Identification of molecular subtypes based on chromatin regulator-related genes and experimental verification of the role of ASCL1 in conferring chemotherapy resistance to breast cancer.

Objective: The aim of this study was to identify the molecular subtypes of breast cancer based on chromatin regulator-related genes. Methods: The RNA sequencing data of The Cancer Genome Atlas-Breast Cancer cohort were obtained from the official website, while the single-cell data were downloaded from the Gene Expression Omnibus database (GSE176078). Validation was performed using the Molecular Taxonomy of Breast Cancer International Consortium dataset. Furthermore, the immune characteristics, tumor stemness, heterogeneity, and clinical characteristics of these molecular subtypes were analyzed. The correlation between chromatin regulators and chemotherapy resistance was examined in vitro using the quantitative real-time polymerase chain reaction (qRT-PCR) and Cell Counting Kit-8 (CCK8) assays. Results: This study identified three stable molecular subtypes with different prognostic and pathological features. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction analyses revealed that the differentially expressed genes were associated with disease processes, such as mitotic nuclear division, chromosome segregation, condensed chromosome, and specific chromosome region. The T stage and subtypes were correlated with the clinical features. Tumor heterogeneity (mutant-allele tumor heterogeneity, tumor mutational burden, purity, and homologous recombination deficiency) and tumor stemness (RNA expression-based stemness score, epigenetically regulated RNA expression-based stemness score, DNA methylation-based stemness score, and epigenetically regulated DNA methylation-based stemness score) significantly varied between the three subtypes. Furthermore, Western blotting, qRT-PCR, and CCK8 assays demonstrated that the expression of ASCL1 was positively correlated with chemotherapy resistance in breast cancer. Conclusion: This study identified the subtypes of breast cancer based on chromatin regulators and analyzed their clinical features, gene mutation status, immunophenotype, and drug sensitivity. The results of this study provide effective strategies for assessing clinical prognosis and developing personalized treatment strategies.

Multiplexed representation of others in the hippocampal CA1 subfield of female mice.

Hippocampal place cells represent the position of a rodent within an environment. In addition, recent experiments show that the CA1 subfield of a passive observer also represents the position of a conspecific performing a spatial task. However, whether this representation is allocentric, egocentric or mixed is less clear. In this study we investigated the representation of others during free behavior and in a task where female mice learned to follow a conspecific for a reward. We found that most cells represent the position of others relative to self-position (social-vector cells) rather than to the environment, with a prevalence of purely egocentric coding modulated by context and mouse identity. Learning of a pursuit task improved the tuning of social-vector cells, but their number remained invariant. Collectively, our results suggest that the hippocampus flexibly codes the position of others in multiple coordinate systems, albeit favoring the self as a reference point.

[Neurotrophin-associated mechanisms of delayed-onset muscle soreness: research progress and perspective].

Delayed-onset muscle soreness (DOMS) is a common phenomenon that occurs following a sudden increase in exercise intensity or unfamiliar exercise, significantly affecting athletic performance and efficacy in athletes and fitness individuals. DOMS is characterized by allodynia and hyperalgesia, and their mechanisms remain unclear. Recent studies have reported that neurotrophic factors, such as nerve growth factor (NGF) and glial cell derived neurotrophic factor (GDNF), are involved in the development and maintenance of DOMS. This article provides a review of the research progress on the signaling pathways related to the involvement of NGF and GDNF in DOMS, hoping to provide novel insights into the mechanisms underlying allodynia and hyperalgesia in DOMS, as well as potential targeted treatment.

Pathological pain: Non-motor manifestations in Parkinson disease and its treatment.

