Cycle Control Research Articles

Roles of Menin in T cell differentiation and function: Current knowledge and perspectives.

The commitment to specific T lymphocytes (T cell) lineages is governed by distinct transcription factors, whose expression is modulated through epigenetic mechanisms. Unravelling these epigenetic mechanisms that regulate T cell differentiation and function holds significant importance for understanding T cells. Menin, a multifunctional scaffolding protein, is implicated in various cellular processes, such as cell proliferation, cell cycle control, DNA repair and transcriptional regulation, primarily through epigenetic mechanisms. Existing research indicates Menin's impact on T cell differentiation and function, while a comprehensive and systematic review is currently lacking to consolidate these findings. In the current review, we have highlighted recent studies on the role of Menin in T cell differentiation and function, focusing mainly on its impact on the memory Th2 maintenance, Th17 differentiation and maintenance, CD4+ T cell senescence, and effector CD8+ T cell survival. Considering Menin's crucial function in maintaining effector T cell function, the potential of inhibiting Menin activity in mitigating inflammatory diseases associated with excessive T cell activation has also been emphasised.

'There's Nothing Wrong With You; You Just Need to Lose Weight'-A Qualitative Exploration of Pelvic Floor Dysfunction Among Women With Multiple Sclerosis and Their Interaction in Seeking Pelvic Healthcare.

Within 10 years of multiple sclerosis (MS) progression, nearly all women will have experienced symptoms associated with bladder, bowel and/or sexual health. Yet despite the impact these symptoms have on physical, psychological and social well-being, it remains an underserved area within the UK healthcare system. This research employs a participatory research approach framed within the principles of intersectional feminism to collaboratively investigate the lived experiences of pelvic floor dysfunction (PFD) and healthcare interactions among UK-based women with MS. Women residing in the United Kingdom with MS were invited to participate in online interviews facilitated by the primary author. A thematic framework analysis offering a structured yet adaptable approach to data collection and interpretation. One focus group involving four women with MS and seven individual, one-to-one interviews with women with MS provided insights into the challenges associated with navigating both MS and PFD. Four main themes included: Navigating MS and PFD; Cycles of Control; Mind, Mobility and Bladder Embodiment; Silenced Voices: The Impact of Taboos/Stigma/Dismissal on Preventing Access and Resistance through Collective Community. Six subthemes were also identified. Taken together, these themes cumulatively reflect PFD as an unmet healthcare need. Our findings underscore negative healthcare experiences, inadequate information provisionand unmet needs related to PFD, emphasising the compounding effects of gender and disability biases. We hope that these insights can lay the groundwork for developing tailored therapeutic interventions and improved PFD healthcare for women with MS. Potential solutions include using existing MS support communities. Women with MS were actively involved in co-producing interview scripts for one-to-one interviews. The primary author shared study findings at an MS group event, engaging in discussions with over 30 individuals, including people with MS and their loved ones. MS advocates played a pivotal role in contextualising the study within the broader lived experience of MS.

Sodium valproate affects the expression of p16INK4a and p21WAFI/Cip1 cyclin‑dependent kinase inhibitors in HeLa cells.

