Orai1 and Orai3 act through distinct signalling axes to promote stemness and tumorigenicity of breast cancer stem cells.

BACKGROUND: One of major challenges in breast tumor therapy is the existence of breast cancer stem cells (BCSCs). BCSCs are a small subpopulation of tumor cells that exhibit characteristics of stem cells. BCSCs are responsible for progression, recurrence, chemoresistance and metastasis of breast cancer. Ca2+ signalling plays an important role in diverse processes in cancer development. However, the role of Ca2+ signalling in BCSCs is still poorly understood. METHODS: A highly effective 3D soft fibrin gel system was used to enrich BCSC-like cells from ER+ breast cancer lines MCF7 and MDA-MB-415. We then investigated the role of two Ca2+-permeable ion channels Orai1 and Orai3 in the growth and stemness of BCSC-like cells in vitro, and tumorigenicity in female NOD/SCID mice in vivo. RESULTS: Orai1 RNA silencing and pharmacological inhibition reduced the growth of BCSC-like cells in tumor spheroids, decreased the expression levels of BCSC markers, and reduced the growth of tumor xenografts in NOD/SCID mice. Orai3 RNA silencing also had similar inhibitory effect on the growth and stemness of BCSC-like cells in vitro, and tumor xenograft growth in vivo. Mechanistically, Orai1 and SPCA2 mediate store-operated Ca2+ entry. Knockdown of Orai1 or SPCA2 inhibited glycolysis pathway, whereas knockdown of Orai3 or STIM1 had no effect on glycolysis. CONCLUSION: We found that Orai1 interacts with SPCA2 to mediate store-independent Ca2+ entry, subsequently promoting the growth and tumorigenicity of BCSC-like cells via glycolysis pathway. In contrast, Orai3 and STIM1 mediate store-operated Ca2+ entry, promoting the growth and tumorigenicity of BCSC-like cells via a glycolysis-independent pathway. Together, our study uncovered a well-orchestrated mechanism through which two Ca2+ entry pathways act through distinct signalling axes to finely control the growth and tumorigenicity of BCSCs.

Promoting the healing of infected diabetic wound by nanozyme-containing hydrogel with anti-bacterial inflammation suppressing, ROS-scavenging and oxygen-generating properties.

Bacterial infections already pose a significant threat to skin wounds, especially in diabetic patients who have difficulty healing wounds. However, wound or bacterial infections are known to produce excess reactive oxygen species (ROS), and hypoxia may further hinder wound healing and the development of chronic wounds. In this study, a multifunctional hydrogel for ROS scavenging and bacterial inhibition was developed by cross-linking polyvinyl alcohol (PVA) and sodium alginate (SA) with graphene oxide (GO) loaded with silver-platinum hybrid nanoparticles (GO@Ag-Pt). The PVA/SA hydrogel loaded with GO@Ag-Pt exhibited the ability to scavenge different types of ROS, generate O2, and kill a broad spectrum of bacteria in vitro. The silver-platinum hybrid nanoparticles significantly increased the antibacterial ability against Escherichia coli and Staphylococcus aureus compared with silver nanoparticles (AgNps). GO@Ag-Pt loaded hydrogel was effective in treating infections caused by S.aureus, thereby significantly promoting wound healing during the inflammatory phase. Hydrogel therapy significantly reduced the level of ROS and alleviated inflammation levels. Notably, our ROS-scavenging, antibacterial hydrogels can be used to effectively treat various types of wounds, including difficult-to-heal diabetic wounds with bacterial infections. Thus, this study proposes an effective strategy for various chronic wound healing based on ROS clearance and bacteriostatic hydrogels.

Channel attention convolutional aggregation network based on video-level features for EEG emotion recognition.

