Der französische Konzern TotalEnergies fördert in den USA mit 17 00 Förderanlagen via Fracking Erdgas, das dann verflüssigt wird. Allein in der Region von Arlington in Texas sind dadurch 420.000 Menschen toxischen Emissionen ausgesetzt. Die Libération publiziert die Ergebnisse einer gemeinsamen mit Disclose durchgeführten Recherche. Das produzierte LNG wird auch nach Frankreich und Europa verschifft.

https://www.liberation.fr/environnement/pollution/ma-petite-fille-etouffe-a-force-de-tousser-le-scandale-du-gaz-de-schiste-americain-que-total-importe-en-france-20230926_TVBMN7L37BCD5FMQPXTC6WDRFM/

Disclose-Veröffentlichung: https://disclose.ngo/fr/article/gaz-de-schiste-totalenergies-au-coeur-dun-scandale-sanitaire-et-environnemental-au-texas

for - sleep hygiene - 4 - walk it out

advice - sleep hygiene - 4 - walk it out - try not to spend too much time in bed awake, - as your brain learns to associate the bed with waking - if you wake up in the night, walk it out for about half an hour

Reviewer #4 (Public Review):

This study provides direct evidence showing that Sema7a plays a role in the axon growth during the formation of peripheral sensory circuits in the lateral-line system of zebrafish. This is a valuable finding because the molecules for axon growth in hair-cell sensory systems are not well understood. The majority of the experimental evidence is convincing, and the analysis is rigorous. The evidence supporting Sema7a's juxtracrine vs. secreted role and involvement in synapse formation in hair cells is less conclusive. The study will be of interest to cell, molecular and developmental biologists, and sensory neuroscientists.

Les témoignages vont souvent dans le sens de ceux pour lesquels cela à fonctionner, entretenant et diffusant l’illusion du mythe de l’amour, faisant l'impasse sur la part de concession, de discussions, de négociations, de réajustements, qui a été inhérente au fonctionnement d’une relation intime et qui est cachée ou tue car cela ne correspond pas à l'image romantique que l'on se fait de la rencontre "idéale".

D'emblée l'article pose comme un constat à valeur d'universalité que nous sommes tous impactés. Il expose l'idée que cela va au-delà de notre usage effectif ou non des réseaux sociaux dans la quête de l'amour. Cette affirmation semble pouvoir être remise en question notamment au regard du fait que nous n'avons pas tous la même utilisation d'internet comme les personnes âgées par exemple qui sont loin d'en comprendre tous les codes et usages.

Propos intéressants à citer en ouverture de l'article mais qui auraient eu besoin d'être agrémentés de quelques données statistiques.

Il est plus aisé de fantasmer ça sur un écran que de le mettre en place pour de vrai et de s’en donner les moyens dans la vie réelle où les contraintes sont plus palpables et vont demander de nombreux efforts.

Mise en évidence du fonctionnement épistolaire de ces conversations, principe fondamental. Le temps pour l’autre est pris quand on a le temps soit même de se connecter sur la plateforme, de répondre à un sms. Il n'y a pas de contrainte d’écouter l’autre ou de répondre à ses sollicitations quand nous ne nous sentons pas disponible, donc pas de déconvenue, contournement des efforts de concession, de disponibilités, etc qui incombent à la relation.

A supposer qu’il y ait une méthode pour trouver l’amour. Une recette toute faite qu’il faudrait appliquer comme un process. On revient à l'idée que l'on est sur une certaine rentabilité, une forme de taylorisme de l'amour.

L’humain est un être complexe, nous ne pouvons pas nous réduire à des cases « j’aime faire la cuisine, j’aime faire du jogging, etc… ». Nous avons besoin d'entretenir des subtilités en lien avec ce que nous aimons car cela contribue à dire au monde qui nous sommes. Ce sont les subtilités qui font que je vais trouver cela touchant ou ridicule mais risible, etc… Il est des choses qui à l’écrit n’émettent pas du tout la même vibration qu’à l’oral. Une phrase écrite peut renvoyer à plusieurs réalité et il n'y aura que la façon d'exprimer cette phrase à l'oral qui en montrera les nuances et qui font que je suis unique. Si je dis « j’aime courir sous la pluie car je sens l’odeur des herbes, des arbres, du bitume mouillé » mais que la personne ne me voit pas entrain d’exprimer cette idée à partir de ma personnalité propre, elle peut trouver cela très touchant ou complètement mièvre, ou ne pas savoir à quoi je fais référence exactement. Les mots sont vides de sens sans le para-verbal et le non verbal.

Le corps est passif, il n’est pas en mouvement, il n’est pas investi dans cette rencontre avec l’autre. Ce qui est actif et activé c’est notre cerveau et les fantasmes qui s'y jouent. L’équilibre est à trouver dans une satisfaction corporelle et intellectuelle. Simultanément.

Apport de psychologie pure. En lien direct avec le thème de la revue.

Revanche pseudo-féministe illusoire car en réalité il n’y a pas de rapport de force à établir entre les hommes et les femmes il s’agirait davantage que chacun respecte l’autre pour ce qu’il est avec ses qualités et ses défauts pour pleinement apprécier la rencontre. Le besoin de plaire rejoint la validation sociale qui est un booster d’estime de soi.

Quelques pourcentages sont cités afin de donner une représentation globale. Il n'est pas précisé ce qui est entendu par "unions amoureuses". Une relation amoureuse durable ou brève ? conforme aux attentes de l’utilisateur ou non ? Il manque des critères objectivables.

Site dont le logo est un homme dans un caddie. Peut-on s’attendre à autre chose qu’à un rapport de consommation de la relation amoureuse ?

Là encore des deux côtés on n’assume pas la part de l’échec, la déconvenue, qui peut-être possible mais plus encore, on n’assume pas la réalité de ce qu’est un être humain. Soulève un problème plus profond : en mettant à distance derrière un écran on oublie peut-être qu’un humain réel c’est aussi quelqu’un qui a des problèmes de santé, des problèmes personnels, qui subit une dégradation lente et partielle de son corps… Pose finalement la question du virtuel : est-ce que ce ne serait pas la distance qui nous ferait oublier la réalité des rapports humains ? De la même façon que l’on observe des commentaires haineux ou inappropriée sous le contenu de personnes exposées sur internet tels que les influenceurs pour ne citer qu’eux.

