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63 papers

Muscle fibre denervation in ageing.

Soendenbroe C. · Jul 1, 2026

Muscle fibre denervation describes the loss of effective neural input from a motor neuron to one or more muscle fibres. In ageing, denervation is increasingly recognised as an important contributor to progressive declines in muscle strength and functional capacity, yet it remains heterogeneous and difficult to define in humans. This ambiguity reflects both biological complexity and current methodological limitations. The purpose of the present review is to synthesise current human evidence for muscle fibre denervation in ageing, clarify key conceptual distinctions, and evaluate methodological approaches used to assess denervation in humans. Muscle fibre denervation can occur through structural disconnection of the motor neuron from the fibre or through functional impairment of neuromuscular transmission. Evidence for denervation in ageing is derived from histological, molecular, electrophysiological, and circulating biomarker approaches, each capturing distinct and only partially overlapping aspects of neuromuscular integrity. Importantly, no single measure provides a comprehensive assessment of denervation. Experimental models of disuse in humans reveal a functional denervation phenotype, characterised by molecular and electrophysiological changes that partially resemble those observed with ageing. Physical activity appears to mitigate against aspects of muscle fibre denervation; however, the mechanisms underlying these effects remain incompletely understood. Collectively, the available evidence indicates that denervation in ageing is a multifaceted and dynamic process that requires multimodal, longitudinal approaches to define, detect, and ultimately target denervation-related mechanisms to preserve neuromuscular function across the human lifespan.

Biochemistry, Genetics and Molecular Biology

PolyProline Predictor: A web server for empirical sequence-based prediction of polyproline II helices.

López-Sánchez R et al. · Jul 1, 2026

Polyproline II (PPII) helices are extended left-handed secondary structures increasingly recognized for their roles in molecular recognition, signaling and within intrinsically disordered regions of proteins. Despite their functional importance, predicting regions with propensity to form PPII helices from sequence alone remains challenging due to subtle sequence determinants and their frequent misclassification as random coil. Here, we present PolyProline Predictor (PPP), a user-friendly web server (https://rmni.iqf.csic.es/software/polypropre/) for empirical, sequence-based prediction of PPII helices. Unlike machine learning approaches, PPP aligns query sequences against a curated database of experimentally validated PPII helices, providing an interpretable, composition-, and position-sensitive similarity map. PPP successfully identified conserved PPII motifs in diverse proteins, and predicted the presence of similar motifs in regions lacking experimental structures but modeled by AlphaFold as extended PPII conformations, such as glycine-rich plant proteins, mycobacterial PE_PGRS virulence factors, and the "disordered" C-terminal tails of GroEL and its homologs, as well as the amyloid-flanking region of the necroptosis effector RIPK3. Molecular dynamics simulations further supported persistent PPII helical bundles in three glycine-rich mycobacterial proteins and more heterogeneous, transient PPII populations in plant proteins and RIPK3. Circular dichroism and nuclear magnetic resonance (NMR) spectroscopy validated these predictions for RIPK3, revealing partially populated PPII conformations flanking its amyloid core. Such motifs may regulate its amyloid assembly, offering structural insight into mechanisms of functional amyloid formation. By combining experimental evidence with interpretable prediction, PPP fills a critical gap in bioinformatics tools and enables systematic exploration of regions with propensity to form PPII helices across proteomes, redefining the structural landscape of low-complexity regions.

Biochemistry, Genetics and Molecular Biology

Effects of Selective Sphingosine-1-Phosphate Receptor 1 Agonist, TRV045, on Evoked Pain Tests: An Exploratory, Four-Way Cross-Over Study in Healthy Volunteers.