Electroencephalogram (EEG) emotion recognition plays a vital role in affective computing. A limitation of the EEG emotion recognition task is that the features of multiple domains are rarely included in the analysis simultaneously because of the lack of an effective feature organization form. This paper proposes a video-level feature organization method to effectively organize the temporal, frequency and spatial domain features. In addition, a deep neural network, Channel Attention Convolutional Aggregation Network, is designed to explore deeper emotional information from video-level features. The network uses a channel attention mechanism to adaptively captures critical EEG frequency bands. Then the frame-level representation of each time point is obtained by multi-layer convolution. Finally, the frame-level features are aggregated through NeXtVLAD to learn the time-sequence-related features. The method proposed in this paper achieves the best classification performance in SEED and DEAP datasets. The mean accuracy and standard deviation of the SEED dataset are 95.80% and 2.04%. In the DEAP dataset, the average accuracy with the standard deviation of arousal and valence are 98.97% ± 1.13% and 98.98% ± 0.98%, respectively. The experimental results show that our approach based on video-level features is effective for EEG emotion recognition tasks.

Traceable Optical Physical Unclonable Functions Based on Germanium Vacancy in Diamonds.

Physical unclonable functions (PUFs) have emerged as an unprecedented solution for modern information security and anticounterfeiting by virtue of their inherent unclonable nature derived from distinctive, randomly generated physical patterns that defy replication. However, the creation of traceable optical PUF tags remains a formidable challenge. Here, we demonstrate a traceable PUF system whose unclonability arises from the random distribution of diamonds and the random intensity of the narrow emission from germanium vacancies (GeV) within the diamonds. Tamper-resistant PUF labels can be manufactured on diverse and intricate structural surfaces by blending diamond particles into polydimethylsiloxane (PDMS) and strategically depositing them onto the surface of objects. The resulting PUF codes exhibit essentially perfect uniformity, uniqueness, reproducibility, and substantial encoding capacity, making them applicable as a private key to fulfill the customization demands of circulating commodities. Through integration of a digitized "challenge-response" protocol, a traceable and highly secure PUF system can be established, which is seamlessly compatible with contemporary digital information technology. Thus, the GeV-PUF system holds significant promise for applications in data security and blockchain anticounterfeiting, providing robust and adaptive solutions to address the dynamic demands of these domains.

Rare-earth-free up and down-conversion dual-emission carbon dots for Cu2+ sensing.

In this work, up- and down-conversion dual-emission CDs without rare-earth (UD D-CDs) were synthesized using RhB and 1,4-Diaminoanthraquinone as precursors. The synthesized UD D-CDs exhibited dual emissions at 496 and 580 nm under 260 and 865 nm excitation, respectively. The fluorescence emission mechanism, including contributions from carbon nuclei, surface states, molecular states, and internal defect states, was discussed through the separation and purification of UD D-CDs. Based on the interaction between UD D-CDs and copper ions (Cu2+), a dual-mode ratio fluorescence probe was developed to detect and quantify Cu2+. The up-conversion ratio fluorescent probe shows a linear range of 0.0500-15.0 µM, with a detection limit as low as 2.76 nM. This method has been successfully applied to detecting Cu2+ in human serum and has potential applications in biochemical analysis and biological imaging. The successful preparation of up-conversion fluorescent carbon dots without rare earth elements and the ability to perform low-damage detection in high-background biological samples provide a new approach to constructing non-rare earth up-conversion probes.

Therapeutic and prognostic effect of disulfidptosis-related genes in lung adenocarcinoma.

