Magnetic porous microspheres enhancing the anaerobic digestion of sewage sludge: Synergistic free and attached methanogenic consortia.

The addition of exogenous materials is a commonly reported method for promoting the anaerobic digestion (AD) of sludge. However, most exogenous materials are nano-sized and their use encounters problems relating to a need for continuous replenishment, uncontrollability and non-recyclability. Here, magnetic porous microspheres (MPMs), which can be controlled by magnetic forces, were prepared and used to enhance the methanogenesis of sludge. It was observed that the MPMs were spherical particles with diameters of approximately 100 µm and had a stable macroporous hybrid structure of magnetic cores and polymeric shells. Furthermore, the MPMs had good magnetic properties and a strong solid-liquid interfacial electron transfer ability, suggesting that MPMs are excellent carriers for methanogenic consortia. Experimental results showed that the addition of MPMs increased methane production and the proportion of methane in biogas from AD by 100.0 % and 21.2 %, respectively, indicating the MPMs notably enhanced the methanogenesis of sludge. Analyses of variations in key enzyme activities and electron transfer in sludge samples with and without MPMs in AD revealed that the MPMs significantly enhanced the activities of key enzymes involved in hydrolysis, acidification and methanation. This was achieved mainly by enhancing the extracellular electron transfer to strengthen the proton motive force on the cell membrane, which provides more energy generation for methanogenic metabolism. A careful examination of the variations in the morphology, pore structure and magnetism of the MPMs before and after AD revealed that the MPMs increased the prevalence of many highly active anaerobes, and that this did not weaken the magnetic performance. The microbial community structure and metatranscriptomic analysis further indicated that the acetotrophic methanogens (i.e., Methanosaeta) were mainly in a free state and that CO2-reducing methanogens (i.e., Methanolinea and Methanobacterium) mainly adhered to the MPMs. The above synergistic metabolism led to efficient methanogenesis, which indicates that the MPMs optimised the spatial ecological niche of methanogenic consortia. These findings provide an important reference for the development of magnetic porous materials promoting AD.

Potential roles of hydroxybenzoate paralytic shellfish toxins in modulating toxin biokinetics in scallops.

Paralytic shellfish toxins (PSTs) produced by some marine dinoflagellates can cause severe human intoxication via vectors like bivalves. Toxic dinoflagellate Gymnodinium catenatum produce a novel group of hydroxybenzoate PSTs named GC toxins, but their biokinetics in bivalves haven't been well examined. In this experiment, we analyzed PSTs in bay scallops Argopecten irradians exposed to G. catenatum (strain MEL11) to determine their accumulation, elimination, anatomical distribution, and biotransformation. To our surprise, up to 30% of the PSTs were accumulated in the adductor muscle of scallops at the end of the experiment, and the toxicity of adductor muscle exceeded the regulatory limit of 800 µg STXeq/kg in only 6 days. High concentration of toxins in the adductor muscle are likely linked to the rapid transfer of GC toxins from viscera to other tissues. Moreover, most GC toxins in scallops were found rapidly transformed to decarbamoyl toxins through enzyme-mediated hydrolysis, which was further supported by the in vitro incubation experiments. Our study demonstrates that GC toxins actively participate in toxin distribution and transformation in scallops, which may increase the risks of food poisoning associated with the consumption of scallop adductor muscle. ENVIRONMENTAL IMPLICATION: The negative impacts of harmful algal blooms (HABs) have become a global environmental concern under the joint effects of cultural eutrophication and climate change. Our study, targeted on the biokinetics of paralytic shellfish toxins in scallops exposed to Gymnodinium catenatum producing unique GC toxins, aims to elucidate potential risks of seafood poisoning associated with GC toxins. The findings of this study will help us to understand the roles of GC toxins in seafood poisoning, and to develop effective management strategies against toxic algal blooms and phycotoxins.

Evaporation-driven interfacial restructuring induces highly efficient methanogenesis of waste biomass.