In addition to motor symptoms, non-motor manifestations of Parkinson's disease (PD), i.e. pain, depression, sleep disturbance, and autonomic disorders, have received increasing attention. As one of the non-motor symptoms, pain has a high prevalence and is considered an early pre-motor symptom in the development of PD. In relation to pathological pain and its management in PD, particularly in the early stages, it is hypothesized that the loss of dopaminergic neurons causes a functional deficit in supraspinal structures, leading to an imbalance in endogenous descending modulation. Deficits in dopaminergic-dependent pathways also affect non-dopaminergic neurotransmitter systems that contribute to the pathological processing of nociceptive input, the integration, and modulation of pain in PD. This review examines the onset and progression of pain in PD, with a particular focus on alterations in the central modulation of nociception. The discussion highlights the importance of abnormal endogenous descending facilitation and inhibition in PD pain, which may provide potential clues to a better understanding of the nature of pathological pain and its effective clinical management.

DNA double-strand break-capturing nuclear envelope tubules drive DNA repair.

Current models suggest that DNA double-strand breaks (DSBs) can move to the nuclear periphery for repair. It is unclear to what extent human DSBs display such repositioning. Here we show that the human nuclear envelope localizes to DSBs in a manner depending on DNA damage response (DDR) kinases and cytoplasmic microtubules acetylated by α-tubulin acetyltransferase-1 (ATAT1). These factors collaborate with the linker of nucleoskeleton and cytoskeleton complex (LINC), nuclear pore complex (NPC) protein NUP153, nuclear lamina and kinesins KIF5B and KIF13B to generate DSB-capturing nuclear envelope tubules (dsbNETs). dsbNETs are partly supported by nuclear actin filaments and the circadian factor PER1 and reversed by kinesin KIFC3. Although dsbNETs promote repair and survival, they are also co-opted during poly(ADP-ribose) polymerase (PARP) inhibition to restrain BRCA1-deficient breast cancer cells and are hyper-induced in cells expressing the aging-linked lamin A mutant progerin. In summary, our results advance understanding of nuclear structure-function relationships, uncover a nuclear-cytoplasmic DDR and identify dsbNETs as critical factors in genome organization and stability.

Gold-Catalyzed Reactions of Enynals with Alkenes for Synthesis Binaphthyl Derivatives.

A PPh3Au[B(C6F5)4]-catalyzed reaction of enynals and alkenes for the construction of binaphthyl derivatives was described. This transformation was achieved through o-Quinodimethane (o-QDM) intermediate's extended conjugated addition process. The reaction has the advantages of wide substrate scopes, mild reaction conditions, high efficiency, and good scalability.

Pathway Activation Analysis for Pan-Cancer Personalized Characterization Based on Riemannian Manifold.

The pathogenesis of carcinoma is believed to come from the combined effect of polygenic variation, and the initiation and progression of malignant tumors are closely related to the dysregulation of biological pathways. Quantifying the alteration in pathway activation and identifying coordinated patterns of pathway dysfunction are the imperative part of understanding the malignancy process and distinguishing different tumor stages or clinical outcomes of individual patients. In this study, we have conducted in silico pathway activation analysis using Riemannian manifold (RiePath) toward pan-cancer personalized characterization, which is the first attempt to apply the Riemannian manifold theory to measure the extent of pathway dysregulation in individual patient on the tangent space of the Riemannian manifold. RiePath effectively integrates pathway and gene expression information, not only generating a relatively low-dimensional and biologically relevant representation, but also identifying a robust panel of biologically meaningful pathway signatures as biomarkers. The pan-cancer analysis across 16 cancer types reveals the capability of RiePath to evaluate pathway activation accurately and identify clinical outcome-related pathways. We believe that RiePath has the potential to provide new prospects in understanding the molecular mechanisms of complex diseases and may find broader applications in predicting biomarkers for other intricate diseases.

Aromatic Perspectives: An In-Depth review on Extracting, influencing Factors, and the origins of raisin aromas.

