Factor Activity Research Articles

Expression of Concern for Correlation between Sun Protection Factor and Antioxidant Activity, Phenol and Flavonoid Contents of Some Medicinal Plants [Iran J Pharm Res. 2014;13(3): e125511

Expression of Concern for Correlation between Sun Protection Factor and Antioxidant Activity, Phenol and Flavonoid Contents of Some Medicinal Plants [Iran J Pharm Res. 2014;13(3): e125511

The effects of laparoscopic sleeve gastrectomy on serum levels of growth hormone and insulin-like growth factor 1

Background. It is unclear exactly how bariatric surgery affects the body’s metabolic and physiological functions. The purpose of the study was to assess the activity of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels in obese individuals before and six months after laparoscopic sleeve gastrectomy. Materials and methods. This study included 52 patients with a body mass index (BMI) ranging from 35 to 56 kg/m2 who qualified for laparoscopic sleeve gastrectomy and had completed data at the 6-month postoperative follow-up. All patients were clinically examined by a team of surgeons and a physician before operation. The serum levels of GH and IGF-1 were assessed pre- and post-operatively. Results. The study included 52 patients with obesity who were undergoing laparoscopic gastric sleeve surgery. Their mean age was 32.04 ± 6.90 years. More than half of the patients, 27 (51.9 %), were aged 19 to 32 years, 32 (61.5 %) patients were females, and 38 (73.1 %) had a BMI of 35–49.9 kg/m2. There was a significant increase in the serum GH after the sleeve gastrectomy compared to the pre-operative level (0.95 ± 0.30 vs 0.62 ± 0.40 ng/ml, p = 0.0001). IGF-1 also significantly increased after the surgery: 117.13 ± 32.40 vs 102.63 ± 33.90 ng/ml (p = 0.0001). Concerning BMI, there was no significant difference in the GH mean for patients with a BMI of 35–49.9 and 50–56 kg/m2 pre- and post-operatively: 0.6 vs 0.8 (p = 0.07) and 0.9 vs 1 (p = 0.5), respectively. On the other hand, IGF-1 exhibited a significant difference before and after surgery: 107.7 vs 88.9 ng/ml (p = 0.02) and 123.2 vs 100.7 (p = 0.03). Conclusions. This study concludes that sleeve gastrectomy significantly increases the serum level of both GH and IGF-1 and, consequently, their effects on disturbed lipid and protein metabolism in morbidly obese patients.

MiRNAs in the diagnosis and therapy of cardiac and mediastinal tumors: a new dawn for cardio-oncology?

Dysfunctions in miRNA production have been recently investigated as predictors of neoplasms and their therapeutic strategies. In this review, we summarize the available knowledge on miRNAs and cardiac tumors (such as myxoma) and mediastinal tumors (such as thymoma) and propose new avenues for future research. MiRNAs are crucial for cardiac development through the expression of cardiac transcription factors (miR-335-5p), hinder the cell cycle by modulating the activity of transcription factors (miR-126-3p, miR-320a), modulate the production of inflammatory factors such as interleukins (miR-217), and interfere with cell proliferation or apoptosis (miR-218, miR-634 and miR-122). Current and future research on miRNAs is essential, as a deep understanding could lead to a revolution in the field of diagnostics and prevention of neoplastic diseases.

PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia

The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

A small molecule that reshapes the chromatin dynamics of FOXA1

In this issue, Won etal.1 report a covalent ligand binding the pioneer transcription factor FOXA1, altering its function and remodeling chromatin. This important finding highlights the potential of small molecules to modulate transcription factor activity and demonstrates the promise of chemical proteomics in discovering first-in-class ligands.

Palmitic Acid Induced a Dedifferentiation Profile at the Transcriptome Level: A Collagen Synthesis but no Triglyceride Accumulation in Hepatocyte-Like Cells Derived From Human-Induced Pluripotent Stem Cells Cultivated Inside Organ on a Chip.

