Castration-resistant prostate cancer (CRPC) constitutes an advanced stage of prostate cancer (PCa) that emerges following conventional androgen deprivation therapy (ADT). Docetaxel (DTX), a standard chemotherapeutic agent, is integral to the therapeutic regimen for CRPC. However, the development of resistance to DTX has significantly impeded its clinical efficacy. Histone lactylation and elevated lactate production are emerging as critical factors in cancer biology, yet their roles in CRPC and DTX resistance remain poorly understood. This study investigated the relationship between histone lactylation, lactate production, and DTX resistance in CRPC. Clinical analysis revealed significantly increased pan-lactylated protein (Pan Kla) expression in CRPC tissues compared to PCa, accompanied by elevated lactate production and lactate dehydrogenase (LDH) activity. Higher Pan Kla expression was linked to poor prognosis in CRPC. DTX-resistant CRPC (CRPC-R) samples exhibited significantly elevated Pan Kla and histone lactylation modifications, especially at H3K18la and H4K12la sites. Inhibition of lactate production using 2-deoxyglucose (2-DG) and oxamate reduced DTX resistance, suppressed cell migration, induced G0/G1 phase arrest, and promoted autophagy. Moreover, CNN1 was identified as a potential downstream target of histone lactylation modifications in CRPC. Elevated CNN1 expression correlated with increased lactylation and DTX resistance, whereas its inhibition reversed the effects of lactate inhibition on cell cycle progression and autophagy. In vivo, CNN1 overexpression counteracted the tumor-suppressive effects of lactate inhibition, restoring tumor growth and autophagy levels. These findings suggested that histone lactylation and lactate metabolism, mediated by CNN1, play a crucial role in DTX resistance and tumor progression in CRPC, offering potential therapeutic targets for overcoming chemoresistance in CRPC.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition with severe pulmonary inflammation and high mortality. Investigate Nur77/NR4A1's protective effect on macrophage polarization and lung repair in LPS-induced ARDS in mice. 144 C57BL/6 mice divided into 4 groups. ARDS induced with LPS. CsnB used to activate Nur77. Lung injury assessed via histopathology, cytokine levels, and macrophage markers. CsnB reduced lung injury, promoted M2 macrophage polarization, reduced M1 markers, and accelerated tissue repair. Nur77/NR4A1 regulates macrophage polarization and protects against inflammatory lung injury, offering a potential ARDS therapeutic target.

Aging is closely associated with imbalanced transcription. Regulated transcription in different organs is significantly different during aging, indicating that organ-specific transcriptomics is critical for understanding this process. Here we analyze the transcriptomics of the intestines of 3-, 15-, 30-, 40- and 50-days old female flies, which include young, middle-aged, and old flies. We find that the differential expression of protein-coding genes and lncRNAs is significant in aging, and fly age is characterized by well-separated gene expression trajectories. The highly clustered differentially expressed genes are connected to specific biological processes and signalling pathways. In particular, the Imd and Toll pathways are the top two immune signalling pathways that are highly regulated, and members with increased expression in the Imd pathway span all upstream activating events and include many ubiquitylation-associated factors and regulators of NF-κB factor Relish. Increased expression of Toll pathway members includes sensing mediators for all kinds of microorganisms and multiple proteases in the proteolytic processing cascade. Moreover, the expression of molecular markers of intestinal cells is greatly changed. Enterocyte markers are the most significantly influenced, and enteroendocrine markers AstA and NPF, as well as intestinal stem cell (ISC)/enteroblast (EB) markers Esg and Klu are expressed at low levels in young flies and much higher levels in aged flies. Furthermore, lncRNAs show similar expression trends and clustering patterns to those of protein-coding genes. Lastly, we find that ISC/EB-specific knock-down of 13 out of 19 genes that are highly differentially expressed reduces the lifespan of the fly. Together, the characterized transcriptomics and newly identified functional genes in aging will provide potential targets for preventing intestinal aging and associated disorders.