Mise en évidence d’une mutation sociale : nouvelle révolution pour les femmes, à la manière de mai 68 les règles, l’ordre établi jusqu’à lors est remis en question.

Lien causale proposé ici : les applications de rencontres contribuent à l’augmentation de la rapidité dans le fonctionnement de la société. Nous pouvons « swiper » d’un geste simple, presque intuitif. Il n’y a quasiment plus de place pour l'attente, la déconvenue, pour « la part d’échec » qui fait pourtant parti du processus d’acclimatation à l’autre.

Les utilisateurs sont exigeants, voir intransigeants car ils ont les moyens de l’être étant donné que la personne peut être remplacée par une simple nouvelle recherche si elle ne correspond pas aux attentes.

Constatation d’une régression par rapport à une avancée des mœurs. Mise en perspective avec l'évolution sociale. Alain Héril nous rappelle que le lieu de révolution des mœurs qu’a été mai 68 a permis de faire rentrer une composante essentielle dans la relation à l’autre : la part d’échec possible lorsque deux individus se côtoient pour essayer d’entretenir une relation amoureuse. A l’extrême opposé, sur les sites de rencontre, la possibilité de l’échec n’existe pas, et est même gommée puisqu’ils proposent du « sur-mesure » et entretiennent « le mythe de l’amour ».

DOI: 10.1016/j.celrep.2024.113955

Resource: (ZFIN Cat# ZDB-ALT-081212-4,RRID:ZFIN_ZDB-ALT-081212-4)

Curator: @abever99

SciCrunch record: RRID:ZFIN_ZDB-ALT-081212-4

What is this?

Reviewer #4 (Public Review):

Summary:

In their revised manuscript "Conformational dynamics of a nicotinic receptor neurotransmitter binding site," Singh and colleagues present molecular docking and dynamics simulations to explore the initial conformational changes associated with agonist binding in the muscle nicotinic acetylcholine receptor, in context with the extensive experimental literature on this system. Their central findings are of a consistently preferred pose for agonists upon initial association with a resting channel, followed by a dramatic rotation of the ligand and contraction of a critical loop over the binding site. Principal component analysis also suggests the formation of an intermediate complex, not yet captured in structural studies. Binding free energy estimates are consistent with the evolution of a higher-affinity complex following agonist binding, with a ligand efficiency notably similar to experimental values. Snapshot comparisons provide a structural rationale for these changes on the basis of pocket volume, hydration, and rearrangement of key residues at the subunit interface.

Strengths:

Docking results are clearly presented and remarkably consistent. Simulations are produced in triplicate with each of four different agonists, providing an informative basis for internal validation. They identify an intriguing transition in ligand pose, not well documented in experimental structures, and potentially applicable to mechanistic or even pharmacological modeling of this and related receptor systems. The paper seems a notable example of integrating quantitative structure-function analysis with systematic computational modeling and simulations, likely applicable to the wider journal audience.

Weaknesses:

The response to initial review is somewhat disappointing, declining in some places to implement suggested clarifications, and propagating apparent errors in at least one table (Fig 2-source data 1). Some legends (e.g. Fig 2-supplement 4, Fig 3, Fig 4) and figure shadings (e.g. Fig 2-supplement 2, Fig 6-supplement 2) remain unclear. Apparent convergence of agonist-docked simulations towards a desensitized state (l 184) is difficult to interpret in absence of comparative values with other states, systems, etc. In more general concerns, aside from the limited timescales (200 ns) that do not capture global rearrangements, it is not obvious that landscapes constructed on two principal components to identify endpoint and intermediate states (Fig 3) are highly robust or reproducible, nor whether they relate consistently to experimental structures.

step 4 - self-centered vs selfish

Reviewer #3 (Public Review):

Summary:

The molecular mechanism of regulated exocytosis has been extensively studied in the context of synaptic transmission. However, in addition to neurotransmitters, neurons also secrete neuropeptides and neurotrophins, which are stored in dense core vesicles (DCVs). These factors play a crucial role in cell survival, growth, and shaping the excitability of neurons. The mechanism of release for DCVs is similar, but not identical, to that used for SV exocytosis. This results in slow kinetic and low release probabilities for DCV compared to SV exocytosis. There is a limited understanding of the molecular mechanisms that underlie these differences. By investigating the role of rabphilin-3A (RPH3A), Hoogstraaten et al. uncovered for the first time a protein that inhibits DCV exocytosis in neurons.

Strengths:

In the current work, Hoogstraaten et al. investigate the function of rabphilin-3A (RPH3A) in DVC exocytosis. This RAB3 effector protein has been shown to possess a Ca2+ binding site and an independent SNAP25 binding site. Using colocalization analysis of confocal imaging the authors show that in hippocampal neurons RPH3A is enriched at pre- and post-synaptic sites and associates specifically with immobile DCVs. Using site-specific RPH3A mutants they found that the synaptic location was due to its RAB3 interaction site. They further could show that RPH3A inhibits DCV exocytosis due to its interaction with SNAP25. They came to that conclusion by comparing NPY-pHluorin release in WT and RPH3A KO cells and by performing rescue experiments with RPH3A mutants. Finally, the authors showed that by inhibiting stimulated DCV release, RPH3A controlled the axon and dendrite length possibly through the reduced release of neurotrophins. Thereby, they pinpoint how the proper regulation of DCV exocytosis affects neuron physiology.

Weaknesses:

Data context<br /> One of the findings is that RPH3A accumulates at synapses and is mainly associated with immobile DCVs. However, Farina et al. (2015) showed that 66% of all DCVs are secreted at synapses and that these DCVs are immobile prior to secretion. To provide additional context to the data, it would be valuable to determine if RPH3A KO specifically enhances secretion at synapses. Additionally, the authors propose that RPH3A decreases DCV exocytosis by sequestering SNAP25 availability. At first glance, this hypothesis appears suitable. However, due to RPH3A synaptic localization, it should also limit SV exocytosis, which it does not. In this context, the only explanation for RPH3A's specific inhibition of DCV exocytosis is that RPH3A is located at a synapse site remote from the active zone, thus protecting the pool of SNAP25 involved in SV exocytosis from binding to RPH3A. This hypothesis could be tested using super-resolution microscopy.