Bakker WA et al. · Jul 1, 2026

Introduction Preclinical evidence suggests that dysregulation of the ceramide-sphingosine-1-phosphate (S1P) axis may have analgesic properties. However, currently approved S1PR1 modulators such as fingolimod are hindered for this indication as they induce lymphopenia. The aim of the current study was to evaluate whether the novel, selective S1PR1 agonist TRV045 has analgesic effects in a validated evoked pain test battery in healthy volunteers. Methods In this randomized, double-blind, double-dummy, placebo-controlled, four-way cross-over study, 25 male or female healthy volunteers were randomized to receive either placebo or TRV045 50, 150 or 300 mg at separate occasions. The primary endpoint was heat pain detection threshold on UVB-induced inflammatory pain. Secondary endpoints included analgesic reduction of capsaicin-induced allodynia and pain detection and tolerance thresholds to evoked cold, electrical, pressure and heat pain. Furthermore, safety, tolerability and pharmacokinetics were monitored throughout the study. Data analyses included a repeated-measures mixed-effects model. Results TRV045 was well tolerated, without serious adverse events. Compared to placebo, TRV045 did not reduce heat pain detection thresholds on UVB-exposed skin, but significantly reduced the secondary area of capsaicin-induced pain for the higher dose levels: 150 mg: -304.10 mm 2 (95% CI: -494.78 to -113.43, p = 0.002); 300 mg: -298.51 mm 2 (-486.83 to -110.20, p = 0.002). No effects on peripheral lymphocyte count were observed. Conclusion TRV045 is a well-tolerated S1PR1 modulator with analgesic properties in healthy volunteers as measured by the capsaicin-induced pain model, which provides initial clinical evidence that selective S1PR1 modulation may be an appropriate novel target for the treatment of neuropathic pain. Significance statement Selective S1PR1 modulation produced analgesic effects in a validated human experimental pain model. This study provides clinical proof-of-concept for S1PR1 as a promising therapeutic target for neuropathic pain.

Biochemistry, Genetics and Molecular Biology

Formulation of Peptide-Based Nanoparticles Using a Microfluidic Device.

Hammoum T et al. · Jul 1, 2026

Peptide-based nanoparticles (PBN) have emerged as a promising alternative to lipid nanoparticles (LNP) for nucleic acid delivery and efficient cellular uptake. In this study, we evaluated the formulation of WRAP5 (W- and R-rich amphipathic peptide 5)-based PBN using a microfluidic device and assessed the impact of key process parameters, flow rate ratio (FRR), total flow rate (TFR), and mixing channel design, on nanoparticle characteristics. Across 72 formulations encapsulating small interfering RNA (siRNA) or plasmid DNA (pDNA), dynamic light scattering revealed consistent mean sizes ranging from 50 to 70 nm, with a low polydispersity index (PdI < 0.22), independent of FRR, TFR, or mixer type. Stability studies demonstrated that siRNA-loaded PBN exhibited moderate size increases during storage at 4°C, whereas pDNA-loaded PBN remained highly stable for up to 70 days. Biological assays confirmed robust activity: WRAP5:siRNA PBN achieved approximately 50% CDK4 silencing in GIST-T1 cells, and WRAP5:pDNA PBN mediated efficient mCHERRY expression in HeLa cells, regardless of formulation method or storage duration. These findings highlight the robustness and scalability of WRAP5-based PBN, contrasting with LNP systems that require stringent control of FRR and TFR, and partially underscore their potential for nucleic acid delivery applications.

Biochemistry, Genetics and Molecular Biology

The yeast mitochondrial porin represses Snf1/AMP kinase signaling to attenuate viral replication.

Chau S et al. · Jul 1, 2026

Although fungi are broadly infected with mycoviruses, the antiviral mechanisms fungal cells use to oppose viral replication are not well understood. Here, we discover a new mitochondrially controlled signaling mechanism in the budding yeast Saccharomyces cerevisiae that limits replication of L-A, an RNA mycovirus that endemically infects this organism. We show that Por1, the mitochondrial voltage dependent anion channel, prevents hyper-replication of L-A in stationary phase cells that have exhausted media nutrients. By investigating known stationary phase regulators, we find that deletion of the AMP-activated kinase homolog SNF1 reverses hyper-replication of L-A observed in por1Δ cells. This epistatic relationship suggests that Por1 negatively regulates Snf1 in stationary phase cells and derepressed Snf1 promotes L-A hyper-replication. We confirm this model, first demonstrating that POR1 prevents the accumulation of activated Snf1 throughout stationary phase. By investigating Snf1 signaling targets, we show that this POR1-SNF1 regulatory mechanism acts in stationary phase cells to limit amino acid availability that sustain L-A replication. POR1-SNF1 signaling represents a novel physiological control mechanism to limit viral replication in a eukaryotic cell.

