PD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featured with enhanced adaptive immunosuppression.

Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.

Relationship between age and remimazolam dose required for inducing loss of consciousness in older surgical patients.

Background: Remimazolam is a new ultra-short-acting benzodiazepine for procedural sedation and general anaesthesia, characterised by rapid onset of action, quick recovery, and organ-independent metabolism. Older patients tend to sustain more treatment-emergent adverse events (TEAEs) and worse perioperative prognoses after receiving remimazolam. However, few studies have investigated the appropriate dose of remimazolam for loss of consciousness (LOC) in geriatric patients. We designed this study to provide evidence for dose references and elucidate the relationship between age and remimazolam requirement for inducing LOC during anaesthesia induction. Methods: Exactly 120 patients scheduled for general surgery under general anaesthesia were included and divided into two groups: Group A (60 patients, 18-64 years) and Group B (60 patients, ≥ 65 years). LOC, defined as a Modified Observer's Assessment of Alertness and Sedation score at 1 had been reached, emerged after all participants received a continuous infusion of remimazolam at a rate of 0.05 mg/kg/min. Results: The remimazolam required for inducing LOC was 0.26 and 0.19 mg/kg in groups A and B, respectively, and the remimazolam dose in group B decreased by 26.9% compared to group A. According to the bivariate linear correlation analysis, remimazolam requirement was negatively correlated with age. Multivariable linear regression models and further adjustments for potential impact factors indicated that age was an independent factor for the remimazolam dose required for LOC. Conclusion: This study demonstrated that age was significantly and independently correlated with the remimazolam requirement for inducing LOC. To obtain haemodynamic stability during the induction of general anaesthesia, appropriately reducing the remimazolam dose is recommended for geriatric patients.

SEEI: spherical evolution with feedback mechanism for identifying epistatic interactions.

BACKGROUND: Detecting epistatic interactions (EIs) involves the exploration of associations among single nucleotide polymorphisms (SNPs) and complex diseases, which is an important task in genome-wide association studies. The EI detection problem is dependent on epistasis models and corresponding optimization methods. Although various models and methods have been proposed to detect EIs, identifying EIs efficiently and accurately is still a challenge. RESULTS: Here, we propose a linear mixed statistical epistasis model (LMSE) and a spherical evolution approach with a feedback mechanism (named SEEI). The LMSE model expands the existing single epistasis models such as LR-Score, K2-Score, Mutual information, and Gini index. The SEEI includes an adaptive spherical search strategy and population updating strategy, which ensures that the algorithm is not easily trapped in local optima. We analyzed the performances of 8 random disease models, 12 disease models with marginal effects, 30 disease models without marginal effects, and 10 high-order disease models. The 60 simulated disease models and a real breast cancer dataset were used to evaluate eight algorithms (SEEI, EACO, EpiACO, FDHEIW, MP-HS-DHSI, NHSA-DHSC, SNPHarvester, CSE). Three evaluation criteria (pow1, pow2, pow3), a T-test, and a Friedman test were used to compare the performances of these algorithms. The results show that the SEEI algorithm (order 1, averages ranks = 13.125) outperformed the other algorithms in detecting EIs. CONCLUSIONS: Here, we propose an LMSE model and an evolutionary computing method (SEEI) to solve the optimization problem of the LMSE model. The proposed method performed better than the other seven algorithms tested in its ability to identify EIs in genome-wide association datasets. We identified new SNP-SNP combinations in the real breast cancer dataset and verified the results. Our findings provide new insights for the diagnosis and treatment of breast cancer. AVAILABILITY AND IMPLEMENTATION: https://github.com/scutdy/SSO/blob/master/SEEI.zip .

Dynamic co-evolution of transposable elements and the piRNA pathway in African cichlid fishes.