Nonalcoholic fatty liver disease (NAFLD) is one of the main causes of critical liver diseases leading to steatosis, steatohepatitis, fibrosis, and ultimately to liver cirrhosis and hepatic carcinoma. In this study, the effect of palmitic acid (PA), one of the most abundant dietary fatty acids, was investigated using an organ-on-a-chip (OoC) technology on hepatocyte-like cells derived from human-induced pluripotent stem cells (hiPSCs). After 1 week of hepatic maturation, followed by 1 week of exposure, the transcriptomic analysis showed lower liver transcription factor activity. It also revealed that 318 genes were differentially expressed between the control and 0.5-mM PA conditions. The 0.5-mM PA conditions were characterized by the downregulation of hepatic markers (liver transcription factors, phase I and phase II metabolism genes) of lipidic genes (metabolism and transport). In parallel, the 0.5-mM PA treatment upregulated several extracellular matrix genes (such as collagen genes). The physiopathological staining demonstrated no lipid accumulation in our model and confirmed the secretion of collagen in the 0.5-mM PA conditions. However, the production of albumin, the metabolic biotransformation by the cytochrome P450 enzymes, and the biliary acid concentrations were not altered by the PA treatments. Overall, our data illustrated the response to PA characterized by an early stage of dedifferentiation observed at the transcriptomic levels associated with a modification of the collagenic profile but without lipid accumulation. We believe that our model provides new insight of the onset of palmitic lipotoxicity in the early stage of NAFLD.

Venous Thromboembolism in Pancreatic Cancer: Unraveling the Paradox of Mortality and Hospitalization Outcomes

Background: Pancreatic cancer is known for its aggressive nature and poor prognosis, with a five-year survival rate of less than 10%. Patients diagnosed with pancreatic cancer face a myriad of complications, one of the most significant being venous thromboembolism (VTE). VTE primarily includes deep venous thrombosis (DVT) and pulmonary embolism (PE), and it represents a major cause of morbidity and mortality in this patient population. The increased risk of VTE in pancreatic cancer patients is attributed to multiple factors. Malignancy itself is a well-recognized hypercoagulable state, largely due to the secretion of pro-coagulant factors by tumor cells. Additionally, pancreatic cancer can induce a systemic inflammatory response, leading to widespread activation of pro-coagulant factors and platelets. This hypercoagulable state is further exacerbated by factors such as immobilization, surgery, chemotherapy, and the presence of central venous catheters, which are common in these patients. Several studies have highlighted the prevalence of VTE in pancreatic cancer patients, suggesting that up to 20-30% of these patients may develop VTE at some point during their disease course. The management of VTE in pancreatic cancer patients is complex, as it requires a balance between preventing thrombosis and minimizing the risk of bleeding, particularly in the context of anticoagulant therapy. Methods: We analyzed real-world evidence from the 2021 Nationwide Inpatient Sample database the Agency of Healthcare Research and Quality (AHRQ). The study included all hospitalized pancreatic cancer patients with both a primary diagnosis of venous thromboembolism. We conducted a comparative analysis of demographic characteristics and clinical outcomes between a cohort of pancreatic cancer patients with VTE as a primary diagnosis and those without VTE. Results: In 2021, there were 76,315 patients with a discharge diagnosis of pancreatic cancer. 2,580 patients (3.38%) had a relevant diagnosis of VTE or PE at the time of hospitalization. The mean age for patients in both the VTE and non-VTE groups was 68 years. 51.1 percent of patients in the VTE group were female compared to 46.5 percent of patients in the non-VTE group (p<0.0001). The mortality rate was 8.62% in the non-VTE group, compared to 6.78% in the VTE group (p<0.0001). Furthermore, patients with pancreatic cancer who developed venous thromboembolism (VTE) were found to have no significant difference in mortality compared to those without VTE during the index hospitalization (p<0.179) after adjusting for sex, race, and age. The odds ratio for length of stay in the VTE group was 1.57 (95% CI: 0.75-3.32, p = 0.230). This suggests that there is no statistically significant difference in hospital stay duration between patients with pancreatic cancer who develop VTE and those who do not. The mean total hospitalization charges for the VTE group was $59,556 and $74,249 for the non-VTE group. Discussion: The presence of VTE in hospitalized pancreatic cancer patients is a critical factor that influences clinical management but does not necessarily worsen the short-term prognosis or increase hospitalization duration. Differences in clinical management between the two groups could also contribute to our findings. Patients who develop VTE may receive more intensive monitoring and treatment, potentially improving their overall outcomes. Conversely, variations in the use of prophylactic anticoagulation and differences in the aggressiveness of VTE treatment could impact mortality and length of stay, independent of the presence of VTE. The non-significant difference in length of stay between the VTE and non-VTE groups may reflect hospital practices and discharge criteria rather than patient outcomes. Hospitals with varying policies on discharge timing and criteria can influence length of stay without directly correlating with mortality. Furthermore, differences in post-hospitalization care and follow-up may play a role, as patients discharged sooner might receive better outpatient care, which is not captured in the dataset. Further research should aim to include a sensitivity analysis and more covariates related to disease severity, co-morbidities, and treatment specifics. This can improve the adjustment for confounding factors and provide a more comprehensive understanding of the factors influencing mortality and length of stay.