p16INK4a and p21WAF1/Cip1 are cyclin-dependent kinase inhibitors involved in cell cycle control, which can function as oncogenes or tumor suppressors, depending on the context of various extracellular and intracellular signals, and cell type. In human papillomavirus-induced cervical cancer, p16 INK4a shows oncogenic activity and functions as a diagnostic marker of cervical neoplasia, whereas p21 WAF1/Cip1 acts as a tumor suppressor and its downregulation is associated with the progression of malignant transformation. Several histone deacetylase (HDAC) inhibitors promote the positive and negative regulation of a number of genes, including p16 INK4a and p21 WAF1/Cip1; however, the effects of sodium valproate (VPA) on these genes and on the proteins they encode remain uncertain in HeLa cervical cancer cells. In the present study, these effects were investigated in HeLa cells treated with 0.5 or 2 mM VPA for 24 h, using reverse transcription-quantitative PCR, confocal microscopy and western blotting. The results revealed a decrease in the mRNA expression levels of p16 INK4a and a tendency for p16INK4a protein abundance to decrease in the presence of 2 mM VPA. By contrast, an increase in the protein expression levels of p21WAF1/Cip1 was detected in the presence of 0.5 and 2 mM VPA. Furthermore, VPA was confirmed to inhibit HDAC activity and induce global hyperacetylation of histone H3. Notably, VPA was shown to suppress p16 INK4a, a biomarker gene of cervical carcinoma, and to increase the abundance of the tumor suppressor protein p21WAF1/Cip1, thus contributing to the basic knowledge regarding the antitumorigenic potential of VPA. Exploration of epigenetic changes associated with the promoters of p16 INK4a and p21 WAF1/Cip1, such as histone H3 methylation, may provide further information and improve the understanding of these findings.

Immobilization of multilayer sodium alginate/polysaccharide antibacterial material composite beads as glufosinate controlled release matrices

To find a new way to slow down the release of glufosinate (GA) pesticide and to solve the susceptibility to decomposition by soil microorganisms, a series of novel antibacterial polysaccharide-based sustained release beads (PSRB) were prepared. The PSRB was prepared by immobilization of GA loaded polysaccharide-based chitosan quaternary ammonium salt (PS-HACC) microcapsules in the core and layers of the multilayer sodium alginate beads. The PSRB was characterized by FI-IR spectroscopy, XRD, SEM, and BET to reveal their composition and surface morphology. The optimal conditions of the slow release beads were as follows, the concentration of Ca2+, pH, temperature and the coating layer number was 0.1 mol/L, 7, 25 °Cand 3, respectively. The kinetic study showed that the slow release of PSRB was in accordance with the Higuchi kinetic model, and the FI-IR and XRD analyses revealed that the PS-HACC and GA were successfully cross-linked to the PSRB. BET showed that PSRB were greater than PSRB3 at surface area, pore volume and pore size. Inhibition circles experiments demonstrated that WPSRB3 has good antibacterial activity. The weed control in soybean with PSRB3 application is perfect and the weed control cycle is long. Therefore, this technology can provide a potential way to control GA release, improve utilization efficiency, reduce pesticide use and environmental pollution, and at the same time, provide a potential way to achieve ecological agriculture.

UPF1 plays critical roles in early B cell development

The ATP-dependent RNA helicase UPF1 plays a crucial role in various mRNA degradation pathways, most importantly in nonsense-mediated mRNA decay (NMD). Here, we show that UPF1 is upregulated during the early stages of B cell development and is important for early B cell development in the bone marrow. B-cell-specific Upf1 deletion in mice severely impedes the early to late LPre-B cell transition, in which VH-DHJH recombination occurs at the Igh gene. Furthermore, UPF1 is indispensable for VH-DHJH recombination, without affecting DH-JH recombination. Intriguingly, the genetic pre-arrangement of the Igh gene rescues the differentiation defect in early LPre-B cells under Upf1 deficient conditions. However, differentiation is blocked again following Ig light chain recombination, leading to a failure in development into immature B cells. Notably, UPF1 interacts with and regulates the expression of genes involved in immune responses, cell cycle control, NMD, and the unfolded protein response in B cells. Collectively, our findings underscore the critical roles of UPF1 during the early LPre-B cell stage and beyond, thus orchestrating B cell development.

Network analysis of driver genes in human cancers.