Methanogenesis of waste biomass (WB) is a promising method for global sustainable development, reduction of pollution and carbon emission levels, and recovering bioenergy. Unlike in the methanogenesis of organic wastewater, in which microbial cells come into direct contact with the dissolved substrate, the 'solid-liquid-solid' modes in WB and between WB and microbial cells, which involve numerous solid-liquid interfaces, greatly hinder the methanogenesis efficiency of WB. Amongst all WB, waste activated sludge is the most complex, poorly biodegradable and representative. Herein, we highlight the role of water evaporation-driven solid-liquid interfacial restructuring of sludge in determining its methanogenesis efficiency. Non-free water evaporation increased surface roughness and adhesion, and compressed pore structure with numerous capillaries in sludge, resulting in a new solid-liquid interface of sludge with great capillary force and highly ordered interfacial water molecules, which provides an extremely favourable condition for high mass transfer and proton-coupled electron transfer (PCET) in sludge. This restructuring was confirmed to induce the enhancement of solid-liquid interfacial noncovalent interactions and electron transfer efficiency in the subsequent methanogenesis process (P < 0.05), promoting the effective contact between the sludge substrate and microbial cells, thereby enriching the methanogenic consortia (i.e., Clostridia and Methanosarcina were increased by 290.0 % and 239.7 %, respectively) and improving the activities of key enzymes. Stable isotope tracing and metagenomic analysis further reveal that this restructuring promoted the participation of water molecules in the methane formation by PCET-driven release of protons from water, and enhanced main methanogenesis metabolic pathways, especially the metabolic pathway of CO2-reduction methanogenesis (+65.2 %), thereby resulting in a great advance in methane generation (+147 %, P < 0.001). The findings can provide a reference for regulating directional anaerobic biotransformation of water-rich multiphase complex substrates by interfacial restructuring inducement.

α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata.

Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4ß2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-ß-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.

Copper-catalyzed carbonylative multi-component borylamidation of alkenes for synthesizing γ-boryl amides with CO as both methylene and carbonyl sources.

A multi-component carbonylation reaction is an efficient strategy for the synthesis of valuable carbonyl compounds from simple and readily available substrates. However, there remain challenges in carbonylation reactions where two CO molecules are converted to different groups in the target product. Considering the merit of complex amides, we reported here a copper-catalyzed multi-component borylamidation for the synthesis of γ-boryl amides. This method provides access to a wide range of functional γ-boryl amides from alkenes, amines, B2pin2, and CO with good yields and excellent diastereomeric ratios. Notably, two CO molecules were converted to methylene and carbonyl groups in the target amides. A series of amines were successfully involved in the transformation, including arylamines, aliphatic amines, and hydrochloride salts of secondary aliphatic amines.

Long trimer-immunization interval and appropriate adjuvant reduce immune responses to the soluble HIV-1-envelope trimer base.

Soluble 'SOSIP'-stabilized HIV-1 envelope glycoprotein (Env) trimers elicit dominant antibody responses targeting their glycan-free base regions, potentially diminishing neutralizing responses. Previously, using a nonhuman primate model, we demonstrated that priming with fusion peptide (FP)-carrier conjugate immunogens followed by boosting with Env trimers reduced the anti-base response. Further, we demonstrated that longer immunization intervals further reduced anti-base responses and increased neutralization breadth. Here, we demonstrate that long trimer-boosting intervals, but not long FP immunization intervals, reduce the anti-base response. Additionally, we identify that FP priming before trimer immunization enhances antibody avidity to the Env trimer. We also establish that adjuvants Matrix M and Adjuplex further reduce anti-base responses and increase neutralizing titers. FP priming, long trimer-immunization interval, and an appropriate adjuvant can thus reduce anti-base antibody responses and improve Env-directed vaccine outcomes.

RAD54B promotes gastric cancer cell migration and angiogenesis via the Wnt/ß-catenin pathway.