BPDCN MYB fusions regulate cell cycle genes, impair differentiation and induce myeloid-dendritic cell leukemia.

MYB fusions are recurrently found in select cancers, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), an acute leukemia with poor prognosis. They are markedly enriched in BPDCN compared to other blood cancers, and in some patients are the only obvious somatic mutation detected. This suggests they may alone be sufficient to drive dendritic cell transformation. MYB fusions are hypothesized to alter the normal transcription factor activity of MYB, but mechanistically how they promote leukemogenesis is poorly understood. Using CUT&RUN chromatin profiling, we found that in BPDCN leukemogenesis, MYB switches from being a regulator of dendritic cell lineage genes to aberrantly regulating G2/M cell cycle control genes. MYB fusions found in BPDCN patients increased the magnitude of DNA binding at these locations, and this was linked to BPDCN-associated gene expression changes. Furthermore, expression of MYB fusions in vivo impaired dendritic cell differentiation and induced transformation to generate a mouse model of myeloid-dendritic acute leukemia. Therapeutically, we present evidence that all-trans retinoic acid (ATRA) may cause loss of MYB protein and cell death in BPDCN.

PARP1 condensates differentially partition DNA repair proteins and enhance DNA ligation

Poly(ADP-ribose) polymerase 1 (PARP1) is one of the first responders to DNA damage and plays crucial roles in recruiting DNA repair proteins through its activity – poly(ADP-ribosyl)ation (PARylation). The enrichment of DNA repair proteins at sites of DNA damage has been described as the formation of a biomolecular condensate. However, it remains unclear how exactly PARP1 and PARylation contribute to the formation and organization of DNA repair condensates. Using recombinant human single-strand repair proteins in vitro, we find that PARP1 readily forms viscous biomolecular condensates in a DNA-dependent manner and that this depends on its three zinc finger (ZnF) domains. PARylation enhances PARP1 condensation in a PAR chain length-dependent manner and increases the internal dynamics of PARP1 condensates. DNA and single-strand break repair proteins XRCC1, LigIII, Polβ, and FUS partition in PARP1 condensates, although in different patterns. While Polβ and FUS are both homogeneously mixed within PARP1 condensates, FUS enrichment is greatly enhanced upon PARylation whereas Polβ partitioning is not. XRCC1 and LigIII display an inhomogeneous organization within PARP1 condensates; their enrichment in these multiphase condensates is enhanced by PARylation. Functionally, PARP1 condensates concentrate short DNA fragments, which correlates with PARP1 clusters compacting long DNA and bridging DNA ends. Furthermore, the presence of PARP1 condensates significantly promotes DNA ligation upon PARylation. These findings provide insight into how PARP1 condensation and PARylation regulate the assembly and biochemical activities of DNA repair factors, which may inform on how PARPs function in DNA repair foci and other PAR-driven condensates in cells.

Screening Activity of Brain Cancer-Derived Factors on Primary Human Brain Pericytes

