First Report of Mango Stem-end Rot Caused by Pestalotiopsis kenyana in Yunnan Province, China.

Stem End Rot (SER) is a devastating post-harvest disease of mango fruits causing severe losses during storage. In 22 July 2023, 31 out of 50 intact mangoes (cv. Sensation) collected from five orchards in Huaping county (26°37'N 101°15') showed typical symptoms of SER after stored for 9 d in room temperature (24-28℃). Initially, small dark brown to black spots appeared around the fruit peduncle, which rapidly expanded through the pulp tissues. The symptomatic mangoes were surface disinfected by 3% NaClO for 30 s after soaking in 75% alcohol for 3 min, and cleaned by sterile water for 3 times. Tissues were cut from the edge of lesions, dried by sterile filter paper, transferred to PDA and cultured at 28 ℃ for 5 d (Tovar-Pedraza et al., 2020). The single-spore isolation method was used to obtain pure culture. Thirty eight isolates presented four distinct kind of morphology on PDA medium. Among them, 11 isolates with same morphology were significantly distinct from common pathogens of SER. The colonies were white and pale yellow on reverse side. Mycelia grew fast and reached the edge of 90 mm Petri dish after cultured for 5d. Pycnidia were black and scattered on the mycelial mats after 15-20 d. Conidia were fusoid, straight to slightly curved, four septa, and brown. Pigmented median cells doliiform, 14.97 - 18.62(16.11 ±0.89)×5.61- 7.28 (6.61±0.51) µm. Apical cell hyaline, subcylindrical; 1-3 tubular transparent apical appendages 12.27 - 16.68 (13.65±3.78)×1.14 - 1.99 (1.59±0.36) µm. Basal cell conical with a truncate base, hyaline, and 1-2 tubulose basal appendages with 2.85 - 7.97 (5.18±1.88)×0.99 - 1.85 (1.38±0.29) µm (n=50). These fungi were described as Pestalotiopsis kenyana. based on morphological characters (Maharachchikumbura et al., 2014) which were different from isolates characterized as other common SER pathogens (Botryosphaeria, Neofusicoccum). Based on morphology, HPSX-4 was selected for further identification. ITS region, tef1-α, ß-tub of HPSX-4 were amplified and sequenced (Xun et al., 2023). The sequences were deposited in GenBank (ITS:OR889126, tef1-α:OR913431, ß-tub: OR913432). The ITS, tef1-α, ß-tub sequence of HPSX-4 showed 100% (525/525)，99.59% (241/242), and 100% (742/742) identity to the P. kenyana CBS442.67 sequences (ITS: NR147549，tef1-α: KM199502, ß-tub: KM199395), respectively. HPSX-4 clustered with P. kenyana CBS 442.67 (type strain) based on maximum likelihood method by MEGA 7.0.21(Minh et al., 2013). Pathogenicity test was performed on 12 healthy mangoes (cv. Golek) by placing mycelial plugs around the peduncle and the middle of the fruit by pin-prick method according to Feng et al.(2023). Sterile PDA were used as control (three mangoes). Every inoculated fruit was incubated at 28°C, 95% ± 3% humidity with three replicates for each treatment. The experiment was repeated three times. Typical symptoms of SER were observed. There were no symptoms in the control group. The strain was reisolated and identified as P. kenyana with the method mentioned above which fulfilled Koch's postulates. This is the first report of P. kenyana causing SER disease on Mangifera indica L.. This study expands our understanding of the pathogen range of mango SER which conducive to prevent and control the SER caused by P. kenyana.

Online Charge-Generation Derivatization by Electrochemical Radical Cations of Thianthrene: Mass Spectrometry Imaging of Estrogens in Biological Tissues.