Apoptosis-induced proliferation (AiP) is an evolutionarily conserved process implicated in tissue regeneration and tumorigenesis. Studies in Drosophila have identified activation of the stress response molecule c-Jun N-terminal kinase (JNK) as a critical step in mediating AiP. Interestingly, JNK activation can be further amplified to drive tissue overgrowth during this process. However, the mechanisms that coordinate the initial activation of JNK and its subsequent amplification remain poorly understood. In this study, we identified distinct functions for two members of the microRNA cluster miR-309/3/286/4/5/6 − 1/6 − 2/6 − 3, specifically miR-286 and miR-6, in regulating JNK signaling during AiP. We found that miR-6 promoted the initial activation of JNK, whereas miR-286 inhibited its amplification. During AiP, the expression of miR-286 was reduced, and we identified Calx, a gene encoding a sodium/calcium exchanger involved in intracellular calcium homeostasis, as a direct target of miR-286. Loss of miR-286 led to increased Calx expression and enhanced JNK amplification. Genetically, these promoted AiP through calcium signaling. Together, our findings revealed a microRNA-based regulatory mechanism that coordinates different stages of JNK activation during AiP.

In our recent studies, we investigated the phenomenon of obesity resistance in the Asian house shrew, Suncus murinus, which may be a suitable model to study the mechanisms of obesity resistance. In this study, we characterized the gut microbiota of S. murinus by analyzing the microbiota using libraries of cloned bacterial 16S rRNA gene sequences to explore their relationship with natural obesity-resistance properties. Our findings revealed a distinct microbial profile of S. murinus, primarily dominated by Firmicutes and Proteobacteria, with a notable absence of Bacteroidetes. This composition is consistent with the obesity-resistance properties of animals. The low microbiota diversity observed in S. murinus may be associated with its unique gastrointestinal tract morphology, lack of fermentative chambers (such as a cecum), and insectivorous dietary habits. Lactic acid bacteria were abundant in the gut microbiota of S. murinus, suggesting the potential importance of lactic acid fermentation processes in this species. Helicobacter, a known human pathogen, is also present in significant quantities in the gut of S. murinus. Further research is warranted to explore the specific functions and interactions of these microbial groups in S. murinus and their broader ecological implications to contribute to the study of the mechanism of obesity in humans.

Rb/E2f and DREAM complexes play vital roles in regulating cell cycle progression. To date, how they coordinate their functions to regulate cell cycle-dependent gene expression is not clear. Here, we identified a long noncoding RNA (lncRNA), which we named DREAMer, that bridges the interaction between E2f1 and the dREAM complex to regulate endoreplication specifically in Drosophila salivary gland. We show that E2f1 directly stimulates DREAMer expression, whereas DREAMer mediates the repression of e2f1 transcription by modulating the recruitment of the dREAM complex to the e2f1 promoter via a direct interaction with the dREAM component E2f2. The depletion of DREAMer impairs dREAM binding, leading to derepression of e2f1 transcription, which ultimately increases E2f1 activity and promotes the endoreplication. Furthermore, the transcriptomic analysis revealed profound changes in cell cycle-related gene expression in DREAMerKO salivary glands. Together, our findings reveal an lncRNA-mediated link between the dREAM complex and E2f1, which regulates endoreplication during development.

In view of the phenomena such as under-exposure of light strips and noise interference caused by complex surfaces of objects, it is difficult for traditional light strip center extraction algorithm to achieve light strip center extraction. Therefore, this paper studies the extraction of light strip center line based on semantic segmentation network algorithm based on deep learning, uses deep learning algorithm to presegment light strips, and then uses gray prime-core method to extract light strips subpixel. Improve the stability and accuracy of center line extraction.

Testicular aging manifests as impaired spermatogenesis and morphological alterations in Drosophila. Nonetheless, the comprehensive molecular regulatory framework remains largely undisclosed. This investigation illustrates the impact of copper overload on testicular aging and underscores the interplay between copper overload and lncRNA. Copper overload triggers Cuproptosis through the mitochondrial TCA cycle, facilitating intracellular interactions with Ferroptosis, thereby governing testicular aging. Dysfunction of lncRNA:CR43306 also contributes to testicular aging in Drosophila, emphasizing the significance of lncRNA:CR43306 as a novel aging-associated lncRNA. Moreover, copper overload exacerbates spermatid differentiation defects mediated by lncRNA:CR43306 deficiency through oxidative stress, copper, and iron transport. Therapeutically, Ferrostatin-1 and Resveratrol emerge as potential remedies for addressing testicular aging. This study offers perspectives on the regulatory mechanisms involving copper overload and lncRNA:CR43306 deficiency in the context of testicular aging.