Biochemistry, Genetics and Molecular Biology

Association Between Dietary Advanced Glycation End Products (AGEs) and Pancreatic Fat Accumulation: Evidence From a Case-Control Study.

Shahparvari MR et al. · Jul 1, 2026

Background Pancreatic steatosis (PS) is a metabolic condition associated with obesity, insulin resistance, and fatty liver disease. Advanced Glycation End Products (AGEs), abundant in processed and high-temperature-cooked foods, have been linked to several metabolic disorders; however, their relationship with PS has not been previously examined. Methods In this case-control study, 278 individuals with gallstones, aged 55.7 ± 15.1 years, were classified as cases (with PS, n = 89) or controls (without PS, n = 189). PS was defined based on increased echogenicity of the pancreatic parenchyma relative to surrounding structures. Dietary intake was assessed using a food frequency questionnaire. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for PS across quartiles of dietary AGE intake. The fully adjusted model included age, sex, total energy intake, body mass index, smoking status, and alcohol consumption. Results Higher dietary AGE intake was significantly associated with an increased likelihood of PS. In the crude model, odds of PS did not differ significantly across quartiles of dietary AGE intake compared with the lowest quartile. After adjustment for age and sex, individuals in the highest quartile had higher odds of PS (OR = 3.56; CI: 1.1-11.6; p = 0.040). In the fully adjusted model, significant associations were observed for the third (OR = 2.76; CI: 1.69-11.1) and fourth (OR = 3.3; CI: 1.79-13.7) quartiles of dietary AGE intake compared with the lowest quartile. A significant positive trend in the odds of PS was observed across increasing quartiles of dietary AGE intake (p for trend = 0.024). Conclusion Our findings suggest a potential role of dietary AGEs in pancreatic fat accumulation; however, causality cannot be inferred. Larger prospective and interventional studies are needed to confirm these associations and to determine whether reducing dietary AGE exposure can beneficially influence pancreatic fat.

Biochemistry, Genetics and Molecular Biology

Targeting the Lipid Metabolism Proteins FASN and GPAM in Alveolar Type II Cells Decreases Lung Metastasis.

Liu XZ et al. · Jul 1, 2026

Cancer cells that seed in the lung require lipids often produced by alveolar type II (AT2) cells. However, whether overt metastases depend on AT2 cell-derived lipids and whether AT2 cells can be targeted to reduce metastasis growth remains unknown. We discovered that breast cancer-derived lung metastases stimulate the proliferation of AT2 cells in their vicinity and reprogram them into lipid feeder cells in mice and patients using spatial analysis. Mechanistically, the metastasis secretome activates the transcription factor sterol regulatory element-binding transcription factor 1 (SREBP-1) in AT2 cells, enhancing the expression of key de novo lipid synthesis genes, including fatty acid synthase (FASN) and glycerol-3-phosphate acyltransferase 1 (GPAM). Deleting Fasn selectively in AT2 cells or targeting FASN and GPAM systemically significantly impairs lung metastasis growth in mice. In summary, we discovered that overt metastases reprogram AT2 cells and that targeting the lipid metabolism of AT2 cells impairs metastasis growth. Significance Current therapies in oncology targeting the cancer or immune cell compartment of tumors show limited efficacy against breast cancer-derived metastases. We discovered that decreasing the lipid metabolism of lung resident AT2 cells is sufficient to impair lung metastasis growth in mice without apparent adverse effects.

Biochemistry, Genetics and Molecular Biology

When can AlphaFold predict the oligomeric states of proteins?