Background/Objectives: Brain cancers offer poor prognoses to patients accompanied by symptoms that drastically impact the patient and their family. Brain tumours recruit local non-transformed cells to provide trophic support and immunosuppression within the tumour microenvironment, supporting tumour progression. Given the localisation and supportive role of pericytes at the brain vasculature, we explored the potential for brain pericytes to contribute to the brain cancer microenvironment. Methods: To investigate this, primary brain pericytes were treated with factors commonly upregulated in brain cancers. Immunofluorescent labelling identified changes to brain pericyte cell signalling, cytometric bead array measured inflammatory secretion, and flow cytometry investigated brain pericyte phagocytosis. Results: The TGFβ superfamily cytokines TGFβ and GDF-15 activated SMAD2/3 and inhibited C/EBP-δ, revealing a potential mechanism behind the pleiotropic action of TGFβ on brain pericytes. IL-17 induced secretion of IL-6 without activating NFκB, STAT1, SMAD2/3, or C/EBP-δ signalling pathways. IL-27 and IFNγ induced STAT1 signalling and significantly reduced brain pericyte phagocytosis. The remaining brain cancer-derived factors did not induce a measured response, indicating that these factors may act on other cell types or require co-stimulation with other factors to produce significant effects. Conclusions: We identify several brain cancer-secreted factors which alter relevant brain pericyte functions. This reveals mechanisms through which brain tumours may regulate brain pericyte activity and these data start to uncover the supportive role these cells may play in brain cancers.

Analisis Penambahan Jumlah Tenaga Kerja dalam Meningkatkan Pendapatan pada Mie Ayam Baso H. Lili Karawang

Revenue is the revenue earned through the results of economic activities related to the sales activities of production factors owned by the company. As known in the theory of production factors, the quantity of output associated with income directly depends on the amount of labor owned. In increasing production supported by efficient resources and running according to the system, appropriate income can be obtained from the level of production. Theoretically, a positive contribution of labor to the increase of business income can occur, especially by involving a large number of workers. This study was conducted to analyze the additional number of workers in increasing revenue at Baso H. Lili Chicken Noodle in Karawang. The type used in this research is descriptive quantitative. The results of this study indicate that Mie Ayam Baso H. Lili Karawang has experienced an increase in labor since the beginning of the business until now, initially only having 3 workers per branch as of 2005, but currently in 2023 it has approximately 7 to 15 workers in each branch. After the additional workforce, H. Lili Karawang's Baso Chicken Noodle business experienced an increase in income generated with an average of IDR Rp 588.858.818 or the same as around 408%.

The Influence of Atorvastatin Treatment on Homocysteine Metabolism and Oxidative Stress in an Experimental Model of Diabetic Rats.

In our experimental study, we evaluated the influence of treatment with atorvastatin on the antioxidant activity of intracellular and extracellular systems factors, homocysteine levels (Hcy), and lipid profiles in obese and diabetic rats. Twenty-one male Wistar rats, aged 6 months, 450-550 g, were allocated into three groups. From the beginning of the study, the first group (G-I, control) received only standard food, while the second and third groups (G II-obese, G III-diabetic) were administered a high-fat diet (HFD) with 2% cholesterol. After 2 weeks of accommodation, the specimens in G-III were injected intraperitoneal (i.p.) streptozotocin (35 mg of body weight, pH 4.5), intervention followed by the onset of type 2 diabetes mellitus. Following confirmation of diabetes onset, the specimens in G III were administered concomitantly with the HFD a daily gavage of atorvastatin 20 mg of body weight/day for 20 days. We measured, at the beginning and the end of the study, the Hcy levels, lipid profile, vitamin B12, B6, folic acid, and various parameters of oxidative stress (OS)-total antioxidant status (TAS), glutathione peroxidase (GPX) and superoxide dismutase (SOD). After treatment with atorvastatin, the lipid profile in G III significantly improved compared to the other two groups, but enzymatic markers of oxidative stress did not closely parallel this trend. However, after the treatment of statin, we observed an important reduction in Hcy values. Our results demonstrate that treatment with atorvastatin can be used not only for its lipid-lowering properties and antioxidant effects but also to reduce Hcy concentration in this experimental model of diabetic rats. Moreover, atorvastatin therapy improves lipid profiles, reduces inflammation, suppresses oxidation, and decreases Hcy levels, potentially preventing major adverse cardiovascular events.

