Metabolic Heterogeneity of Tumor Cells and its Impact on Colon Cancer Metastasis: Insights from Single-Cell and Bulk Transcriptome Analyses.

Background: Metabolic reprogramming plays a crucial role in the development of colorectal cancer (CRC), influencing tumor heterogeneity, the tumor microenvironment, and metastasis. While the interaction between metabolism and CRC is critical for developing personalized treatments, gaps remain in understanding how tumor cell metabolism affects prognosis. Our study introduces novel insights by integrating single-cell and bulk transcriptome analyses to explore the metabolic landscape within CRC cells and its mechanisms influencing disease progression. This approach allows us to uncover metabolic heterogeneity and identify specific metabolic genes impacting metastasis, which have not been thoroughly examined in previous studies. Methods: We sourced microarray and single-cell RNA sequencing datasets from the Gene Expression Omnibus (GEO) and bulk sequencing data for CRC from The Cancer Genome Atlas (TCGA). We employed Gene Set Variation Analysis (GSVA) to assess metabolic pathway activity, consensus clustering to identify CRC-specific transcriptome subtypes in bulkseq, and rigorous quality controls, including the exclusion of cells with high mitochondrial gene expression in scRNA seq. Advanced analyses such as AUCcell, infercnvCNV, Non-negative Matrix Factorization (NMF), and CytoTRACE were utilized to dissect the cellular landscape and evaluate pathway activities and tumor cell stemness. The hdWGCNA algorithm helped identify prognosis-related hub genes, integrating these findings using a random forest machine learning model. Results: Kaplan-Meier survival curves identified 21 significant metabolic pathways linked to prognosis, with consensus clustering defining three CRC subtypes (C3, C2, C1) based on metabolic activity, which correlated with distinct clinical outcomes. The metabolic activity of the 13 cell subpopulations, particularly the epithelial cell subpopulation with active metabolic levels, was evaluated using AUCcell in scRNA seq. To further analyze tumor cells using infercnv, NMF disaggregated these cells into 10 cellular subpopulations. Among these, the C2 subpopulation exhibited higher stemness and tended to have a poorer prognosis compared to C6 and C0. Conversely, the C8, C3, and C1 subpopulations demonstrated a higher level of the five metabolic pathways, and the C3 and C8 subpopulations tended to have a more favorable prognosis. hdWGCNA identified 20 modules, from which we selected modules primarily expressed in high metabolic tumor subgroups and highly correlated with clinical information, including blue and cyan. By applying variable downscaling of RF to a total of 50 hub genes, seven gene signatures were obtained. Furthermore, molecules that were validated to be protective in GEO were screened alongside related molecules, resulting in the identification of prognostically relevant molecules such as UQCRFS1 and GRSF1. Additionally, the expression of GRSF1 was examined in colon cancer cell lines using qPCR and phenotypically verified by in vitro experiments. Conclusion: Our findings emphasize that high activity in specific metabolic pathways, including pyruvate metabolism and the tricarboxylic acid cycle, correlates with improved colon cancer outcomes, presenting new avenues for metabolic-based therapies. The identification of hub genes like GRSF1 and UQCRFS1 and their link to favorable metabolic profiles offers novel insights into tumor neovascularization and metastasis, with significant clinical implications for targeting metabolic pathways in CRC therapy.

Antiferromagnetic phase transition in a 3D fermionic Hubbard model.

The fermionic Hubbard model (FHM)1 describes a wide range of physical phenomena resulting from strong electron-electron correlations, including conjectured mechanisms for unconventional superconductivity. Resolving its low-temperature physics is, however, challenging theoretically or numerically. Ultracold fermions in optical lattices2,3 provide a clean and well-controlled platform offering a path to simulate the FHM. Doping the antiferromagnetic ground state of a FHM simulator at half-filling is expected to yield various exotic phases, including stripe order4, pseudogap5, and d-wave superfluid6, offering valuable insights into high-temperature superconductivity7-9. Although the observation of antiferromagnetic correlations over short10 and extended distances11 has been obtained, the antiferromagnetic phase has yet to be realized as it requires sufficiently low temperatures in a large and uniform quantum simulator. Here we report the observation of the antiferromagnetic phase transition in a three-dimensional fermionic Hubbard system comprising lithium-6 atoms in a uniform optical lattice with approximately 800,000 sites. When the interaction strength, temperature and doping concentration are finely tuned to approach their respective critical values, a sharp increase in the spin structure factor is observed. These observations can be well described by a power-law divergence, with a critical exponent of 1.396 from the Heisenberg universality class12. At half-filling and with optimal interaction strength, the measured spin structure factor reaches 123(8), signifying the establishment of an antiferromagnetic phase. Our results provide opportunities for exploring the low-temperature phase diagram of the FHM.