Raisins, derived from dried grapes, represent a valuable commodity rich in secondary metabolites, particularly volatile organic compounds (VOCs). The primary objective of this review is to identify the VOCs that are influencing the aromatic profile of raisins to improve consumer preferences. However, extensive research has been done to optimize grape drying methods for different raisin attributes. In the context of this review, an in-depth investigation of published literature revealed the extraction of over 120 VOCs from raisins using SPME. Furthermore, we explored factors shaping raisin aroma and the sources of VOC generation. This review aims to pinpoint research gaps and provide an opportunity for future developments in studying raisins' aroma. This involves integrating advanced analytical techniques, examining processing method impacts, and considering consumer perception to enhance the overall understanding of raisin aromas. The outcomes are anticipated to provide valuable insights for the industry and the scientific community.

Tangshen Formula alleviates inflammatory injury against aged diabetic kidney disease through modulating gut microbiota composition and related amino acid metabolism.

Diabetic kidney disease (DKD) is leading causes and one of the fastest growing causes of chronic kidney disease worldwide, and leads to high morbidity and mortality. Emerging evidences have revealed gut microbiota dysbiosis and related metabolism dysfunction play a dominant role in DKD progression and treatment through modulating inflammation. Our previous studies showed that Tangshen Formula (TSF), a Chinese herbal prescription, exhibited anti-inflammatory effect on DKD, but underlying mechanism that involved gut microbiota and related metabolism in aged model remained obscure. Here, BTBR ob/ob mice were used to establish aged DKD model, and 16S rRNA sequence and untargeted metabolomic analyses were employed to investigate the correlation between colonic microbiota and serum metabolism. The aged ob/ob mice exhibited obvious glomerular and renal tubule injury and kidney function decline in kidney, while TSF treatment significantly attenuated these abnormalities. TSF also exhibited potent anti-inflammatory effect in aged ob/ob mice indicating by reduced proinflammatory factor IL-6 and TNF-α, MCP-1 and COX-2 in serum, kidney and intestine, which suggested the involvement of gut microbiota with TSF effect. The 16S rDNA sequencing of the colonic microbiome and untargeted serum metabolomics analysis revealed significant differences in gut microbiota structure and serum metabolomic profiles between WT and ob/ob mice. Notably, TSF treatment reshaped the structure of gut microbiota and corrected the disorder of metabolism especially tryptophan metabolism and arginine biosynthesis. TSF increased Anaeroplasma and Barnesiella genera and decreased Romboutsia, Akkermansia, and Collinsella genera, and further elevated tryptophan, 5-hydroxyindoleacetate, glutamic acid, aspartate and reduced 4-hydroxy-2-quinolinecarboxylic acid, indole-3-acetic acid, xanthurenic acid, glutamine. Further correlation analysis indicated that disturbed gut microbiota was linked to tryptophan metabolism and arginine biosynthesis to regulate inflammation in aged DKD. Our data revealed that TSF attenuated renal inflammation by modulating gut microbiota and related amino acid metabolism in aged DKD model, highlighting gut microbiota and related metabolism functioned as potential therapeutic target for DKD in elderly patients.

G-quadruplexes on chromosomal DNA negatively regulates topoisomerase 1 activity.

Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. Previous researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. However, the reason for its retention on chromosomal DNA remained unclear. In this study, we discovered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) structures. G4 structures, formed during transcription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relieved the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop levels in cells. Additionally, the activation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors towards cancer cells. Our study uncovers a negative regulation mechanism of human Top1 and highlights a novel pathway for activating Top1.

Laparoscopic repair of perineal hernia and unilateral inguinal hernia after rectal cancer surgery: A case report.

