Cellular Processes Research Articles

The Functional Role of microRNAs and mRNAs in Diabetic Kidney Disease: A Review.

Diabetes is a group of diseases marked by poor control of blood glucose levels. Diabetes mellitus (DM) occurs when pancreatic cells fail to make insulin, which is required to keep blood glucose levels stable, disorders, and so on. High glucose levels in the blood induce diabetic effects, which can cause catastrophic damage to bodily organs such as the eyes and lower extremities. Diabetes is classified into many forms, one of which is controlled by hyperglycemia or Diabetic Kidney Disease (DKD), and another that is not controlled by hyperglycemia (nondiabetic kidney disease or NDKD) and is caused by other factors such as hypertension, hereditary. DKD is associated with diabetic nephropathy (DN), a leading cause of chronic kidney disease (CKD) and end-stage renal failure. The disease is characterized by glomerular basement membrane thickening, glomerular sclerosis, and mesangial expansion, resulting in a progressive decrease in glomerular filtration rate, glomerular hypertension, and renal failure or nephrotic syndrome. It is also represented by some microvascular complications such as nerve ischemia produced by intracellular metabolic changes, microvascular illness, and the direct impact of excessive blood glucose on neuronal activity. Therefore, DKD-induced nephrotic failure is worse than NDKD. MicroRNAs (miRNAs) are important in the development and progression of several diseases, including diabetic kidney disease (DKD). These dysregulated miRNAs can impact various cellular processes, including inflammation, fibrosis, oxidative stress, and apoptosis, all of which are implicated during DKD. MiRNAs can alter the course of DKD by targeting several essential mechanisms. Understanding the miRNAs implicated in DKD and their involvement in disease development might lead to identifying possible therapeutic targets for DKD prevention and therapy. Therefore, this review focuses specifically on DKD-associated DN, as well as how in-silico approaches may aid in improving the management of the disease.

RDR100: A Robust Computational Method for Identification of Krüppel-like Factors

Background: Krüppel-like factors (KLFs) are a family of transcription factors containing zinc fingers that regulate various cellular processes. KLF proteins are associated with human diseases, such as cancer, cardiovascular diseases, and metabolic disorders. The KLF family consists of 18 members with diverse expression profiles across numerous tissues. Accurate identification and annotation of KLF proteins is crucial, given their involvement in important biological functions. Although experimental approaches can identify KLF proteins precisely, large-scale identification is complicated, slow, and expensive. Methods: In this study, we developed RDR100, a novel random forest (RF)-based framework for predicting KLF proteins based on their primary sequences. First, we identified the optimal encodings for ten different features using a recursive feature elimination approach, and then trained their respective model using five distinct machine learning (ML) classifiers. Results: The performance of all models was assessed using independent datasets, and RDR100 was selected as the final model based on its consistent performance in cross-validation and independent evaluation. Conclusion: Our results demonstrate that RDR100 is a robust predictor of KLF proteins. RDR100 web server is available at https://procarb.org/RDR100/.

Protective Roles and Therapeutic Effects of Gallic Acid in the Treatment of Cardiovascular Diseases: Current Trends and Future Directions.

Cardiovascular diseases (CVDs) are serious life-threatening illnesses and significant problematic issues for public health having a heavy economic burden on all society worldwide. The high incidence of these diseases as well as high mortality rates make them the leading causes of death and disability. Therefore, finding novel and more effective therapeutic methods is urgently required. Gallic acid, an herbal medicine with numerous biological properties, has been utilized in the treatment of various diseases for thousands of years. It has been demonstrated that gallic acid possesses pharmacological potential in regulating several molecular and cellular processes such as apoptosis and autophagy. Moreover, gallic acid has been investigated in the treatment of CVDs both in vivo and in vitro. Herein, we aimed to review the available evidence on the therapeutic application of gallic acid for CVDs including myocardial ischemia-reperfusion injury and infarction, drug-induced cardiotoxicity, hypertension, cardiac fibrosis, and heart failure, with a focus on underlying mechanisms.