[Impact of cecal ligation and puncture-induced sepsis on the proliferation and differentiation of intestinal stem cells].

OBJECTIVE: To analyze the impact of cecal ligation and puncture (CLP)-induced sepsis on the proliferation and differentiation of intestinal epithelial cells. METHODS: (1) Animal experiment: sixteen male C57BL/6 mice were divided into sham operation group (Sham group) and CLP-induced sepsis model group (CLP group) by random number table method, with 8 mice in each group. After 5 days of operation, the jejunal tissues were taken for determination of leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5) and intestinal alkaline phosphatase (IAP) by polymerase chain reaction (PCR). The translation of LGR5 was detected by Western blotting. The expression of proliferating cell nuclear antigen (Ki67) was analyzed by immunohistochemistry. IAP level was detected by modified calcium cobalt staining and colorimetry. Immunofluorescence staining was used to detect the expression of Paneth cell marker molecule lysozyme 1 (LYZ1) and goblet cell marker molecule mucin 2 (MUC2). (2) Cell experiment: IEC6 cells in logarithmic growth stage were divided into blank control group and lipopolysaccharide (LPS) group (LPS 5 µg/mL). Twenty-four hours after treatment, PCR and Western blotting were used to analyze the transcription and translation of LGR5. The proliferation of IEC6 cells were detected by 5-ethynyl-2'-deoxyuridine (EdU) staining. The transcription and translation of IAP were detected by PCR and colorimetric method respectively. RESULTS: (1) Animal experiment: the immunohistochemical results showed that the positive rate of Ki67 staining in the jejunal tissue of CLP group was lower than that of Sham group [(41.7±2.5)% vs. (48.7±1.4)%, P = 0.01]. PCR and Western blotting results showed that there were no statistical differences in the mRNA and protein expressions of LGR5 in the jejunal tissue between the CLP group and Sham group (Lgr5 mRNA: 0.7±0.1 vs. 1.0±0.2, P = 0.11; LGR5/ß-actin: 0.83±0.17 vs. 0.68±0.19, P = 0.24). The mRNA (0.4±0.1 vs. 1.0±0.1, P < 0.01) and protein (U/g: 47.3±6.0 vs. 73.1±15.3, P < 0.01) levels of IAP in the jejunal tissue were lower in CLP group. Immunofluorescence saining analysis showed that the expressions of LYZ1 and MUC2 in the CLP group were lower than those in the Sham group. (2) Cell experiment: PCR and Western blotting results showed that there was no significant difference in the expression of LGR5 between the LPS group and the blank control group (Lgr5 mRNA: 0.9±0.1 vs. 1.0±0.2, P = 0.33; LGR5/ß-actin: 0.71±0.18 vs. 0.69±0.04, P = 0.81). The proliferation rate of IEC6 cells in the LPS group was lower than that in the blank control group, but there was no significant difference [positivity rate of EdU: (40.5±3.8)% vs. (46.5±3.6)%, P = 0.11]. The mRNA (0.5±0.1 vs. 1.0±0.2, P < 0.01) and protein (U/g: 15.0±4.0 vs. 41.2±10.4, P < 0.01) of IAP in the LPS group were lower than those in the blank control group. CONCLUSIONS: CLP-induced sepsis inhibits the proliferation and differentiation of intestinal epithelial cells, impairing the self-renewal ability of intestinal epithelium.

Natural mineral and industrial solid waste-based adsorbent for perfluorooctanoic acid and perfluorooctane sulfonate removal from surface water: Advances and prospects.