Cancer is a heterogeneous disease that results from genetic alteration of cell cycle and proliferation controls. Identifying mutations that drive cancer, understanding cancer type specificities, and delineating how driver mutations interact with each other to establish disease is vital for identifying therapeutic vulnerabilities. Such cancer specific patterns and gene co-occurrences can be identified by studying tumor genome sequences, and networks have proven effective in uncovering relationships between sequences. We present two network-based approaches to identify driver gene patterns among tumor samples. The first approach relies on analysis using the Directed Weighted All Nearest Neighbors (DiWANN) model, which is a variant of sequence similarity network, and the second approach uses bipartite network analysis. A data reduction framework was implemented to extract the minimal relevant information for the sequence similarity network analysis, where a transformed reference sequence is generated for constructing the driver gene network. This data reduction process combined with the efficiency of the DiWANN network model, greatly lowered the computational cost (in terms of execution time and memory usage) of generating the networks enabling us to work at a much larger scale than previously possible. The DiWANN network helped us identify cancer types in which samples were more closely connected to each other suggesting they are less heterogeneous and potentially susceptible to a common drug. The bipartite network analysis provided insight into gene associations and co-occurrences. We identified genes that were broadly mutated in multiple cancer types and mutations exclusive to only a few. Additionally, weighted one-mode gene projections of the bipartite networks revealed a pattern of occurrence of driver genes in different cancers. Our study demonstrates that network-based approaches can be an effective tool in cancer genomics. The analysis identifies co-occurring and exclusive driver genes and mutations for specific cancer types, providing a better understanding of the driver genes that lead to tumor initiation and evolution.

PreDBP-PLMs: Prediction of DNA-binding proteins based on pre-trained protein language models and convolutional neural networks

The recognition of DNA-binding proteins (DBPs) is the crucial step to understanding their roles in various biological processes such as genetic regulation, gene expression, cell cycle control, DNA repair, and replication within cells. However, conventional experimental methods for identifying DBPs are usually time-consuming and expensive. Therefore, there is an urgent need to develop rapid and efficient computational methods for the prediction of DBPs. In this study, we proposed a novel predictor named PreDBP-PLMs to further improve the identification accuracy of DBPs by fusing the pre-trained protein language model (PLM) ProtT5 embedding with evolutionary features as input to the classic convolutional neural network (CNN) model. Firstly, the ProtT5 embedding was combined with different evolutionary features derived from the position-specific scoring matrix (PSSM) to represent protein sequences. Then, the optimal feature combination was selected and input to the CNN classifier for the prediction of DBPs. Finally, the 5-fold cross-validation (CV), the leave-one-out CV (LOOCV), and the independent set test were adopted to examine the performance of PreDBP-PLMs on the benchmark datasets. Compared to the existing state-of-the-art predictors, PreDBP-PLMs exhibits an accuracy improvement of 0.5 % and 5.2 % on the PDB186 and PDB2272 datasets, respectively. It demonstrated that the proposed method could serve as a useful tool for the recognition of DBPs.

P-165 Benefits of ultra-low oxygen tension (2%) in patients with low quality embryos or previous arrest: the patient as its own control