BACKGROUND: Gastric cancer is an epidemic malignancy that is commonly diagnosed at the late stage. Evidence has elucidated that RAD54B exerts a crucial role in the progress of various tumors, but its specific role and mechanism in gastric cancer remain gloomy. MATERIALS AND METHODS: The level of RAD54B was detected by western blot. RAD54B expression was downregulated or upregulated in both MKN45 and AGS cells by the transfection of shRAD54B or overexpression plasmid, respectively. The role of RAD54B in the growth, migration, invasion and tube formation of gastric cancer was evaluated by Edu, colony formation, transwell and tube formation assays. In addition, the molecular mechanism of RAD54B in gastric cancer was also determined by western blot. Moreover, in vivo experiment was conducted in xenografted mice. RESULTS: The expression of RAD54B was discovered to be upregulated in gastric cancer based on the ATGC and GEPIA databases, which was also confirmed in gastric cancer cell lines. Moreover, overexpression of RAD54B enhanced the growth, migration, invasion, tube formation and Wnt/ß-catenin signaling axis in AGS and MKN45 cells. As expected, knockdown of RAD54B in AGS and MKN45 cells reversed these promotions. More importantly, in vivo assay also verified that RAD54B accelerated the growth of gastric cancer and Wnt/ß-catenin signaling pathway. CONCLUSIONS: Both loss-of-function and gain-of-function assays demonstrated that RAD54B facilitated gastric cancer cell progress and angiogenesis through the Wnt/ß-catenin axis.

A high-precision jujube disease spot detection based on SSD during the sorting process.

The development of automated grading equipment requires achieving high throughput and precise detection of disease spots on jujubes. However, the current algorithms are inadequate in accomplishing these objectives due to their high density, varying sizes and shapes, and limited location information regarding disease spots on jujubes. This paper proposes a method called JujubeSSD, to boost the precision of identifying disease spots in jujubes based on a single shot multi-box detector (SSD) network. In this study, a diverse dataset comprising disease spots of varied sizes and shapes, varying densities, and multiple location details on jujubes was created through artificial collection and data augmentation. The parameter information obtained from transfer learning into the backbone feature extraction network of the SSD model, which reduced the time of spot detection to 0.14 s. To enhance the learning of target detail features and improve the recognition of weak information, the traditional convolution layer was replaced with deformable convolutional networks (DCNs). Furthermore, to address the challenge of varying sizes and shapes of disease spot regions on jujubes, the path aggregation feature pyramid network (PAFPN) and balanced feature pyramid (BFP) were integrated into the SSD network. Experimental results demonstrate that the mean average precision at the IoU (intersection over union) threshold of 0.5 (mAP@0.5) of JujubeSSD reached 97.1%, representing an improvement of approximately 6.35% compared to the original algorithm. When compared to existing algorithms, such as YOLOv5 and Faster R-CNN, the improvements in mAP@0.5 were 16.84% and 8.61%, respectively. Therefore, the proposed method for detecting jujube disease spot achieves superior performance in jujube surface disease detection and meets the requirements for practical application in agricultural production.

Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models.

ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb repressive complex 2 (PRC2) to specific gene loci to repress transcription through trimethylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development of myeloid malignancies. Standard therapies for myeloid malignancies have limited efficacy when mutated ASXL1 is present. We discovered upregulation of lysine demethylase 6B (KDM6B), a demethylase for H3K27me3, in ASXL1-mutant leukemic cells, which further reduces H3K27me3 levels and facilitates myeloid transformation. Here, we demonstrated that heterozygous deletion of Kdm6b restored H3K27me3 levels and normalized dysregulated gene expression in Asxl1Y588XTg hematopoietic stem/progenitor cells (HSPCs). Furthermore, heterozygous deletion of Kdm6b decreased the HSPC pool, restored their self-renewal capacity, prevented biased myeloid differentiation, and abrogated progression to myeloid malignancies in Asxl1Y588XTg mice. Importantly, administration of GSK-J4, a KDM6B inhibitor, not only restored H3K27me3 levels but also reduced the disease burden in NSG mice xenografted with human ASXL1-mutant leukemic cells in vivo. This preclinical finding provides compelling evidence that targeting KDM6B may be a therapeutic strategy for myeloid malignancies with ASXL1 mutations.