PER: and polyfluorinated alkyl substances, especially perfluorooctanoic acid and perfluorooctane sulfonic acid (PFOX), have attracted considerable attention lately because of their widespread occurrence in aquatic environment and potential biological toxicity to animals and human beings. The development of economical, efficient, and engineerable adsorbents for removing PFOX in water has become one of the research focuses. This review summarized the recent progress on natural mineral and industrial solid based adsorbent (NM&ISW-A) and removal mechanisms concerning PFOX onto NM&ISW-A, as well as proposed the current challenges and future perspectives of using NM&ISW-A for PFOX removal in water. Kaolinite and montmorillonite are usually used as model clay minerals for PFOX removal, and have been proved to adsorb PFOX by ligand exchange and electrostatic attraction. Fe-based minerals, such as goethite, magnetite, and hematite, have better PFOX adsorption capacity than clay minerals. The adsorbent prepared from industrial solid waste by high temperature roasting has great potential application prospects. Fabricating nanomaterials, amination modification, surfactant modification, fluorination modification, developing versatile composites, and designing special porous structure are beneficial to improve the adsorption performance of PFOX onto NM&ISW-A by enhancing the specific surface area, positive charge, and hydrophobicity. Electrostatic interaction, hydrophobic interaction, hydrogen bond, ligand and ion exchange, and self-aggregation (formation of micelle or hemimicelle) are the main adsorption mechanisms of PFOX by NM&ISW-A. Among them, electrostatic and hydrophobic interactions play a considerable role in the removal of PFOX by NM&ISW-A. Therefore, NM&ISW-A with electrostatic functionalities and considerable hydrophobic segments enables rapid, efficient, and high-capacity removal of PFOX. The future directions of NM&ISW-A for PFOX removal include the preparation and regeneration of engineerable NM&ISW-A, the development of coupling technology for PFOX removal based on NM&ISW-A, the in-depth research on adsorption mechanism of PFOX by NM&ISW-A, as well as the development of NM&ISW-A for PFOX alternatives removal. This review paper would be helpful the comprehensive understanding of NM&ISW-A potential for PFOX removal and the PFOX removal mechanisms, and identifies the gaps for future research and development.

Comparative efficacy of six programmed cell death Protein-1 inhibitors as first-line treatment for advanced non-small cell lung cancer: a multicenter retrospective cohort study.

The purpose of this study was to assess the comparative efficacy of six programmed cell death-1 inhibitors (nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, and camrelizumab) that have been used as first-line therapy for Chinese patients with advanced non-small cell lung cancer (NSCLC), which remains unclear. We determined the differences in efficacy by observing patient survival data, with the goal of informing future treatment options. Retrospective data analysis from June 2015 to April 2023 included 913 patients across six groups: nivolumab (123%, 13.5%), pembrolizumab (421%, 46.1%), sintilimab (239%, 26.1%), tislelizumab (64%, 7.0%), toripalimab (39%, 4.3%), and camrelizumab (27%, 3.0%). The median progression-free survival (PFS) for each group was 16.0, 16.1, 18.4, 16.9, 23.7, and 12.8 months, and the median overall survival (OS) was 33.7, 36.1, 32.5, not reached, 30.9 and 46.0 months for the nivolumab, sintilimab, pembrolizumab, tislelizumab, toripalimab, and camrelizumab groups, respectively. While differences existed in the objective response rates among groups (p < 0.05), there were no significant differences (all p > 0.05) in PFS or OS. The findings suggest comparable efficacy among these PD-1 inhibitors for NSCLC treatment, underscoring their collective suitability and aiding treatment decisions.

Cell Division and Motility Enable Hexatic Order in Biological Tissues.

Biological tissues transform between solid- and liquidlike states in many fundamental physiological events. Recent experimental observations further suggest that in two-dimensional epithelial tissues these solid-liquid transformations can happen via intermediate states akin to the intermediate hexatic phases observed in equilibrium two-dimensional melting. The hexatic phase is characterized by quasi-long-range (power-law) orientational order but no translational order, thus endowing some structure to an otherwise structureless fluid. While it has been shown that hexatic order in tissue models can be induced by motility and thermal fluctuations, the role of cell division and apoptosis (birth and death) has remained poorly understood, despite its fundamental biological role. Here we study the effect of cell division and apoptosis on global hexatic order within the framework of the self-propelled Voronoi model of tissue. Although cell division naively destroys order and active motility facilitates deformations, we show that their combined action drives a liquid-hexatic-liquid transformation as the motility increases. The hexatic phase is accessed by the delicate balance of dislocation defect generation from cell division and the active binding of disclination-antidisclination pairs from motility. We formulate a mean-field model to elucidate this competition between cell division and motility and the consequent development of hexatic order.