Abstract Study question Is reduction in oxygen tension from 5% to 2% after D3 of extended culture beneficial for blastocyst development in patients with previous failed culture? Summary answer Ultra-low oxygen tension in extended culture improves blastocyst development (overall blastulation rate OBR), quality (top blastulation rate TPR) and increases the pregnancy rate (PR). What is known already The practice ESHRE guidelines recommends human embryo culture at low oxygen concentrations (2-8%). Traditionally atmospheric conditions (20% O2) were used but better outcomes were observed at low monophasic 5% O2. Human embryo leaves the oviduct (5-7% O2) to cross the uterus-tubal junction around D3-4 and reaches the uterin ultra-low O2 tension (2%). This decreasing gradient coincides with the shift from pre-compaction oxidative phosphorylation in the oviduct, to post-compaction glycolysis in the uterus. Few studies with ultra-low 2% O2 incubation suggested that the best O2 level may be stage-dependent and its reduction after D3 may be a more physiological approach. Study design, size, duration Prospective observational study in a single private hospital during 2023. 71 patients experienced a failed cycle of extended culture (n = 29 cIVF, n = 37 ICSI and n = 5 Sibling oocytes) with a poor embryo quality and low OBR, under standard monophasic 5% O2 incubation. In the subsequent cycle for these 71 patients (n = 24 cIVF and n = 46 ICSI and n = 1 Sibling oocytes) the O2 level was reduced to 2% from D3 onwards. Participants/materials, setting, methods After a failed extended culture, considered as the control cycle, the patients were enrolled for the study. Blastocysts were rated by Gardner’s classification. In the control cycle embryos were cultured under monophasic 5% O2 until D6. In the subsequent cycle embryos were cultured under 5% O2 until D3 and in ultra-low 2% O2 from D3 to D6. Sage 1-Step™ media was used for both cycles. The statistical analyses were done by chi-square and fisher test. Main results and the role of chance 71 patients were included in the study regardless of age, indication or technique. Each patient was its own control. The mean age was not different between the 2 groups (36.5±4 vs 37.2±4) but the attempt rank was logically statistically higher in the study cycle (2.1±1.4 vs 3.4±1, p<0.001). Oocyte maturity (75% vs 76.4%) and fertilization rate (66.8 vs 70.3%) were similar between groups. The average embryo quality at D3 was poor in both groups. OBR and TBR (40.7% vs 52.4%, p=0.004 and 15.8% vs 37.5%, p<0.001) were statistically higher after culture in ultra-low O2 conditions. Extended culture failure with absence of usable blastocyst (57.7% vs 19.7%, p<0.001) was statistically lower in ultra-low incubation group and the pregnancy rate PR per cycle (3.6% vs 25%, p=0.004) was seven fold higher after ultra-low culture. Limitations, reasons for caution The small size of the sample needs to be expanded in order to confirm the encouraging findings in a larger population. The study will continue during 2024 and will compel the live birth rate and the cumulative live birth rate. Wider implications of the findings Providing embryos with the most physiologic culture system would improve IVF cost-effectiveness and a better infertility management. Embryo energetic adaptation to suboptimal conditions results in impaired viability and lower pregnancy rates. In our study extended culture of low-quality embryos under 2% O2 after D3 yielded better culture and pregnancy outcomes. Trial registration number NA

Co-administration of GnRH-agonist and hCG (double trigger) for final oocyte maturation increases the number of top-quality embryos in patients undergoing IVF/ICSI cycles

BackgroundThe utilization of a double trigger, involving the co-administration of gonadotropin-releasing hormone agonist (GnRH-a) and human chorionic gonadotropin (hCG) for final oocyte maturation, is emerging as a novel approach in gonadotropin-releasing hormone antagonist (GnRH-ant) protocols during controlled ovarian hyperstimulation (COH). This protocol involves administering GnRH-a and hCG 40 and 34 h prior to ovum pick-up (OPU), respectively. This treatment modality has been implemented in patients with low/poor oocytes yield. This study aimed to determine whether the double trigger could improve the number of top-quality embryos (TQEs) in patients with fewer than three TQEs.MethodsThe stimulation characteristics of 35 in vitro fertilization (IVF) cycles were analyzed. These cycles were triggered by the combination of hCG and GnRHa (double trigger cycles) and compared to the same patients’ previous IVF attempt, which utilized the hCG trigger (hCG trigger control cycles). The analysis involved cases who were admitted to our reproductive center between January 2018 and December 2022. In the hCG trigger control cycles, all 35 patients had fewer than three TQEs.ResultsPatients who received the double trigger cycles yielded a significantly higher number of 2PN cleavage embryos (3.54 ± 3.37 vs. 2.11 ± 2.15, P = 0.025), TQEs ( 2.23 ± 2.05 vs. 0.89 ± 0.99, P < 0.001), and a simultaneously higher proportion of the number of cleavage stage embryos (53.87% ± 31.38% vs. 39.80% ± 29.60%, P = 0.043), 2PN cleavage stage embryos (43.89% ± 33.01% vs. 27.22% ± 27.13%, P = 0.014), and TQEs (27.05% ± 26.26% vs. 14.19% ± 19.76%, P = 0.019) to the number of oocytes retrieved compared with the hCG trigger control cycles, respectively. The double trigger cycles achieved higher rates of cumulative clinical pregnancy (20.00% vs. 2.86%, P = 0.031), cumulative persistent pregnancy (14.29% vs. 0%, P < 0.001), and cumulative live birth (14.29% vs. 0%, P < 0.001) per stimulation cycle compared with the hCG trigger control cycles.ConclusionCo-administration of GnRH-agonist and hCG for final oocyte maturation, 40 and 34 h prior to OPU, respectively (double trigger) may be suggested as a valuable new regimen for treating patients with low TQE yield in previous hCG trigger IVF/intracytoplasmic sperm injection (ICSI) cycles.