INTRODUCTION: Perineal hernia (PH) is a rare complication that can occur after abdominoperineal resection for rectal cancer. Laparoscopic repair of PHs has gained increasing popularity compared to open approaches due to advantages such as superior visualization, decreased invasiveness, and faster recovery. This case report highlights the successful use of laparoscopic tension-free mesh repair for concurrent perineal and inguinal hernias after rectal cancer surgery. CASE DESCRIPTION: A 51-year-old man underwent laparoscopic-assisted abdominoperineal resection for rectal cancer. About 2 months postoperatively, he developed reducible masses in the perineal and left groin regions, associated with urinary symptoms and sensation of prolapse. Physical exam revealed protruding masses that enlarged with Valsalva. Pelvic CT confirmed PH and left inguinal hernia. INTERVENTIONS: Laparoscopic tension-free repair of the PH and inguinal hernia was performed on this patient. The repair was completed by the steps of adhesion separation, mesh placement, and fixation. OUTCOMES: The 98-minute surgery was successful without complications. The patient recovered well, ambulating on postoperative day 2 and getting discharged on day 6. CONCLUSION: This case demonstrates that laparoscopic tension-free repair with mesh is an effective approach for treating PH and concurrent inguinal hernia following rectal cancer surgery, resulting in successful outcomes and low recurrence rates. The laparoscopic technique provides benefits of minimal invasiveness and rapid recovery.

Charge-density wave mediated quasi-one-dimensional Kondo lattice in stripe-phase monolayer 1T-NbSe2.

The heavy fermion physics is dictated by subtle competing exchange interactions, posing a challenge to their understanding. One-dimensional (1D) Kondo lattice model has attracted special attention in theory, because of its exact solvability and expected unusual quantum criticality. However, such experimental material systems are extremely rare. Here, we demonstrate the realization of quasi-1D Kondo lattice behavior in a monolayer van der Waals crystal NbSe2, that is driven into a stripe phase via Se-deficient line defects. Spectroscopic imaging scanning tunneling microscopy measurements and first-principles calculations indicate that the stripe-phase NbSe2 undergoes a novel charge-density wave transition, creating a matrix of local magnetic moments. The Kondo lattice behavior is manifested as a Fano resonance at the Fermi energy that prevails the entire film with a high Kondo temperature. Importantly, coherent Kondo screening occurs only in the direction of the stripes. Upon approaching defects, the Fano resonance exhibits prominent spatial 1D oscillations along the stripe direction, reminiscent of Kondo holes in a quasi-1D Kondo lattice. Our findings provide a platform for exploring anisotropic Kondo lattice behavior in the monolayer limit.

Experimental evidence for cancer resistance in a bat species.

Mammals exhibit different rates of cancer, with long-lived species generally showing greater resistance. Although bats have been suggested to be resistant to cancer due to their longevity, this has yet to be systematically examined. Here, we investigate cancer resistance across seven bat species by activating oncogenic genes in their primary cells. Both in vitro and in vivo experiments suggest that Myotis pilosus (MPI) is particularly resistant to cancer. The transcriptomic and functional analyses reveal that the downregulation of three genes (HIF1A, COPS5, and RPS3) largely contributes to cancer resistance in MPI. Further, we identify the loss of a potential enhancer containing the HIF1A binding site upstream of COPS5 in MPI, resulting in the downregulation of COPS5. These findings not only provide direct experimental evidence for cancer resistance in a bat species but also offer insights into the natural mechanisms of cancer resistance in mammals.

[Alignment method for metabolite chromatographic peaks using an N-acyl glycine retention index system].

Peak alignment is a crucial data-processing step in untargeted metabolomics analysis that aims to integrate metabolite data from multiple liquid chromatography-mass spectrometry (LC-MS) batches for enhanced comparability and reliability. However, slight variations in the chromatographic separation conditions can result in retention time (RT) shifts between consecutive analyses, adversely affecting peak alignment accuracy. In this study, we present a retention index (RI)-based chromatographic peak-shift correction (CPSC) strategy to address RT shifts and align chromatographic peaks for metabolomics studies. A series of N-acyl glycine homologues (C2-C23) was synthesized as calibrants, and an LC RI system was established. This system effectively corrected RT shifts arising from variations in flow rate, gradient elution, instrument systems, and chromatographic columns. Leveraging the RI system, we successfully adjusted the RT of raw data to mitigate RT shifts and then implemented the Joint Aligner algorithm for peak alignment. We assessed the accuracy of the RI-based CPSC strategy using pooled human fecal samples as a test model. Notably, the application of the RI-based CPSC strategy to a long-term dataset spanning 157 d as an illustration revealed a significant enhancement in peak alignment accuracy from 15.5% to 80.9%, indicating its ability to substantially improve peak-alignment precision in multibatch LC-MS analyses.

