Multiple peer reviews

Chloride ions evoke taste sensations by binding to the extracellular ligand-binding domain of sweet/umami taste receptors

1. Nanako Atsumi
2. Keiko Yasumatsu
3. Yuriko Takashina
4. Chiaki Ito
5. Norihisa Yasui
6. Robert F Margolskee
7. Atsuko Yamashita

• Curated by eLife

  eLife assessment

  This fundamental study presents solid evidence for T1r (sweet /umami) taste receptors as chloride (Cl-) receptors, based on a combination of state-of-the-art techniques to demonstrate that T1r receptors from Medaka fish bind chloride and that this binding induces a conformational change in the heteromeric receptor. This conformational change leads to low-concentration chloride-specific action potential firing in nerves from neurons containing these receptors in mice, results that represent an important advance in our understanding of the logic of taste perception.

• Curated by Biophysics Colab

  Endorsement statement (17 November 2022)

  The preprint by Atsumi et al. describes how chloride binding to sweet- and umami-sensing proteins (T1R taste receptors) can evoke taste sensation. The authors use an elegant combination of structural, biophysical and electrophysiological approaches to locate a chloride binding site in the ligand-binding domain of medaka fish T1r2a/3 receptors. They convincingly show that low mM concentrations of chloride induce conformational changes and, using single fiber recordings, establish that mouse chorda tympani nerves are activated by chloride in a T1R-dependent manner. This suggests that chloride binding to sweet receptors could mediate the commonly reported sweet taste sensation following ingestion of low concentrations of table salt. The findings will be of broad relevance to those studying taste sensation and ligand recognition in GPCRs.

  (This endorsement by Biophysics Colab refers to version 2 of this preprint, which has been revised in response to peer review of version 1.)

Reviewed by eLife, Biophysics Colab

Longitudinal, Multi-Platform Metagenomics Yields a High-Quality Genomic Catalog and Guides an In Vitro Model for Cheese Communities

1. Christina C. Saak
2. Emily C. Pierce
3. Cong B. Dinh
4. Daniel Portik
5. Richard Hall
6. Meredith Ashby
7. Rachel J. Dutton

Reviewed by Arcadia Science

Single-molecule imaging with cell-derived nanovesicles reveals early binding dynamics at a cyclic nucleotide-gated ion channel

1. Vishal R. Patel
2. Arturo M. Salinas
3. Darong Qi
4. Shipra Gupta
5. David J. Sidote
6. Marcel P. Goldschen-Ohm

• Curated by Biophysics Colab

  Endorsement statement (30 August 2021)

  The preprint by Patel et al. describes the development of a single molecule approach for studying individual ligand binding events in membrane proteins within native lipid environments. The approach represents an elegant way to investigate the dynamics of ligand binding, and potential relationships with conformational changes, in molecules embedded within physiological membranes. The work makes an important contribution that will be of interest to scientists working on molecular mechanisms in ion channels and other membrane proteins.

  (This endorsement by Biophysics Colab refers to version 2 of this preprint, which has been revised in response to peer review of version 1.)

Reviewed by Biophysics Colab

Fast ATP-Dependent Subunit Rotation in Reconstituted F _o F ₁ -ATP Synthase Trapped in Solution

1. Thomas Heitkamp
2. Michael Börsch

• Curated by Biophysics Colab

  Endorsement statement (21 September 2021)

  The preprint by Heitkamp and Börsch describes visualization of the fast ATP-dependent subunit rotation in reconstituted FoF1-ATP synthase using single-molecule FRET techniques. Using a highly innovative method for trapping single molecules, the authors were able to see the static and dynamic disorder of enzymes in solution, not possible in previous studies. The work makes important contributions to both understanding the structural dynamics of FoF1-ATP synthase and the development of methodologies to study single-molecule dynamics of other proteins in solution.

  (This endorsement refers to version 5 of this preprint, which was peer reviewed by Biophysics Colab.)