In mares resistant to endometrial infection, periovulatory treatment with ecbolic drugs does not influence uterine clearance or luteal development

We aimed to determine associations between experimentally impaired uterine clearance or treatment with ecbolic drugs on luteal development in estrous mares after insemination. In a crossover design, eight mares were treated with saline (CON), clenbuterol (CLEN), oxytocin (OXY) and carbetocin (CARB) from the day of first insemination until 2 days after ovulation. Between treatments, the mares rested for one cycle. Estrous mares were examined for the presence of free intrauterine fluid by transrectal ultrasound. Endometrial swabs for cytology and bacteriology were collected on days 1 and 14. Blood samples were collected daily before AI until day 14 after ovulation for determination of progesterone and PGF2α metabolites (PGFM). Differences between treatments were compared by a general linear model for repeated measures (SPSS 29). One mare was excluded because of a uterine infection in the control cycle. In all other mares, only minor amounts of free intrauterine fluid were present after insemination and decreased over time (P<0.05) with no treatment x time interaction. There was no effect of treatment on polymorphonucleated cells (PMN) in endometrial cytology after ovulation or PGFM secretion. Progesterone release from day 1–14 as well as pregnancy rate and conceptus size on day 14 was not influenced by treatment. In conclusion, treatment with clenbuterol does not impair uterine clearance in estrous mares resistant to endometritis. Repeated injection of the oxytocin analogue carbetocin during the early postovulatory period is not detrimental to corpus luteum function and can be recommended to enhance uterine clearance.

Recent advances in sleep cycle regulation and hormonal imbalance: a comprehensive review

A vital physiological function, sleep is necessary for general health and wellbeing. It is essential for several body processes, including as metabolism, immunological response, emotional control, and cognitive function. A complicated mechanism involving intricate connections between brain circuits, neurotransmitters, and hormone cues governs the sleep-wake cycle. Scientific research has recently made significant progress in understanding the mechanisms behind the control of the sleep cycle and how it relates to hormone imbalance. The goal of this thorough review is to examine the most recent research in this area, with a particular emphasis on the interaction between hormone variations and sleep regulation.

Fracture Pre-propping and Temporary Plugging for Formation Damage Control in Deep Naturally Fractured Tight Reservoirs

Summary To address the challenges of formation damage related to drill-in fluid loss into deep reservoir fractures during the drill-in process, we propose pre-propping and temporary plugging (PPTP) technology as an integrated solution in this paper. The PPTP approach combines high-strength bridging (HSB) materials with self-degrading filling (SDF) materials for efficient fracture plugging during lost circulation and effective fracture propping during oil and gas production from deep naturally fractured reservoirs. HSB material with good mechanical properties and SDF material with a controllable degradation cycle are developed and systematically evaluated. Fracture plugging tests and stress sensitivity experiments are conducted to evaluate the transformation effect of fracture plugging zones on fracture propping zones. Research results show that the developed HSB material exhibits a high compressive capacity and friction coefficient, which maintains a crushing rate below 3% under 60 MPa pressure and an average friction coefficient of 1.56. The degradation ratio of SDF material increases with temperature and pH value. The degradation cycle can reach up to 168 hours under the conditions of 120°C and pH = 13, which ensures continuous stable fracture plugging and lost-circulation control during the drill-in process. The PPTP technology, combining HSB and SDF components, efficiently plugs fractures with widths ranging from 1.0 mm to 3.0 mm, with a maximum plugging pressure of up to 10.16 MPa. HSB material props the fractures after SDF degrades, preventing fracture closure and converting the fracture plugging zone into a propping zone. The stress sensitivity damage of reservoir fractures can be effectively mitigated, preserving and enhancing fracture conductivity. Thus, the PPTP technology shows great potential for the integration solution of drill-in fluid loss and formation damage in deep naturally fractured reservoirs.

