Molecular Biology

eLife Assessment

This manuscript presents a useful computational framework for systematically characterising how heterogeneity in initial conditions or biophysical parameters shapes the dynamic behaviour of protein signalling networks, with potential relevance to understanding adaptive drug resistance. While the approach represents a significant methodological contribution, the extent to which its conclusions are biologically informative remains debated, as the model is only qualitatively compared with experimental data and lacks quantitative validation. As a result, the strength of evidence supporting the mechanistic claims is viewed as incomplete.

eLife Assessment

This manuscript addresses an important and conceptually ambitious question by using a synthetic biology strategy to perturb ATP homeostasis in yeast and examine its causal relationship with lifespan. While the experimental approach and lifespan data are intriguing, the current evidence is incomplete and internally inconsistent, particularly regarding intracellular ATP measurements, transporter directionality, mitochondrial dependence, and the proposed mechanistic model. Substantial clarification, additional controls, and further experimentation will be necessary before the main conclusions can be considered robust and the biological significance of the findings can be fully assessed.

eLife Assessment

This is a solid paper on intermittent fasting that will be of interest to readers. The data presented are certainly valuable as a resource. The findings of both shared and tissue-specific signatures, both at the proteomic and transcriptomic levels, align well with what has been established and bring new insight into metabolic adaptation and its consequences in muscle, cortex, and liver. The organ specific changes unveiled by proteomics in response to IF reveal unique rewiring of metabolic, signaling and physiological function.

eLife Assessment

This study uses the yeast two-hybrid assay to identify proteins that may interact with yeast Set1 and other subunits of COMPASS/Set1C, the histone H3K4 methyltransferase, providing also some evidence for Set1 sumoylation and a role of SET1C methylating other factors in vitro. The results are valuable, and they should contribute to understanding the functions of the conserved SET1C complex, as they suggest potential functional connections with RNA biogenesis, chromatin remodeling, and non-histone methylation, whose implications would yet need to be explored. Nevertheless, apart from the fact that only a small subset of the Y2H interactions is further examined, the validating experiments are only partial or inconclusive, the strength of evidence being at this point incomplete.

eLife Assessment

This study presents a high-quality cryo-EM structure of the human kinase PINK1 in complex with the HSP90-CDC37 chaperone complex, capturing a partially folded intermediate in which the C-lobe and C-terminal extension are structured while the N-lobe remains unfolded and engaged by the HSP90 clamp. The structural data are broadly consistent with a recently published structure of the same complex, providing useful insight into early steps of PINK1 maturation and highlighting residues linked to familial Parkinson's disease. However, the mechanistic conclusions remain incomplete because the manuscript does not experimentally validate key hypotheses raised by the structure, including the functional roles of the C-lobe interface, the HPNI motif, the C-terminal extension, or the proposed competition between HSP90 and TOM20.

eLife Assessment

The authors provide a useful resource and approach to identify early-stage biomarkers of MASLD progression, notably when no other apparent symptoms have arisen. The strength of evidence to support new MASLD signatures is solid as the work combines metabolomic and transcriptomic measures in blood and liver biopsies.

[Editors' note: this paper was reviewed by Review Commons.]

eLife Assessment

This important study provides a comprehensive comparison of the mechanisms through which different inhibitors affect the SARS-CoV-2 main protease, a pivotal antiviral drug target, and suggests a potentially broad-spectrum strategy to inhibit this critical viral enzyme by disrupting its dimerization states. However, whereas the biophysical analyses of the dimer stability are convincing, evidence supporting this new mode of mechanism to inhibit the main protease is incomplete and would benefit from a correlation of the biophysical observations with functional activity. With the functional validation part strengthened, this work would be of interest to biochemists and virologists working on anti-coronavirus drug discovery.

eLife Assessment

This study reports an mRNA-based strategy for restoring sperm motility in a mouse model of monogenic male infertility. The work is technically innovative and potentially valuable, as it demonstrates feasibility of in vivo testicular mRNA delivery without genomic integration of foreign DNA. However, although partial recovery of sperm motility is supported, the evidence for meaningful restoration of fertility remains incomplete, with weak IVF outcomes and difficult-to-interpret ICSI results. In addition, mechanistic questions regarding the persistence of mRNA and the specificity of germ-cell targeting remain insufficiently resolved, limiting the strength of the authors' conclusions.

eLife Assessment

This paper provides important findings towards understanding the role of the lncRNA EPB41L4A-AS1 in a human cell line. The data is generally convincing, supported by extensive and clever integrative analysis. The work provides insights into how this lncRNA regulates gene expression via complex mechanisms; however the biological relevance awaits validation in other models.

eLife Assessment

This useful study by Palo et al proposes that FRG1 functions as a negative regulator of Nonsense-Mediated mRNA decay (NMD) by associating with the exon junction complex (EJC) and destabilizing UPF1 independently of DUX4. The authors present solid evidence to dissect the relationship between FRG1 and DUX4 in NMD. However, the evidence to support the claim that FRG1 is a component of the EJC or the NMD machinery is incomplete.