Technical weakness<br /> One technical weakness of this work consists in the proper counting of labeled DCVs. This is significant since most findings in this manuscript rely on this analysis. Since the data was acquired with epi-fluorescence or confocal microscopy, it doesn't provide the resolution to visualize individual DCVs when they are clumped. The authors use a proxy to count the number of DCVs by measuring the total fluorescence of individual large spots and dividing it by the fluorescence intensity of discrete spots assuming that these correspond to individual DCVs. This is an appropriate method but it heavily depends on the assumption that all DCVs are loaded with the same amount of NPY-pHluorin or chromogranin B (ChgB ). Due to the importance of this analysis for this manuscript, I suggest that the authors show that the number of DCVs per µm2 is indeed affected by RPH3A KO using super-resolution techniques such as dSTORM, STED, SIM, or SRRF.

Reviewer #4 (Public Review):

Summary:<br /> Recent progress in root economics has revealed global-scale axes of covaried root traits that reflect various root resource acquisition strategies. These covariance patterns are powerful tools for understanding root functional diversity. However, roots do not function in isolation for below-ground resource acquisition. Rather, symbiotic fungi and rhizosphere microorganisms often collaborate with plant roots, forming a root-microbial-soil continuum. This study seeks to provide novel insights into this continuum by extending the existing framework of root economics to include the structures of root-associated microorganisms. I find this topic highly relevant. Considering the role of soil microorganisms is undoubtedly crucial for a more comprehensive understanding of below-ground resource strategies.

Major comments:<br /> A key finding of this study is a relationship between root N and the tendency for roots to associate with particular types of mycorrhizal associations (Line 27, Fig. 2). The authors concluded that this indicates "a linkage from simple root traits to fungal-mediated carbon nutrient cycling" (line 27) and integrates "microbial functions into the root economics framework," (line 32). If substantiated, this correlation could represent a significant discovery about the connection between root functional traits and root-associated fungi. It suggests that low root N, indicative of low metabolic activity within the root economics framework, is linked with forming EcM associations. However, I am not fully convinced this is the case based on the current data presentation and interpretation.

First, there is no biological interpretation of this relationship between root N and mycorrhizal type. It merely noted that root N is indicative of root metabolic activity, and thus by relating root N to fungal composition, "the trait-related root economics and fungal-driven nutrient economics may be integrated into a unified framework" (lines 221-224). Why would roots with low N and low metabolic activity tend to favor EcM associations? What are the potential mechanisms? Biological interpretation is essential for understanding whether a statistical correlation reflects a causal and meaningful relationship or is coincidental.

I am also concerned that this relationship may be spurious, especially when it lacks biological interpretation. EcM is underrepresented in this study (8 EcM species, of which more than half are conifers and oaks vs. 44 AM) and seems to cluster at higher elevations (line 231). Thus, the tree species/individual data points are not independent, but phylogenetically and geographically clustered. The unique properties at higher elevations (e.g., distinct plant community structures, low levels of mineral N) may drive both the lower root N and the prevalence of EcM associations. This scenario aligns with the observation that at higher elevations, AM roots also exhibited low root N (Line 231). In this case, root N may not directly relate to mycorrhizal type but is characteristic of certain locations (or closely related species), and it would be misleading to suggest that low root N/metabolic activity, a proxy in fast-slow root economics, is directly linked to the preference for a particular mycorrhizal type (lines 27-28, 220 - 224). In summary, because the studied tree species appear to be clustered both phylogenetically and geographically, these factors need to be carefully taken into account in the statistical analysis and data interpretation to understand the underlying causes of the apparent relationship and prevent overinterpretation. I also recommend, if possible, providing a visual presentation of the geographical and phylogenetic distribution of the studied tree species.

That being said, this dataset is undoubtedly valuable in revealing the shifts in the compositional structures of root-associated soil microorganisms. However, integrating the traits of microbial composition to root trait economics would require more caution and careful examination of the potential driving causes.

DOI: 10.7554/eLife.42455

Resource: (ZFIN Cat# ZDB-ALT-150424-4,RRID:ZFIN_ZDB-ALT-150424-4)

Curator: @scibot

SciCrunch record: RRID:ZFIN_ZDB-ALT-150424-4

What is this?

Reviewer #4 (Public Review):

The members of the Kimmins lab perform a dietary study in mice to investigate the impact of obesity of fathers on the development of their offspring. To do so, they expose male mice to a high fat diet and determine the distribution and occupancy levels of the histone H3 lysine 4 trimethylation (H3K4me3) mark in spermatozoa and perform gene expression studies on placenta tissue obtained from mouse embryos during mid-gestation development. The authors report changes in H3K4me3 occupancy in sperm as well as in transcriptomes of placentas of male and female embryonic offspring. While the authors perform extensive computational analysis of the transcriptomic and chromatin immunoprecipitation data, the authors do not go much beyond making correlative statements at mainly the genome wide level between changes for H3K4me3 in sperm and transcriptional changes in placenta, the latter of which are in part related to changes in cellular composition (as deduced from transcriptional data). Given that both parental mice had the same genetic background, it was not possible to deduce parental specific contributions to transcriptional changes as observed in placentas of offspring. In all, the study falls short in increasing mechanistic insights into this important biological phenomenon.

Reviewer #4 (Public Review):

Summary:<br /> The authors set out to address whether TTX resistance in a subset of snakes is due to mutations near the selectivity filters of their Nav1.4 channels. They present an investigation of the properties of two heterologously expressed Nav1.4 channels, bearing the Nav1.4EPN and Nav1.4LVNV mutations found in TTX-resistant snakes. After assessing their sensitivity to TTX, they have studied the biophysical properties of these mutants by electrophysiological methods and discovered that the voltage dependence of their activation and inactivation remains unchanged compared to the TTX-sensitive Nav1.4. These experiments revealed some kinetic differences in Nav1.4LVNV and that both Nav1.4EPN and Nav1.4LVNV show a reduced unitary conductance. The authors also assessed muscle properties (resistance, force development, and contraction timing) of two groups of snakes (in vivo and in dissected muscles) with Nav1.4EPN and Nav1.4LVNV mutations. These experiments showed a reduced performance for the skeletal muscles of snakes bearing Nav1.4EPN and Nav1.4LVNV background. Finally, the authors have built homology models of Nav1.4EPN and Nav1.4LVNV channels to hypothesize a molecular explanation of the altered properties.