Nonsingular fast terminal sliding mode tracking control for underwater glider with actuator physical constraints.

An adaptive finite-time composite control (AFTCC) scheme is designed for the pitch angle trajectory tracking control of Underwater Glider (UG) with actuator physical constraints, uncertain dynamics and external disturbances. Firstly, a novel nonsingular fast terminal sliding mode control (NFTSMC) law is designed that can avoid singular problems, significantly reduce chattering, and achieve finite-time convergence of the system states. Secondly, a novel fixed-time extended state observer (FxTESO) is established to estimate the pitch angular velocity and lumped disturbances within a fixed time. Furthermore, a novel adaptive fixed-time saturation compensation system (AFxTSCS) is proposed to mitigate the effect caused by actuator saturation, and it can adjust the parameter adaptively when the actuator is in saturation or out of saturation. Finally, the AFTCC scheme, which is based on the NFTSMC framework and combines FxTESO and AFxTSCS, is designed to achieve the pitch angle trajectory tracking of UG, and the finite-time convergence of the whole closed-loop system is proved by the Lyapunov stability theory, and the simulations verify the availability and superiority of the proposed AFTCC scheme.

ALYREF-mediated RNA 5-Methylcytosine modification Promotes Hepatocellular Carcinoma Progression Via Stabilizing EGFR mRNA and pSTAT3 activation.

5-Methylcytosine (m5C) is one of the most ubiquitous modifications of mRNA and contributes to cancer pathogenesis. Aly/REF export factor (ALYREF), an m5C reader, is associated with the prognosis of liver hepatocellular carcinoma (LIHC). However, the effects of ALYREF on the progression of LIHC and the underlying molecular mechanisms remains elusive. Through an analysis of an online database and 3 independent LIHC cohorts, we found that ALYREF was markedly elevated in human liver cancer tissues and was significantly correlated with LIHC clinicopathological parameters, including Ki67+ cell rate, high-grade TNM stage, and poor prognosis. Several experiments were conducted to investigate the molecular basis and functional role of ALYREF-related progression in this study. ALYREF could enhance LIHC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and tumor formation in vivo. Mechanistically, ALYREF promoted the progression of human LIHC through EGFR pathways. Furthermore, ALYREF could directly bind to the m5C modification site of EGFR 3' untranslated region (3' UTR) to stabilize EGFR mRNA. Collectively, ALYREF played a crucial oncogenic role in LIHC via the stabilization of EGFR mRNA and subsequent activation of the STAT3 signaling pathway. Our results may help to elucidate the potential mechanisms of ALYREF-induced m5C modification in the progression of human LIHC.

Gene signatures to therapeutics: Assessing the potential of ivermectin against t(4;14) multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow. The translocation, (t)(4;14), results in high-risk MM with limited treatment alternatives. Thus, there is an urgent need for identification and validation of potential treatments for this MM subtype. Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets. AIM: To elucidate the molecular basis and search for potential effective drugs of t(4;14) MM subtype by employing a comprehensive approach. METHODS: The transcriptional signature of t(4;14) MM was sourced from the Gene Expression Omnibus. Two datasets, GSE16558 and GSE116294, which included 17 and 15 t(4;14) MM bone marrow samples, and five and four normal bone marrow samples, respectively. After the differentially expressed genes were identified, the Cytohubba tool was used to screen for hub genes. Then, the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Using the STRING database and Cytoscape, protein-protein interaction networks and core targets were identified. Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis, respectively. RESULTS: In this study, a total of 258 differentially expressed genes with enriched functions in cancer pathways, namely cytokine receptor interactions, nuclear factor (NF)-κB signaling pathway, lipid metabolism, atherosclerosis, and Hippo signaling pathway, were identified. Ten hub genes (cd45, vcam1, ccl3, cd56, app, cd48, btk, ccr2, cybb, and cxcl12) were identified. Nine drugs, including ivermectin, deforolimus, and isoliquiritigenin, were predicted by the Connectivity Map database to have potential therapeutic effects on t (4;14) MM. In molecular docking, ivermectin showed strong binding affinity to all 10 identified targets, especially cd45 and cybb. Ivermectin inhibited t(4;14) MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro. Furthermore, ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14) MM cells. CONCLUSION: Collectively, the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14) MM diagnosis and treatment, with ivermectin emerging as a potential therapeutic alternative.