Estrogens play a significant role in endocrinology and oncology. Although separation methods coupled with mass spectrometry (MS) have emerged as a powerful tool for studying estrogens, imaging the spatial distributions of estrogens is crucial but remains challenging due to its low endogenous concentration and poor ionization efficiency. Charge-generation derivatization, such as N-alkylpyridinium quaternization and S-methyl thioetherification, represents a method wherein neutral molecules involving analytes and derivatization reagents undergo chemical reactions to establish permanent charges directly onto the analytes to improve detection sensitivity. Here, we developed a novel derivatization reagent, thianthrene (TT), which enabled oxidization to radical cations ([TT]•+) using an electrochemical method and completed the online charge-generation derivatization of estrogens on a mass spectrometry imaging platform. In this strategy, [TT]•+ can efficiently and selectively derivatize estrogens via an electrophilic aromatic substitution reaction. Results indicated that derivatization with [TT]•+ can significantly enhance imaging sensitivity (3 orders of magnitude), enabling the visualization of estrogen and its metabolites in ovarian and breast tissues. Furthermore, a higher mass intensity of these estrogens was captured in breast para-cancerous tissues than in cancerous tissues, which might provide estrogens spatial dimension information for further research on the initiation and progression of breast cancer.

Validamycin A Inhibited FB1 Biosynthesis by the Target FvNth in Fusarium verticillioides.

Validamycin A (VMA) is an antifungal antibiotic derived from Streptomyces hygroscopicus commonly used in plant disease management. Surprisingly, VMA was discovered to impede the production of fumonisin B1 (FB1) in agricultural settings. However, the specific target of VMA in Fusarium verticillioides remained unclear. To unravel the molecular mechanism of VMA, ultrastructural observations unveiled damage to mitochondrial membranes. Trehalase (FvNth) was pinpointed as the target of VMA by utilizing a 3D-printed surface plasmon resonance sensor. Molecular docking identified Trp285, Arg447, Asp452, and Phe665 as the binding sites between VMA and FvNth. A ΔFvnth mutant lacking amino acids 250-670 was engineered through homologous recombination. Transcriptome analysis indicated that samples treated with VMA and ΔFvnth displayed similar expression patterns, particularly in the suppression of the FUM gene cluster. VMA treatment resulted in reduced trehalase and ATPase activity as well as diminished production of glucose, pyruvic acid, and acetyl-CoA. Conversely, these effects were absent in samples treated with ΔFvnth. This research proposes that VMA hinders acetyl-CoA synthesis by trehalase, thereby suppressing the FB1 biosynthesis. These findings present a novel target for the development of mycotoxin control agents.

GSH exhaustion via inhibition of xCT-GSH-GPX4 pathway synergistically enhanced DSF/Cu-induced cuproptosis in myelodysplastic syndromes.

The clinical application of the therapeutic approach in myelodysplastic syndromes (MDS) remains an insurmountable challenge for the high propensity for progressing to acute myeloid leukemia and predominantly affecting elderly individuals. Thus, the discovery of molecular mechanisms underlying the regulatory network of different programmed cell death holds great promise for the identification of therapeutic targets and provides insights into new therapeutic avenues. Herein, we found that disulfiram/copper (DSF/Cu) significantly repressed the cell viability, increased reactive oxygen species (ROS) accumulation, destroyed mitochondrial morphology, and altered oxygen consumption rate. Further studies verified that DSF/Cu induces cuproptosis, as evidenced by the depletion of glutathione (GSH), aggregation of lipoylated DLAT, and induced loss of Fe-S cluster-containing proteins, which could be rescued by tetrathiomolybdate and knockdown of ferredoxin 1 (FDX1). Additionally, GSH contributed to the tolerance of DSF/Cu-mediated cuproptosis, while pharmacological chelation of GSH triggered ROS accumulation and sensitized cell death. The xCT-GSH-GPX4 axis is the ideal downstream component of ferroptosis that exerts a powerful protective mechanism. Notably, classical xCT inhibitors were capable of leading to the catastrophic accumulation of ROS and exerting synergistic cell death, while xCT overexpression restored these phenomena. Simvastatin, an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, has beneficial effects in repurposing for inhibiting GPX4. Similarly, the combination treatment of DSF/Cu and simvastatin dramatically decreased the expression of GPX4 and Fe-S proteins, ultimately accelerating cell death. Moreover, we identified that the combination treatment of DSF/Cu and simvastatin also had a synergistic antitumor effect in the MDS mouse model, with the reduced GPX4, increased COX-2 and accumulated lipid peroxides. Overall, our study provided insight into developing a novel synergistic strategy to sensitize MDS therapy by targeting ferroptosis and cuproptosis.

[Effects of Fly Ash on the Efficiency and Bacterial Community Structure of Urban Multi-source Organic Solid Waste].