Strengths:<br /> • Three levels of analysis are performed in this study: 1) functional characterization of mutated Nav1.4 channels through electrophysiology; 2) molecular level comparisons between human and snake Nav1.4 channels structures through homology modelling; 3) organismal performance/muscle strength experiments on snakes that carry Nav1.4 mutants that render them virtually TTX resistant.

Weaknesses:<br /> • While there is reason to believe that there is a causal link between the observed changes in Nav1.4 and the changes on the organismal level, the evidence presented is not definitive. Specifically, the conclusions from the biophysical/electrophysiological experiments are extrapolated to be causal for the altered muscle performance in TTX-resistant snakes, although there might be alternative explanations. First, the reduction in muscle force could also originate from changes in the calcium release apparatus or other alterations in the electrical properties of the muscle (are there changes in length or duration of muscle action potentials? Is there a change in the fraction of muscle cells that fail action potentials, as would be expected for a significant reduction in conductance?). Second, it remains unclear if, among the different snake Nav channels (e.g. Nav1.6 in motor neurons), Nav1.4 is the only one to display side chain alterations in these TTX-resistant snakes.

• Some of the data presented as part of the NSNA is not sufficiently convincing and should be supplemented with additional evidence or carefully discussed with regard to its limitations.

• The mutations studied are located close to the selectivity filter of Nav1.4. This means that the most likely consequence of the mutations is altered sodium selectivity, possibly along with changes to block extracellular calcium. But these possibilities are not currently addressed.

• The description and accuracy of the homology model remains somewhat unclear, as no validation of the modeled channel has been presented. Therefore, the accuracy of the homology model remains vague, which calls into question to what degree the molecular features of this model can be linked to the electrophysiological findings.

Volunteer 'Readers' for the Oxford English Dictionary were encouraged to write down interesting headwords along with their appearances in-situ along with the associated bibliographical information. The recommended paper size was 4 x 6-inch pieces of paper which were commonly called 'slips'.

(Double check this against the historical requests from James Murray.)

DOI: 10.1016/j.neuron.2024.01.001

Resource: (ZFIN Cat# ZDB-ALT-130110-4,RRID:ZFIN_ZDB-ALT-130110-4)

Curator: @evieth

SciCrunch record: RRID:ZFIN_ZDB-ALT-130110-4

What is this?

Reviewer #4 (Public Review)

Summary:<br /> Cav1.4 voltage-gated calcium channels play an important role in neurotransmission at mammalian photoreceptor synapses. Mutations in the CACNA1f gene lead to congenital stationary night blindness that particularly affects the rod pathway. Mouse Cav1.4 knockout and Cav1.4 knockin models suggest that Cav1.4 is also important for the cone pathway. Deletion of Cav1.4 in the knockout models leads to signaling malfunctions and to abundant morphological re-arrangements of the synapse suggesting that the channel not only has a role in the influx of Ca2+ but also in the morphological organization of the photoreceptor synapse. Of note, also additional Cav-channels have been previously detected in cone synapses by different groups, including L-type Cav1.3 (Wu et al., 2007; pmid; Kersten et al., 2020; pmid), and also T-type Cav3.2 (Davison et al., 2021; pmid 35803735).

In order to study a conductivity-independent role of Cav1.4 in the morphological organization of photoreceptor synapses, the authors generated the knockin (KI) mouse Cav1.4 G369i in a previous study (Maddox et al., eLife 2020; pmid 32940604). The Cav1.4 G369i KI channel no longer works as a Ca2+-conducting channel due to the insertion of a glycine in the pore-forming unit (Madox et al. elife 2020; pmid 32940604). In this previous study (Madox et al. elife 2020; pmid 32940604), the authors analyzed Cav1.4 G369i in rod photoreceptor synapses. In the present study, the authors analyzed cone synapses in this KI mouse.

For this purpose, the authors performed a comprehensive set of experimental methods including immunohistochemistry with antibodies (also with quantitative analyses), electrophysiological measurements of presynaptic Ca2+ currents from cone photoreceptors in the presence/absence of inhibitors of L-type- and T-type- calcium channels, electron microscopy (FIB-SEM), ERG recordings and visual behavior tests of the Cav G369i KI in comparison to the Cav1.4 knockout and wild-type control mice.

The authors found that the non-conducting Cav channel is properly localized in cone synapses and demonstrated that there are no gross morphological alterations (e.g., sprouting of postsynaptic components that are typically observed in the Cav1.4 knockout). These findings demonstrate that cone synaptogenesis relies on the presence Cav1.4 protein but not on its Ca2+ conductivity. This result, obtained at cone synapses in the present study, is similar to the previously reported results observed for rod synapses (Maddox et al., eLife 2020, pmid 32940604). No further mechanistic insights or molecular mechanisms were provided that demonstrated how the presence of the Cav channels could orchestrate the building of the cone synapse.

Strengths:<br /> The study has been expertly performed. A comprehensive set of experimental methods including immunohistochemistry with antibodies (also with quantitative analyses), electrophysiological measurements of presynaptic Ca2+ currents from cone photoreceptors in the presence/absence of inhibitors of L-type- and T-type- calcium channels, electron microscopy (FIB-SEM), ERG recordings and visual behavior tests of the Cav G369i KI in comparison to the Cav1.4 knockout and wild-type control mice.

Weaknesses:<br /> The study has been expertly performed but remains descriptive without deciphering the underlying molecular mechanisms of the observed phenomena, including the proposed homeostatic switch of synaptic calcium channels. Furthermore, a relevant part of the data in the present paper (presence of T-type calcium channels in cone photoreceptors) has already been identified/presented by previous studies of different groups (Macosko et al., 2015; pmid 26000488; Davison et al., 2021; pmid 35803735; Williams et al., 2022; pmid 35650675). The degree of novelty of the present paper thus appears limited.