Enhancement of triclocarban biodegradation: Metabolic division of labor in co-culture of Rhodococcus sp. BX2 and Pseudomonas sp. LY-1.

Triclocarban (TCC) and its metabolite, 3,4-dichloroaniline (DCA), are classified as emerging organic contaminants (EOCs). Significant concerns arise from water and soil contamination with TCC and its metabolites. These concerns are especially pronounced at high concentrations of up to approximately 20 mg/kg dry weight, as observed in wastewater treatment plants (WWTPs). Here, a TCC-degrading co-culture system comprising Rhodococcus rhodochrous BX2 and Pseudomonas sp. LY-1 was utilized to degrade TCC (14.5 mg/L) by 85.9% in 7 days, showing improved degradation efficiency compared with monocultures. A combination of high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), genome sequencing, transcriptomic analysis, and quantitative reverse transcription-PCR (qRT-PCR) was performed. Meanwhile, through the combination of further experiments involving heterologous expression and gene knockout, we proposed three TCC metabolic pathways and identified four key genes (tccG, tccS, phB, phL) involved in the TCC degradation process. Moreover, we revealed the internal labor division patterns and connections in the co-culture system, indicating that TCC hydrolysis products were exchanged between co-cultured strains. Additionally, mutualistic cooperation between BX2 and LY-1 enhances TCC degradation efficiency. Finally, phytotoxicity assays confirmed a significant reduction in the plant toxicity of TCC following synergistic degradation by two strains. The in-depth understanding of the TCC biotransformation mechanisms and microbial interactions provides useful information for elucidating the mechanism of the collaborative biodegradation of various contaminants.

Prognosis of immune checkpoint inhibitor-related myocarditis: Retrospective experience of a single institution.

BACKGROUND: Myocarditis related to immune checkpoint inhibitors (ICIs) treatment is a rare but potentially life-threatening adverse event. To gain insight into this condition, we analyzed the clinical characteristics and prognosis of patients with ICI-related myocarditis. METHODS: Data on the clinical characteristics, management, and outcomes of patients diagnosed with ICI-related myocarditis between August 2018 and August 2023 in our institution were gathered retrospectively from medical records. Outcomes included the occurrence of major adverse cardiac events (MACE). RESULTS: Among 8875 patients who received ICI therapy, 31 patients experienced ICI-related myocarditis. These 31 patients had a mean age of 62 ± 12 years and included 24 (77.4 %) males and 19 patients (61.3 %) with at least one risk factor for cardiovascular disease. The median duration from ICI initiation to the onset of myocarditis symptoms was 6.3 weeks (interquartile range, 4.3-8.1 weeks). Twenty-one patients (67.7 %) developed grade 3-4 myocarditis. Thirteen patients (42 %) experienced MACE after myocarditis onset, and 15 patients (48.4 %) showed a troponin rise > 4 times the maximum limit of the standard range. On receiver operating characteristic curve analysis, troponin level could predict MACE in patients with ICI-related myocarditis with an area under the curve of 0.82 (95 % confidence interval [CI]: 0.66-0.98, p = 0.003). From Kaplan-Meier analysis, the occurrence of MACE (p = 0.002) was an independent influencing factor on patients' overall survival. CONCLUSIONS: ICI-related myocarditis frequently leads to MACE, which is associated with poor prognosis. Elevated troponin levels and electrocardiogram abnormalities in these patients may help predict the occurrence of MACE.

Inhibition of NLRP3 inflammasome activation by A20 through modulation of NEK7.

The NLRP3 inflammasome, a pivotal component of innate immunity, has been implicated in various inflammatory disorders. The ubiquitin-editing enzyme A20 is well known to regulate inflammation and maintain homeostasis. However, the precise molecular mechanisms by which A20 modulates the NLRP3 inflammasome remain poorly understood. Here, our study revealed that macrophages deficient in A20 exhibit increased protein abundance and elevated mRNA level of NIMA-related kinase 7 (NEK7). Importantly, A20 directly binds with NEK7, mediating its K48-linked ubiquitination, thereby targeting NEK7 for proteasomal degradation. Our results demonstrate that A20 enhances the ubiquitination of NEK7 at K189 and K293 ubiquitinated sites, with K189 playing a crucial role in the binding of NEK7 to A20, albeit not significantly influencing the interaction between NEK7 and NLRP3. Furthermore, A20 disrupts the association of NEK7 with the NLRP3 complex, potentially through the OTU domain and/or synergistic effect of ZnF4 and ZnF7 motifs. Significantly, NEK7 deletion markedly attenuates the activation of the NLRP3 inflammasome in A20-deficient conditions, both in vitro and in vivo. This study uncovers a mechanism by which A20 inhibits the NLRP3 inflammasome.

