging. This probe enables single-molecule localization microscopy (SMLM) under physiological conditions without harmful additives or intense lasers and exhibits spontaneous blinking orchestrated by biological nucleophiles, such as glutathione or hydroxide anion. With a low duty cycle (∼0.1%) and high-emission rate (∼6 × 104 photons/s under 400 W/cm2), the squaraine probe surpasses the benchmark Cy5 dye by 4-fold and Si-rhodamine by a factor of 1.7 times. Live-cell SMLM with the probe reveals intricate structural details of cell membranes, which demonstrates the high potential of squaraine dyes for next-generation super-resolution imaging.

Pathological image profiling identifies onco-microbial, tumor immune microenvironment, and prognostic subtypes of colorectal cancer.

Histology slide, tissue microbes, and the host gene expression can be independent prognostic factors of colorectal cancer (CRC), but the underlying associations and biological significance of these multimodal omics remain unknown. Here, we comprehensively profiled the matched pathological images, intratumoral microbes, and host gene expression characteristics in 527 patients with CRC. By clustering these patients based on histology slide features, we classified the patients into two histology slide subtypes (HSS). Onco-microbial community and tumor immune microenvironment (TIME) were also significantly different between the two subtypes (HSS1 and HSS2) of patients. Furthermore, variation in intratumoral microbes-host interaction was associated with the prognostic heterogeneity between HSS1 and HSS2. This study proposes a new CRC classification based on pathological image features and elucidates the process by which tumor microbes-host interactions are reflected in pathological images through the TIME.

Thiolation for Enhancing Photostability of Fluorophores at the Single-Molecule Level.

Fluorescent probes are essential for single-molecule imaging. However, their application in biological systems is often limited by the short photobleaching lifetime. To overcome this, we developed a novel thiolation strategy for squaraine dyes. By introducing thiolation of the central cyclobutene of squaraine (thio-squaraine), we observed a ≈5-fold increase in photobleaching lifetime. Our single-molecule data analysis attributes this improvement to improved photostability resulting from thiolation. Interestingly, bulk measurements show rapid oxidation of thio-squaraine to its oxo-analogue under irradiation, giving the perception of inferior photostability. This discrepancy between bulk and single-molecule environments can be ascribed to the factors in the latter, including larger intermolecular distances and restricted mobility, which reduce the interactions between a fluorophore and reactive oxygen species produced by other fluorophores, ultimately impacting photobleaching and photoconversion rate. We demonstrate the remarkable performance of thio-squaraine probes in various imaging buffers, such as glucose oxidase with catalase (GLOX) and GLOX+trolox. We successfully employed these photostable probes for single-molecule tracking of CD56 membrane protein and monitoring mitochondria movements in live neurons. CD56 tracking revealed distinct motion states and the corresponding protein fractions. This investigation is expected to propel the development of single-molecule imaging probes, particularly in scenarios where bulk measurements show suboptimal performance.

Human Pluripotent Stem Cells Derived Endothelial Cells Repair Choroidal Ischemia.

Choroidal atrophy is a common fundus pathological change closely related to the development of age-related macular degeneration (AMD), retinitis pigmentosa, and pathological myopia. Studies suggest that choroidal endothelial cells (CECs) that form the choriocapillaris vessels are the first cells lost in choroidal atrophy. It is found that endothelial cells derived from human pluripotent stem cells (hPSC-ECs) through the MESP1+ mesodermal progenitor stage express CECs-specific markers and can integrate into choriocapillaris. Single-cell RNA-seq (scRNA-seq) studies show that hPSC-ECs upregulate angiogenesis and immune-modulatory and neural protective genes after interacting with ex vivo ischemic choroid. In a rat model of choroidal ischemia (CI), transplantation of hPSC-ECs into the suprachoroidal space increases choroid thickness and vasculature density. Close-up examination shows that engrafted hPSC-ECs integrate with all layers of rat choroidal vessels and last 90 days. Remarkably, EC transplantation improves the visual function of CI rats. The work demonstrates that hPSC-ECs can be used to repair choroidal ischemia in the animal model, which may lead to a new therapy to alleviate choroidal atrophy implicated in dry AMD, pathological myopia, and other ocular diseases.