East African cichlid fishes have diversified in an explosive fashion, but the (epi)genetic basis of the phenotypic diversity of these fishes remains largely unknown. Although transposable elements (TEs) have been associated with phenotypic variation in cichlids, little is known about their transcriptional activity and epigenetic silencing. Here, we describe dynamic patterns of TE expression in African cichlid gonads and during early development. Orthology inference revealed an expansion of piwil1 genes in Lake Malawi cichlids, likely driven by PiggyBac TEs. The expanded piwil1 copies have signatures of positive selection and retain amino acid residues essential for catalytic activity. Furthermore, the gonads of African cichlids express a Piwi-interacting RNA (piRNA) pathway that target TEs. We define the genomic sites of piRNA production in African cichlids and find divergence in closely related species, in line with fast evolution of piRNA-producing loci. Our findings suggest dynamic co-evolution of TEs and host silencing pathways in the African cichlid radiations. We propose that this co-evolution has contributed to cichlid genomic diversity.

Wheat flour-derived amyloid fibrils for efficient removal of organic dyes from contaminated water.

Amyloid fibrils derived from different proteins have been proved as a promising material for adsorption of various pollutants from wastewater, which showed advantages of low cost and eco-friendliness. However, most of the amyloid fibrils derived from animal-based proteins with high environmental footprint, while more sustainable amyloid fibrils derived from plant materials are desirable. In this study, a plant-derived amyloid fibril was extracted from the commonly used wheat flour with a simple and scalable protein purification and fibrillization process. Interestingly, the amyloid fibrils showed good adsorption capacity towards typical organic dyes (Eosin Y (EY) and Congo red (CR)) from contaminated water. Adsorption kinetic analysis indicated the adsorption process to EY or CR by wheat flour amyloid well fitted with a pseudo-second-order model. The adsorption also followed a Langmuir isothermal model with adsorption capacities of 333 mg/g and 138 mg/g towards CR and EY, respectively. This work demonstrated the feasibility to utilize the plant-based amyloid fibril for organic dyes removal from contaminated water, which provided an affordable, sustainable and scalable tool for organic dyes removal from wastewater.

Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation.

BACKGROUND: Cellular senescence frequently occurs during anti-cancer treatment, and persistent senescent tumor cells (STCs) unfavorably promote tumor progression through paracrine secretion of the senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) have recently emerged as a novel component of the SASP and primarily mediate the tumor-promoting effect of the SASP. Of note, the potential effect of EVs released from STCs on tumor progression remains largely unknown. METHODS: We collected tumor tissues from two cohorts of colorectal cancer (CRC) patients to examine the expression of p16, p21, and SERPINE1 before and after anti-cancer treatment. Cohort 1 included 22 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgical resection. Cohort 2 included 30 patients with metastatic CRC (mCRC) who received first-line irinotecan-contained treatment. CCK-8, transwell, wound-healing assay, and tumor xenograft experiments were carried out to determine the impacts of EVs released from STCs on CRC progression in vitro and in vivo. Quantitative proteomic analysis was applied to identify protein cargo inside EVs secreted from STCs. Immunoprecipitation and mass spectrometer identification were utilized to explore the binding partners of SERPINE1. The interaction of SERPINE1 with p65 was verified by co-immunoprecipitation, and their co-localization was confirmed by immunofluorescence. RESULTS: Chemotherapeutic agents and irradiation could potently induce senescence in CRC cells in vitro and in human CRC tissues. The more significant elevation of p16 and p21 expression in patients after anti-cancer treatment displayed shorter disease-free survival (DFS) for LARC or progression-free survival (PFS) for mCRC. We observed that compared to non-STCs, STCs released an increased number of EVs enriched in SERPINE1, which further promoted the progression of recipient cancer cells. Targeting SERPINE1 with a specific inhibitor, tiplaxtinin, markedly attenuated the tumor-promoting effect of STCs-derived EVs. Additionally, the patients with greater increment of SERPINE1 expression after anti-cancer treatment had shorter DFS for LARC or PFS for mCRC. Mechanistically, SERPINE1 bound to p65, promoting its nuclear translocation and subsequently activating the NF-κB signaling pathway. CONCLUSIONS: We provide the in vivo evidence of the clinical prognostic implications of therapy-induced senescence. Our results revealed that STCs were responsible for CRC progression by producing large amounts of EVs enriched in SERPINE1. These findings further confirm the crucial role of therapy-induced senescence in tumor progression and offer a potential therapeutic strategy for CRC treatment.