What to listen for in jazz Kernfeld 1995

Reviewer #4 (Public Review):

Summary:<br /> In their manuscript "Conformational dynamics of a nicotinic receptor neurotransmitter binding site," Singh and colleagues present cogent molecular docking and dynamics simulations to explore the initial conformational changes associated with agonist binding in the muscle nicotinic acetylcholine receptor, aligned with the extensive experimental literature on this system. Their central findings are of a consistently preferred pose for agonists upon initial association with a resting channel, followed by a dramatic rotation of the ligand and contraction of a critical loop over the binding site. Principal component analysis also suggests the formation of an intermediate complex, not yet captured in structural studies. Binding free energy calculations are consistent with the evolution of a higher-affinity complex following agonist binding, with a ligand efficiency notably similar to experimental values. Snapshot comparisons provide a structural rationale for these changes on the basis of pocket volume, hydration, and rearrangement of key residues at the subunit interface.

Strengths:<br /> Docking results are clearly presented and remarkably consistent. Simulations are produced in triplicate with each of four different agonists, providing an informative basis for internal validation. They identify an intriguing transition in ligand pose, not well documented in experimental structures, and potentially applicable to mechanistic or even pharmacological modeling of this and related receptor systems. The paper seems a notable example of integrating quantitative structure-function analysis with systematic computational modeling and simulations, likely applicable to the wider journal audience.

Weaknesses:<br /> Timescales (200 ns) do not capture global rearrangements of the extracellular domain, let alone gating transitions of the channel pore, though this work may provide a launching point for more extended simulations. A more general concern is the reproducibility of the simulations, and how representative states are defined. It is not clear whether replicates were included in principal component analysis or subsequent binding energy calculations, nor how simulation intervals were associated with specific states. Structural analysis largely focuses on snapshots, with limited direct evidence of consistency across replicates or clusters. Figure legends and tables could be clarified.

Reviewer #4 (Public Review):

Overview:

The present manuscript by Zhou and colleagues investigates the impact of a new combination of compounds termed CHIR99021 and A-485 on stimulating cardiac cell regeneration. This manuscript fits the journal and addresses an important contribution to scientific knowledge. However, the following major revisions need to be addressed as stated below.

Major comments:

-The authors should include more information that clarifies and justifies their hypothesis.<br /> -The story line is not well developed and thus not convincing since the results from different sections are not well connected.<br /> -The main text needs to be improved, and authors should explain their purpose in choosing to study ISL1-CMs. Also, to well argument why they conducted this study and its significance.<br /> -Page 3, row 57-58: Please add the references.<br /> -Page 3-4, row 67-68, authors stated "When CMs resumed contraction, they were treated with individual small molecules from a collection of over 4,000 compounds for 3 days (SI Appendix, Fig. S1C and Table S1), and then fixed and immunostained with ISL1". Please explain better, and show the results of the selected screening compounds.<br /> -Authors must make an effort to discuss their findings in a bold way in order to provide a comprehensive and articulate explanation of their results to the readers. There is much information missing from this section. This should also propose new research avenues and foresee the challenges in future investigations.<br /> -Authors must include a conclusion and future perspectives of this study.<br /> - Page 4, row 73, the authors stated that the unique compound combination 'CHIR99021 and A-485' was found to be the most efficient in promoting ISL1 expression with a healthy cell state. However, the authors should prove that by showing at least the cell viability of these compound combinations at different concentrations and timings as a supplementary figure.<br /> -There is some missing information in the methods part, for example, "Images were captured using a confocal Zeiss LSM710 and Olympus IX83 inverted microscope"; authors should include the objective used and the image size, and should include which method they used to analyze the acquired images.<br /> -Figure S3A shows that the TNNT2 mRNA expression was completely absent after 60 hours of 2C administration. Authors should explain this further.<br /> -Figure 3J, there is high variability in the graph of mCherry cells (%). Please choose a better graph, or increase the independent experiment.<br /> -Authors did not explain/discuss their results of the DNA-binding motif analysis of ISL1 in the cells treated with A-485 or 2C (Figure 7K).<br /> -Figure S1B and D: the image's labeling is not clear. In the exact same figure S1B, how can the authors explain the reduction of ISL cells? Do the authors make the treatment with the compound CHIR99021 as shown in figure S1A? If so, the authors should clarify the ISL reduction in Figure S1B.<br /> -Figure 1H: please improve the immunoblot, the level of B-actin does not match among the different conditions, or provide a relative quantification of the proteins.<br /> -Please indicate further information in the methodology part about the compounds used in this study.<br /> -Figures are not well justified and figure legends are not sufficient enough to explain the figures.<br /> -Please improve the figure legends by including more further information; for example, in Figure 2SH it is highlighted only the "DAPI (4′,6-diamidino-2- phenylindole) staining labeled nuclei as blue" but how about the other markers?<br /> -Figure 2F: the graph shows some high variations in "ns" between NC at 2C and in 60h+3d. I would recommend increasing the independent experiments. Similar observation goes also for figure 2E.<br /> -Authors should provide limitations of this study.

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• for: futures, clear vision of desirable future, desirable future - 4 pillars

• desirable future: 4 pillars

  • security
    • we can manage, alleviate, adapt to the dangers of the polycrisis
  • opportunity
    • people can express their agency and grow and explore
  • justice
    • equality and fair distribution of wealth. Everyone deserves to live a life based upon holistic wellbeing
  • identity
    • we all need to feel like we belong

• for: social tipping point, STP, social tipping point - misapplication, social tipping points - 4 application errors

• title: Social tipping points everywhere?—Patterns and risks of overuse

• author: Manjana Miikoreit

• date: Nov 17, 2022

• abstract

  • The last few years have witnessed an explosion of interest in the concept of social tipping points (STPs),
    • understood as nonlinear processes of transformative change in social systems.
  • A growing body of interdisciplinary scholarship has been focusing in particular on social tipping related to climate change.
  • In contrast with tipping point studies in the natural sciences–for example
    • climate tipping points and
    • ecological regime shifts–
  • STPs are often conceptualized as desirable, offering potential solutions to pressing problems.
  • Drawing on
    • a well-established definition for tipping points, and
    • a qualitative review of articles that explicitly treat social tipping points as potential solutions to climate change,
  • this article identifies four deleterious patterns in the application of the STP concept in this recent wave of research on nonlinear social change:
    • (i) premature labeling,
    • (ii) not defining system boundaries and scales of analysis,
    • (iii) not providing evidence for all characteristics of tipping processes, and
    • (iv) not making use of existing social theories of change.
  • Jointly, these patterns create a trend of overusing the concept.
  • Recognizing and avoiding these patterns of “seeing the world through tipping point glasses” is important for
    • the quality of scientific knowledge generated in this young field of inquiry and for
    • future science-policy interactions related to climate change.
  • Future research should seek to
    • identify empirical evidence for STPs while remaining open to the possibility that
      • many social change processes are not instances of tipping, or that
      • certain systems might not be prone to nonlinear change.