Enhancing long-term frequency stability of a single-mode optoelectronic oscillator based on phase conjugation.

We propose and experimentally demonstrate what we believe to be a novel single-mode optoelectronic oscillator (OEO) with low frequency drift based on phase conjugation. The long-term frequency stabilization of the OEO is achieved by using photonic microwave phase-conjugate passive compensation. Besides, since there happens to be a nonlinear coupled double loop structure in the OEO, single-mode oscillation can be achieved. The experimental results show that the side mode suppression ratio (SMSR) of the radio frequency (RF) signal from the OEO at 9.93 GHz is enhanced from 5 dB to 68 dB after side mode suppression, and the maximum frequency drift within 600 s reduced from 1.51 ppm to 0.04 ppm, optimized by a factor of about 40. The OEO has a simple structure, no external injection, and the phase noise is not limited by the injected signal.

Comparative transcriptome analysis reveals key pathways and regulatory networks in early resistance of Glycine max to soybean mosaic virus.

As a high-value oilseed crop, soybean [Glycine max (L.) Merr.] is limited by various biotic stresses during its growth and development. Soybean mosaic virus (SMV) is a devastating viral infection of soybean that primarily affects young leaves and causes significant production and economic losses; however, the synergistic molecular mechanisms underlying the soybean response to SMV are largely unknown. Therefore, we performed RNA sequencing on SMV-infected resistant and susceptible soybean lines to determine the molecular mechanism of resistance to SMV. When the clean reads were aligned to the G. max reference genome, a total of 36,260 genes were identified as expressed genes and used for further research. Most of the differentially expressed genes (DEGs) associated with resistance were found to be enriched in plant hormone signal transduction and circadian rhythm according to Kyoto Encyclopedia of Genes and Genomes analysis. In addition to salicylic acid and jasmonic acid, which are well known in plant disease resistance, abscisic acid, indole-3-acetic acid, and cytokinin are also involved in the immune response to SMV in soybean. Most of the Ca2+ signaling related DEGs enriched in plant-pathogen interaction negatively influence SMV resistance. Furthermore, the MAPK cascade was involved in either resistant or susceptible responses to SMV, depending on different downstream proteins. The phytochrome interacting factor-cryptochrome-R protein module and the MEKK3/MKK9/MPK7-WRKY33-CML/CDPK module were found to play essential roles in soybean response to SMV based on protein-protein interaction prediction. Our findings provide general insights into the molecular regulatory networks associated with soybean response to SMV and have the potential to improve legume resistance to viral infection.

Climate Change ECHO: Telementoring to Improve Climate Literacy for Health Professionals.

Introduction: Climate change is a global public health crisis. Most clinicians and public health professionals do not receive adequate education to manage and communicate climate-related health impacts to their patients. Methods: From July 2021 to February 2022, the Project ECHO Climate Change and Human Health program completed 22 weekly trainings for health professionals. These virtual telementoring sessions were designed to improve both knowledge and self-efficacy about climate-related health impacts and climate change‒related communication skills. Results: Between July 2021 and February 2022, a total of 804 unique participants (from 44 states and 25 countries) attended the sessions. Participants were nurses (24.7%), physicians (16.8%), and public health professionals (8.5%). They completed weekly Zoom polls measuring their knowledge and self-efficacy. On average, participants strongly agreed or agreed that they had learned skills taught in each session (average percentage of those who strongly agreed or agreed=94.6%, range=66.7%-100.0%). Participants (31%) also completed a weekly postsession survey. A total of 91% rated the sessions as excellent or very good regarding evidenced-basis, and 89% rated sessions as excellent or very good regarding improved communication skills with patients and colleagues. Conclusions: Given the global climate crisis, the Climate Change and Human Health ECHO is successfully building resources and capacity for clinicians and public health professionals.