Role of Rhodomyrtus tomentosa (Aiton) Hassk. in regulating the expression of fibroblast growth factor family in the liver of rat in a breast cancer model

Context: Cellular abnormalities in the ducts and breast tissue cause breast cancer to invade nearby tissues like the liver. The fibroblast growth factor (FGF) signals are sent to its receptor and regulate various cellular processes to maintain liver homeostasis. However, this condition has few and inefficient treatments. Breast cancer is characterized by the development of cellular abnormalities within the ducts and breast tissue, leading to the invasion of adjacent tissues, such as the liver. Aims: To examine the impact of Rhodomyrtus tomentosa administration on the expression of the FGF family in cancer animal models, with a specific focus on the liver. Methods: Cancer model rats were administered at dosages of 100, 200, and 300 mg/kg BW for 30 days. Liver tissue and blood serum samples were extracted from the rat. Liver tissue was stained for immunohistochemistry using FGF1, FGF15, FGF19, and FGF21, and blood samples were collected for ELISA analysis. Results: The study found that DMBA in hepatocyte cells degrades parenchyma, making it hydrophilic and necrosating. Hepatocyte cell function improved with the greatest dose of R. tomentosa. The elevation was associated with an area around the portal vein where recently dividing hepatocytes form clusters. Conclusions: The promise of R. tomentosa as a candidate for the development of hepatoprotective medicines in cancer treatment arises from its ability to influence the expression of crucial liver health markers, including FGF1, FGF15, FGF19, and FGF21.

Upregulation and epigenetic modification of the creatine transporter SLC6A8 in non-small cell lung cancer.

Lung cancer is a major cause of cancer-related death worldwide and effective therapies, besides surgery, are available only for a small proportion of patients. Since cellular respiration is known to be broadly altered in malignant tumors, the cellular processes of respiration can be a potential therapeutic target. One important element of cellular respiration is creatine and its transport by the creatine transporter SLC6A8. Here we describe the expression of SLC6A8 at the RNA and protein level, epigenetic modifications as well as survival analysis in NSCLC tissues and matched controls. We analyzed epigenetic modifications of the SLC68A gene in 32 patients, of which 18 were additionally analyzed by transcriptome analysis. The expression of SLC6A8 at the protein level was assessed by immunohistochemistry using an independent cohort and correlated with clinicopathological data including survival. Kaplan-Meier analysis was performed to analyze the possible effects of the transcriptional levels of SLC6A8 in another separate cohort (n=1925). SLC6A8 loci are epigenetically modified in NSCLC compared with tumor-free controls. SLC6A8 is upregulated in NSCLC at the RNA and protein level. High mRNA expression of SLC6A8 was associated with an overall poor prognosis in lung adenocarcinoma patients and displayed the strongest adverse prognostic effect in male smokers with adenocarcinomas. Results of transcriptome analysis were partially confirmed at the protein level. Our results suggest an important role of creatine and its transport via SLC6A8 in NSCLC.

Involvement of ArlI, ArlJ, and CirA in archaeal type IV pilin-mediated motility regulation.