• for: 4 Deg world, William Rees,

DOI: 10.1016/j.ydbio.2022.09.007

Resource: ZFIN_ZDB-GENO-140310-4

Curator: @scibot

SciCrunch record: RRID:ZFIN_ZDB-GENO-140310-4

What is this?

https://www.ebay.com/itm/305189692899

The Merchants Box Co. manufactured a variety of wooden index card boxes in the 1960s.

I've seen some marked 1960 and 1962. Dates of manufacture? Sizes? Definitely 4x6".

Barbara Tuchman took her notes on four-by-six inch index cards.

She repeated the oft-advised mantra to only write on one side of a sheet.

What manual did she read this in? She specifically puts quotes on "Never write on the back of anything." so perhaps it might be something that could be tracked down?

Who was the earliest version of this quote? And was it always towards the idea of cutting up slips or pages and not wanting to lose material on the back? or did it also (later? when?) include ease-of-use and user interface features even when not cutting things up?

At what point did double sided become a thing for personal printed materials? Certainly out of a duty to minimize materials, but it also needed the ability to duplex print pages or photocopy them that way.

• for: major cultural paradigms, modernity - leaving, cultural transition, cultural evolution, MET, Major Evolutionary Transition, kiey insight - 4 major cultural paradigms

• comment

• key insight: 4 major cultural paradigms

  • This matrix doesn't quite capture what Ruben is proposing because he later talks about neo-indigenous, which means taking elements of modernity but within an overall indigenous framework, so a hybrid
  • It would be worth exploring implications for an evolutionary framework of Major Evolutionary Transitions (MET)

Reviewer #4 (Public Review):

The study compares the number of sporozoites expelled by mosquitoes with different Plasmodium infection burden. To my knowledge this is the first report comparing the number of expelled P. falciparum sporozoites and their relation to oocyst burden (intact and ruptured) and residual sporozoites in salivary glands. The study provides important evidence on malaria transmission biology although conclusions cannot be drawn on direct impact on transmission.

Although there is some evidence from malaria challenge studies that the burden of sporozoites injected into a host is directly correlated with the likelihood of infection, this has been done using experimental infection models which administer sporozoites intravenously. It is unclear whether the same correlation occurs with natural infections and what the actual threshold for infection may be. Host immunity and other host related factors also play a critical role in transmission and need to be taken into consideration; these have not been mentioned by the authors. This is of particular importance as host immunity is decreasing with reduction in transmission intensity.

The natural infections reported in the study were not natural as the authors described. Gametocyte enrichment was done to attain high oocyst infection numbers. Studying natural infections would have been better without the enrichment step. The infected mosquitoes have much larger infection burden than what occurs in the wild.<br /> Nevertheless, the findings support the same results as in the experiments conducted in the Netherlands and therefore are of interest. I suggest the authors change the wording. Rather than calling these "natural" infections, they could be called, for example, "experimental infections with wild parasite strains".

I do not believe the study results generate sufficient evidence to conclude that lower infection burden in mosquitoes is likely to result in changes to transmission potential in the field. In study limitations section, the authors say "In addition, our quantification of sporozoite inoculum size is informative for comparisons between groups of high and low-infected mosquitoes but does not provide conclusive evidence on the likelihood of achieving secondary infections. Given striking differences in sporozoite burden between different Plasmodium species - low sporozoite densities appear considerably more common in mosquitoes infected with P. yoelli and P. Berghei the association between sporozoite inoculum and the likelihood of achieving secondary infections may be best examined in controlled human infection studies. However, in the abstract conclusion the authors state "Whilst sporozoite expelling was regularly observed from mosquitoes with low infection burdens, our findings indicate that mosquito infection burden is associated with the number of expelled sporozoites and may need to be considered in estimations of transmission potential." Kindly consider ending the sentence at "expelled sporozoites." Future studies on CHMI can be recommended as a conclusion if authors feel fit.

https://www.calendarsquick.com/printables/free.html

Reviewer #4 (Public Review):

This work by Fleck et al. and colleagues documented the auxin feeding-induced effects in adult flies, since auxin could be used in temporally controlled gene expression using a modified Gal4/Gal80 system. Overall, the experiments were well-designed and carefully executed. The results were quantified with appropriate statistical analyses. The paper was also well-written and the results were presented logically. The findings demonstrate that auxin-fed flies have significantly lower triglyceride levels than the control flies using Ultra High-pressure Liquid Chromatography-Mass Spectrometry (UHPLC-MS)-based metabolomics assays. Further transcriptome analyses using the whole flies show changes in genes involved in fatty acid metabolism. However, female oogenesis and fecundity do not seem to be affected, at least using the current assays. These results indicate that auxin may not be used in experiments involving lipid-related metabolism, but could be appropriate to be applied for other biological processes.

Massebah for pagan worship: - Exodus 23:24 (https://hypothes.is/a/r3m5QmyDEe6SC8eLYcJE1Q) - Hosea 10:1 (https://hypothes.is/a/4PK2GGyDEe6wZg_r2YpVCA ) - 2 Kings 18:4 - 2 Kings 23:14

Massebah for worship of Yahweh: - Genesis 28:18 Jacob's pillow (https://hypothes.is/a/NF5p8Gx6Ee65Rg_J4tfaMQ)<br /> - Genesis 31:44-45 Jacob and Laban's covenant - Exodus 24:4 - Joshua 24:25-27

Link to https://hypothes.is/a/r3m5QmyDEe6SC8eLYcJE1Q

In neighboring cultures in which both have oral practices relating to massebah, one is not just destroying "sacred stones" to stamp out their religion, but it's also destroying their culture and cultural memory as well as likely their laws and other valuable memories for the function of their society.