Estrogen-mediated DNMT1 and DNMT3A recruitment by EZH2 silences miR-570-3p that contributes to papillary thyroid malignancy through DPP4.

BACKGROUND: Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. Studies have indicated that estrogen can regulate the expression of miRNAs in numerous malignancies. MiR-570-3p has been shown to have a regulatory function in various cancers. However, studies of the regulatory function of miR-570-3p and a direct link between estrogen (especially estradiol E2) and miR-570-3p in PTC have not been done. METHODS: Expression of miR-570-3p and its downstream target DPP4 in PTC tissues and cells was predicted using bioinformatics and validated by qRT-PCR and western blot assays. We then performed a series of gain-and-loss experiments to assess the functional significance of miR-570-3p/DPP4 axis in PTC progression in vitro and in vivo. Additionally, the methylation of the miR-570-3p promoter region was examined via bioinformatics analysis and MSP. Finally, the effects of E2 on PTC progression and the correlation between DNMT1/DNMT3A and EZH2 were predicted by bioinformatic tools and proved by luciferase reporter, ChIP, and co-IP assays. RESULTS: In PTC tumor tissues and cell lines, there was a lower expression level and a higher methylation level of miR-570-3p compared to normal tissues and cell lines. DPP4 was identified as the downstream target of miR-570-3p. Overexpression of miR-570-3p reduced the proliferative, migratory, and invasive capabilities, and promoted apoptosis, while overexpression of DPP4 reversed these effects in PTC cells. It was also discovered that DNMT1 and DNMT3A increased the CpG methylation level of the miR-570-3p promoter in an EZH2-dependent manner, which led to decreased expression of miR-570-3p. Furthermore, we observed that estrogen (E2) enhanced the methylation of miR-570-3p and suppressed its expression levels, resulting in augmented tumor growth in vivo in PTC. CONCLUSION: Estrogen regulates the EZH2/DNMTs/miR-570-3p/DPP4 signaling pathway to promote PTC progression.

Fabrication of a magnetic functionalized chitosan hydrogel for effective extraction of aflatoxins from cereals.

A magnetic adsorbent was synthesized by coupling magnetic nanoparticles, UiO-66-NH2 and 1-butyl-trimethylimidazole bromide ([BMIM][Br]) to chitosan (CS)-based composite conveniently. A series of modern characterizations were employed to assess its properties. The results showed that UiO-66-NH2 was uniformly distributed within the composite via in-situ growth, which can enhance the porosity obviously. The introduction of various ligands enables the composite to exhibit excellent extraction performance for four aflatoxins (AFs) through multiple interactions. The adsorption mechanism was elucidated and the main factors affecting extraction efficiency were evaluated. Under optimal conditions, the limits of detection (LODs) ranged from 0.08 to 0.56 µg/kg. The established method was successfully utilized to determine AFs from cereal samples (rice, glutinous rice, wheat, soybean, paddy, and corn) with satisfactory recovery of 77% âˆ¼ 119% with relative standard deviations (RSDs) of 1.0% âˆ¼ 11.7% (n = 5). The adsorbent demonstrated sufficient robustness for repeated use at least six times without obvious damage of extraction property.

Intertwined role of mechanism identification by DFT-XAFS and engineering considerations in the evolution of P adsorbents.

Adsorption method exhibits promising potential in effectively removal of phosphate from wastewater, yet it faces tremendous challenges in practical application. Limited comprehension of adsorption mechanisms and the lack of evaluation method for scaling up application are the two main obstacles. To fully realize the practical application of P adsorbents, we reviewed advanced tools, including density functional theory (DFT) and/or X-ray absorption fine structure (XAFS) to elucidate mechanisms, underscored the significance of thermodynamics and kinetics in engineering design, and proposed strategies for regenerating and reusing P adsorbents. Specifically, we delved into the utilization of DFT and XAFS to gain insights into adsorption mechanisms, focusing on active site verification and molecular interaction configurations. Additionally, we explored precise calculation methods for adsorption thermodynamics and adsorption kinetics, encompassing thermodynamic equilibrium constants, reactor selection, and the regeneration, recovery, and disposal of P adsorbents. Our comprehensive review aims to serve as a guiding light in advancing the development of highly efficient P adsorbents for engineering applications.