Disulfidptosis, a new form of cell death, may be induced by disulfide stress associated with cystine disulfide buildup, which can promote cell toxicity, leading to cell death. Nevertheless, the role of direct prognosis and the mechanism underlying the regulation of disulfidptosis-related genes (DRGs) in lung adenocarcinoma (LUAD) are still unknown. This study aimed to investigate the role of DRGs in LUAD prognosis and diagnosis through multiomics analysis. First, copy number variations (CNVs) and mutations in the 10 genes were assessed. Considering that five differentially expressed genes (DEGs) were associated with disulfidptosis, a novel DRG score that can be utilized to anticipate LUAD prognosis was developed. Next, the generated receiver operating characteristic (ROC) and survival curves demonstrated that the model had an excellent predictive quality in LUAD in both the training and validation cohorts. Meanwhile, substantial functional disparities between the high DRG group and the low DRG group were observed, and the second gap mitosis (G2M) checkpoint, E2 promoter-binding factor (E2F) targets, and myelocytomatosis (MYC) target activities were consistently higher in the high DRG group than in the low DRG group. Additionally, the T-cell dysfunction score and tumor inflammation signature (Merck18) were negatively correlated with DRGs, whereas myeloid-derived suppressor cells (MDSCs) were positively correlated with DRGs. Moreover, DRGs were negatively linked to most of the immunological checkpoints. Meanwhile, samples of low DRGs benefited more from immune checkpoint blockade (ICB). The correlation analysis between DRGs and clinical characteristics revealed increasing malignancy with increasing DRG scores. Drug sensitization experiment results indicated that sensitivity to cisplatin, vincristine, docetaxel, and gemcitabine was higher in the high DRG group than in the low DRG group. The function of model genes in LUAD was also verified using immunohistochemistry, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, 5-ethynyl-2'-deoxyuridine (EDU), and clonogenic formation.

Temperature-Tolerant Versatile Conductive Zwitterionic Nanocomposite Organohydrogel toward Multisensory Applications.

Conductive hydrogels (CHs) are emerging materials for next generation sensing systems in flexible electronics. However, the fabrication of competent CHs with excellent stretchability, adhesion, self-healing, photothermal conversion, multisensing, and environmental stability remains a huge challenge. Herein, a nanocomposite organohydrogel with the above features is constructed by in situ copolymerization of zwitterionic monomer and acrylamide in the existence of carboxylic cellulose nanofiber-carrying reduced graphene oxide (rGO) plus a solvent displacement strategy. The synergy of abundant dipole-dipole interactions and intermolecular hydrogen bonds enables the organohydrogel to exhibit high stretchability, strong adhesion, and good self-healing. The presence of glycerol weakens the formation of hydrogen bonds between water molecules, endowing the organohydrogel with excellent environmental stability (-40 to 60 °C) to adapt to different application scenarios. Importantly, the multimodal organohydrogel presents excellent sensing behavior, including a high gauge factor of 16.3 at strains of 400-1440% and a reliable thermal coefficient of resistance (-4.2 °C-1) over a wide temperature widow (-40 to 60 °C). Moreover, the organohydrogel displays a highly efficient and reliable photothermal conversion ability due to the favorable optical absorbing behavior of rGO. Notably, the organohydrogel can detect accurate human activities at ambient temperature, demonstrating potential applications in flexible intelligent electronics.

Construction of an Ohmic Contact Cathode by Two Metal Sulfides for efficient Capture and Catalysis of Polysulfide.

The slow reaction kinetics and severe shuttle effect of lithium polysulfide make Li-S battery electrochemical performance difficult to meet the demands of large electronic devices such as electric vehicles. Based on this, an electrocatalyst constructed by metal phase material (MoS2) and semiconductor phase material (SnS2) with ohmic contact is designed for inhibiting the dissolution of lithium polysulfide with improving the reaction kinetics. According to the density-functional theory calculations, it is found that the heterostructured samples with ohmic contacts can effectively reduce the reaction-free energy of lithium polysulfide to accelerate the sulfur redox reaction, in addition to the excellent electron conduction to reduce the overall activation energy. The metallic sulfide can add more sulfophilic sites to promote the capture of polysulfide. Thanks to the ohmic contact design, the carbon nanotube-MoS2-SnS2 achieved a specific capacity of 1437.2 mAh g-1 at 0.1 C current density and 805.5 mAh g-1 after 500 cycles at 1 C current density and is also tested as a pouch cell, which proves to be valuable for practical applications. This work provides a new idea for designing an advanced and efficient polysulfide catalyst based on ohmic contact.

Fabrication of micron-sized boronate-decorated polyethyleneimine-grafted magnetic agarose beads for specific enrichment of ribonucleic acid.

