Evaluated articles

eLife Assessment

This important study advances our understanding of how cellular quality control machinery influences cystic fibrosis (CF) drug responsiveness by systematically analyzing the effects of the chaperone calnexin on more than two hundreds of CFTR (cystic fibrosis transmembrane regulator) variants. The evidence supporting the conclusions is convincing, with a comprehensive deep mutational scanning methodology and rigorous quantitative analysis. The findings reveal that calnexin is critical for both CFTR protein expression and corrector drug efficacy in a variant-specific manner, providing invaluable insights that could guide the development of personalized CF therapies. This work will be of significant interest to researchers in protein folding, CF drug development, and genetic disease therapeutics.

eLife Assessment

In this important contribution, Yan and colleagues describe a powerful and compelling strategy to generate concatamers of the BK channel and their fusion constructs with the auxiliary gamma subunits, which allows exploring contributions of individual subunits of the tetrameric channel to its gating and the study of heteromeric channel complexes of defined composition. Distinct examples are presented, which illustrate great diversity in the stoichiometric control of BK channel gating, depending on the site and nature of molecular perturbations. The molecular approaches could be extended to other membrane proteins whose N and C termini face opposite sides of the membrane.

eLife Assessment

This is a valuable study that explores the role of the conserved transcription factor POU4-2 in the maintenance, regeneration, and function of planarian mechanosensory neurons. The authors present convincing evidence provided by gene expression and functional studies to demonstrate that POU4-2 is required for the maintenance and regeneration of mechanosensory neurons and mechanosensory function in planarians. Furthermore, the authors identify conserved genes associated with human auditory and rheosensory neurons as potential targets of this transcription factor.

eLife Assessment

This study demonstrates the cartilage-protective effects of osteoactivin in inflammatory experimental models. The work offers valuable insights advancing current knowledge regarding regulation of joint inflammation and tissue degeneration. The evidence provided is compelling and suggests that osteoactivin may serve as a promising therapeutic target for inflammatory joint diseases.

eLife Assessment

This important work provides mechanistic insights into the development of cardiac arrhythmia and establishes a new experimental use case for optogenetics in studying cardiac electrophysiology. The agreement between computational models and experimental observations provides a convincing level of evidence that wave train-induced pacemaker activity can originate in continuously depolarized tissue, with the limitation that there may be differences between depolarization arising from constant optogenetic stimulation, as opposed to pathophysiological tissue depolarization. Future experiments in vivo and in other tissue preparations would extend the generality of these findings.

eLife Assessment

This study presents a valuable finding about how receptor-ligand binding pathways with multi-site phosphorylation can show non-monotonic responses to increasing ligand affinity and to kinase activity. The authors provide compelling evidence through a simple ordinary differential equation model of such signaling networks with the key new ingredient of ligand-induced receptor degradation. The work will be of interest to physicists and biologists working on signal transduction and biological information processing.

eLife Assessment

The authors present an important approach to identify imported P. falciparum malaria cases, combining genetic and epidemiological/travel data. This tool has the potential to be expanded to other contexts. The data was analyzed using convincing methods, including a novel statistical model. This study may be of interest to researchers in public health and infectious diseases beyond malaria.

eLife Assessment

The findings are valuable, given that they highlight the flexible and future-oriented nature of working memory. However, the evidence for the claims about context/color generalization, behavioural relevance of context decoding, dimensionality reduction, neural geometry, the XOR representation, and the specific contribution of working memory is incomplete. The work could be reframed in terms of prospective remapping.

eLife Assessment

This study provides novel and convincing evidence that both dopamine D1 and D2 expressing neurons in the nucleus accumbens shell are crucial for the expression of cue-guided action selection, a core component of decision-making. The research is systematic and rigorous in using optogenetic inhibition of either D1- or D2-expressing medium spiny neurons in the NAc shell to reveal attenuation of sensory-specific Pavlovian-Instrumental transfer, while largely sparing value-based decision on an instrumental task. The important findings in this report build on prior research and resolve some conflicts in the literature regarding decision-making.

eLife Assessment

This study provides important findings on the understanding of circannual timing in mammals, for which iodothyronine deiodinases (DIOs) have been suggested to be of critical importance, yet functional genetic evidence has been missing. The authors convincingly implicate dio3, the major inactivator of the biologically active thyroid hormone T3, in circannual timing in Djungarian hamsters, using a combination of correlative and gene knock-out experiments; thus this provides key insights into the evolution and function of animal annual timing mechanisms.