A novel method of swin transformer with time-frequency characteristics for ECG-based arrhythmia detection.

Introduction: Arrhythmia is an important indication of underlying cardiovascular diseases (CVD) and is prevalent worldwide. Accurate diagnosis of arrhythmia is crucial for timely and effective treatment. Electrocardiogram (ECG) plays a key role in the diagnosis of arrhythmia. With the continuous development of deep learning and machine learning processes in the clinical field, ECG processing algorithms have significantly advanced the field with timely and accurate diagnosis of arrhythmia. Methods: In this study, we combined the wavelet time-frequency maps with the novel Swin Transformer deep learning model for the automatic detection of cardiac arrhythmias. In specific practice, we used the MIT-BIH arrhythmia dataset, and to improve the signal quality, we removed the high-frequency noise, artifacts, electromyographic noise and respiratory motion effects in the ECG signals by the wavelet thresholding method; we used the complex Morlet wavelet for the feature extraction, and plotted wavelet time-frequency maps to visualise the time-frequency information of the ECG; we introduced the Swin Transformer model for classification and achieve high classification accuracy of ECG signals through hierarchical construction and self attention mechanism, and combines windowed multi-head self-attention (W-MSA) and shifted window-based multi-head self-attention (SW-MSA) to comprehensively utilise the local and global information. Results: To enhance the confidence of the experimental results, we evaluated the performance using intra-patient and inter-patient paradigm analyses, and the model classification accuracies reached 99.34% and 98.37%, respectively, which are better than the currently available detection methods. Discussion: The results reveal that our proposed method is superior to currently available methods for detecting arrhythmia ECG. This provides a new idea for ECG based arrhythmia diagnosis.

Overexpression of solute carrier family 6 member 12 promotes cell injury in Parkinson's disease via MAPK signaling pathway.

BACKGROUND: Neurotransmitter transport disorders may play a crucial role in Parkinson's Disease (PD), and Solute carrier family 6 member 12 (SLC6A12) encodes a neurotransmitter transporter. However, the relationship between SLC6A12 and PD remains largely unexplored. METHODS: We utilized the GEO database (107 samples) and clinical data (80 samples) to investigate the role of SLC6A12 in PD through differential expression analysis, ROC analysis, and RT-qPCR experiments. Subsequently, in vitro model, axon length measurement, CCK8 assay, flow cytometry, and JC-1 assays were conducted. Additionally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, protein-protein interaction (PPI) network, gene set enrichment analysis (GSEA), and western blot experiments were assessed to explore the functional and mechanistic pathways of SLC6A12 in PD. Finally, CIBERSORT analysis was performed to investigate the correlation between SLC6A12 and immune cells in PD. RESULTS: The expression of SLC6A12 was significantly higher in individuals with PD compared to healthy controls. Inhibiting SLC6A12 expression in PD models enhanced neuronal growth and proliferation activity while reducing cell apoptosis. Furthermore, SLC6A12 was found to be involved in neuronal development, synaptic function, and neural protein transport processes in PD, potentially regulating the MAPK signaling pathway through the Ras/Raf/MEK/ERK axis, contributing to the pathological process of PD. Additionally, SLC6A12 was implicated in immune environment disturbances in PD, notably affecting CD4 T cell expression. CONCLUSION: This study documented the pathogenicity of SLC6A12 in PD for the first time, expanding the understanding of its molecular function and providing a potential target for precise treatment of PD.

Polygenic risk scores for autoimmune related diseases are significantly different in cancer exceptional responders.