Deubiquitinases (DUBs) are essential for the maintenance of protein homeostasis and assembly of proteins into functional complexes. Despite growing interest in DUBs biological functions, the roles of DUBs in regulating intestinal stem cells (ISCs) and gut homeostasis remain largely unknown. Here, we perform an in vivo RNAi screen through induced knock-down of DUBs expression in adult midgut ISCs and enteroblasts (EBs) to identify DUB regulators of intestinal homeostasis in Drosophila. We screen 43 DUBs and identify 8 DUBs that are required for ISCs homeostasis. Knocking-down of usp1, CG7857, usp5, rpn8, usp10 and csn5 decreases the number of ISCs/EBs, while knocking-down of CG4968 and usp8 increases the number of ISCs/EBs. Moreover, knock-down of usp1, CG4968, CG7857, or rpn8 in ISCs/EBs disrupts the intestinal barrier integrity and shortens the lifespan, indicating the requirement of these DUBs for the maintenance of gut homeostasis. Furthermore, we provide evidences that USP1 mediates ISC lineage differentiation via modulating the Notch signaling activity. Our study identifies, for the first time, the deubiquitinases required for the maintenance of intestinal homeostasis in Drosophila, and provide new insights into the functional links between the DUBs and intestinal homeostasis.

Long noncoding RNAs (lncRNAs) play important regulatory roles in stem cell self-renewal, pluripotency maintenance, and differentiation. Till now, there is very limited knowledge about how lncRNAs regulate intestinal stem cells (ISCs), and lncRNAs mediating ISC regeneration in Drosophila have yet been characterized. Here, we identify a lncRNA, CR46040, that is essential for the injury-induced ISC regeneration in Drosophila. Loss of CR46040 greatly impairs ISC proliferation in response to tissue damage caused by dextran sulfate sodium (DSS) treatment. We demonstrate that CR46040 is a genuine lncRNA that has two isoforms transcribed from the same transcription start site and works in trans to regulate intestinal stem cells. Mechanistically, CR46040 knock-out flies failed to fully activate JNK, JAK/STAT, and HIPPO signaling pathways after tissue damage, which are required for ISC proliferation after intestinal injury. Moreover, CR46040 knock-out flies are highly susceptible to DSS treatment and enteropathogenic bacteria Erwinia carotovora ssp. carotovora 15 (Ecc15) infection. Our findings characterize, for the first time, a lncRNA that mediates damage-induced ISC proliferation in Drosophila and provide new insights into the functional links among the long noncoding RNAs, ISC proliferation, and tissue homeostasis.

The COVID-19 pandemic has profoundly changed our lives. While healthcare resources were redistributed and mobilized to focus on dealing with the COVID-19 crisis, there have been unmet medical needs of patients with other diseases such as syphilis, weaving an integral but neglected component of the pandemic story. In different countries, the epidemiology of newly reported syphilis underwent diverse changes during the COVID-19 pandemic. Asymptomatic cases experienced the largest decline in number. From the perspective of transmission, on one hand, the implementation of lockdown measures led to a higher degree of abstinence and sex distancing in many countries, thereby reducing the transmission of syphilis. On the other hand, vertical transmission was reported to have increased significantly during COVID-19. Meanwhile, the volume of STI clinic capacity declined, and STI staff were redeployed to facilitate the contact tracing of COVID-19. As a result, many STI centers converted traditional in-person clinical services to telemedicine and self-testing. However, syphilis testing and clinical treatment cannot fully adapt to this conversion. In syphilis diagnosis, COVID-19 infection and vaccination were reported to cause false positivity in syphilis serological tests. Diverse cutaneous manifestations of COVID-19 could resemble the skin lesions in syphilis patients, requiring differential diagnosis from clinicians. As for the post-pandemic years, consequent to service interruptions and diagnosis delays, a surge in the number of confirmed cases of syphilis is expected. The COVID-19 pandemic has also been a meaningful lesson for the control and prevention of infectious diseases. The experience in combating COVID-19 has underscored the importance of maintaining a robust and wellsupported medical system for the provision of sexual health services and better healthcare equality even during eras of crisis, not least for syphilis patients.

Gastric cancer (GC) is the leading cause of cancer-related death worldwide, and reducing its mortality has become an urgent public health issue. Gastric microecological dysbiosis (including bacteria, fungi, viruses, acid suppressants, antibiotics, and surgery) can lead to gastric immune dysfunction or result in a decrease in dominant bacteria and an increase in the number and virulence of pathogenic microorganisms, which in turn promotes development of GC. This review analyzes the relationship between gastric microecological dysbiosis and GC, elucidates dynamic alterations of the microbiota in Correa's cascade, and identifies certain specific microorganisms as potential biomarkers of GC to aid in early screening and diagnosis. In addition, this paper presents the potential of gastric microbiota transplantation as a therapeutic target for gastric cancer, providing a new direction for future research in this field.