eLife Assessment

These findings are among some of the first to identify a behavioral and neurobiological substrate that disentangles nonassociative from associative fear responses following stress, providing a fundamental push forward in the field. The evidence supporting this is convincing and uses a variety of conceptual and technological approaches. This investigation will be of interest to neuroscientists and behaviourists broadly, as well as clinicians for its relevance to post-traumatic stress disorder.

eLife Assessment

The authors show that innate defensive behavior in mice is shaped by threat intensity, reward value, and social hierarchy, highlighting how value and social context influence instinctive decisions. The authors provide useful behavioural findings supported by strong data, yet the evidence is incomplete due to ambiguities about methodology and the computational model that remains largely descriptive.

eLife Assessment

This valuable study presents a theoretical framework for building continuous attractor networks that integrate with a wide range of topologies, which are of increasing relevance to neuroscientists. While the work offers solid evidence for most claims, the evidence supporting biological plausibility and key claims - such as the existence of a continuum of stable states and robustness across geometries - is currently incomplete and would benefit from further analysis or discussion. The study will be of interest to computational and systems neuroscientists working on neural dynamics and network models of cognition.

eLife Assessment

Avoidance of UV and blue light by the nematode C. elegans is mediated by the unusual transmembrane protein LITE-1, a non-canonical photoreceptor. In this valuable work, the authors provide convincing evidence that LITE-1 function is also required for avoidance of very high concentrations of the food-associated cue diacetyl, suggesting that it may also function as a diacetyl chemoreceptor. While the evidence for this idea is incomplete, these intriguing findings suggest an unexpected complexity in the function of this unusual photoreceptor.

eLife Assessment

This study examines how the neuronal cytoskeleton contributes to the formation of the axonal membrane-associated periodic skeleton (MPS) in embryonic dorsal root ganglia (DRG) neurons, using STED imaging. Conclusions are supported by convincing methods, data, and analyses. This useful work confirms previous data and improves our understanding of the roles of microtubules and actin dynamics in the chronological recruitment of MPS components.

eLife Assessment

This is a methodologically rich manuscript that is important for revealing the center-surround inhibition profile of expectation in orientation space. The analyses are compelling in validating the critical role of predictive coding feedback. The findings provide novel insights into how expectation optimizes perception via enhancement and suppression.

eLife Assessment

This study introduces a valuable simulation-based inference (SBI) framework to identify degenerate compensatory mechanisms that stabilize network activity despite neuronal hyperexcitability, a feature common to many brain disorders. By estimating posterior distributions of network parameters, the authors highlight factors such as threshold potential and interneuron-to-principal cell connectivity as key compensators for increased intrinsic excitability and interneuron loss. While the approach is promising and could become a key tool for probing network degeneracy, the study is currently incomplete. To fully realize its potential, the framework requires improved scalability and more rigorous cross-validation.

eLife Assessment

This study provides valuable insights into humans' ability to generalize knowledge of learned graph structures to new experiences that share the same structure but are built from different stimuli. However, the evidence for the authors' claims is incomplete, with the main claims of structural generalization and compositionality only partially supported by MEG and behavioral data. This study will be of interest to cognitive neuroscientists studying structure learning and generalization.

eLife Assessment

This study investigated the role of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the renal glomerular podocytes by characterizing the mice with dual deletion of both receptors in vivo as well as the cultured murine podocytes with induced deletion of both receptors in vitro. The solid data presented in this paper demonstrated the critical requirement of both IR and IGF1R signaling in normal podocyte physiology in mice, albeit a more detailed characterization of the mouse model is desired. Interestingly, long-range sequencing revealed significant retention of introns in mRNAs, due to an altered spliceosome level resulted from the loss of IR and IGF1 signaling in cultured podocytes. This new finding suggests an essential role of IR and IGF1R signaling in regulating RNA metabolism in podocyte, which provides useful information for the understanding of physiology and metabolism of podocytes. However, the underlying molecular mechanism for such a regulation is still unclear and awaits further studies.

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

eLife Assessment

This paper performs a valuable critical reassessment of anatomical and functional data, proposing a reclassification of the mouse visual cortex in which almost all the higher visual areas are consolidated into a single area V2. However, the evidence supporting this unification is incomplete, as the key experimental observations that the model attempts to reproduce do not accurately reflect the literature. This study will likely be of interest to neuroscientists focused on the mouse visual cortex and the evolution of cortical organization.