A Lightweight Pixel-Level Unified Image Fusion Network.

In recent years, deep-learning-based pixel-level unified image fusion methods have received more and more attention due to their practicality and robustness. However, they usually require a complex network to achieve more effective fusion, leading to high computational cost. To achieve more efficient and accurate image fusion, a lightweight pixel-level unified image fusion (L-PUIF) network is proposed. Specifically, the information refinement and measurement process are used to extract the gradient and intensity information and enhance the feature extraction capability of the network. In addition, these information are converted into weights to guide the loss function adaptively. Thus, more effective image fusion can be achieved while ensuring the lightweight of the network. Extensive experiments have been conducted on four public image fusion datasets across multimodal fusion, multifocus fusion, and multiexposure fusion. Experimental results show that L-PUIF can achieve better fusion efficiency and has a greater visual effect compared with state-of-the-art methods. In addition, the practicability of L-PUIF in high-level computer vision tasks, i.e., object detection and image segmentation, has been verified.

Boosting Dye-Sensitized Luminescence by Enhanced Short-Range Triplet Energy Transfer.

Dye-sensitization can enhance lanthanide-based upconversion luminescence, but is hindered by interfacial energy transfer from organic dye to lanthanide ion Yb3+ . To overcome these limitations, modifying coordination sites on dye conjugated structures and minimizing the distance between fluorescence cores and Yb3+ in upconversion nanoparticles (UCNPs) are proposed. The specially designed near-infrared (NIR) dye, disulfo-indocyanine green (disulfo-ICG), acts as the antenna molecule and exhibits a 2413-fold increase in luminescence under 808 nm excitation compared to UCNPs alone using 980 nm irradiation. The significant improvement is attributed to the high energy transfer efficiency of 72.1% from disulfo-ICG to Yb3+ in UCNPs, with majority of energy originating from triplet state (T1 ) of disulfo-ICG. Shortening the distance between the dye and lanthanide ions increases the probability of energy transfer and strengthens the heavy atom effect, leading to enhanced T1 generation and improved dye-triplet sensitization upconversion. Importantly, this approach also applies to 730 nm excitation Cy7-SO3 sensitization system, overcoming the spectral mismatch between Cy7 and Yb3+ and achieving a 52-fold enhancement in luminescence. Furthermore, the enhancement of upconversion at single particle level through dye-sensitization is demonstrated. This strategy expands the range of NIR dyes for sensitization and opens new avenues for highly efficient dye-sensitized upconversion systems.

Radiotherapy plus immune checkpoint inhibitor in prostate cancer.

The immune checkpoint inhibitor (ICI) is a promising strategy for treating cancer. However, the efficiency of ICI monotherapy is limited, which could be mainly attributed to the tumor microenvironment of the "cold" tumor. Prostate cancer, a type of "cold" cancer, is the most common cancer affecting men's health. Radiotherapy is regarded as one of the most effective prostate cancer treatments. In the era of immune therapy, the enhanced antigen presentation and immune cell infiltration caused by radiotherapy might boost the therapeutic efficacy of ICI. Here, the rationale of radiotherapy combined with ICI was reviewed. Also, the scheme of radiotherapy combined with immune checkpoint blockades was suggested as a potential option to improve the outcome of patients with prostate cancer.

Evaluating the effectiveness and cost-effectiveness of free influenza vaccination policy for older adults in Yinzhou, China: Study protocol of a real-world analyses.