Lin Y et al. · Jul 1, 2026

Homooligomerisation is a prevalent and important process that many proteins undergo to form the quaternary structures required for biological function. However, determining oligomeric states and structures experimentally remains technically challenging and time-consuming for many proteins. Here, we show that the protein structure prediction tools AlphaFold2-Multimer and AlphaFold3 can be used to quickly and accurately predict oligomeric states and structures for a range of soluble and membrane proteins. Across over 4700 proteins, AlphaFold2-Multimer provides reliable oligomeric state predictions in the majority of cases, however accuracy is more limited for proteins lacking close structural representatives in the AlphaFold training set, highlighting the dependence of these methods on robust training data. Together, our results suggest both the utility and current limitations of AlphaFold-based oligomeric state prediction, highlight cases where multiple physiologically relevant assemblies may be plausible, and provide practical guidance for minimizing computational cost, identifying challenging cases, and applying these methods to proteins lacking experimental structural data.

Biochemistry, Genetics and Molecular Biology

A Roadmap for Using Hybridisation Capture-Based Target Enrichment of Ancient Environmental DNA in Palaeoecology.

Foster NR et al. · Jul 1, 2026

Recovering ancient DNA from environmental samples is transforming the way we understand historical ecosystems. While high-throughput sequencing of the total DNA in environmental samples (shotgun metagenomic sequencing) reveals the taxonomic contents of these samples, the genetic signals of some taxa (e.g., eukaryotes) can be weak compared to the background levels of DNA from organisms such as bacteria, requiring deep sequencing approaches that are costly. Thus, to increase cost-effectiveness, pre-sequencing enrichment of target DNA can be advantageous. One technique to enrich this target DNA is hybridisation capture, where short RNA or DNA baits are designed to match, bind and isolate specific stretches of DNA. Hybridisation capture has previously been applied to recover DNA from ancient skeletal remains, but it is only beginning to emerge as an approach to characterise organisms from ancient environmental samples. Thus, there is limited information on establishing hybridisation capture workflows for ancient environmental DNA applications, including the limitations and advantages. This mini review focuses on establishing a roadmap for the applications of hybridisation capture to ancient environmental DNA samples.

Biochemistry, Genetics and Molecular Biology

Engineering Extracellular Vesicles for Anti-Aging Therapy: Mechanisms, Applications, and Perspectives.

Huang X et al. · Jul 1, 2026

Aging is a multifactorial process driven by interconnected hallmarks, including chronic inflammation, mitochondrial dysfunction, genomic and epigenetic alterations, and dysregulated intercellular communication. Extracellular vesicles (EVs), naturally derived nanoscale membrane vesicles capable of transporting diverse bioactive cargoes across tissues and biological barriers, have emerged as a highly promising platform for regenerative and anti-aging therapeutics. In this review, we systematically summarize the multifaceted anti-aging mechanisms of EVs, including suppression of the senescence-associated secretory phenotype (SASP), remodeling of the immune microenvironment, mitochondrial restoration and metabolic reprogramming, DNA damage repair, epigenetic modulation, recovery of proteostasis, activation of regenerative signaling pathways, and cross-organ communication-mediated rejuvenation. Beyond mechanistic insights, we integrate the targeting biology and cellular entry properties of EVs, encompassing natural tropism determinants, engineered targeting strategies, biodistribution profiles, receptor-ligand interactions, intracellular trafficking, and subcellular cargo release. Unlike previous reviews focusing on a single EV source or isolated pathways, we establish a comprehensive framework connecting molecular mechanisms with delivery engineering, tissue targeting, biosafety assessment, scalable manufacturing, and clinical translation. We address major technical bottlenecks limiting EV therapeutics-including EV heterogeneity, suboptimal delivery efficiency, endosomal degradation, and the lack of standardized quality-control frameworks-while highlighting emerging solutions such as bioengineered EVs, hybrid vesicle platforms, biomaterial-assisted delivery systems, and ultrasound-enhanced targeting technologies. By bridging fundamental biology, nanomedicine engineering, and clinical translation, this review provides a strategic roadmap for the development of next-generation precision anti-aging nanotherapeutics with systemic regulatory capacity, translational feasibility, and broad clinical potential.

Biochemistry, Genetics and Molecular Biology