Ti–Mn-based hydrogen storage alloys are considered to be one of the most promising hydrogen storage alloys for proton exchange membrane fuel cell applications, because of their good hydrogen absorption and desorption kinetics, low price, good activation performance, possession of high electrochemical capacity, and good cycling performance. The structure, performance characteristics, crystal structure of hydrides, development and application status of Ti–Mn-based hydrogen storage alloys were reviewed, and the methods to improve Ti–Mn-based hydrogen storage alloys were discussed: optimization of the preparation process, element substitution, and surface treatment. (1) In the study of the alloy preparation process, it was found that the use of the annealing process can significantly improve the high rate discharge performance, and cycling stability performance, increasing the maximum discharge capacity of the alloy electrode. In addition, using vacuum plasma spraying to prepare the electrode has better cycling stability and kinetic performance. (2) In element substitution, the effects of using Zr elements to partially replace Ti and Mn with Cr, V, Mo, and Fe on the hydrogen storage properties of Ti–Mn-based alloys were investigated. (3) In the study of surface treatment, palladium was plated on the surface of TiMn1.5 alloy by chemical deposition, and the strong affinity of palladium for hydrogen accelerated the cleavage of hydrogen molecules, which significantly improved the hydrogen absorption kinetics of TiMn1.5 alloy. Meanwhile, a new binary alloy system was formed by adding TiMn2 to MgH2, and it was shown that the addition of TiMn2 significantly improved the hydrogen absorption/desorption kinetics of the MgH2 alloy. Finally, the prospect of the application of Ti–Mn-based hydrogen storage alloys is presented, and the insight of further development of the alloy is offered.

Nur77, also known as NR4A1 (nuclear receptor subfamily 4 group A member 1), is a transcription factor belonging to the NR4A subfamily of nuclear receptors. Emerging evidence suggests its involvement in modulating macrophage polarization states. Macrophages are versatile immune cells that can adopt distinct functional states depending on the signals they receive from their microenvironment. Two main polarization states are commonly recognized: the classically activated (M1) phenotype, associated with pro-inflammatory responses, and the alternatively activated (M2) phenotype, linked to tissue repair and immunoregulation. The balance between M1 and M2 polarization is critical for maintaining immune homeostasis in the lung. Several studies have indicated that Nur77/NR4A1 may influence macrophage polarization towards the M1 phenotype. Also, other studies have also indicated a potential role for Nur77 in regulating M2 polarization of macrophages. Research findings suggest a dual role for Nur77 in modulating macrophage polarization, potentially promoting both M1 and M2 phenotypes depending on the context and specific signaling cues. It's important to note that the exact mechanisms underlying Nur77's regulation of macrophage polarization in the lung are still being elucidated. Further research is needed to fully understand the complex interplay between Nur77, other transcription factors, and the signaling pathways involved in lung macrophage polarization. Nonetheless, the current evidence suggests that Nur77/NR4A1 is a key player in orchestrating the immune responses of lung macrophages and may have a role in regulating their polarization towards both M1 and M2 phenotypes.

Supplementary Data from Combined Inhibition of Janus Kinase 1/2 for the Treatment of JAK2V617F-Driven Neoplasms: Selective Effects on Mutant Cells and Improvements in Measures of Disease Severity

Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.

Background ATM (ataxia-telangiectasia mutated) protein kinase is highly conserved in metazoan, and plays a critical role at DNA damage response, oxidative stress, metabolic stress, immunity, RNA biogenesis etc. Systemic profiling of ATM regulated genes, including protein-coding genes, miRNAs, and long non-coding RNAs, will greatly improve our understanding of ATM functions and its regulation. Results 1) differentially expressed protein-coding genes, miRNAs, and long non-coding RNAs in atm mutated flies were identified at physiological condition and after X-ray irradiation. 2) functions of differentially expressed genes in atm mutated flies, regardless of protein-coding genes or non-coding RNAs, are closely related with metabolic process, immune response, DNA damage response or oxidative stress. 3) these phenomena are persistent after irradiation. 4) there is a cross-talk regulation towards miRNAs by ATM, E2f1, and p53 during development and after irradiation. 5) knock-out flies or knock-down flies of most irradiation-induced miRNAs were sensitive to ionizing radiation. Conclusions We provide a valuable resource of protein-coding genes, miRNAs, and long non-coding RNAs, for understanding ATM functions and regulations. Our work provides the new evidence of inter-dependence among ATM-E2F1-p53 for the regulation of miRNAs.