Many prokaryotes use swimming motility to move toward favorable conditions and escape adverse surroundings. Regulatory mechanisms governing bacterial flagella-driven motility are well-established; however, little is yet known about the regulation underlying swimming motility propelled by the archaeal cell surface structure, the archaella. Previous research showed that the deletion of the adhesion pilins (PilA1-6), subunits of the type IV pili cell surface structure, renders the model archaeon Haloferax volcanii non-motile. In this study, we used ethyl methanesulfonate mutagenesis and a motility assay to identify motile suppressors of the ∆pilA[1-6] strain. Of the eight suppressors identified, six contain missense mutations in archaella biosynthesis genes, arlI and arlJ. In trans expression of arlI and arlJ mutant constructs in the respective multi-deletion strains ∆pilA[1-6]∆arlI and ∆pilA[1-6]∆arlJ confirmed their role in suppressing the ∆pilA[1-6] motility defect. Additionally, three suppressors harbor co-occurring disruptive missense and nonsense mutations in cirA, a gene encoding a proposed regulatory protein. A deletion of cirA resulted in hypermotility, while cirA expression in trans in wild-type cells led to decreased motility. Moreover, quantitative real-time PCR analysis revealed that in wild-type cells, higher expression levels of arlI, arlJ, and the archaellin gene arlA1 were observed in motile early-log phase rod-shaped cells compared to non-motile mid-log phase disk-shaped cells. Conversely, ∆cirA cells, which form rods during both early- and mid-log phases, exhibited similar expression levels of arl genes in both growth phases. Our findings contribute to a deeper understanding of the mechanisms governing archaeal motility, highlighting the involvement of ArlI, ArlJ, and CirA in pilin-mediated motility regulation.IMPORTANCEArchaea are close relatives of eukaryotes and play crucial ecological roles. Certain behaviors, such as swimming motility, are thought to be important for archaeal environmental adaptation. Archaella, the archaeal motility appendages, are evolutionarily distinct from bacterial flagella, and the regulatory mechanisms driving archaeal motility are largely unknown. Previous research has linked the loss of type IV pili subunits to archaeal motility suppression. This study reveals three Haloferax volcanii proteins involved in pilin-mediated motility regulation, offering a deeper understanding of motility regulation in this understudied domain while also paving the way for uncovering novel mechanisms that govern archaeal motility. Understanding archaeal cellular processes will help elucidate the ecological roles of archaea as well as the evolution of these processes across domains.

Identifying Reproducible Transcription Regulator Coexpression Patterns with Single Cell Transcriptomics.

The proliferation of single cell transcriptomics has potentiated our ability to unveil patterns that reflect dynamic cellular processes, rather than cell type compositional effects that emerge from bulk tissue samples. In this study, we leverage a broad collection of single cell RNA-seq data to identify the gene partners whose expression is most coordinated with each human and mouse transcription regulator (TR). We assembled 120 human and 103 mouse scRNA-seq datasets from the literature, constructing a single cell coexpression network for each. We aimed to understand the consistency of TR coexpression profiles across a broad sampling of biological contexts, rather than examine the preservation of context-specific networks. Our workflow therefore explicitly prioritizes the patterns that are most reproducible across cell types, helping to characterize each TR's coexpression patterns. Towards this goal, we quantify the similarity of TR coexpression profiles within and across species, characterizing the consistency of each TR's coexpression across datasets. We create single cell coexpression rankings for each TR, demonstrating that this aggregated information recovers literature curated targets on par with ChIP-seq data. We then combine the coexpression and ChIP-seq information to identify candidate regulatory interactions supported across methods and species. Finally, we highlight interactions for the important neural TR ASCL1 to demonstrate how our compiled information can be adopted for community use.

Dual-targeted fluorescent probe for tracking polarity and phase transition processes during lipophagy.

Eukaryotic cells regulate various cellular processes through membrane-bound and membrane-less organelles, enabling active signal communication and material exchange. Lysosomes and lipid droplets are representative organelles, contributing to cell lipophagy when their interaction and metabolism are disrupted. Our limited understanding of the interacting behaviours and physicochemical properties of different organelles during lipophagy hinders accurate diagnosis and treatment of related diseases. In this contribution, we report a fluorescent probe, PTZ, engineered for dual-targeting of lipid droplets and lysosomes. PTZ can track liquid-liquid phase separation and respond to polarity shifts through ratiometric fluorescence emission, elucidating the lipophagy process from the perspective of organelle behavior and physicochemical properties. Leveraging on the multifunctionality of PTZ, we have successfully tracked the polarity and dynamic changes of lysosomes and lipid droplets during lipophagy. Furthermore, an unknown homogeneous transition of lipid droplets and lysosomes was discovered, which provided a new perspective for understanding lipophagy processes. And this work is expected to serve as a reference for diagnosis and treatment of lipophagy-related diseases.

Skin Response to Chronic Crowding Stress in Shy, Bold Behavioral Groups of Male and Female Zebrafish.