Interdependence of coagulation with immunotherapy and BRAF/MEK inhibitor therapy: results from a prospective study

Immune checkpoint inhibitor (ICI) therapies effectively treat a broadening spectrum of cancer entities but induce various immune-related side effects (irAEs). Recent reports suggest a correlation between ICI-induced systemic inflammation and thromboembolic events as well as an increased effectiveness by coadministration of anticoagulants. With cancer patients having a higher risk of thrombotic events per se, it is crucial to dissect and characterize the mechanisms that cause pro-coagulative effects induced by systemic tumor therapies and their potential interplay with anti-tumor response. A total of 31 patients with advanced skin cancer treated with either ICIs (n = 24) or BRAF/MEK inhibitors (n = 7) were longitudinally assessed for blood and coagulation parameters before as well as 7, 20 and 40 days after initiation of systemic tumor therapy. Changes were analyzed and compared between both groups. In addition, the influence of coagulation parameters on progression-free, recurrence-free and overall survival was investigated. The ICI cohort presented significantly increased factor VIII activity after one week of therapy (p 0.0225); while, protein S activity was reduced during the whole observation period. Additionally, von Willebrand factor activity and tissue factor concentrations increased under immunotherapy. Similar changes occurred under BRAF/MEK inhibitor therapy (BRAF/MEKi). Increased baseline levels of von Willebrand factor antigen and factor VIII:C before the start of ICI therapy correlated with a significantly higher risk of recurrence for patients receiving adjuvant immunotherapy. The findings suggest the induction of a pro-coagulant state under ICI and BRAF/MEKi and a role of coagulation parameters in the efficacy of ICI therapies.

Hemostasis in patients with primary myelofibrosis treated with ruxolitinib

Aim. To evaluate the effect of ruxolitinib therapy on hemostasis in patients with primary myelofibrosis (PMF).Materials and methods. 30 patients with PMF were examined, 16 of them received ruxolitinib (group 1) at the time of examination and 14 were untreated (group 2). The control group consisted of 30 healthy individuals. A complete blood count was performed, the platelets aggregation, the activity of Willebrand factor, factor VIII and natural anticoagulants were evaluated. In the thrombin generation test, the endogenous thrombin potential (ETP, nM×min) was determined; sensitivity to thrombomodulin and coagulation index were calculated. Kruskal-Wallis test with post hoc Dunn test was used to compare groups.Results. Hemoglobin and platelet count were lower in group 1 compared to group 2 and control. Platelet aggregation with collagen was lower in patients with PMF than in the control group, and lower in group 1 than in group 2: 2.2 (1.6; 5.7) % vs 41.6 (3.4; 64.8) %, p < 0.05. In patients in group 1, the activity of Willebrand factor – 150.0 (122.5; 195) % and factor VIII – 173 (148.5; 200) % was higher (p < 0.05) than in the control: 97 (84.8; 110) % and 104 (85; 130) % respectively. Antithrombin did not differ in the PMF and control group. Protein S was reduced in both groups with PMF: group 1 – 70 (58; 86,6) %, group 2 – 65 (43,6; 107,5) %, control – 102 (86; 109,0) %, p < 0.001. ETP and sensitivity to thrombomodulin in groups 1 and 2 were low, p < 0.001. The coagulation index tended to higher values than in the control: 5.3 (3.0; 11.4) – group 1; 3.2 (2.4; 7.3) – group 2; control – 1.9 (1.6; 2.2), p = 0.073.Conclusion. Ruxolitinib therapy leads to the failure of the platelet hemostasis, the procoagulant activity of plasma with an increase in the activity of Willebrand factor and factor VIII and a decrease in the activity of protein S.

Exploring the spatial effects influencing the EGFR/ERK pathway dynamics with machine learning surrogate models

The fate of cells is regulated by biochemical reactions taking place inside of them, known as intracellular pathways. Cells display a variety of characteristics related to their shape, structure and contained fluid, which influences the diffusion of proteins and their interactions. To gain insights into the spatial effects shaping intracellular regulation, we apply machine learning (ML) to explore a previously developed spatial model of the epidermal growth factor receptor (EGFR) signaling. The model describes the reactions between molecular species inside of cells following the transient activation of EGF receptors. To train our ML models, we conduct 10,000 numerical simulations in parallel where we calculate the cumulative activation of molecules and transcription factors under various conditions such as different diffusion speeds, inactivation rates, and cell structures. We take advantage of the low computational cost of ML algorithms to investigate the effects of cell and nucleus sizes, the diffusion speed of proteins, and the inactivation rate of the Ras molecules on the activation strength of transcription factors. Our results suggest that the predictions by both neural networks and random forests yielded minimal mean square error (MSEs), while linear generalized models displayed a significant larger MSE. The exploration of the surrogate models has shown that smaller cell and nucleus radii as well, larger diffusion coefficients, and reduced inactivation rates increase the activation of transcription factors. These results are confirmed by numerical simulations. Our ML algorithms can be readily incorporated within multiscale models of tumor growth to embed the spatial effects regulating intracellular pathways, enabling the use of complex cell models within multiscale models while reducing the computational cost.