View this in light also of the people of Israel keeping their own sacred stones (Hosea 10:1) as well as the destruction of pillars dedicated to Baal in 2 Kings 18:4 and 2 Kings 23:14.

(Link and) Compare this to the British fencing off the land in Australia and thereby destroying Songlines and access to them and the impact this had on Indigenous Australians.

It's also somewhat similar to the colonialization activity of stamping out of Indigenous Americans and First Nations' language in North America, though the decimation of their language wasn't viewed in as reciprocal way as it might be viewed now. (Did colonizers of the time know about the tremendous damage of language destruction, or was it just a power over function?)

connect this to:

The helps whereof by this art memorative, they would prove to be as effectual, by these conceived fictions in the eye of the mind,12 as those we remember by the visible eye of the body, for example whereof say they, concerning the latter we read in the holy Scriptures of 12 stones, that were erected in the river Jordan in memory of the wonderful transpassage of the Israelites, Josh. 24.27.—The Memory Arts in Renaissance England by William E. Engel, Rory Loughnane, and Grant Williams

Description of the arrangement? Circle? Further or suggested usage?

Link to Genesis 28:18: https://hypothes.is/a/NF5p8Gx6Ee65Rg_J4tfaMQ

Reviewer #4 (Public Review):

This is an admirable piece of work. The authors build on a previous dataset they assembled, but expand it to include all stages of early development in the nematode Caenorhabditis elegans. Cell collection was done manually, which is very impressive, and is clearly far better than pooled unidentified cells. I will not comment on the specific sequencing and analysis, since this is not my expertise, but will comment on the general conclusions and comparative framework in which the authors place their results.

While the Introduction and Discussion sections are actually fairly short, much of the presentation of the results is based on a certain comparative framework, which is explicitly a comparison between C. elegans and Drosophila melanogaster. This is an important perspective, but I feel the authors' interpretation is in some places exaggerated and in other places almost trivial.

Drosophila and C. elegans are two of the main models for developmental biology. However, it has been clear for over two decades that both species are highly derived and specialized and therefore, treating them as representative for their taxa is problematic. Much of the authors' discussion hinges on the question of comparing syncytial and lineage-dependent development. The syncytial early development of Drosophila is very specific and is clearly a recent innovation within a restricted group of flies. The canonical Drosophila segmentation cascade is mostly a novelty and most elements within the cascade are recent. Specifically, the expression of gap genes in regional stripes is not found very broadly. Conversely, the polarizing role of Caudal is very ancient and is probably found in all Bilateria. When making comparisons with a distantly related species, it is important to keep this in mind. Not as much is known about development of other nematodes, but the little that is known indicates that C. elegans is also unusual, and specifically the eutelic development (conserved cell lineages in development) is not found in all nematodes.

The authors suggest that regional expression of transcription factors in stripes is a conserved characteristic of development. This is true for Hox genes and has been known for decades. The regional expression they show for other genes is not convincing as "stripes". It is no surprise that developmental transcription factors are regionalized, but linking this to the stripes of Drosophila gap genes and even more so to Drosophila pair-rule and segment-polarity genes is a bit far-fetched. Yes, many genes are expressed in restricted domains along the A-P axis, but that is all that can be said based on the data. Calling them "Drosophila-like" is unfounded.

No 5G, no LTE. 😒

...your frontline had better have WiFi! Or at least a hotspot!

No, it's 2023. Nobody is looking for LTE. They want 5G.

https://en.wikipedia.org/wiki/Opinions_(TV_series)

A British talk program on Channel 4 from the 1980s-1990s focused on the opinions of public figures.

A potential precursor to TED talks?

Reviewer #4 (Public Review):

Summary:<br /> The work by Dasgupta et al identifies Sema7a as a novel guidance molecule in hair cell sensory systems. The authors use the both genetic and imaging power of the zebrafish lateral-line system for their research. Based on expression data and immunohistochemistry experiments, the authors demonstrate that Sema7a is present in lateral line hair cells. The authors then examine a sema7a mutant. In this mutant, Sema7a proteins levels are nearly eliminated. Importantly, the authors show that when Sema7a is absent, afferent terminals show aberrant projections and fewer contacts with hair cells. Lastly the authors show that ectopic expression of the secreted form of Sema7a is sufficient to recruit aberrant terminals to non-hair cell targets. The sema7a innervation defects are well quantified. Overall, the paper is extremely well written and easy to follow.

Strengths:<br /> 1. The axon guidance phenotypes in sema7a mutants are novel, striking and thoroughly quantified.<br /> 2. By combining both loss of function sema7a mutants and ectopic expression of the secreted form of Sema7a the authors demonstrate the Sema7a is both necessary and sufficient to guide sensory axons

Weaknesses:<br /> 1. Control. There should be an uninjected heatshock control to ensure that heatshock itself does not cause sensory afferents to form aberrant arbors. This control would help support the hypothesis that exogenously expressed Sema7a (via a heatshock driven promoter) is sufficient to attract afferent arbors.<br /> 2. Synapse labeling. The numbers obtained for postsynaptic labeling in controls do not match up with the published literature - they are quite low. Although there are clear differences in postsynaptic counts between sema7a mutants and controls, it is worrying that the numbers are so low in controls. In addition, the authors do not stain for complete synapses (pre- and post-synapses together). This staining is critical to understand how Sema7a impacts synapse formation.<br /> 3. Hair cell counts. The authors need to provide quantification of hair cell counts per neuromast in mutant and control animals. If the counts are different, certain quantification may need to be normalized.<br /> 4. Developmental delay. It is possible that loss of Sema7a simply delays development. The latest stage examined was 4 dpf, an age that is not quite mature in control animals. The authors could look at a later age, such as 6 dpf to see if the phenotypes persist or recover.

Reviewer #4 (Public Review):

This manuscript describes a complex, highly ambitious set of modeling and experimental studies that appear designed to compare the structural and functional properties of beta cell subpopulations within the islet network in terms of their influence on network synchronization. The authors conclude that the most functionally coupled cell subpopulations in the islet network are not those that are most structurally coupled via gap junctions but those that are most metabolically active.

Strengths of the paper include (1) its use of an interdisciplinary collection of methods including computer simulations, FRAP to monitor functional coupling by gap junctions, the monitoring of Ca2+ oscillations in single beta cells embedded in the network, and the use of sophisticated approaches from probability theory. Most of these methods have been used and validated previously. Unfortunately, however, it was not clear what the underlying premise of the paper actually is, despite many stated intentions, nor what about it is new compared to previous studies, an additional weakness.