In recent years, there has been a burgeoning interest in exploring the nuances of animal stress physiology, particularly in relation to parameters such as sex, and behavioral phenotype-dependent variations, that is crucial for understanding phenotypic variation and its role in evolutionary selection. However, a significant dearth remains in how chronic stressors affect organismal stress physiology concerning the aforesaid parameters. This void is even wider pertaining to the response of peripheral tissues, such as the skin, the organ with the highest surface contact area with the environment. Hence, we behaviorally grouped the zebrafishes based on their boldness and the body condition, whole-body cortisol response, along with examining the transcriptional response, global DNA methylome, and oxidative DNA damage in the skin upon chronic crowding. Upon baseline conditions, clear distinction between bold and shy phenotypes were found, particularly in males. The boldness index score distribution exhibited greater uniformity in males than in females. Regarding the body condition response to chronic crowding, shy males showed a significant relative decline compared to their bold counterparts, while this trend did not hold true for females. qPCR data revealed distinctive expression patterns in key genes which play critical roles in cellular processes such as stress mediated gene regulation, immune response, oxidative stress protection, and maintenance of genomic integrity through epigenetic modifications across behavioral phenotypes and sexes under both with and without chronic crowding stress. Global DNA methylation levels significantly declined only in chronically crowded shy males, and sex/behavioral phenotype-dependent trends in oxidative DNA damage were identified.

Twin Scholarships of Glycomedicine and Precision Medicine in Times of Single-Cell Multiomics.

Systems biology and multiomics research expand the prospects of planetary health innovations. In this context, this mini-review unpacks the twin scholarships of glycomedicine and precision medicine in the current era of single-cell multiomics. A significant growth in glycan research has been observed over the past decade, unveiling and establishing co- and post-translational modifications as dynamic indicators of both pathological and physiological conditions. Systems biology technologies have enabled large-scale and high-throughput glycoprofiling and access to data-intensive biological repositories for global research. These advancements have established glycans as a pivotal third code of life, alongside nucleic acids and amino acids. However, challenges persist, particularly in the simultaneous analysis of the glycome and transcriptome in single cells owing to technical limitations. In addition, holistic views of the complex molecular interactions between glycomics and other omics types remain elusive. We underscore and call for a paradigm shift toward the exploration of integrative glycan platforms and analysis methods for single-cell multiomics research and precision medicine biomarker discovery. The integration of multiple datasets from various single-cell omics levels represents a crucial application of systems biology in understanding complex cellular processes and is essential for advancing the twin scholarships of glycomedicine and precision medicine.

SRSF9 promotes cell proliferation and migration of glioblastoma through enhancing CDK1 expression

BackgroundGlioblastoma (GBM) is a highly aggressive and prevalent brain tumor that poses significant challenges in treatment. SRSF9, an RNA-binding protein, is essential for cellular processes and implicated in cancer progression. Yet, its function and mechanism in GBM need clarification.MethodsBioinformatics analysis was performed to explore differential expression of SRSF9 in GBM and its prognostic relevance to glioma patients. SRSF9 and CDK1 expression in GBM cell lines and patients’ tissues were quantified by RT-qPCR, Western blot or immunofluorescence assay. The role of SRSF9 in GBM cell proliferation and migration was assessed by MTT, Transwell and colony formation assays. Additionally, transcriptional regulation of CDK1 by SRSF9 was investigated using ChIP-PCR and dual-luciferase assays.ResultsThe elevated SRSF9 expression correlates to GBM stages and poor survival of glioma patients. Through gain-of-function and loss-of-function strategies, SRSF9 was demonstrated to promote proliferation and migration of GBM cells. Bioinformatics analysis showed that SRSF9 has an impact on cell growth pathways including cell cycle checkpoints and E2F targets. Mechanistically, SRSF9 appears to bind to the promoter of CDK1 gene and increase its transcription level, thus promoting GBM cell proliferation.ConclusionsThese findings uncover the cellular function of SRSF9 in GBM and highlight its therapeutic potential for GBM.

Chemical Dynamics of Selenium Nanoparticles in Archaeal Systems.