Reviewed by Biophysics Colab

KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity

1. Marjorie Fournier
2. Amélie Rodrigue
3. Larissa Milano
4. Jean-Yves Bleuyard
5. Anthony M Couturier
6. Jacob Wall
7. Jessica Ellins
8. Svenja Hester
9. Stephen J Smerdon
10. László Tora
11. Jean-Yves Masson
12. Fumiko Esashi

Reviewed by eLife, Review Commons

Heritable functional architecture in human visual cortex

1. Ivan Alvarez
2. Nonie J. Finlayson
3. Shwe Ei
4. Benjamin de Haas
5. John A. Greenwood
6. D. Samuel Schwarzkopf

• Curated by eLife

  Evaluation Summary:

  The paper was viewed as generally sound. There main concern was that the findings were viewed as incremental without a demonstration of a link between the heritability of pRF properties and visual perception. The speculation in the Discussion about shared perceptual experience is intriguing, but psychophysical (or other) evidence would be needed to really make that point clearly. In addition, there was some discussion about the non-independence of vertices and correlation values. In the end, we all agreed that non-independent vertices may inflate correlation coefficient values, but that this is unlikely to substantially affect conclusions drawn from comparisons of monozygotic and dizygotic twins.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Reviewed by eLife

Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome

1. Joanna Mattis
2. Ala Somarowthu
3. Kevin M Goff
4. Evan Jiang
5. Jina Yom
6. Nathaniel Sotuyo
7. Laura M Mcgarry
8. Huijie Feng
9. Keisuke Kaneko
10. Ethan M Goldberg

• Curated by eLife

  Evaluation Summary:

  Dravet syndrome, a severe seizure disorder resulting from a sodium channel mutation, is widely thought to result from impaired synaptic inhibition. Here the authors present multi-level evidence that excess synaptic excitation in the dentate gyrus is a locus of pathology. These results provide new insight into pathological mechanisms in Dravet syndrome that will be of interest to a broad range of neuroscientists studying epilepsy, as well as the role of the hippocampus and synaptic alterations in neurological disease.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Reviewed by eLife

The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy

1. Yang Guo
2. Ze-Yan Yu
3. Jianxin Wu
4. Hutao Gong
5. Scott Kesteven
6. Siiri E Iismaa
7. Andrea Y Chan
8. Sara Holman
9. Silvia Pinto
10. Andy Pironet
11. Charles D Cox
12. Robert M Graham
13. Rudi Vennekens
14. Michael P Feneley
15. Boris Martinac

• Curated by eLife

  Evaluation Summary:

  In this work, the authors subjected mice with cardiomyocyte-specific deletion of ion channel TRPM4 to transverse aortic constriction-induced pressure overload, which is a well-validated model for heart failure. The study showed that cell-specific loss of TRPM4 in cardiomyocytes could protect against pathological left ventricular hypertrophy which is associated with an attenuation of pathological changes in the expression several genes that become dysregulated during the development pathological hypertrophy. These findings are likely to contribute to understanding of pressure overload-induced hypertrophy heart disease and the pathophysiology of heart failure.

  (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Reviewed by eLife

Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers

1. Eduardo J. Fernandez-Perez
2. Braulio Muñoz
3. Denisse A. Bascuñan
4. Christian Peters
5. Nicolas O. Riffo-Lepe
6. Maria P. Espinoza
7. Peter J. Morgan
8. Caroline Filippi
9. Romain Bourboulou
10. Urmi Sengupta
11. Rakez Kayed
12. Jérôme Epsztein
13. Luis G. Aguayo

• Curated by eLife

  Summary: This study provides new information about how amyloid beta (Ab) oligomers (Abo) may contribute to hyperexcitability which is important because Abo and hyperexcitability have been suggested to occur early in the development of Alzheimer's disease (AD). The authors added Abo intracellularly (iAbo) using dialysis from a patch pipette. Their data suggest iAbo led to increased synaptic excitation mediated presynaptically by retrograde signalling of nitric oxide (NO). Furthermore, they present data suggesting that there is spread of this increase in excitation to neighboring neurons.