Microarray Analysis of Tumor Suppressor Proteins p53 and p63: Their Role in Tumor Cell Dynamics

Background: Microarray technology has become essential in cancer research, providing insights into gene expression patterns and regulatory networks governed by key transcription factors. This review focuses on using microarray technology to elucidate genes regulated by tumor suppressor proteins p53 and p63. These proteins maintain genomic stability, regulate the cell cycle, and induce programmed cell death. Dysregulation of p53 and p63 is common in various cancers, highlighting their significance in cancer biology. Methods: Microarray technology enables high-throughput analysis of thousands of genes simultaneously. Researchers compare gene expression profiles in cancer cells and tissues with functional p53 and p63 against those with impaired function. This comparative analysis identifies numerous downstream target genes and pathways influenced by these transcription factors. Results: Microarray studies have revealed a wide array of genes regulated by p53 and p63, involved in DNA repair, apoptosis, cell cycle control, and epithelial differentiation. These findings enhance our understanding of molecular mechanisms driving cancer initiation, progression, and therapeutic resistance. Additionally, microarray technology enables the stratification of cancer subtypes based on distinct gene expression signatures associated with p53 and p63 status, offering insights into patient prognosis, treatment responses, and personalized therapeutic strategies. Conclusion: Microarray technology has significantly advanced our knowledge of gene regulatory networks orchestrated by p53 and p63 in cancer. Despite limitations like data interpretation and cross-hybridization, advancements in bioinformatics and complementary technologies are improving study accuracy and reliability, promising better cancer diagnostics, prognostics, and targeted therapies.

Integrating network pharmacology and computational biology to propose Yiqi Sanjie formula's mechanisms in treating NSCLC: molecular docking, ADMET, and molecular dynamics simulation.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths globally. Current treatments often do not fully meet efficacy and quality of life expectations. Traditional Chinese medicine (TCM), particularly the Yiqi Sanjie formula, shows promise but lacks clear mechanistic understanding. This study addresses this gap by investigating the therapeutic effects and underlying mechanisms of Yiqi Sanjie formula in NSCLC. We utilized network pharmacology to identify potential NSCLC drug targets of the Yiqi Sanjie formula via the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Compounds with favorable oral bioavailability and drug-likeness scores were selected. Molecular docking was conducted using AutoDock Vina with structural data from the Protein Data Bank and PubChem. Molecular dynamics (MD) simulations were performed with Desmond Molecular Dynamics System, analyzing interactions up to 500 nanoseconds using the OPLS4 force field. ADMET predictions were executed using SwissADME and ADMETlab 2.0, assessing pharmacokinetic properties. Using network pharmacology tools, we performed Search Tool for the Retrieval of Interaction Genes/Proteins (STRING) analysis for protein-protein interaction, Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathway enrichment, and gene ontology (GO) for functional enrichment, identifying crucial signaling pathways and biological processes influenced by the hit compounds bifendate, xambioona, and hederagenin. STRING analysis indicated substantial connectivity among the targets, suggesting significant interactions within the cell cycle regulation and growth factor signaling pathways as outlined in our KEGG results. The GO analysis highlighted their involvement in critical biological processes such as cell cycle control, apoptosis, and drug response. Molecular docking simulations quantified the binding efficiencies of the identified compounds with their targets-CCND1, CDK4, and EGFR-selected based on high docking scores that suggest strong potential interactions crucial for NSCLC inhibition. Subsequent MD simulations validated the stability of these complexes, supporting their potential as therapeutic interventions. Additionally, the novel identification of ADH1B as a target underscores its prospective significance in NSCLC therapy, further expanded by our comprehensive bioinformatics approach. Our research demonstrates the potential of integrating network pharmacology and computational biology to elucidate the mechanisms of the Yiqi Sanjie formula in NSCLC treatment. The identified compounds could lead to novel targeted therapies, especially for patients with overexpressed targets. The discovery of ADH1B as a therapeutic target adds a new dimension to NSCLC treatment strategies. Further studies, both in vitro and in vivo, are needed to confirm these computational findings and advance these compounds towards clinical trials.