Methanogenic archaea, characterized by their cell membrane lipid molecules consisting of isoprenoid chains linked to glycerol-1-phosphate via ether bonds, exhibit exceptional adaptability to extreme environments. However, this distinct lipid architecture also complicates the interactions between methanogenic archaea and nanoparticles. This study addresses this challenge by exploring the interaction and transformation of selenium nanoparticles (SeNPs) within archaeal Methanosarcina acetivorans C2A. We demonstrated that the effects of SeNPs are highly concentration-dependent, with chemical stimulation of cellular processes at lower SeNPs concentrations as well as oxidative stress and metabolic disruption at higher concentrations. Notably, we observed the formation of a protein corona on SeNPs, characterized by the selective adsorption of enzymes critical for methylotrophic methanogenesis and those involved in selenium methylation, suggesting potential alterations in protein function and metabolic pathways. Furthermore, the intracellular transformation of SeNPs into both inorganic and organic selenium species highlighted their bioavailability and dynamic transformation within archaea. These findings provide vital insights into the nano-bio interface in archaeal systems, contributing to our understanding of archaeal catalysis and its broader applications.

YjgA plays dual roles in enhancing PTC maturation.

Ribosome biogenesis is a highly regulated cellular process that involves the control of numerous assembly factors. The small protein YjgA has been reported to play a role in the late stages of 50S assembly. However, the precise molecular mechanism underlying its function remains unclear. In this study, cryo-electron microscopy (cryo-EM) structures revealed that depletion of YjgA or its N-terminal loop in Escherichia coli both lead to the accumulation of immature 50S particles with structural abnormalities mainly in peptidyl transferase center (PTC) and H68/69 region. CryoDRGN analysis uncovered 8 and 6 distinct conformations of pre50S for ΔyjgA and YjgA-ΔNloop, respectively. These conformations highlighted the role of the N-terminal loop of YjgA in integrating uL16 and stabilizing H89 in PTC, which was further verified by the pull-down assays of YjgA and its mutants with uL16. Together with the function of undocking H68 through the binding of its C-terminal CTLH-like domain to the base of the L1 stalk, YjgA facilitates the maturation of PTC. This study identified critical domains of YjgA contributing to 50S assembly efficiency, providing a comprehensive understanding of the dual roles of YjgA in accelerating ribosome biogenesis and expanding our knowledge of the intricate processes governing cellular protein synthesis.

Regulatory roles of N6-methyladenosine (m6A) methylation in RNA processing and non-communicable diseases.

Post-transcriptional RNA modification is an emerging epigenetic control mechanism in cells that is important in many different cellular and organismal processes. N6-methyladenosine (m6A) is one of the most prevalent, prolific, and ubiquitous internal transcriptional alterations in eukaryotic mRNAs, making it an important topic in the field of Epigenetics. m6A methylation acts as a dynamical regulatory process that regulates the activity of genes and participates in multiple physiological processes, by supporting multiple aspects of essential mRNA metabolic processes, including pre-mRNA splicing, nuclear export, translation, miRNA synthesis, and stability. Extensive research has linked aberrations in m6A modification and m6A-associated proteins to a wide range of human diseases. However, the impact of m6A on mRNA metabolism and its pathological connection between m6A and other non-communicable diseases, including cardiovascular disease, neurodegenerative disorders, liver diseases, and cancer remains in fragmentation. Here, we review the existing understanding of the overall role of mechanisms by which m6A exerts its activities and address new discoveries that highlight m6A's diverse involvement in gene expression regulation. We discuss m6A deposition on mRNA and its consequences on degradation, translation, and transcription, as well as m6A methylation of non-coding chromosomal-associated RNA species. This study could give new information about the molecular process, early detection, tailored treatment, and predictive evaluation of human non-communicable diseases like cancer. We also explore more about new data that suggests targeting m6A regulators in diseases may have therapeutic advantages.

Mining the Dynamical Properties of Substrate and FAD Binding Pockets of LSD1: Hints for New Inhibitor Design Direction.