BACKGROUND: Influenza causes excessive morbidity and mortality among older adults. While influenza vaccine provides protection against its infection, the vaccination coverage in China among older adults has been very low. Previous evidence on the cost-effectiveness of government-sponsored free influenza vaccination programs in China was primarily based on literature data, which might not always reflect real-world patient populations. The Yinzhou Health Information System (YHIS) is a regional database that captures electronic health records, insurance claims data, etc. for all residents in Yinzhou district, Zhejiang province, China. We will use YHIS to study the effectiveness, influenza-related direct medical cost and cost-effectiveness analysis (CEA) of the free influenza vaccination program for older adults. In this paper, we describe the study design and innovations in detail. METHODS: We will establish a retrospective cohort of permanent older residents aged 65 and over, using YHIS between 2016 and 2021. We will estimate the vaccine coverage rate, influenza incidence rate and influenza-related direct medical cost from 2016 to 2021. Regression discontinuity will be used to estimate vaccine effectiveness for the 2020/2021 season. We will build a decision tree model to compare the cost-effectiveness of three influenza vaccination options (free trivalent influenza vaccine, free quadrivalent influenza vaccine, and no policy) from both societal and health system perspectives. Parameter inputs will be gathered from both YHIS and published literature. We will calculate the incremental cost-effectiveness ratio with cost and quality-adjusted life years (QALYs) discounted at 5 % annually. DISCUSSION: Our CEA solidifies multiple sources including regional real-world data and literature for a rigorous evaluation of the government-sponsored free influenza vaccination program. The results will provide real-world evidence from real-world data on the cost-effectiveness of a real-world policy. Our findings are expected to support evidence-based policy making and to promote health for older adults.

Antitumor Activity of s-Triazine Derivatives: A Systematic Review.

1,3,5-triazine derivatives, also called s-triazines, are a series of containing-nitrogen heterocyclic compounds that play an important role in anticancer drug design and development. To date, three s-triazine derivatives, including altretamine, gedatolisib, and enasidenib, have already been approved for refractory ovarian cancer, metastatic breast cancer, and leukemia therapy, respectively, demonstrating that the s-triazine core is a useful scaffold for the discovery of novel anticancer drugs. In this review, we mainly focus on s-triazines targeting topoisomerases, tyrosine kinases, phosphoinositide 3-kinases, NADP+-dependent isocitrate dehydrogenases, and cyclin-dependent kinases in diverse signaling pathways, which have been extensively studied. The medicinal chemistry of s-triazine derivatives as anticancer agents was summarized, including discovery, structure optimization, and biological applications. This review will provide a reference to inspire new and original discoveries.

Homolog of Pea SGR Controls Stay-Green in Faba Bean (Vicia faba L.).

Faba bean is an important legume crop consumed as a vegetable or snack food, and its green cotyledons could present an attractive color for consumers. A mutation in SGR causes stay-green in plants. In this study, vfsgr was identified from a green-cotyledon-mutant faba bean, SNB7, by homologous blast between the SGR of pea and the transcriptome of faba bean. Sequence analysis revealed that a SNP at position 513 of the CDS of VfSGR caused a pre-stop codon, resulting in a shorter protein in the green-cotyledon faba bean SNB7. A dCaps marker was developed according to the SNP that caused the pre-stop, and this marker was completely associated with the color of the cotyledon of faba bean. SNB7 stayed green during dark treatment, while the expression level of VfSGR increased during dark-induced senescence in the yellow-cotyledon faba bean HST. Transient expression of VfSGR in Nicotiana. benthamiana leaves resulted in chlorophyll degradation. These results indicate that vfsgr is the gene responsible for the stay-green of faba bean, and the dCaps marker developed in this study provides a molecular tool for the breeding of green-cotyledon faba beans.

Early-life propofol exposure does not affect later-life GABAergic inhibition, seizure induction, or social behavior.