Influence of magma intrusion on coal geochemical characteristics: a case study of Tiefa Daxing coal mine.

Magma intrusion has an important influence on the physical and mechanical properties of coal and rock. In the area of magma intrusion, disasters such as gas outburst are prone to occur. Revealing its invasion law will be conducive to disaster management and energy development. For this purpose, changes in industrial analysis components of coal, mineral composition, major oxides, trace elements, and rare earth elements of coal under the thermal metamorphism of magma intrusion were analyzed. It is found that the moisture and volatile matter contents of the thermally affected coals in the mining face are generally lower than that of normal coals, while moisture and volatile matter contents are reduced towards to the magma intrusion contact. For example, the moisture and volatile matter of coal sample M01 decreased by 64.6% and 38.6% respectively compared with coal sample M05. During magma intrusion, some minerals remain on the surface of the coal body, resulting in changes in the mineral composition of the coal body. The decrease in carbon atom net spacing, the increase in crystallite aggregation and ductility, and aromaticity in thermally affected coals have a positive impact on the improvement of coal metamorphism. Due to the influences of magmatic intrusion, the variation rules of major oxides in coal are different, and the closer to the magmatic intrusion zone, the easier the major oxides are to be depleted. However, magma intrusion will not lead to the loss of all major oxides in thermally affected coals, such as content of CaO is 54.8%, which is higher than that of coal not affected by magmatic hydrothermal fluid. Most of the trace elements in the thermally affected coals of the No. 9 coal seam are depleted. The contents of rare earth elements are low on the whole coalbasis, with an average of 29.48 µg/g, and the distribution pattern towards to magmatic intrusion shows a wide and gentle "V" curve with left high and right low, showing the characteristics of enrichment of light rare earth elements.

Integrated neutrophil-to-lymphocyte ratio and handgrip strength better predict survival in patients with cancer cachexia.

OBJECTIVES: Systemic inflammation and skeletal muscle strength play crucial roles in the development and progression of cancer cachexia. In this study we aimed to evaluate the combined prognostic value of neutrophil-to-lymphocyte ratio (NLR) and handgrip strength (HGS) for survival in patients with cancer cachexia. METHODS: This multicenter cohort study involved 1826 patients with cancer cachexia. The NLR-HGS (NH) index was defined as the ratio of neutrophil-to-lymphocyte ratio to handgrip strength. Harrell's C index and receiver operating characteristic (ROC) curve analysis were used to assess the prognosis of NH. Kaplan-Meier analysis and Cox regression models were used to evaluate the association of NH with all-cause mortality. RESULTS: Based on the optimal stratification, 380 women (NH > 0.14) and 249 men (NH > 0.19) were classified as having high NH. NH has shown greater predictive value compared to other indicators in predicting the survival of patients with cancer cachexia according to the 1-, 3-, and 5-y ROC analysis and Harrell's C index calculation. Multivariate survival analysis showed that higher NH was independently associated with an increased risk of death (hazard ratio = 1.654, 95% confidence interval = 1.389-1.969). CONCLUSION: This study demonstrates that the NH index, in combination with NLR and HGS, is an effective predictor of the prognosis of patients with cancer cachexia. It can offer effective prognosis stratification and guidance for their treatment.

RUNX1 C-terminal mutations impair blood cell differentiation by perturbing specific enhancer-promoter networks.