Exploiting high-performance magnetic beads for specific enrichment of ribonucleic acid (RNA) has important significance in the biomedical research field. Herein, a simple strategy was proposed for fabricating boronate-decorated polyethyleneimine-grafted magnetic agarose beads (BPMAB), which can selectively isolate cis-diol-containing substances through boronate affinity. The size of the basic magnetic agarose beads was controlled through the emulsification of the water-in-oil emulsion with a high-speed shear machine, which enhanced the specific surface area of BPMAB. Subsequently, to modify more boronic acid ligands, branched PEI with excellent hydrophilicity and numerous reaction sites was grafted. 2,4-Difluoro-3-formylphenyl boronic acid (2,4-DFPBA) was covalently immobilized for selectively capturing cis-diol-containing substances under physiological condition (pH 7.4). The BPMAB with a diameter range from 1.86 µm to 11.60 µm possessed clearly spherical structure, and excellent magnetic responsiveness and suspension ability in aqueous solution. ß-Nicotinamide adenine dinucleotide (ß-NAD), a short-chain cis-diol carrying agent, was selected as a target molecule for evaluating the adsorption property of BPMAB and the maximum adsorption capacity of BPMAB for ß-NAD could reach 205.11 mg g-1. In addition, the BPMAB as adsorbent was used to selectively enrich RNA from mammalian cells. The maximum adsorption capacity of BPMAB for RNA was 140.50 mg g-1. Under optimized conditions, the BPMAB-based MSPE successfully enriched the high-quality total RNA with 28S to 18S ribosomal RNA ratios ranging from 2.06 to 2.16. According to the PCR analysis of GADPH gene, the extracted total RNA was successfully reverse transcribed into cDNA. Therefore, we believe that the BPMAB-based MSPE could be applicable for the specific enrichment of RNA from complex biological systems.

Multiomics analysis of homologous recombination deficiency across cancer types.

There remains ongoing debate regarding the association of homologous recombination deficiency (HRD) with patient survival across various malignancies, highlighting the need for a comprehensive understanding of HRD's role in different cancer types. Based on data from databases, we conducted a multivariable omics analysis on HRD in 33 cancer types, focusing mainly on 23 cancers in which HRD was significantly associated with patient overall survival (OS) rates. This analysis included the mechanisms related to patient prognosis, gene expression, gene mutation, and signaling pathways. In this study, HRD was found to be significantly associated with patient prognosis, but its impact varied among different cancers. HRD was linked to different outcomes for patients with distinct tumor subtypes and was correlated with clinical features such as clinical stage and tumor grade. Driver gene mutations, including TP53, MUC4, KRAS, HRAS, FLG, ANK3, BRCA2, ATRX, FGFR3, NFE2L2, MAP3K1, PIK3CA, CIC, FUBP1, ALB, CTNNB1, and MED12, were associated with HRD across specific cancer types. We also analyzed differentially expressed genes (DEGs) and differentially methylated regions (DMRs) in relation to HRD levels in these cancers. Furthermore, we explored the correlation between HRD and signaling pathways, as well as immune cell infiltration. Overall, our findings contribute to a comprehensive understanding of HRD's multifaceted role in cancer.

CTHRC1 is associated with BRAF(V600E) mutation and correlates with prognosis, immune cell infiltration, and drug resistance in colon cancer, thyroid cancer, and melanoma.

Colon cancer, thyroid cancer, and melanoma are common malignant tumors that seriously threaten human health globally. The B-Raf proto-oncogene, serine/threonine kinase (BRAF)(V600E) mutation is an important driver gene mutation in these cancer types. In this study, we identified that collagen triple helix repeat containing 1 (CTHRC1) expression was associated with the BRAF(V600E) mutation in colon cancer, thyroid cancer, and melanoma. Based on database analysis and clinical tissue studies, CTHRC1 was verified to correlate with poor prognosis and worse clinicopathological features in colon cancer and thyroid cancer patients, but not in patients with melanoma. Several signaling pathways, immune cell infiltration, and immunotherapy markers were associated with CTHRC1 expression. Additionally, a high level of CTHRC1 was correlated with decreased sensitivity to antitumor drugs (vemurafenib, PLX-4720, dabrafenib, and SB-590885) targeting the BRAF(V600E) mutation. This study provides evidence of a significant correlation between CTHRC1 and the BRAF(V600E) mutation, suggesting its potential utility as a diagnostic and prognostic biomarker in human colon cancer, thyroid cancer, and melanoma.