The early developing brain is especially vulnerable to anesthesia, which can result in long lasting functional changes. We examined the effects of early-life propofol on adult excitatory-inhibitory balance and behavior. Postnatal day 7 male mice were exposed to propofol (250 mg/kg i.p.) and anesthesia was maintained for 2 h; control mice were given the same volume of isotonic saline and treated identically. The behavior and electrophysiology experiments were conducted when the mice were adults. We found that a 2-h neonatal propofol exposure did not significantly reduce paired pulse inhibition, alter the effect of muscimol (3 µM) to inhibit field excitatory postsynaptic potentials or alter the effect of bicuculline (100 µM) to increase the population spike in the CA1 region of hippocampal slices from adult mice. Neonatal propofol did not alter the evoked seizure response to pentylenetetrazol in adult mice. Neonatal propofol did not affect anxiety, as measured in the open field apparatus, depression-like behavior, as measured by the forced swim test, or social interactions with novel mice, in either the three-chamber or reciprocal social tests. These results were different from those with neonatal sevoflurane which demonstrated reduced adult GABAergic inhibition, increased seizure susceptibility and reduced social interaction. Even though sevoflurane and propofol both prominently enhance GABA inhibition, they have unique properties that alter the long-term effects of early-life exposure. These results indicate that clinical studies grouping several general anesthetic agents in a single group should be interpreted with great caution when examining long-term effects.

High-Strength ß-Phase Magnesium-Lithium Alloy Prepared by Multidirectional Rolling.

Magnesium-lithium alloys are popular in the lightweight application industry for their very low density. However, as the lithium content increases, the strength of the alloy is sacrificed. Improving the strength of ß-phase Mg-Li alloys is urgently needed. The as-rolled Mg-16Li-4Zn-1Er alloy was multidirectionally rolled at various temperatures in comparison to conventional rolling. The results of the finite element simulations showed that multidirectional rolling, as opposed to conventional rolling, resulted in the alloy effectively absorbing the input stress, leading to reasonable management of stress distribution and metal flow. As a result, the alloy's mechanical qualities were improved. By modifying the dynamic recrystallization and dislocation movement, both high-temperature (200 °C) and low-temperature (-196 °C) rolling greatly increased the strength of the alloy. During the multidirectional rolling process at -196 °C, a large number of nanograins with a diameter of 56 nm were produced and a strength of 331 MPa was obtained.

Fine mapping of QTL conferring resistance to calcareous soil in mungbean reveals VrYSL3 as candidate gene for the resistance.

Iron is a crucial nutrient for biological functions in plants. High-pH and calcareous soil is a major stress causing iron deficiency chlorosis (IDC) symptoms and yield losses in crops. Use of calcareous soil-tolerance genetic resources is the most effective preventative method to combat the effects of high-pH and calcareous soils. A previous study using a mungbean recombinant inbred line (RIL) population of the cross Kamphaeg Saen 2 (KPS2; IDC susceptible) × NM-10-12 identified a major quantitative trait locus (QTL), qIDC3.1, which controls resistance and explains more than 40% of IDC variation. In this study, we fine-mapped qIDC3.1 and identified an underlying candidate gene. A genome wide association analysis (GWAS) using 162 mungbean accessions identified single nucleotide polymorphisms (SNPs) on chromosome 6; several SNPs were associated with soil plant analysis development (SPAD) values and IDC visual scores of mungbeans planted on calcareous soil, respectively. These SNPs corresponded to qIDC3.1. Using the same RIL population as in the previous study and an advanced backcross population developed from KPS2 and IDC-resistant inbred line RIL82, qIDC3.1 was further confirmed and fine-mapped to an interval of 217 kilobases harboring five predicted genes, including LOC106764181 (VrYSL3), which encodes a yellow stripe1-like-3 (YSL3) protein, YSL3 is involved in iron deficiency resistance. Gene expression analysis revealed that VrYSL3 was highly expressed in mungbean roots. In calcareous soil, expression of VrYSL3 was significantly up-regulated, and it was more obviously upregulated in the roots of RIL82, than in those of KPS2. Sequence comparison of VrYSL3 between the RIL82 and KPS2 revealed four SNPs that result in amino acid changes in the VrYSL3 protein and a 20-bp insertion/deletion in the promoter where a cis-regulatory element resides. Transgenic Arabidopsis thaliana plants overexpressing VrYSL3 showed enhanced iron and zinc contents in the leaves. Taken together, these results indicate that VrYSL3 is a strong candidate gene responsible for calcareous soil resistance in mungbean.