Dimerized sesquiterpenoid [4 + 2] adducts with ferroptosis-promoting activity from Inula britannica Linn.

Inubritanolides C and D (1 and 2), two exo sesquiterpenoid [4 + 2] adducts with unprecedented interconverting conformations of twist-chair and chair, together with two previously undescribed endo [4 + 2] dimers (3 and 4) were discovered from Inula britannica flowers. Dimers 1 and 2 have an undescribed carbon skeleton comprising of eudesmanolide and guaianolide units with the linkage mode of C-11/C-1' and C-13/C-3' via a Diels-Alder cycloaddition reaction. Their structures were elucidated using 1D/2D NMR, X-ray diffraction, ECD, and variable-temperature NMR experiments. Dimer 2 displayed a strong inhibitory effect on breast cancer cells by promoting lipid ROS production, showing its potential as ferroptosis inducer.

Abiotic and biotic roles of metals in the anaerobic digestion of sewage sludge: A review.

Anaerobic digestion (AD) is a promising technique for sludge treatment and resource recovery. Metals are very important components of sludge and can have substantial effects on its complex nature and microbial activity. However, systematic reviews have not addressed how metals in sludge affect AD and how they can be regulated to improve AD. This paper comprehensively reviews the effects of metals on the AD of sludge from both abiotic and biotic perspectives. First, we introduce the contents and basic characteristics (e.g., chemical forms) of intrinsic metals in sewage sludge. Then, we summarise the main mechanism by which metals influence sludge properties and the methods for removing metals and thus improving AD. Next, we analyze the effects of both intrinsic and exogenous metals on the enzymes and microbial communities involved in anaerobic bioconversion, focusing on the types, critical concentrations and valence states of the metals. Finally, we propose ideas for future research on the roles of metals in the AD of sludge. In summary, this review systematically clarifies the roles of metals in the AD of sludge and provides a reference for improving AD by regulating these metals.

Impacts and mechanism of coal fly ash on kitchen waste composting performance: The perspective of microbial community.

Aerobic composting is eco-friendly and sustainable practice for kitchen waste (KW) disposal to restore soil fertility and reduce environmental risks. However, KW compact structure, perishable nature, acidification by anaerobic acidogens, inhibits the metabolism of aerobic microbes, insufficient breakdown of organic matters, and prolong the composting duration. This study, co-composted coal fly ash (FA), to regulate bacterial dynamics, co-occurrence patterns and nutrients transformation in KW composting. Our results indicated, FA created suitable environment by increasing pH and temperature, which facilitated the proliferation and reshaping of microbial community. FA fostered the relative abundances of phlya (Proteobacteria, Chloroflexi and Actinobacteriota) and genera (Bacillus, Paenibacillus and Lysinibacillus), which promoted the nutrients transformation (phosphorus and nitrogen) in KW compost. FA enhanced the mutualistic correlations between bacterial communities, promoted the network complexity (nodes & edges) and contains more positive connections, which reflect the FA amendment effects. KW mature compost seed germination index reached >85% of FA treatment, indicated the final products fully met the Chinese national standard for organic fertilizer. These findings might provide opportunity to advance the KW composting and collaborative management of multiple waste to curb the current environmental challenges.

Genome-wide association analysis of left ventricular imaging-derived phenotypes identifies 72 risk loci and yields genetic insights into hypertrophic cardiomyopathy.