A small number of cancer patients respond exceptionally well to therapies and survive significantly longer than patients with similar diagnoses. Profiling the germline genetic backgrounds of exceptional responder (ER) patients, with extreme survival times, can yield insights into the germline polymorphisms that influence response to therapy. As ERs showed a high incidence in autoimmune diseases, we hypothesized the differences in autoimmune disease risk could reflect the immune background of ERs and contribute to better cancer treatment responses. We analyzed the germline variants of 51 ERs using polygenic risk score (PRS) analysis. Compared to typical cancer patients, the ERs had significantly elevated PRSs for several autoimmune-related diseases: type 1 diabetes, hypothyroidism, and psoriasis. This indicates that an increased genetic predisposition towards these autoimmune diseases is more prevalent among the ERs. In contrast, ERs had significantly lower PRSs for developing inflammatory bowel disease. The left-skew of type 1 diabetes score was significant for exceptional responders. Variants on genes involved in the T1D PRS model associated with cancer drug response are more likely to co-occur with other variants among ERs. In conclusion, ERs exhibited different risks for autoimmune diseases compared to typical cancer patients, which suggests that changes in a patient's immune set point or immune surveillance specificity could be a potential mechanistic link to their exceptional response. These findings expand upon previous research on immune checkpoint inhibitor-treated patients to include those who received chemotherapy or radiotherapy.

Quantitative morphological analysis framework of infant cranial sutures and fontanelles based on CT images.

Characterizing the suture morphological variation is a crucial step to investigate the influence of sutures on infant head biomechanics. This study aimed to establish a comprehensive quantitative framework for accurately capturing the cranial suture and fontanelle morphologies in infants. A total of 69 CT scans of 2-4 month-old infant heads were segmented to identify semilandmarks at the borders of cranial sutures and fontanelles. Morphological characteristics, including length, width, sinuosity index (SI), and surface area, were measured. For this, an automatic method was developed to determine the junction points between sutures and fontanelles, and thin-plate-spline (TPS) was utilized for area calculation. Different dimensionality reduction methods were compared, including nonlinear and linear principal component analysis (PCA), as well as deep-learning-based variational autoencoder (VAE). Finally, the significance of various covariates was analyzed, and regression analysis was performed to establish a statistical model relating morphological parameters with global parameters. This study successfully developed a quantitative morphological framework and demonstrate its application in quantifying morphologies of infant sutures and fontanelles, which were shown to significantly relate to global parameters of cranial size, suture SI, and surface area for infants aged 2-4 months. The developed framework proved to be reliable and applicable in extracting infant suture morphology features from CT scans. The demonstrated application highlighted its potential to provide valuable insights into the morphologies of infant cranial sutures and fontanelles, aiding in the diagnosis of suture-related skull fractures. Infant suture, Infant fontanelle, Morphological variation, Morphology analysis framework, Statistical model.

Impact of high-altitude acclimatization and de-acclimatization on the intestinal microbiota of rats in a natural high-altitude environment.

Introduction: Intestinal microorganisms play an important role in the health of both humans and animals, with their composition being influenced by changes in the host's environment. Methods: We evaluated the longitudinal changes in the fecal microbial community of rats at different altitudes across various time points. Rats were airlifted to high altitude (3,650 m) and acclimatized for 42 days (HAC), before being by airlifted back to low altitude (500 m) and de-acclimatized for 28 days (HADA); meanwhile, the control group included rats living at low altitude (500 m; LA). We investigated changes in the gut microbiota at 12 time points during high-altitude acclimatization and de-acclimatization, employing 16S rRNA gene sequencing technology alongside physiological indices, such as weight and daily autonomous activity time. Results: A significant increase in the Chao1 index was observed on day 14 in the HAC and HADA groups compared to that in the LA group, indicating clear differences in species richness. Moreover, the principal coordinate analysis revealed that the bacterial community structures of HAC and HADA differed from those in LA. Long-term high-altitude acclimatization and de- acclimatization resulted in the reduced abundance of the probiotic Lactobacillus. Altitude and age significantly influenced intestinal microbiota composition, with changes in ambient oxygen content and atmospheric partial pressure being considered key causal factors of altitude-dependent alterations in microbiota composition. High-altitude may be linked to an increase in anaerobic bacterial abundance and a decrease in non-anaerobic bacterial abundance. Discussion: In this study, the hypobaric hypoxic conditions at high-altitude increased the abundance of anaerobes, while reducing the abundance of probiotics; these changes in bacterial community structure may, ultimately, affect host health. Overall, gaining a comprehensive understanding of the intestinal microbiota alterations during high-altitude acclimatization and de-acclimatization is essential for the development of effective prevention and treatment strategies to better protect the health of individuals traveling between high- and low-altitude areas.

Prevalence and viral suppression of hepatitis B virus infection among people living with HIV on antiretroviral therapy in Sierra Leone.