Hypertension-induced heart failure disrupts cardiac sympathetic innervation.

About 26 million people worldwide live with heart failure (HF), and hypertension is the primary cause in 25% of these cases. Autonomic dysfunction and sympathetic hyperactivity accompany cardiovascular diseases, including HF. However, changes in cardiac sympathetic innervation in HF are not well understood. We hypothesized that cardiac sympathetic innervation is disrupted in hypertension-induced HF. Male and female C57BL6/J mice were infused with Angiotensin II (AngII) for 4 weeks to generate hypertension leading to HF; controls were infused with saline. AngII-treated mice displayed HF phenotype including reduced cardiac function, hypertrophy, and fibrosis. AngII-treated mice also had significantly reduced sympathetic nerve density in the left ventricle, intraventricular septum, and right ventricle. In the left ventricle, the subepicardium remained normally innervated, while the subendocardium was almost devoid of sympathetic nerves. Loss of sympathetic fibers led to loss of norepinephrine content in the left ventricle. Several potential triggers for axon degeneration were tested and ruled out. AngII-treated mice had increased premature ventricular contractions after isoproterenol and caffeine injection. Although HF can induce a cholinergic phenotype and neuronal hypertrophy in stellate ganglia, AngII treatment did not induce a cholinergic phenotype or activation of trophic factors in this study. Cardiac neurons in the left stellate ganglion were significantly smaller in AngII-treated mice, while neurons in the right stellate were unchanged. Our findings show that AngII-induced HF disrupts sympathetic innervation, particularly in the left ventricle. Further investigations are imperative to unveil the mechanisms of denervation in HF and to develop neuromodulatory therapies for patients with autonomic imbalance.

The cyanobacterial circadian clock couples to pulsatile processes using pulse amplitude modulation.

Cellular processes are dynamic and often oscillatory, requiring precise coordination for optimal cell function.1,2,3,4,5,6,7 How distinct oscillatory processes can couple within a single cell remains an open question. Here, we use the cyanobacterial circadian clock8,9 as a model system to explore the coupling of oscillatory and pulsatile gene circuits. The cyanobacterial circadian clock generates 24-h oscillations in downstream targets10,11,12,13,14,15 to time processes across the day/night cycle.9,16,17,18,19,20,21,22 This timing is partly mediated by the clock's modulation of the activity of alternative sigma factors,14,23,24,25 which direct RNA polymerase to specific promoters.26 Using single-cell time-lapse microscopy and modeling, we find that the clock modulates the amplitude of expression pulses of the alternative sigma factor RpoD4, which occurs only at cell division. This pulse amplitude modulation (PAM), analogous to AM regulation in radio transmission,27 allows the clock to robustly generate a 24-h rhythm in rpoD4 expression despite rpoD4's pulsing frequency being non-circadian. By modulating cell division rates, we find that, as predicted by our model, PAM regulation generates the same 24-h period in rpoD4 pulse amplitude over a range of rpoD4 pulse frequencies. Furthermore, we identify a functional significance of rpoD4 expression levels: deletion of rpoD4 results in smaller cell sizes, whereas an increase in rpoD4 expression leads to larger cell sizes in a dose-dependent manner. Thus, our work reveals a link between the cell cycle, clock, and RpoD4 in cyanobacteria and suggests that PAM regulation can be a general mechanism for biological clocks to robustly modulate pulsatile downstream processes.

Diversity of Transcriptional Regulatory Adaptation in E. coli.