To achieve efficient resource utilization of fly ash and multi-source organic waste, a composting experiment was carried out to investigate the effects of fly ash on co-aerobic composting using kitchens, chicken manure, and sawdust (15:5:2). The effects of different application doses (5 % and 10 %, calculated in total wet weight of organic solid waste) of fly ash on physical and chemical properties, nutrient elements, and bacterial community structure during co-composting were evaluated. The results showed that the addition dose of 5 % and 10 % fly ash significantly increased the highest temperature (56.6 ℃ and 56.9 ℃) and extended the thermophilic period to nine days. Compared with that in the control, the total nutrient content of compost products in the treatments of 5 % FA and 10 % FA was increased by 4.09 % and 13.55 %, respectively. The bacterial community structure changed greatly throughout the composting, and the bacterial diversity of all treatments increased obviously. In the initial stage of composting, Proteobacteria was the dominant phylum of bacteria, with a relative abundance ranging from 35.26 % to 39.40 %. In the thermophilic period, Firmicutes dominated; its relative abundance peaked at 52.46 % in the 5 % FA treatment and 67.72 % in the 10 % FA treatment. Bacillus and Thermobifida were the predominant groups in the thermophilic period of composting. The relative abundance of Bacillus and Thermobifida in the 5 % FA and 10 % FA treatments were 33.41 % and 62.89 %(Bacillus) and 33.06 % and 12.23 %(Thermobifida), respectively. The results of the redundancy analysis (RDA) revealed that different physicochemical indicators had varying degrees of influence on bacteria, with organic matter, pH, available phosphorus, and available potassium being the main environmental factors influencing bacterial community structure. In summary, the addition of fly ash promoted the harmlessness and maturation of co- aerobic composting of urban multi-source organic waste, while optimizing microbial community structure and improving the quality and efficiency of composting.

FvOshC Is a Key Global Regulatory Target in Fusarium verticillioides for Fumonisin Biosynthesis and Disease Control.

Fusarium verticillioides has a substantial impact on maize production, commonly leading to maize ear rot and the production of fumonisin, a mycotoxin that poses health risks to both humans and animals. Currently, there is a lack of molecular targets for preventing the disease and controlling the toxin. The biological functions of oxysterol-binding proteins (OSBP) in filamentous fungi remain unclear. In this research, 7 oxysterol-binding protein-related proteins were identified in F. verticillioides, and these proteins were obtained through prokaryotic expression and purification. FvOshC was identified as the specific protein that binds to ergosterol through fluorescence titration. Gene knockout complementation techniques confirmed that FvOSHC plays a positive role, establishing it as a novel global regulatory protein involved in the pathogenicity and FB1 biosynthesis in F. verticillioides. Additionally, the interaction between FvOshC and FvSec14 was identified using yeast two-hybrid techniques. Moreover, computer-aided drug design technology was utilized to identify the receptor molecule Xanthatin based on FvOshC. The inhibitory effect of Xanthatin on the growth of F. verticillioides and the synthesis of FB1 was significantly demonstrated. These findings provide valuable insights that can aid in the management of mycotoxin pollution.

Genomic characterization of a novel ureolytic bacteria, Lysinibacillus capsici TSBLM, and its application to the remediation of acidic heavy metal-contaminated soil.

Soil heavy metal contamination is an essential challenge in ecological and environmental management, especially for acidic soils. Microbially induced carbonate precipitation (MICP) is an effective and environmentally friendly remediation technology for heavy metal contaminated sites, and one of the key factors for its realization lies in the microorganisms. In this study, Lysinibacillus capsici TSBLM was isolated from heavy metal contaminated soil around a gold mine, and inferred to be a novel ureolytic bacteria after phylogenomic inference and genome characterization. The urease of L. capsici TSBLM was analyzed by genetic analysis and molecular docking, and further applied this bacteria to the remediation of Cu and Pb in solution and acidic soils to investigate its biomineralization mechanism and practical application. The results revealed L. capsici TSBLM possessed a comprehensive urease gene cluster ureABCEFGD, and the encoded urease docked with urea at the lowest binding energy site (ΔG = -3.43 kcal/mol) connected to three amino acids threonine, aspartic, and alanine. The urease of L. capsici TSBLM is synthesized intracellularly but mainly functions extracellularly. L. capsici TSBLM removes Cu/Pb from the solution by generating heavy metal carbonates or co-precipitating with CaCO3 vaterite. For acidic heavy metal-contaminated soil, the carbonate-bound states of Cu and Pb increased significantly from 7 % to 16 % and from 23 % to 35 % after 30 days by L. capsici TSBLM. Soil pH improved additionally. L. capsici TSBLM maintained the dominant status in the remediated soil after 30 days, demonstrating good environmental adaptability and curing persistence. The results provided new strain resources and practical application references for the remediation of acidic heavy metal contaminated soil based on MICP.