  Major Comments:

  1. The nature of the described effects of intracellular iAbo are quite unexpected, occurring within a minute of obtaining intracellular recording configuration, which contrasts with at least on previous study. While some controls for intracellular application of oligomers are provided, with reverse iAbo failing to reproduce the effect (Fig 2S1) and the effect being blocked by the antibody A11 (Fig 2S2), further controls are necessary to explain this rapid effect, which seems faster than that for the diffusion of the fluorescent tag into the cell (Fig 1S1). Note that Pusch and Neher (Pflug Arch 1988) determined diffusion time for different substances. That paper or others should be cited, and then some estimation of equilibrium time based on diffusibility of ab oligomers should be provided. Equations 17 and 18 in that paper provide some estimates based on molecular weight or diffusion coefficient. One point in Pusch and Neher is there is extreme variability between access times across cells and that it depends on access resistance, of course. Finally, the Pusch and Neher calculations were for small spherical cells - diffusion into spatially extended cells with long dendrites where the synapses are will take even longer. This is especially critical, as one of the major papers of precedent for this work is that of Ripoli, et al. 2014 (cited in the manuscript) in which the authors of that work examined effects of patch applied Ab42 over the course of 20 minutes, with internal controls showing differences between initial responses, right after break in, and 20 minutes later when the oligomer and/or monomers will have had a chance to equilibrate with the intracellular contents. It is not clear how such a rapid effect as indicated in the figures could be achieved by such a large molecule as Ab. The data suggest a time to effect of seconds to minutes, and the peak effect occurs before the fluorescence peaks, which seems hard to explain.

  2. The data need reorganization in terms of their results using h-iAbo or iAbo. There needs to be a clear demonstration of why both were used if the results are generalized with both (or not) and if they can actually use both interchangeably.

  3. The authors need to clearly indicate whether the experiments were done in culture or in slices. The authors need to provide a rationale on why specific experiments were done in culture and others in slices.

  4. There are aspects of the observed phenomenon that have not been taken adequately into account. For example, the authors have not investigated the effects of application of oligomeric beta-amyloid to either the extracellular space or the presynaptic neurons, two other compartments of the synapse.

  5. Aspects of the data raise questions: 1) Western blots appear to have multiple bands 2) evidence that the fluorescent probe accurately measures NO. 3) The bursts of activity are not quantified. What was defined as a burst? What was the burst frequency and did it change over the recording period? 4)The external solution for cultures contain 5.4 mM K+ which is quite high, and can induce hyperexcitability. Similarly, the use of 100uM AMPA and GABA seem very high. Justifying these high concentrations is important. They should lead to hyperexcitability and toxicity (AMPA) over time. Another point of concern is that the concentration of K+ for the slice work is 3 mM, much different than cultures. There are also differences in Mg2+ and Ca2+, making data hard to compare in the two preparations. 5) sample sizes are unclear 6) Intracellular Ab produces increases in both EPSCs and IPSCs. However, in Fig 3, the IPSC measures using a charge transfer quantification, did not show a significant change in response to iAbo, in contrast to EPSCs. 7) With regard to the inhibition, In the schematic on Fig. 10, I find this incomplete and slightly inaccurate since it shows one terminal releasing both glutamate and GABA with NO increasing both. While this is obviously an oversimplification, it's slightly inaccurate since NO was not directly shown to increase sIPSCs. Were NOS blockers able to disrupt the increase in sIPSCs? Moreover, there are many papers that have shown that PKC can also phosphorylate GABA receptors and increase their conductance. What could be the reason that this was not involved here? This needs to be discussed.

  6. How this work relates to other studies is necessary. For example, how this study is related to others about Ab exposure is lacking. Also, regarding hyperexcitability, many possible causes exist. These should be summarized in the introduction and the authors should comment how their results fit with these studies. Regarding PKC and NO, PKC and NO have several known actions throughout the brain and body. How do the effects the authors have identified relate to all these other effects? For example, if PKC is activated by another mechanism, would it occlude effects of Ab? What are the changes in PKC and NO in AD? Regarding the ability of the data to address AD, a major issue is whether the results are relevant to AD or represent interesting pharmacological data about what Ab can potentially do in some of its forms in normal tissue.

  Reviewer #2 opted to reveal their name to the authors in the decision letter after review.

Reviewed by eLife

Human complex exploration strategies are extended via noradrenaline-modulated heuristics

1. M Dubois
2. J Habicht
3. J Michely
4. R Moran
5. RJ Dolan
6. TU Hauser

Reviewed by eLife