Stabilization of GTSE1 by cyclin D1-CDK4/6 promotes cell proliferation: relevance in cancer prognosis.

Cyclin D1 is the activating subunit of the cell cycle kinases CDK4 and CDK6, and its dysregulation is a well-known oncogenic driver in many human cancers. The biological function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G2 and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unknown substrate of cyclin D1-CDK4/6. The phosphorylation of GTSE1 mediated by cyclin D1-CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 also during the G1 phase of the cell cycle. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1's role in cell cycle control and oncogenesis beyond RB phosphorylation.

Characterizing the tumor suppressor activity of FLCN in Birt-Hogg-Dubé syndrome through transcriptiomic and proteomic analysis.

Birt-Hogg-Dubé (BHD) syndrome patients are uniquely susceptible to all renal tumour subtypes. The underlying mechanism of carcinogenesis is unclear. To study cancer development in BHD, we used human proximal kidney (HK2) cells and found that long-term folliculin (FLCN) knockdown was required to increase their tumorigenic potential, forming larger spheroids in non-adherent conditions. Transcriptomic and proteomic analysis uncovered links between FLCN, cell cycle control and the DNA damage response (DDR) machinery. HK2 cells lacking FLCN had an altered transcriptome profile with cell cycle control gene enrichment. G1/S cell cycle checkpoint signaling was compromised with heightened protein levels of cyclin D1 (CCND1) and hyperphosphorylation of retinoblastoma 1 (RB1). A FLCN interactome screen uncovered FLCN binding to DNA-dependent protein kinase (DNA-PK). This novel interaction was reversed in an irradiation-responsive manner. Knockdown of FLCN in HK2 cells caused a marked elevation of γH2AX and RB1 phosphorylation. Both CCND1 and RB1 phosphorylation remained raised during DNA damage, showing an association with defective cell cycle control with FLCN knockdown. Furthermore, Flcn-knockdown C. elegans were defective in cell cycle arrest by DNA damage. This work implicates that long-term FLCN loss and associated cell cycle defects in BHD patients could contribute to their increased risk of cancer.

Deciphering COPS5 influence on immune infiltration and prognosis in head and neck squamous cell carcinoma

Head and Neck Squamous Cell Carcinoma (HNSCC) is a widespread malignancy originating from the mucous epithelium of the oral cavity, pharynx, and larynx. Despite advances in diagnostic and therapeutic modalities, the prognosis of HNSCC remains challenging. This study investigates the intricate relationship among COPS5, immune infiltration patterns, and prognostic implications in HNSCC. Through comprehensive analyses of 519 HNSCC cases from TCGA and single-cell data from the GEO database, we utilize the CIBERSORT algorithm to discern immune cell dynamics influenced by COPS5 expression. Notably, Treg cells emerge as a central point in the interplay between COPS5 and immune modulation. Further analyses, encompassing differential gene expression, immune-related gene set enrichment, and protein-protein interaction networks, elucidate the molecular landscape associated with COPS5 in HNSCC. A prognostic risk model, incorporating CD27, TNFRSF4, FADD, and PSMD14, is formulated and validated across diverse datasets. The model demonstrates robust predictive power, underscoring its potential as a valuable prognostic tool. These genes, essential for immune regulation and cell cycle control, provide insights into the intricate mechanisms influencing HNSCC progression. In conclusion, this study not only reveals the impact of COPS5 on immune dynamics in HNSCC but also introduces a concise and effective prognostic model.