The transcriptional regulatory network (TRN) in bacteria is thought to rapidly evolve in response to selection pressures, modulating transcription factor (TF) activities and interactions. In order to probe the limits and mechanisms surrounding the short-term adaptability of the TRN, we generated, evolved, and characterized knockout (KO) strains in Escherichia coli for 11 regulators selected based on measured growth impact on glucose minimal media. All but one knockout strain (Δlrp) were able to recover growth and did so requiring few convergent mutations. We found that the TF knockout adaptations could be divided into four categories: (i) Strains (ΔargR, ΔbasR, Δlon, ΔzntR, and Δzur) that recovered growth without any regulator-specific adaptations, likely due to minimal activity of the regulator on the growth condition, (ii) Strains (ΔcytR, ΔmlrA, and ΔybaO) that recovered growth without TF-specific mutations but with differential expression of regulators with overlapping regulons to the KO'ed TF, (iii) Strains (Δcrp and Δfur) that recovered growth using convergent mutations within their regulatory networks, including regulated promoters and connected regulators, and (iv) Strains (Δlrp) that were unable to fully recover growth, seemingly due to the broad connectivity of the TF within the TRN. Analyzing growth capabilities in evolved and unevolved strains indicated that growth adaptation can restore fitness to diverse substrates often despite a lack of TF-specific mutations. This work reveals the breadth of TRN adaptive mechanisms and suggests these mechanisms can be anticipated based on the network and functional context of the perturbed TFs.

Single-cell transcriptomics reveals IRF7 regulation of the tumor microenvironment in isocitrate dehydrogenase wild-type glioma.

Mutations in isocitrate dehydrogenase (IDH) are important markers of glioma prognosis. However, few studies have examined the gene expression regulatory network (GRN) in IDH-mutant and wild-type gliomas. In this study, single-cell RNA sequencing and spatial transcriptome sequencing were used to analyze the GRN of cell subsets in patients with IDH-mutant and wild-type gliomas. Through gene transcriptional regulation analysis, we identified the M4 module, whose transcription factor activity is highly expressed in IDH wild-type gliomas compared to IDH-mutants. Enrichment analysis revealed that these genes were predominantly expressed in microglia and macrophages, with significant enrichment in interferon-related signaling pathways. Interferon regulatory factor 7 (IRF7), a transcription factor within this pathway, showed the highest percentage of enrichment and was primarily localized in the core region of wild-type IDH tumors. A machine-learning prognostic model identified novel subgroups within the wild-type IDH population. Additionally, IRF7 was shown to promote the proliferation and migration of T98G and U251 cells in vitro, and its knockdown affected glioma cell proliferation in vivo. This study systematically established the regulatory mechanism of IDH transcriptional activity in gliomas at the single-cell level and drew a corresponding cell map. The study presents a transcriptional regulatory activity map for IDH wild-type gliomas, involving single-cell RNA sequencing and spatial transcriptomics to identify gene regulatory networks, machine learning models for IDH subtyping, and experimental validation, highlighting the role of IRF7 in glioma progression.

Exploration and identification of diabetes targets in nursing: CDH1 and DVL1.

Diabetes is a chronic disease caused by absolute or relative insufficiency of insulin secretion and impaired insulin utilization. CDH1 and DVL1 role in diabetes and its nursing care is unclear. The diabetes dataset GSE21321 and GSE19790 profiles were downloaded from the gene expression omnibus (GEO) database. Perform differentially expressed genes (DEGs) screening, weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network construction and analysis, functional enrichment analysis, gene set enrichment analysis (GSEA), immune infiltration analysis, and Comparative Toxicogenomics Database (CTD) analysis. Gene expression heat map was drawn. TargetScan was used to screen the miRNA that regulates central DEGs. 1983 DEGs were obtained. According to Gene Ontology (GO) analysis, they were mainly enriched in signal regulation, catenin complexes, and signal receptor binding. In Kyoto Encyclopedia of Gene and Genome (KEGG) analysis, they were mainly concentrated in the Rap1 signaling pathway, cAMP signaling pathway, and Hippo signaling pathway. The DEGs are mainly enriched in cell signaling, Wnt signaling vesicles, growth factor activity, and the interaction between neural active ligands and receptors. In the enrichment project of Metascape, BMP signaling pathways and cell population proliferation can be seen in the GO enrichment project. The soft threshold power in WGCNA is set to 5. A total of 15 modules were generated. Core gene expression heatmap showed that core genes (CTNNB1, CDH1, DVL1) were highly expressed in diabetes samples. CTD analysis showed thatCTNNB1, CDH1, DVL1were associated with weight gain, inflammation, and necrosis. CDH1 and DVL1 are highly expressed in diabetes and may become molecular targets for diabetes and its care.