Mammalian integrated stress responses in stressed organelles and their functions.

The integrated stress response (ISR) triggered in response to various cellular stress enables mammalian cells to effectively cope with diverse stressful conditions while maintaining their normal functions. Four kinases (PERK, PKR, GCN2, and HRI) of ISR regulate ISR signaling and intracellular protein translation via mediating the phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α) at Ser51. Early ISR creates an opportunity for cells to repair themselves and restore homeostasis. This effect, however, is reversed in the late stages of ISR. Currently, some studies have shown the non-negligible impact of ISR on diseases such as ischemic diseases, cognitive impairment, metabolic syndrome, cancer, vanishing white matter, etc. Hence, artificial regulation of ISR and its signaling with ISR modulators becomes a promising therapeutic strategy for relieving disease symptoms and improving clinical outcomes. Here, we provide an overview of the essential mechanisms of ISR and describe the ISR-related pathways in organelles including mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. Meanwhile, the regulatory effects of ISR modulators and their potential application in various diseases are also enumerated.

Road extraction through Yangwang-1 nighttime light data: A case study in Wenzhou, China.

The extraction of roadways from remote sensing imagery constitutes a pivotal task, with far-reaching implications across diverse domains such as urban planning, management of transportation systems, emergency response initiatives, and environmental monitoring endeavors. Satellite images captured during daytime have customarily served as the primary resource for this extraction process. However, the emergence of Nighttime Light (NTL) remote sensing data introduces an innovative dimension to this arena. The exploration of NTL data for road extraction remains in its nascent stage, and this study seeks to bridge this gap. We present a refined U-Net model (CA U-Net) integrated with Cross-Attention Mechanisms, meticulously designed to extract roads from Yangwang-1 NTL images. This model incorporates several enhancements, thereby improving its proficiency in identifying and delineating road networks. Through extensive experimentation conducted in the urban landscape of Wenzhou City, the model delivers highly accurate results, achieving an F1 score of 84.46%. These outcomes significantly surpass the performance benchmarks set by Support Vector Machines (SVM) and the Optimal Threshold (OT) method. This promising development paves the way towards maximizing the utility of NTL data for comprehensive mapping and analysis of road networks. Furthermore, the findings underscore the potential of utilizing Yangwang-1 data as a reliable source for road extraction and reaffirm the viability of deploying deep learning frameworks for road extraction tasks utilizing NTL data.

CircRNA and Stroke: New Insight of Potential Biomarkers and Therapeutic Targets.

Stroke, the second-largest cause of death and the leading cause of disability globally, presents significant challenges in terms of prognosis and treatment. Identifying reliable prognosis biomarkers and treatment targets is crucial to address these challenges. Circular RNA (circRNA) has emerged as a promising research biomarkers and therapeutic targets because of its tissue specificity and conservation. However, the potential role of circRNA in stroke prognosis and treatment remains largely unexplored. This review briefly elucidate the mechanism underlying circRNA's involvement in stroke pathophysiology. Additionally, this review summarizes the impact of circRNA on different forms of strokes, including ischemic stroke and hemorrhagic stroke. And, this article discusses the positive effects of circRNA on promoting cerebrovascular repair and regeneration, maintaining the integrity of the blood-brain barrier (BBB), and reducing neuronal injury and immune inflammatory response. In conclusion, the significance of circRNA as a potential prognostic biomarker and a viable therapeutic target was underscored.