Memantine alleviates cognitive impairment and hippocampal morphology injury in a mouse model of chronic alcohol exposure.

Alcohol-related cognitive impairment (ARCI) is highly prevalent among patients with alcohol abuse and dependence. The pathophysiology of ARCI, pivotal for refined therapeutic approaches, is not fully elucidated, posing a risk of progression to severe neurological sequelae such as Korsakoff's syndrome (KS) and Alcohol-Related Dementia (ARD). This study ventures into the underlying mechanisms of chronic alcohol-induced neurotoxicity, notably glutamate excitotoxicity and cytoskeletal disruption, and explores the therapeutic potential of Memantine, a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor known for its neuroprotective effect against excitotoxicity. Our investigation centers on the efficacy of Memantine in mitigating chronic alcohol-induced cognitive and hippocampal damages in vivo. Male C57BL/6J mice were subjected to 30 % (v/v, 6.0 g/kg) ethanol via intragastric administration alongside Memantine co-treatment (10 mg/kg/day, intraperitoneally) for six weeks. The assessment involved Y maze, Morris water maze, and novel object recognition tests to evaluate spatial and recognition memory deficits. Histopathological evaluations of the hippocampus were conducted to examine the extent of alcohol-induced morphological changes and the potential protective effect of Memantine. The findings reveal that Memantine significantly improves chronic alcohol-compromised cognitive functions and mitigates hippocampal pathological changes, implicating a moderating effect on the disassembly of actin cytoskeleton and microtubules in the hippocampus, induced by chronic alcohol exposure. Our results underscore Memantine's capability to attenuate chronic alcohol-induced cognitive and hippocampal morphological harm may partly through regulating cytoskeleton dynamics, offering valuable insights into innovative therapeutic strategies for ARCI.

One-step solvothermal synthesis of full-color fluorescent carbon dots for information encryption and anti-counterfeiting applications.

Multicolor fluorescent carbon dots (CDs) have received extensive attention due to their excellent fluorescence tunable performance. In this study, multicolor CDs with color tunable and high fluorescence quantum yields (QYs) were successfully prepared under the same conditions by a one-step solvothermal method using 2-aminoterephthalic acid (ATA) and Nile Blue A (NBA) as reaction reagents, achieving a wide color field coverage. Detailed studies on the relevant mechanisms have been carried out for blue, green and red CDs, indicating that the regulating mechanism of multicolor luminescence is determined by the size of the sp2 conjugated domains, which is due to the increase of particle size that causes an increase in the size of the sp2 conjugated domains, resulting in the narrowing of the band gap and the red-shift of the emission wavelength. It was found that the CDs have the advantages of simple preparation, high photostability and high quantum yield. They were used as fluorescent ink and mixed with polyvinyl alcohol (PVA) to form CD/PVA composites, which were successfully applied in the field of information encryption and anti-counterfeiting. This work provides a new strategy for the synthesis of panchromatic tunable fluorescent CDs and their application in the field of information encryption and anti-counterfeiting.

Predictive Value of Smoking Index Combined with NT-proBNP for Patients with Pulmonary Hypertension Due to Chronic Lung Disease: A Retrospective Study.