Left ventricular regional wall thickness (LVRWT) is an independent predictor of morbidity and mortality in cardiovascular diseases (CVDs). To identify specific genetic influences on individual LVRWT, we established a novel deep learning algorithm to calculate 12 LVRWTs accurately in 42,194 individuals from the UK Biobank with cardiac magnetic resonance (CMR) imaging. Genome-wide association studies of CMR-derived 12 LVRWTs identified 72 significant genetic loci associated with at least one LVRWT phenotype (P < 5 × 10-8), which were revealed to actively participate in heart development and contraction pathways. Significant causal relationships were observed between the LVRWT traits and hypertrophic cardiomyopathy (HCM) using genetic correlation and Mendelian randomization analyses (P < 0.01). The polygenic risk score of inferoseptal LVRWT at end systole exhibited a notable association with incident HCM, facilitating the identification of high-risk individuals. The findings yield insights into the genetic determinants of LVRWT phenotypes and shed light on the biological basis for HCM etiology.

Development and validation of a new risk assessment model for immunomodulatory drug-associated venous thrombosis among Chinese patients with multiple myeloma.

BACKGROUND: Individuals with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) are at risk of developing venous thromboembolism (VTE), a serious complication. There is no established clinical model for predicting VTE in the Chinese population. We develop a new risk assessment model (RAM) for IMiD-associated VTE in Chinese MM patients. METHODS: We retrospectively selected 1334 consecutive MM patients receiving IMiDs from 16 medical centers in China and classified them randomly into the derivation and validation cohorts. A multivariate Cox regression model was used for analysis. RESULTS: The overall incidence of IMiD-related VTE in Chinese MM patients was 6.1%. Independent predictive factors of VTE (diabetes, ECOG performance status, erythropoietin-stimulating agent use, dexamethasone use, and VTE history or family history of thrombosis) were identified and merged to develop the RAM. The model identified approximately 30% of the patients in each cohort at high risk for VTE. The hazard ratios (HRs) were 6.08 (P < 0.001) and 6.23 (P < 0.001) for the high-risk subcohort and the low-risk subcohort, respectively, within both the derivation and validation cohorts. The RAM achieved satisfactory discrimination with a C statistic of 0.64. The stratification approach of the IMWG guidelines yielded respective HRs of 1.77 (P = 0.053) and 1.81 (P = 0.063). The stratification approach of the SAVED score resulted in HRs of 3.23 (P = 0.248) and 1.65 (P = 0.622), respectively. The IMWG guideline and the SAVED score-based method yielded C statistics of 0.58 and 0.51, respectively. CONCLUSIONS: The new RAM outperformed the IMWG guidelines and the SAVED score and could potentially guide the VTE prophylaxis strategy for Chinese MM patients.

Propionate promotes gluconeogenesis by regulating mechanistic target of rapamycin (mTOR) pathway in calf hepatocytes.

Enhancing hepatic gluconeogenesis is one of the main modes of meeting the glucose requirement of dairy cows. This study attempted to determine whether the gluconeogenesis precursor propionate had an effect on the expression of the main genes involved in gluconeogenesis in calf hepatocytes and elucidate the associated mechanisms. Calf hepatocytes were obtained from 5 healthy calves (1 d old; 30 to 40 kg) and exposed to 0-, 1-, 2.5-, or 5-mM sodium propionate (NaP), which is known to promote the expression of genes involved in the gluconeogenesis pathway, including fructose 1,6-bisphosphatase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase. With regard to the underlying mechanism, propionate promoted the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, hepatocyte nuclear factor 4, and forkhead box O1 (transcription factors that regulate the expression of hepatic gluconeogenic genes) by promoting mammalian target of rapamycin complex 1 (mTORC1), but inhibiting mTORC2 activity (P < 0.01). We also established a model of palmitic acid (PA)-induced hepatic injury in calf hepatocytes and found that PA could inhibit the gluconeogenic capacity of calf hepatocytes by suppressing the expression of gluconeogenic genes, inhibiting mTORC1, and promoting the activity of mTORC2 (P < 0.01). In contrast, NaP provided protection to calf hepatocytes by counteracting the inhibitory effect of PA on the gluconeogenic capacity of calf hepatocytes (P < 0.05). Collectively, these findings indicate that NaP enhances the gluconeogenic capacity of calf hepatocytes by regulating the mTOR pathway activity. Thus, in addition to improving the glucose production potential, propionate may have therapeutic potential for the treatment of hepatic injury in dairy cows.