Lysine-specific demethylase 1 (LSD1), a highly sophisticated epigenetic regulator, orchestrates a range of critical cellular processes, holding promising therapeutic potential for treating diverse diseases. However, the clinical research progress targeting LSD1 is very slow. After 20 years of research, only one small-molecule drug, BEA-17, targeting the degradation of LSD1 and CoREST has been approved by the U.S. Food and Drug Administration. The primary reason for this may be the lack of abundant structural data regarding its intricate functions. To gain a deeper understanding of its conformational dynamics and guide the drug design process, we conducted molecular dynamics simulations to explore the conformational states of LSD1 in the apo state and under the influence of cofactors of flavin adenine dinucleotide (FAD) and CoREST. Our results showed that, across all states, the substrate binding pocket exhibited high flexibility, whereas the FAD binding pocket remained more stable. These distinct dynamical properties are essential for LSD1's ability to bind various substrates while maintaining efficient demethylation activity. Both pockets can be enlarged by merging with adjacent pockets, although only the substrate binding pocket can shrink into smaller pockets. These new pocket shapes can inform inhibitor design, particularly for selectively FAD-competitive inhibitors of LSD1, given the presence of numerous FAD-dependent enzymes in the human body. More interestingly, in the absence of FAD binding, the united substrate and FAD binding pocket are partitioned by the conserved residue of Tyr761, offering valuable insights for the design of inhibitors that disrupt the crucial steric role of Tyr761 and the redox role of FAD. Additionally, we identified pockets that positively or negatively correlate with the substrate and FAD binding pockets, which can be exploited for the design of allosteric or concurrent inhibitors. Our results reveal the intricate dynamical properties of LSD1 as well as multiple novel conformational states, which deepen our understanding of its sophisticated functions and aid in the rational design of new inhibitors.

D-SPIN constructs gene regulatory network models from multiplexed scRNA-seq data revealing organizing principles of cellular perturbation response.

Gene regulatory networks within cells modulate the expression of the genome in response to signals and changing environmental conditions. Reconstructions of gene regulatory networks can reveal the information processing and control principles used by cells to maintain homeostasis and execute cell-state transitions. Here, we introduce a computational framework, D-SPIN, that generates quantitative models of gene regulatory networks from single-cell mRNA-seq datasets collected across thousands of distinct perturbation conditions. D-SPIN models the cell as a collection of interacting gene-expression programs, and constructs a probabilistic model to infer regulatory interactions between gene-expression programs and external perturbations. Using large Perturb-seq and drug-response datasets, we demonstrate that D-SPIN models reveal the organization of cellular pathways, sub-functions of macromolecular complexes, and the logic of cellular regulation of transcription, translation, metabolism, and protein degradation in response to gene knockdown perturbations. D-SPIN can also be applied to dissect drug response mechanisms in heterogeneous cell populations, elucidating how combinations of immunomodulatory drugs can induce novel cell states through additive recruitment of gene expression programs. D-SPIN provides a computational framework for constructing interpretable models of gene-regulatory networks to reveal principles of cellular information processing and physiological control.

A Hypoxia-Epigenetics Axis Drives EMT in Pancreatic Cancer.

Epithelial-to-mesenchymal transition (EMT) is a classical cellular plasticity process induced by various cell-intrinsic and -extrinsic triggers. Although prominent factors, such as TGFβ, mediate EMT via well-characterized pathways, alternative avenues are less well understood. Transcriptomic subtyping of pancreatic ductal adenocarcinoma (PDAC) has demonstrated that basal-like PDACs enrich a mesenchymal-like expression program, emphasizing the relevance of EMT in the disease. In this issue of Cancer Research, Brown and colleagues demonstrate the tight connection of EMT to hypoxia. Through a detailed mechanistic analysis, the authors deciphered that hypoxia-induced signals are integrated by the histone H3 lysine 36 di-methylation (H3K36me2) mark. On the one hand, hypoxia decreased activity of the H3K36me2 eraser KDM2A, while on the other hand promoting stabilization of the H3K36me2 writer NSD2. Hypoxia diminished the expression of a set of serine-threonine phosphatases, subsequently resulting in SRC kinase family-dependent activation of canonical MEK, ERK, and JNK signaling to impinge on NSD2 expression. In addition, reduced expression of the protein phosphatase PP2Cδ was linked to increased NSD2 protein expression. These discoveries illuminate the close relationship of hypoxia signaling to the epigenetic machinery and cellular plasticity processes. See related article by Brown et al., p. 1764.