Targeting lipid peroxidation-associated ferroptosis suppresses lung carcinoma progression by regulating cell cycle arrest

Lung carcinoma is a frequently encountered cancerous growth that affects the respiratory tract and has a high occurrence rate globally. In light of the ongoing worldwide health emergency, the significance of efficient therapeutic agents and strategies is of utmost importance. A meticulous control of the cell cycle is crucial for comprehending the pathophysiology and molecular causes of lung cancer, as well as for the formulation of efficacious therapeutic medicines. The mechanism by which cells synchronize cell cycle with cell survival and death is still not fully understood. In this study, we demonstrate that the halting of the cell cycle has a strong inhibitory impact on ferroptosis, a specific type of controlled cell death triggered by excessive lipid peroxidation at the membranes of cells. Ferroptosis is halted through the mechanism of cell cycle arrest, which involves the deposition of intracellular lipids mediated by diacylglycerol acyltransferase (DGAT). Excessive amounts of polyunsaturated fatty acids (PUFAs) are stored as triacylglycerols (TAGs) within inactive cells. As a result, inhibiting DGAT causes a rearrangement of PUFAs from TAGs to phospholipids and makes arrested cells more susceptible to ferroptosis. We demonstrate that certain lung cancer cells that are resistant to antimitotic drugs and have a slow-cycling behavior exhibit an increase in lipid droplets. Furthermore, we find that the growth of tumors resistant to 5-fluorouracil, lorlatinib, and docetaxel can be effectively suppressed by a combination treatment involving the use of ferroptosis inducers and DGAT inhibitors, which induces ferroptosis. Collectively, these findings demonstrate the involvement of cell cycle arrest in conferring resistance to ferroptosis and propose a potential therapeutic approach for addressing the challenge of slow-cycling malignancies that exhibit resistance to ferroptosis.

Finite‐time control of DC–AC boost converter: The limit cycle approach

AbstractThis paper proposes a novel finite‐time limit cycle controller for DC to AC conversion in power boost converters. The stable limit cycle is categorized as a positive limit set. Achieving the control law, based on the concepts of set stability and finite‐time stability, is a challenging problem. To fulfill the control objective, a novel sliding manifold is suggested concerning the structure of the wanted limit cycle which facilitates conditions for the development of finite‐time stability for the limit cycle. By utilizing the sliding mode control method, a control strategy is proposed that guarantees the desired stable limit cycle is created in the phase plane of the closed‐loop system and the phase trajectories reach it in a finite time and remain on it for all future times. This ensures the finite‐time generation of the biased sinusoidal oscillations in the output of the power boost converter from a DC input source. The simulation results of a practical boost converter have validated the effectiveness and feasibility of the presented algorithm.

Transcriptional immune suppression and up-regulation of double-stranded DNA damage and repair repertoires in ecDNA-containing tumors.

Extrachromosomal DNA is a common cause of oncogene amplification in cancer. The non-chromosomal inheritance of ecDNA enables tumors to rapidly evolve, contributing to treatment resistance and poor outcome for patients. The transcriptional context in which ecDNAs arise and progress, including chromosomally-driven transcription, is incompletely understood. We examined gene expression patterns of 870 tumors of varied histological types, to identify transcriptional correlates of ecDNA. Here, we show that ecDNA-containing tumors impact four major biological processes. Specifically, ecDNA-containing tumors up-regulate DNA damage and repair, cell cycle control, and mitotic processes, but down-regulate global immune regulation pathways. Taken together, these results suggest profound alterations in gene regulation in ecDNA-containing tumors, shedding light on molecular processes that give rise to their development and progression.