Current situation and prospect for the diagnosis and treatment of pediatric critical rare diseases in China.

The onset of critical rare diseases (RDs) in children is rapid and dangerous, accompanied by a high mortality rate, which brings a heavy burden to both families and society. Multiple malformations, neuromuscular diseases, metabolic diseases, and heart diseases are the most common types of RDs in children of China, often manifesting with multiple organ dysfunction. At present, the diagnosis and treatment of critical RDs in children face challenges such as prolonged diagnosis time, a high misdiagnosis rate, limited treatment modalities, and a significant disease burden. However, with the progress in genetic testing technology, the establishment of multidisciplinary diagnosis and treatment platforms, and the implementation of relevant RD policies in China, children with critical RDs will received enhanced medical services, experience improved prognoses, and reintegrate into social life.

Identification and immunoinfiltration analysis of key genes in ulcerative colitis using WGCNA.

Objective: Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease characterized by an unclear pathogenesis. This study aims to screen out key genes related to UC pathogenesis. Methods: Bioinformatics analysis was conducted for screening key genes linked to UC pathogenesis, and the expression of the screened key genes was verified by establishing a UC mouse model. Results: Through bioinformatics analysis, five key genes were obtained. Subsequent infiltration analysis revealed seven significantly different immune cell types between the UC and general samples. Additionally, animal experiment results illustrated markedly decreased body weight, visible colonic shortening and damage, along with a significant increase in the DAI score of the DSS-induced mice in the UC group in comparison with the NC group. In addition, H&E staining results demonstrated histological changes including marked inflammatory cell infiltration, loss of crypts, and epithelial destruction in the colon mucosa epithelium. qRT-PCR analysis indicated a down-regulation of ABCG2 and an up-regulation of IL1RN, REG4, SERPINB5 and TRIM29 in the UC mouse model. Notably, this observed trend showed a significant dependence on the concentration of DSS, with the mouse model of UC induced by 7% DSS demonstrating a more severe disease state compared to that induced by 5% DSS. Conclusion: ABCG2, IL1RN, REG4, SERPINB5 and TRIM29 were screened out as key genes related to UC by bioinformatics analysis. The expression of ABCG2 was down-regulated, and that of IL1RN, REG4, SERPINB5 and TRIM29 were up-regulated in UC mice as revealed by animal experiments.

Inhibition of Alzheimer's disease by 4-octyl itaconate revealed by RNA-seq transcriptome analysis.

AIMS: This study aimed to examine the therapeutic effects and response mechanisms of 4-OI in Alzheimer's disease (AD). METHODS: In this study, network pharmacology was employed to analyze potential targets for AD drug therapy. Immunofluorescence and quantitative reverse transcription polymerase chain reaction (qRT-PCR) techniques were utilized to detect inflammatory phenotypes in a 4-OI-resistant mouse microglia cell line (BV2). We conducted four classical behavioral experiments, namely the open field test, new object recognition test, Y maze test, and Morris water maze, to assess the emotional state and cognitive level of APPswe/PS1dE9 (referred to as APP/PS1) mice after 4-OI treatment. Hematoxylin and eosin (HE) staining, along with immunofluorescence staining, were performed to detect amyloid (Aß) deposition in mouse brain tissue. To explore the potential molecular mechanisms regulating the effects of 4-OI treatment, we performed RNA-SEQ and transcription factor prediction analyses. Additionally, mouse BV2 cells underwent Western blotting analysis to elucidate potential molecular mechanisms underlying the observed effects. RESULTS: We discovered that 4-OI exerts an inhibitory effect on neuroinflammation by promoting autophagy. This effect is attributed to the activation of the AMPK/mTOR/ULK1 pathway, achieved through enhanced phosphorylation of AMPK and ULK1, coupled with a reduction in mTOR phosphorylation. Furthermore, 4-OI significantly enhances neuronal recovery in the hippocampus and diminishes Aß plaque deposition in APP/PS1 mice, improved anxiety in mice, and ultimately led to improved cognitive function. CONCLUSIONS: Overall, the results of this study demonstrated that 4-OI improved cognitive deficits in AD mice, confirming the therapeutic effect of 4-OI on AD.