Genetic Variants That Impact Alternative Polyadenylation in Cancer Represent Candidate Causal Risk Loci.

Alternative polyadenylation (APA) is emerging as a major mechanism of posttranscriptional regulation. APA can impact the development and progression of cancer, suggesting that the genetic determinants of APA might play an important role in regulating cancer risk. Here, we depicted a pan-cancer atlas of human APA quantitative trait loci (apaQTL), containing approximately 0.7 million apaQTLs across 32 cancer types. Systematic multiomics analyses indicated that cancer apaQTLs could contribute to APA regulation by altering poly(A) motifs, RNA-binding proteins (RBP), and chromatin regulatory elements and were preferentially enriched in genome-wide association studies (GWAS)-identified cancer susceptibility loci. Moreover, apaQTL-related genes (aGene) were broadly related to cancer signaling pathways, high mutational burden, immune infiltration, and drug response, implicating their potential as therapeutic targets. Furthermore, apaQTLs were mapped in Chinese colorectal cancer tumor tissues and then screened for functional apaQTLs associated with colorectal cancer risk in 17,789 cases and 19,951 controls using GWAS-ChIP data, with independent validation in a large-scale population consisting of 6,024 cases and 10,022 controls. A multi-ancestry-associated apaQTL variant rs1020670 with a C>G change in DNM1L was identified, and the G allele contributed to an increased risk of colorectal cancer. Mechanistically, the risk variant promoted aberrant APA and facilitated higher usage of DNM1L proximal poly(A) sites mediated by the RBP CSTF2T, which led to higher expression of DNM1L with a short 3'UTR. This stabilized DNM1L to upregulate its expression, provoking colorectal cancer cell proliferation. Collectively, these findings generate a resource for understanding APA regulation and the genetic basis of human cancers, providing insights into cancer etiology. SIGNIFICANCE: Cancer risk is mediated by alternative polyadenylation quantitative trait loci, including the rs1020670-G variant that promotes alternative polyadenylation of DNM1L and increases colorectal cancer risk.

Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk.

Genome-wide association studies have identified numerous variants associated with human complex traits, most of which reside in the non-coding regions, but biological mechanisms remain unclear. However, assigning function to the non-coding elements is still challenging. Here we apply Activity-by-Contact (ABC) model to evaluate enhancer-gene regulation effect by integrating multi-omics data and identified 544,849 connections across 20 cancer types. ABC model outperforms previous approaches in linking regulatory variants to target genes. Furthermore, we identify over 30,000 enhancer-gene connections in colorectal cancer (CRC) tissues. By integrating large-scale population cohorts (23,813 cases and 29,973 controls) and multipronged functional assays, we demonstrate an ABC regulatory variant rs4810856 associated with CRC risk (Odds Ratio = 1.11, 95%CI = 1.05-1.16, P = 4.02 × 10-5) by acting as an allele-specific enhancer to distally facilitate PREX1, CSE1L and STAU1 expression, which synergistically activate p-AKT signaling. Our study provides comprehensive regulation maps and illuminates a single variant regulating multiple genes, providing insights into cancer etiology.

Risk SNP in a transcript of RP11-638I2.4 increases lncRNA-YY1 interaction and pancreatic cancer susceptibility.