Role of exercise in pulmonary hypertension: Evidence from bench to bedside

Background: Pulmonary hypertension (PH) is a debilitating condition characterized by elevated pulmonary arterial pressure and progressive vascular remodeling, leading to exercise intolerance. The progression of PAH is regulated at a cellular and molecular level which influences various physiological processes. Exercise plays an important role in improving function in PH. Although the signalling pathways that regulate cardio-protection through exercise have not been fully understood, the positive impact of exercise on the various physiological systems are well established. Summary: Exercise has emerged as a potential adjunctive therapy for PH, with growing evidence supporting its beneficial effects on various aspects of the disease pathophysiology. This review highlights the contributions of cellular and molecular pathways and physiological processes to exercise intolerance. Preclinical studies have provided insight into the mechanisms underlying exercise-induced improvements in PH which are modulated through improvements in endothelial function, inflammation, oxidative stress, and mitochondrial function. Along with preclinical studies, various clinical studies have demonstrated that exercise training can lead to significant improvements in exercise capacity, hemodynamics, quality of life, and functional status. Moreover, exercise interventions have been shown to improve skeletal muscle function, and enhance pulmonary vascular remodeling, contributing to overall disease management. Further research efforts aimed at better understanding the role of exercise in PH pathophysiology and refining exercise interventions are warranted to realize its full potential in the management of this complex disease. Key messages: Despite the promising benefits of exercise in PH, several challenges remain, including the optimal intensity, duration, and type of exercise training, as well as patient selection criteria and long-term adherence. Additionally, the mechanisms underlying the observed improvements require further elucidation to optimize exercise protocols and personalize treatment strategies. Nonetheless, exercise represents a promising therapeutic approach that can complement existing pharmacological therapies and improve outcomes in PH patients.

Low-frequency ERK and Akt activity dynamics are predictive of stochastic cell division events

Understanding the dynamics of intracellular signaling pathways, such as ERK1/2 (ERK) and Akt1/2 (Akt), in the context of cell fate decisions is important for advancing our knowledge of cellular processes and diseases, particularly cancer. While previous studies have established associations between ERK and Akt activities and proliferative cell fate, the heterogeneity of single-cell responses adds complexity to this understanding. This study employed a data-driven approach to address this challenge, developing machine learning models trained on a dataset of growth factor-induced ERK and Akt activity time courses in single cells, to predict cell division events. The most predictive models were developed by applying discrete wavelet transforms (DWTs) to extract low-frequency features from the time courses, followed by using Ensemble Integration, a data integration and predictive modeling framework. The results demonstrated that these models effectively predicted cell division events in MCF10A cells (F-measure=0.524, AUC=0.726). ERK dynamics were found to be more predictive than Akt, but the combination of both measurements further enhanced predictive performance. The ERK model`s performance also generalized to predicting division events in RPE cells, indicating the potential applicability of these models and our data-driven methodology for predicting cell division across different biological contexts. Interpretation of these models suggested that ERK dynamics throughout the cell cycle, rather than immediately after growth factor stimulation, were associated with the likelihood of cell division. Overall, this work contributes insights into the predictive power of intra-cellular signaling dynamics for cell fate decisions, and highlights the potential of machine learning approaches in unraveling complex cellular behaviors.

Exploring orphan GPCRs in neurodegenerative diseases.

Neurodegenerative disorders represent a significant and growing health burden worldwide. Unfortunately, limited therapeutic options are currently available despite ongoing efforts. Over the past decades, research efforts have increasingly focused on understanding the molecular mechanisms underlying these devastating conditions. Orphan receptors, a class of receptors with no known endogenous ligands, emerge as promising druggable targets for diverse diseases. This review aims to direct attention to a subgroup of orphan GPCRs, in particular class A orphans that have roles in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Multiple sclerosis. We highlight the diverse roles orphan receptors play in regulating critical cellular processes such as synaptic transmission, neuronal survival and neuro-inflammation. Moreover, we discuss the therapeutic potential of targeting orphan receptors for the treatment of neurodegenerative disorders, emphasizing recent advances in drug discovery and preclinical studies. Finally, we outline future directions and challenges in orphan receptor research.