ABSTRACT: The transcription factor RUNX1 is a master regulator of hematopoiesis and is frequently mutated in myeloid malignancies. Mutations in its runt homology domain (RHD) frequently disrupt DNA binding and result in loss of RUNX1 function. However, it is not clearly understood how other RUNX1 mutations contribute to disease development. Here, we characterized RUNX1 mutations outside of the RHD. Our analysis of the patient data sets revealed that mutations within the C-terminus frequently occur in hematopoietic disorders. Remarkably, most of these mutations were nonsense or frameshift mutations and were predicted to be exempt from nonsense-mediated messenger RNA decay. Therefore, this class of mutation is projected to produce DNA-binding proteins that contribute to the pathogenesis in a distinct manner. To model this, we introduced the RUNX1R320∗ mutation into the endogenous gene locus and demonstrated the production of RUNX1R320∗ protein. Expression of RUNX1R320∗ resulted in the disruption of RUNX1 regulated processes such as megakaryocytic differentiation, through a transcriptional signature different from RUNX1 depletion. To understand the underlying mechanisms, we used Global RNA Interactions with DNA by deep sequencing (GRID-seq) to examine enhancer-promoter connections. We identified widespread alterations in the enhancer-promoter networks within RUNX1 mutant cells. Additionally, we uncovered enrichment of RUNX1R320∗ and FOXK2 binding at the MYC super enhancer locus, significantly upregulating MYC transcription and signaling pathways. Together, our study demonstrated that most RUNX1 mutations outside the DNA-binding domain are not subject to nonsense-mediated decay, producing protein products that act in concert with additional cofactors to dysregulate hematopoiesis through mechanisms distinct from those induced by RUNX1 depletion.

Characterization of Coal Particle Methane Desorption and Optimization of Desorption Model Based on Desorption Damage.

In view of the current situation where most studies on gas desorption characteristics are limited to the atmospheric pressure desorption environment, we have independently developed a coal methane desorption instrument to test the nonatmospheric pressure desorption characteristics for coal particle gas beneath the condition of desorption damage. The instrument can arbitrarily adjust the gas pressure in the range of measurement while controlling the instantaneous release of excess gas to keep the desorption environment pressure constant. We measured the methane desorption amount of coal samples with different desorption times within 3 h and calculated the desorption velocity. The results show that the final desorption amount and desorption velocity of gas scale up with the increase of times, and the final desorption amount of coal sample W-01 increases the most, which is 18.5%. With the passage of time, the diffusion coefficient decreases gradually, and the number of desorption times is directly proportional to the diffusion coefficient. Its relative deviation of diffusion coefficient between different desorption times of the same coal sample can reach up to 40%, and the desorption time in the range of 5 to 30 min is the area with high relative deviation. A quantitative index Ki of a double-parameter damage model based on desorption conditions and adsorption pressure is proposed, and the damage extent of each sample is evaluated. The damage quantitative index of coal sample W-01 is the highest, which is 0.87. The methane desorption model of coal under the condition of desorption damage is constructed, and more than 30 groups of experiments are verified.

Lower Melatonin Indicates Poor Short-term Prognosis in Patients with Acute Ischemic Stroke.

AIMS: We evaluated endogenous melatonin levels in the acute phase of cerebral infarction and explored the impact of possible changes in melatonin levels on the prognosis of patients. METHODS: This study recruited acute ischemic stroke (AIS) patients from the Department of the Second Affiliated Hospital of Soochow University between December 2019 and June 2021, along with healthy control subjects. Salivary melatonin samples were collected from each participant between 7 pm and 10 pm, and fasting plasma was collected the following morning to measure the levels of inflammatory markers. The prognosis was assessed through follow-up three months after discharge. The relationship between melatonin levels and plasma inflammatory markers was assessed, followed by an analysis of the effect of melatonin levels on patient prognosis. RESULTS: The study enrolled a total of 160 participants, including 120 AIS patients aged 50 years or older (61.7% male) and 40 age-matched controls (55.0% male). The AIS group exhibited lower salivary melatonin levels at 19 (P = 0.002), 20 (P < 0.001), 21 (P < 0.001), and 22 (P < 0.001) o'clock, and the average melatonin level was also lower (P < 0.001). Logistic regression analysis models indicated an association between low melatonin levels and poor prognosis. Salivary melatonin levels demonstrated good predictive ability for the prognosis of AIS patients. CONCLUSION: Melatonin levels were lower in AIS patients compared to controls. In addition, lower melatonin levels were associated with a poorer prognosis among AIS patients.