Tens of thousands of long non-coding RNAs (lncRNAs) have been identified through RNA-seq analysis, but the biological and pathological significance remains unclear. By integrating the genome-wide lncRNA data with a cross-ancestry meta-analysis of PDAC GWASs, we depicted a comprehensive atlas of pancreatic ductal adenocarcinoma (PDAC)-associated lncRNAs, containing 1,204 lncRNA (445 novel lncRNAs and 759 GENCODE annotated lncRNAs) and 4,368 variants. Furthermore, we found that PDAC-associated lncRNAs could function by altering chromatin activity, transcription factors, and RNA-binding proteins binding affinity. Importantly, genetic variants linked to PDAC are preferentially found at PDAC-associated lncRNA regions, supporting the biological and clinical relevance of PDAC-associated lncRNAs. Finally, we prioritized a novel transcript (MICT00000110172.1) of RP11-638I2.4 as a potential tumor promoter. MICT00000110172.1 is able to reinforce the interaction with YY1, which could reverse the effect of YY1 on pancreatic cancer cell cycle arrest to promote the pancreatic cancer growth. G > A change at rs2757535 in the second exon of MICT00000110172.1 induces a spatial structural change and creates a target region for YY1 binding, which enforces the effect of MICT00000110172.1 in an allele-specific manner, and thus confers susceptibility to tumorigenesis. In summary, our results extend the repertoire of PDAC-associated lncRNAs that could act as a starting point for future functional explorations, and the identification of lncRNA-based target therapy.

Hot and cold tumors: Immunological features and the therapeutic strategies.

The "hotness" or "coldness" of the tumors are determined by the information of the cancer cells themselves, tumor immune characteristics, tumor microenvironment, and signaling mechanisms, which are key factors affecting cancer patients' clinical efficacy. The switch mechanism of "hotness" and "coldness" and its corresponding pathological characteristics and treatment strategies are the frontier and hot spot of tumor treatment. How to distinguish the "hotness" or "coldness" effectively and clarify the causes, microenvironment state, and characteristics are very important for the tumor response and efficacy treatments. Starting from the concept of hot and cold tumor, this review systematically summarized the molecular characteristics, influencing factors, and therapeutic strategies of "hot and cold tumors," and analyzed the immunophenotypes, the tumor microenvironment, the signaling pathways, and the molecular markers that contribute to "hot and cold tumors" in details. Different therapeutic strategies for "cold and hot tumors" based on clinical efficacy were analyzed with drug targets and proteins for "cold and hot tumors." Furthermore, this review combines the therapeutic strategies of different "hot and cold tumors" with traditional medicine and modern medicine, to provide a basis and guidance for clinical decision-making of cancer treatment.

TPM3: a novel prognostic biomarker of cervical cancer that correlates with immune infiltration and promotes malignant behavior in vivo and in vitro.

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) has become increasingly prevalent in younger women. Tropomyosin 3 (TPM3), a thin filament actin-binding protein, has been implicated in various malignancies. In this study, TPM3 expression was evaluated using RNA-seq data from The Cancer Genome Atlas (TCGA), and its relationship with CESC prognosis was examined with receiver operating characteristic (ROC) curves. The effects of TPM3 on cellular proliferation and migration were examined in CESC cell lines using Cell Counting Kit-8 (CCK-8), colony formation, and Transwell assays, while in vivo effects were assessed in mouse xenograft models. Furthermore, differentially expressed genes (DEGs) associated with TPM3 were investigated to determine their tumorigenic functions. Associations between TPM3, chemosensitivity, and immune infiltration were analyzed, as were links between mutations, methylation, and prognosis using the cBioPortal and MethSurv databases. Upregulation of TMP3 mRNA and protein levels was observed in CESC samples, with elevated mRNA levels associated with reduced overall survival. TPM3 showed an area under the curve (AUC) of 0.946 for CESC diagnosis and was found to regulate tumor proliferation and metastasis in vitro and in vivo. Overall, 3099 DEGs were identified and found to be enriched in key CESC progression-related signaling pathways. TPM3 expression was also correlated with intratumoral immune cell infiltration and immune checkpoint activity. Patients with higher TPM3 expression showed distinctive chemosensitivity profiles, and TPM3 gene methylation was linked to poorer CESC patient prognostic outcomes. In conclusion, TPM3 is a key regulator of CESC progression, prognosis, and the tumor immune microenvironment, suggesting its potential as a diagnostic or prognostic biomarker and target for CESC immunotherapy.