OBJECTIVE: Sub-Saharan Africa is one of the regions with the highest burdens of HIV and hepatitis B virus (HBV), but data on the impact of antiretroviral therapy (ART) on HBV DNA suppression is limited. In this study, we aimed to determine the prevalence and associated factors of a positive hepatitis B surface antigen (HBsAg) among people living with HIV, and assess the suppression of ART on HBV replication in people living with HIV in Sierra Leone. METHODS: A cross-sectional study was designed to recruit people living with HIV aged 18 years or older in ten public hospitals in Sierra Leone between August 2022 and January 2023. Statistical analyses were performed using R software. Logistic regression analysis was used to assess factors independently associated with positive HBsAg and HBV DNA suppression. RESULTS: Of the 3106 people living with HIV recruited in this study, 2311 (74.4%) were women. The median age was 36 years, 166 (5.3%) had serological evidence of HBV vaccination. The overall prevalence of HBsAg positivity was 12.0% (95% CI: 10.9% to 13.2%). Male sex (adjusted OR (aOR) 2.11, 95% CI: 1.67 to 2.68; p<0.001) and being separated (aOR 1.83, 95% CI: 1.06 to 3.16, p=0.031; reference group: being married) were independent predictors of HBsAg seropositivity. Among 331 people living with HIV and HBV receiving ART, 242 (73.1%) achieved HBV DNA suppression (below 20 IU/mL). HBV suppression rate was higher in HIV-virally suppressed patients than those with unsuppressed HIV viral load (p<0.001). In addition, the male sex was more likely to have unsuppressed HBV DNA (aOR 1.17, 95% CI: 1.17 to 3.21; p=0.010). CONCLUSIONS: We reported a high prevalence of HBsAg seropositivity and low HBV immunisation coverage in people living with HIV in Sierra Leone. In addition, we observed that ART can efficiently result in a viral suppression rate of HBV infection. Therefore, achieving the global target of eliminating HBV infection by 2030 requires accelerated access to care for people living with HIV and HBV, including HBV testing, antiviral treatment and hepatitis B vaccination.

KaryoXpert: An accurate chromosome segmentation and classification framework for karyotyping analysis without training with manually labeled metaphase-image mask annotations.

Automated karyotyping is of great importance for cytogenetic research, as it speeds up the process for cytogeneticists through incorporating AI-driven automated segmentation and classification techniques. Existing frameworks confront two primary issues: Firstly the necessity for instance-level data annotation with either detection bounding boxes or semantic masks for training, and secondly, its poor robustness particularly when confronted with domain shifts. In this work, we first propose an accurate segmentation framework, namely KaryoXpert. This framework leverages the strengths of both morphology algorithms and deep learning models, allowing for efficient training that breaks the limit for the acquirement of manually labeled ground-truth mask annotations. Additionally, we present an accurate classification model based on metric learning, designed to overcome the challenges posed by inter-class similarity and batch effects. Our framework exhibits state-of-the-art performance with exceptional robustness in both chromosome segmentation and classification. The proposed KaryoXpert framework showcases its capacity for instance-level chromosome segmentation even in the absence of annotated data, offering novel insights into the research for automated chromosome segmentation. The proposed method has been successfully deployed to support clinical karyotype diagnosis.

Single-nucleus transcriptome analysis identifies a novel FKBP5+ endothelial cell subtype involved in endothelial-to-mesenchymal transition in adipose tissue during aging.

Age-associated adipose tissue (AT) dysfunction is multifactorial and often leads to detrimental health consequences. AT is highly vascularized and endothelial cells (ECs) has been recently identified as a key regulator in the homeostasis of AT. However, the alteration of cell composition in AT during aging and the communication between endothelial cells and adipocytes remain poorly understood. In this study, we take advantage of single nucleus RNA sequencing analysis, and discovered a group of FKBP5+ ECs specifically resident in aged AT. Of interest, FKBP5+ ECs exhibited the potential for endothelial-to-mesenchymal transition (EndoMT) and exhibited a critical role in regulating adipocytes. Furthermore, lineage tracing experiments demonstrated that ECs in aged AT tend to express FKBP5 and undergo EndoMT with progressive loss of endothelial marker. This study may provide a basis for a new mechanism of microvascular ECs-induced AT dysfunction during aging.