Synergistic mechanism and environmental behavior of tank-mix adjuvants to topramezone and atrazine.

An effective way to reduce herbicide quantity is to use adjuvants in order to optimize the amount of herbicide and improve its control efficiency. In order to screen for efficient herbicide tank-mix adjuvants, improve the control of weeds in maize fields, reduce the amount of effective ingredients, and improve the adsorption and digestion behavior of herbicides in soil, this study evaluated the synergistic effects and soil behavior of four types of tank-mix adjuvants combined with herbicides. Different types of adjuvants can enhance herbicide production. Surface tension was significantly reduced by 13% after the pesticide solution was applied with AgroSpred™ Prime. The contact angle with the foliar surface was significantly reduced and solution wettability improved using Atp Lus 245-LQ-(TH). The permeability of topramezone and atrazine in leaves of Amaranthus retroflexus L. and Digitaria sanguinalis (L.) Scop. was increased by 22-96% after adding either tank-mix adjuvant. The solution drying time and maximum retention on leaves were not affected by the tank-mix adjuvants. Ethyl and methylated vegetable oils can reduce the adsorption of topramezone in the soil, thus reducing its half-life in soil. The tank-mix adjuvants had no significant effect on soil dissipation or adsorption of atrazine. AgroSpred™ Prime and Atp Lus 245-LQ-(TH) have the best synergistic effect on topramezone and atrazine in the control of A. retroflexus L. and D. sanguinalis (L.) Scop. in maize fields.

Exploring the synergistic interplay of sulfur metabolism and electron transfer in Cr(VI) and Cd(II) removal by Clostridium thiosulfatireducens: Genomic and mechanistic insights.

In this study, a sulfate-reducing bacterium, Clostridium thiosulfatireducens (CT) was reported and the performance and removal mechanism of Cr(VI) and Cd(II) removal were investigated. It is noteworthy that the dsrAB gene is absent in this strain, but the strain is capable of producing sulfide. The conversion rate of Cr(VI) by CT was 84.24 % at a concentration of 25 mg/L, and the conversion rate of Cd(II) was 94.19 % at a concentration of 28 mg/L. The complete genome is 6,106,624 bp and the genome consisted of a single chromosome. The GC content of the chromosomes was 29.65 %. The mechanism of heavy metal removal by CT bacteria mainly includes biosorption, electron transfer and redox, with reduction combined with S2- precipitation as the main pathway. The product characterization results showed that the formation of mainly ionic crystals and precipitates (CdS, Cd(OH)2, Cr(OH)3, Cr2O3) after adsorption. Genome-wide techniques have shown that the clearance of Cr(VI) and Cd(II) by CT is largely dependent on sulfate transport, sulfur metabolism, and energy metabolism to some extent. In addition, genes related to ATP binding, electron carrier activity, transporter protein genes, and DNA repair are also important factors to improve the heavy metal resistance and transformation ability of CT strains. Both the Fe-S cycle and the ROS-resistant system can enhance the electron transfer activity and thus slow down the damage of heavy metals to microorganisms. This study fills the gap in the understanding of the basic properties and heavy metal transformation mechanism of CT.

First report of Botrytis cinerea causing gray mold on Alternanthera philoxeroides in China.