Purpose: Smoking is a major risk factor for the group 3 PH. NT-proBNP is a biomarker for risk stratification in PH. This study aims to investigate the effects of smoking status and smoking index (SI) on group 3 PH and to evaluate the value of SI and SI combined with NT-proBNP in early diagnosis and prediction of disease severity. Patients and Methods: Four hundred patients with group 3 PH at the First Hospital of Shanxi Medical University between January 2020 and December 2021 were enrolled and divided into two groups: mild (30 mmHg ≤ pulmonary artery systolic pressure (PASP)≤50 mmHg) and non-mild (PASP >50 mmHg). The effect of smoking on group 3 PH was analyzed using univariate analysis, and logistic analysis was conducted to evaluate the risk of group 3 PH according to smoking status and SI. Spearman correlation coefficient was used to test the correlation between SI and the index of group 3 PH severity. The predictive value of SI was evaluated using a receiver operating characteristic (ROC) curve. Results: Correlation and logistic analyses showed that SI was associated with PH severity. Smoking status (P=0.009) and SI (P=0.039) were independent risk factors for non-mild group 3 PH, and ROC showed that the predictive value of SI (AUC:0.596) for non-mild PH was better than that of the recognized pro-brain natriuretic peptide (NT-proBNP) (AUC:0.586). SI can be used as a single predictive marker. SI and NT-proBNP can be formulated as prediction models for screening non-mild clinical cases (AUC:0.628). Conclusion: SI is a potentially ideal non-invasive predictive marker for group 3 PH. SI and NT-proBNP could be used to develop a prediction model for screening non-mild PH cases. This can greatly improve the predictive specificity of the established PH marker, NT-proBNP.

Regulate the Solvation Structure and Interface by Nitrate in Phosphate-Based Electrolytes for 4.5 V-Class Ni-Rich Batteries.

Phosphate-based electrolyte propels the advanced battery system with high safety. Unfortunately, restricted by poor electrochemical stability, it is difficult to be compatible with advanced lithium metal anodes and Ni-rich cathodes. To alleviate these issues, the study has developed a phosphate-based localized high-concentration electrolyte with a nitrate-driven solvation structure, and the nitrate-derived N-rich inorganic interface shows excellent performance in stabilizing the LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode interface and modulating the lithium deposition morphology on the anode. The results show that the Li|| NCM811 cell has exceptional long-cycle stability of >80% capacity retention after 800 cycles at 4.3 V, 1 C. A more prominent capacity retention rate of 93.3% after 200 cycles can be reached with the high voltage of 4.5 V. While being compatible with the phosphate-based electrolyte with good flame retardancy and the good electrochemical stability of Ni-rich lithium metal battery (LMBs) systems, the present work expands the construction of anion-rich solvation structures, which is expected to promote the development of the high-performance LMBs with safety.

CD47, a novel YAP target gene, contributes to hepatic stellate cell activation and liver fibrosis induced by high-fat diet.

Activated hepatic stellate cells (HSCs) have been widely recognized as a primary source of pathological myofibroblasts, leading to the accumulation of extracellular matrix and liver fibrosis. CD47, a transmembrane glycoprotein expressed on the surface of various cell types, has been implicated in non-alcoholic fatty liver disease. However, the precise role of CD47 in HSC activation and the underlying regulatory mechanisms governing CD47 expression remain poorly understood. In this study, we employed single-cell RNA sequencing analysis to investigate CD47 expression in HSCs from mice subjected to a high-fat diet. CD47 silencing in HSCs markedly inhibited the expression of fibrotic genes and promoted apoptosis. Mechanistically, we found that Yes-associated protein (YAP) collaborates with TEAD4 to augment the transcriptional activation of CD47 by binding to its promoter region. Notably, disruption of the interaction between YAP and TEAD4 caused a substantial decrease in CD47 expression in HSCs and reduced the development of high-fat diet-induced liver fibrosis. Our findings highlight CD47 as a critical transcriptional target of YAP in promoting HSC activation in response to a high-fat diet. Targeting the YAP/TEAD4/CD47 signaling axis may hold promise as a therapeutic strategy for liver fibrosis.

The role of serum sodium in poor prognosis evaluation of pulmonary hypertension associated with left heart disease.