Single-cell and spatial transcriptomics: Bridging current technologies with long-read sequencing.

Single-cell technologies have transformed biomedical research over the last decade, opening up new possibilities for understanding cellular heterogeneity, both at the genomic and transcriptomic level. In addition, more recent developments of spatial transcriptomics technologies have made it possible to profile cells in their tissue context. In parallel, there have been substantial advances in sequencing technologies, and the third generation of methods are able to produce reads that are tens of kilobases long, with error rates matching the second generation short reads. Long reads technologies make it possible to better map large genome rearrangements and quantify isoform specific abundances. This further improves our ability to characterize functionally relevant heterogeneity. Here, we show how researchers have begun to combine single-cell, spatial transcriptomics, and long-read technologies, and how this is resulting in powerful new approaches to profiling both the genome and the transcriptome. We discuss the achievements so far, and we highlight remaining challenges and opportunities.

A Powerful Strategy for Synthesizing Block Copolymers via Bimetallic Synergistic Catalysis.

Block copolymers, comprising polyether and polyolefin segments, are an important and promising category of functional materials. However, the lack of efficient strategies for the construction of polyether-b-polyolefin block copolymers have hindered the development of these materials. Herein, we propose a simple and efficient method to obtain various block copolymers through the copolymerization of epoxides and acrylates via bimetallic synergistic catalysis. The copolymerization of epoxides and acrylates proceeds in a sequence-controlled manner, where the epoxides-involved homo- or copolymerization occurs first, followed by the homopolymerization of acrylates initiated by the alkoxide species from the propagating polymer chain, thus yielding copolymers with a block structure. Notably, the high monomer compatibility of this powerful strategy provides a platform for synthesizing various polyacrylate-based block copolymers comprising polyether, polycarbonate, polythiocarbonate, polyester, and polyurethane segments, respectively.

Thickness ranges calculation method of double asphalt overlay on concrete pavement.

Asphalt overlay is widely used in maintaining and rehabilitating highway system performance. However, explicit calculation methods for the asphalt overlay thickness range is lacking. Taking stone mastic asphalt (SMA) and asphalt concrete (AC) asphalt overlay on cement concrete pavement as examples, the paper proposed a design method for the asphalt overlay thickness range based on the shear performance of the interlayer. Firstly, the shear stress distribution regularities on the asphalt overlay and Portland cement concrete interlayer was calculated with a multilayer elastic theory. Meanwhile, the shear strength was obtained from a series of direct shear tests. The shear characters of the asphalt overlay met with the Mohr-Coulomb criterion, and the shear strength parameters cohesive force c and interface friction angle φ on the interlayer were acquired. Finally, a method for determining the thickness range of double layer asphalt overlay under different traffic conditions was given. The epoxy resin adhesive was recommended for the highway with severe local premature shear failure compared with the modified emulsion asphalt. Therefore, through the above research, the amount of asphalt used is controlled in a reasonable range, thus improving the pavement structure durability and reducing energy consumption.

Single-mode nanolasers based on FP-WGM hybrid cavity coupling.

As an idealized light source, semiconductor nanowire (NW) lasers have been extensively studied due to its potential applications in many fields such as optoelectronics, nanophononics, optical communication, signal processing, and displays. In this letter, we proposed a novel approach to realize a single-mode nanolaser by forming an Fabry-Perot whispering gallery mode (FP-WGM) hybrid nanocavity between two cross-contact CdS NWs, i.e.xandy-NW. In our method,x-NW supports the regular FP oscillation in the axis direction while the cross section ofy-NW provides a ultrasmall WGM nanocavity with a higherQ-factor and mode election which confirms the specific single mode can be excited. Experimentally, single-mode lasing emission centered at 517 nm was obtained with full width at half maximum of 0.08 nm and lasing threshold of ∼50 kW cm-2. The suggested designing skills projected a general strategy for lasing mode regulation and single-mode realization. The single-mode low-threshold lasing strategy in coupled NWs may open a new avenue for practical applications of NW lasers and further trigger other photonic devices at a visible range.