Alternanthera philoxeroides is a perennial herbaceous plant used as a forage crop (Wang et al. 2005) and is known to have medicinal properties. One of notable active components is flavonoids, which have been found to exhibit anti-Hepatitis B Virus activity (Li et al. 2016). In 2021, a leaf spot on A. philoxeroides was observed in the science and education experimental park of Hebei Agricultural University (38°49'38″ N, 115°26'39″ E). Initial symptoms included leaf tissue water loss, chloro-sis and elliptical lesions scattered across the leaf margin with further development leading to ellipse-shaped disease spots and leaf wilting (Fig. 1A). In the field, 50 plants of A. philoxeroides were randomly selected to investigate and quantify dis-ease. Incidence of leaf disease was approximately 25%, and the infected leaves ex-hibited an average affected area of about 20%. In order to identify the pathogen, three diseased plants were randomly selected from different areas. Stems and leaves of diseased plants were cut into pieces (2 to 3 mm × 5 mm) and disinfested with 1% sodium hypochlorite for 1 minute. After rinsing with sterile water three times, each lesion sample was isolated and purified on PDA at 25°C. Eventually, all samples pro-duced morphologically consistent colonies of pure strains. From the 9 isolates ob-tained, ZLQ-1 was selected as a representative isolate for further study. Colonies were initially white, turning gray from the centre, then gray-brown with cottony aerial hyphae, and finally growing black, stiff, round or irregular sclerotia (0.6 to 4.0 mm × 1.1 to 4.2 mm, n=50) (Fig1. B, C). ZLQ-1 exhibited branched conidia with en-larged apical cells. The conidia of this isolate were unicellular, ovoid or ellipsoid in shape, with dimensions ranging from 5.8 to 16.9 µm × 6.3 to 11.2 µm (n=50) (Fig. 1D). These morphological characteristics were consistent with Botrytis cinerea (Ellis, 1971). The genes of internal transcribed spacer (ITS), heat shock protein (HSP60), DNA-dependent RNA polymerase subunit II (RPB2), and glyceraldehyde-3-phosphate dehydrogenase (G3PDH) were amplified with specific primers ITS1/ITS4, HSP60-F/HSP60-R, RPB2-F/RPB2-R and G3PDH-F/G3PDH-R (Aktaruzzaman et al., 2022). Sequences were deposited into GenBank with accession numbers ON479490 for ITS, ON572246 for G3PDH, ON572248 for HSP60, ON572247 for RPB2. BLASTn analysis showed that the ITS sequence shared 99.62% similarity to B. cinerea (CP009808), and the sequences of the other three nuclear protein-encoding genes (G3PDH, HSP60, and RPB2) showed at least 99.9% identity with the genome of B. ci-nerea (B05.10) (Staats et al. 2005). We have inoculated 10 healthy A. philoxeroides leaves with a suspension of 1x105 spores/mL, and used sterile water treatment as control (Aktaruzzaman et al., 2022). Each leaf was inoculated with 10 µL spore sus-pension. After 7 days in a controlled incubation environment (25℃, 40%RH), the plants inoculated with conidial suspensions displayed lesions covered in a gray-white mycelial layer, resembling those observed in the field (Fig. 1E-G). In con-trast, the plants inoculated with sterile water remained unaffected. Morphological and PCR analysis confirmed that the pathogen responsible for the observed symp-toms was B. cinerea. Koch's postulates were fulfilled as the same pathogen was con-sistently re-isolated from the inoculated leaves and confirmed to be B. cinerea through morphological and molecular methods. This is the first reported case of B. cinerea causing gray mold on A. philoxeroides in China. It is important to monitor and prevent B. cinerea infection during cultivation to ensure the production of healthy Chinese medicine and feed.

An adaptive algorithm for generating 3D point clouds of the human body based on 4D millimeter-wave radar.

The traditional algorithms for generating 3D human point clouds often face challenges in dealing with issues such as phantom targets and target classification caused by electromagnetic multipath effects, resulting in a lack of accuracy in the generated point clouds and requiring manual labeling of the position of the human body. To address these problems, this paper proposes an adaptive method for generating 3D human point clouds based on 4D millimeter-wave radar (Self-Adaptive mPoint, SA-mPoint). This method estimates the rough human point cloud by considering micro-motion and respiration characteristics while combining the echo dynamic with static information. Furthermore, it enhances the density of point cloud generation. It reduces interference from multipath noise through multi-frame dynamic fusion and an adaptive density-based clustering algorithm based on the center points of humans. The effectiveness of the SA-mPoint algorithm is verified through experiments conducted using the TI Millimeter Wave Cascade Imaging Radar Radio Frequency Evaluation Module 77G 4D cascade radar to collect challenging raw data consisting of single-target and multi-target human poses in an open classroom setting. Experimental results demonstrate that the proposed algorithm achieves an average accuracy rate of 97.94% for generating point clouds. Compared to the popular TI-mPoint algorithm, it generates a higher number of point clouds on average (increased by 87.94%), improves the average accuracy rate for generating point clouds (increased by 78.3%), and reduces the running time on average (reduced by 11.41%). This approach exhibits high practicality and promising application prospects.