BACKGROUND: Previous studies have shown that hyponatremia was strongly associated with a poor prognosis of type 1 pulmonary hypertension, and our team's antecedent studies found that low serum sodium was associated with the severity and the length of hospitalization of pulmonary hypertension associated with left ventricular disease (PH-LHD). However, the relationship between serum sodium and the prognosis of PH-LHD remains unclear. This study aims to determine the clinical value of serum sodium in evaluating poor prognosis in patients with PH-LHD. METHODS: We successfully followed 716 patients with PH-LHD. Kaplan-Meier was used to plot survival in PH-LHD patients with different serum sodium levels. The effect of serum sodium on poor prognosis was analyzed using a Cox proportional risk model. The trends between patients serum sodium and survival were visualized by restricted cubic spline (RCS). RESULTS: The survival rates at 1, 2, 3 and 4 years were 52%, 41%, 31% and 31% for the patients with hyponatremia associated with PH-LHD and 71%, 71%, 71% and 54% for the patients with hypernatremia, respectively. The observed mortality rate in the hyponatremia and hypernatremia groups surpassed that of the normonatremic group. The adjusted risks of death (risk ratio) for patients with hyponatremia and hypernatremia were found to be 2.044 and 1.877. Furthermore, the restricted cubic spline demonstrated an L-shaped correlation between serum sodium and all-cause mortality in patients with PH-LHD. CONCLUSIONS: Abnormal serum sodium level is strongly associated with poor prognosis in PH-LHD. Serum sodium may play an important pathogenic role in PH-LHD occurrence and could be used as a marker to assess the survival in patients.

Rhodium(III)-Catalyzed Annulation Synthesis of Difluorinated Quinazolinone Derivatives Using an Amide Carbonyl as the Directing Group.

The use of amide carbonyl groups of substrates as weakly coordinating directing groups has received a significant amount of attention. Recently, difluoromethylene alkynes have been successfully used in fluorination reactions, resulting in the preparation of various fluorine-containing compounds. This work describes a [4+2] annulation method for creating a range of fluorinated quinolino[2,1-b]quinazolinone derivatives. The derivatives are formed through Rh(III)-catalyzed cascade cyclization of 3-phenylquinazolinones and gem-difluoromethylene alkynes.

KLF12 interacts with TRIM27 to affect cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma by regulating L1CAM expression.

Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment.

Updated global epidemiology atlas of human prion diseases.

Introduction: Human prion disease (PrD), a group of fatal and transmissible neurodegenerative diseases, consists of Creutzfeldt-Jakob disease (CJD), kuru, fatal familial insomnia (FFI), Gerstmann-Sträussler-Scheinker disease (GSS), and variably protease-sensitive prionopathy (VPSPr). The emergence of bovine spongiform encephalopathy (BSE) in cattle and variant CJD (vCJD) has greatly threatened public health, both in humans and animals. Since the 1990's, dozens of countries and territories have conducted PrD surveillance programs. Methods: In this study, the case numbers and alternative trends of different types of PrD globally and in various countries or territories from 1993 to 2020 were collected and analyzed based on the data from the websites of the international and national PrD surveillance programs, as well as from relevant publications. Results: The total numbers of the reported PrD and sporadic CJD (sCJD) cases in 34 countries with accessible annual case numbers were 27,872 and 24,623, respectively. The top seven countries in PrD cases were the USA (n = 5,156), France (n = 3,276), Germany (n = 3,212), Italy (n = 2,995), China (n = 2,662), the UK (n = 2,521), Spain (n = 1,657), and Canada (n = 1,311). The annual PrD case numbers and mortalities, either globally or in the countries, showed an increased trend in the past 27 years. Genetic PrD cases accounted for 10.83% of all reported PrD cases; however, the trend varied largely among the different countries and territories. There have been 485 iatrogenic CJD (iCJD) cases and 232 vCJD cases reported worldwide. Discussion: The majority of the countries with PrD surveillance programs were high- and upper-middle-income countries. However, most low- and lower-middle-income countries in the world did not conduct PrD surveillance or even report PrD cases, indicating that the number of human PrD cases worldwide is markedly undervalued. Active international PrD surveillance for both humans and animals is still vital to eliminate the threat of prion disease from a public health perspective.