Identification of the Immune Subtypes for the Prediction of Metastasis in Pancreatic Neuroendocrine Tumors.

INTRODUCTION: Most patients with pancreatic neuroendocrine tumors (pNETs) present with unresectable or metastatic disease. Increasing evidence shows that the immune cell infiltration patterns play a pivotal role in tumor progression in pNETs. Nonetheless, there has been no comprehensive analysis of the effect of immune infiltration patterns on metastasis. METHODS: The gene expression profiling dataset and clinical data were obtained from the Gene Expression Omnibus database. Estimation of Stromal and Immune Cells in Malignant Tumors using the Expression Data and single-sample Gene Set Enrichment Analysis were used to uncover the landscape of the tumor immune microenvironment. Subtypes based on the immune infiltration patterns were identified by the unsupervised clustering algorithm. Differentially expressed genes were identified using the limma packages of R. Functional enrichment analyses of these genes were carried out using STRING, Kyoto Encyclopedia of Genes and Genomes, and Reactome. RESULTS: The landscape of immune cells in pNET samples was constructed, and three immune cell infiltration subtypes (Immunity-H, Immunity-M, and Immunity-L) were identified. Immune cell infiltration degrees and metastasis were positively correlated. A protein-protein interaction network containing 80 genes was constructed, and functional enrichment revealed that these genes were mainly enriched in immune-related pathways. Eleven metastasis-related genes were differentially expressed among three subtypes, including MMP14, MMP2, MMP12, MMP7, SPARC, MMP19, ITGAV, MMP23B, MMP1, MMP25, and MMP9. There is a certain consistency of immune infiltration pattern between the primary tumor and metastatic tumor samples. CONCLUSION: Our findings may deepen the understanding of the immune-mediated regulatory mechanisms underlying pNETs and may provide some promising targets for immunotherapy.

Identification and Functional Characterization of WRKY, PHD and MYB Three Salt Stress Responsive Gene Families in Mungbean (Vigna radiata L.).

WRKY-, PHD-, and MYB-like proteins are three important types of transcription factors in mungbeans, and play an important role in development and stress resistance. The genes' structures and characteristics were clearly reported and were shown to contain the conservative WRKYGQK heptapeptide sequence, Cys4-His-cys3 zinc binding motif, and HTH (helix) tryptophan cluster W structure, respectively. Knowledge on the response of these genes to salt stress is largely unknown. To address this issue, 83 VrWRKYs, 47 VrPHDs, and 149 VrMYBs were identified by using comparative genomics, transcriptomics, and molecular biology methods in mungbeans. An intraspecific synteny analysis revealed that the three gene families had strong co-linearity and an interspecies synteny analysis showed that mungbean and Arabidopsis were relatively close in genetic relationship. Moreover, 20, 10, and 20 genes showed significantly different expression levels after 15 days of salt treatment (p < 0.05; Log2 FC > 0.5), respectively. Additionally, in the qRT-PCR analysis, VrPHD14 had varying degrees of response to NaCl and PEG treatments after 12 h. VrWRKY49 was upregulated by ABA treatment, especially in the beginning (within 24 h). VrMYB96 was significantly upregulated in the early stages of ABA, NaCl, and PEG stress treatments (during the first 4 h). VrWRKY38 was significantly upregulated by ABA and NaCl treatments, but downregulated by PEG treatment. We also constructed a gene network centered on the seven DEGs under NaCl treatment; the results showed that VrWRKY38 was in the center of the PPI network and most of the homologous Arabidopsis genes of the interacted genes were reported to have response to biological stress. Candidate genes identified in this study provide abundant gene resources for the study of salt tolerance in mungbeans.