Inhibiting the compensatory elevation of xCT collaborates with disulfiram/copper-induced GSH consumption for cascade ferroptosis and cuproptosis.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the fourth leading cause of cancer-related death globally, which is characterized by complicated pathophysiology, high recurrence rate, and poor prognosis. Our previous study has demonstrated that disulfiram (DSF)/Cu could be repurposed for the treatment of HCC by inducing ferroptosis. However, the effectiveness of DSF/Cu may be compromised by compensatory mechanisms that weaken its sensitivity. The mechanisms underlying these compensatory responses are currently unknown. Herein, we found DSF/Cu induces endoplasmic reticulum stress with disrupted ER structures, increased Ca2+ level and activated expression of ATF4. Further studies verified that DSF/Cu induces both ferroptosis and cuproptosis, accompanied by the depletion of GSH, elevation of lipid peroxides, and compensatory increase of xCT. Comparing ferroptosis and cuproptosis, it is interesting to note that GSH acts at the crossing point of the regulation network and therefore, we hypothesized that compensatory elevation of xCT may be a key aspect of the therapeutic target. Mechanically, knockdown of ATF4 facilitated the DSF/Cu-induced cell death and exacerbated the generation of lipid peroxides under the challenge of DSF/Cu. However, ATF4 knockdown was unable to block the compensatory elevation of xCT and the GSH reduction. Notably, we found that DSF/Cu induced the accumulation of ubiquitinated proteins, promoted the half-life of xCT protein, and dramatically dampened the ubiquitination-proteasome mediated degradation of xCT. Moreover, both pharmacologically and genetically suppressing xCT exacerbated DSF/Cu-induced cell death. In conclusion, the current work provides an in-depth study of the mechanism of DSF/Cu-induced cell death and describes a framework for the further understanding of the crosstalk between ferroptosis and cuproptosis. Inhibiting the compensatory increase of xCT renders HCC cells more susceptible to DSF/Cu, which may provide a promising synergistic strategy to sensitize tumor therapy and overcome drug resistance, as it activates different programmed cell death.

Efficient estimation for large-scale linkage disequilibrium patterns of the human genome.

In this study, we proposed an efficient algorithm (X-LD) for estimating linkage disequilibrium (LD) patterns for a genomic grid, which can be of inter-chromosomal scale or of small segments. Compared with conventional methods, the proposed method was significantly faster, dropped from O(nm2) to O(n2m)-n the sample size and m the number of SNPs, and consequently we were permitted to explore in depth unknown or reveal long-anticipated LD features of the human genome. Having applied the algorithm for 1000 Genome Project (1KG), we found (1) the extended LD, driven by population structure, universally existed, and the strength of inter-chromosomal LD was about 10% of their respective intra-chromosomal LD in relatively homogeneous cohorts, such as FIN, and to nearly 56% in admixed cohort, such as ASW. (2) After splitting each chromosome into upmost of more than a half million grids, we elucidated the LD of the HLA region was nearly 42 folders higher than chromosome 6 in CEU and 11.58 in ASW; on chromosome 11, we observed that the LD of its centromere was nearly 94.05 folders higher than chromosome 11 in YRI and 42.73 in ASW. (3) We uncovered the long-anticipated inversely proportional linear relationship between the length of a chromosome and the strength of chromosomal LD, and their Pearson's correlation was on average over 0.80 for 26 1KG cohorts. However, this linear norm was so far perturbed by chromosome 11 given its more completely sequenced centromere region. Uniquely chromosome 8 of ASW was found most deviated from the linear norm than any other autosomes. The proposed algorithm has been realized in C++ (called X-LD) and is available at https://github.com/gc5k/gear2, and can be applied to explore LD features in any sequenced populations.