Although the authors state that they are trying to answer 3 critical questions, it was not clear how important these questions are in terms of significance for the field. For example, they state that a major controversy in the field is whether network structure or network function mediates functional synchronization of beta cells within the islet. However, this question is not much debated. As an example, while it is known that there can be long-range functional coupling in islets, no workers in the field believe there is a physical structure within islets that mediates this, unlike the case for CNS neurons that are known to have long projections onto other neurons. Beta cells within the islets are locally coupled via gap junctions, as stated repeatedly by the authors but these mediate short-range coupling. Thus, there are clearly functional correlations over long ranges but no structures, only correlated activity. This weakness raises questions about the overall significance of the work, especially as it seems to reiterate ideas presented previously.

Specific Comments

1. The authors state it is well accepted that the disruption of gap junctional coupling is a pathophysiological characteristic of diabetes, but this is not an opinion widely accepted by the field, although it has been proposed. The authors should scale back on such generalizations, or provide more compelling evidence to support such a claim.<br /> 2. The paper relies heavily on simulations performed using a version of the model of Cha et al (2011). While this is a reasonable model of fast bursting (e.g. oscillations having periods <1 min.), the Ca2+ oscillations that were recorded by the authors and shown in Fig. 2b of the manuscript are slow oscillations with periods of 5 min and not <1 min, which is a weakness of the model in the current context. Furthermore, the model outputs that are shown lack the well-known characteristics seen in real islets, such as fast-spiking occurring on prolonged plateaus, again as can be seen by comparing the simulated oscillations shown in Fig. 1d with those in Fig. 2b. It is recommended that the simulations be repeated using a more appropriate model of slow oscillations or at least using the model of Cha et al but employed to simulate in slower bursting.<br /> 3. Much of the data analyzed whether obtained via simulation or through experiment seems to produce very small differences in the actual numbers obtained, as can be seen in the bar graphs shown in Figs. 1e,g for example (obtained from simulations), or Fig. 2j (obtained from experimental measurements). The authors should comment as to why such small differences are often seen as a result of their analyses throughout the manuscript and why also in many cases the observed variance is high. Related to the data shown, very few dots are shown in Figs. 1e-g or Fig 4e and 4h even though these points were derived from simulations where 100s of runs could be carried out and many more points obtained for plotting. These are weaknesses unless specific and convincing explanations are provided.<br /> 4. The data shown in Fig. 4i,j are intended to compare long-range synchronization at different distances along a string of coupled cells but the difference between the synchronized and unsynchronized cells for gcoup and gKglyc was subtle, very much so.<br /> 5. The data shown in Fig. 5 for Cx36 knockout islets are used to assess the influence of gap junctional coupling, which is reasonable, but it would be reassuring to know that loss of this gene has no effects on the expression of other genes in the beta cell, especially genes involved with glucose metabolism.<br /> 6. In many places throughout the paper, it is difficult to ascertain whether what is being shown is new vs. what has been shown previously in other studies. The paper would thus benefit strongly from added text highlighting the novelty here and not just restating what is known, for instance, that islets can exhibit small-world network properties. This detracts from the strengths of the paper and further makes it difficult to wade through. Even the finding here that metabolic characteristics of the beta cells can infer profound and influential functional coupling is not new, as the authors proposed as much many years ago. Again, this makes it difficult to distill what is new compared to what is mainly just being confirmed here, albeit using different methods.

DOI: 10.1016/j.isci.2023.107734

Resource: (ZFIN Cat# ZDB-ALT-060821-4,RRID:ZFIN_ZDB-ALT-060821-4)

Curator: @evieth

SciCrunch record: RRID:ZFIN_ZDB-ALT-060821-4

What is this?

Surely this won't include the idea of John McPhee's Draft #4 use of a dictionary?

Johnson's dictionary is much like this article describes too.

Perhaps we need more dictionaries with singular voices rather than dictionaries made by committee?

I quite like the idea of this Draft #4 concept.

Reviewer #4 (Public Review):

This manuscript covers an important topic of gender biases in the authorship of scientific publications. Specifically, it investigates potential mechanisms behind these biases, using a solid approach, based on a survey of researchers.

Main strengths

The topic of the MS is very relevant given that across sciences/academia representation of genders is uneven, and identified as concerning. To change this, we need to have evidence on what mechanisms cause this pattern. Given that promotion and merit in academia are still largely based on the number of publications and impact factor, one part of the gap likely originates from differences in publication rates of women compared to men.

Women are underrepresented compared to men in journals with high impact factor. While previous work has detected this gap, as well as some potential mechanisms, the current MS provides strong evidence, based on a survey of close to 5000 authors, that this gap might be due to lower submission rates of women compared to men, rather than the rejection rates. The data analysis is appropriate to address the main research aims. The results interestingly show that there is no gender bias in rejection rates (desk rejection or overall) in three high-impact journals (Science, Nature, PNAS). However, submission rates are lower for women compared to men, indicating that gender biases might act through this pathway. The survey also showed that women are more likely to rate their work as not groundbreaking, and be advised not to submit to prestigious journals

With these results, the MS has the potential to inform actions to reduce gender bias in publishing, and actions to include other forms of measuring scientific impact and merit.

Main weakness and suggestions for improvement

1) The main message/further actions: I feel that the MS fails to sufficiently emphasise the need for a different evaluation system for researchers (and their research). While we might act to support women to submit more to high-impact journals, we could also (and several initiatives do this) consider a broader spectrum of merits (e.g. see https://coara.eu/ ). Thus, I suggest more space to discuss this route in the Discussion. Also, I would suggest changing the terms that imply that prestigious journals have a better quality of research or the highest scientific impact (line 40: journals of the highest scientific impact) with terms that actually state what we definitely know (i.e. that they have the highest impact factor). And think this could broaden the impact of the MS

2) Methods: while methods are all sound, in places it is difficult to understand what has been done or measured. For example, only quite late (as far as I can find, it's in the supplement) we learn the type of authorship considered in the MS is the corresponding authorship. This information should be clear from the very start (including the Abstract).

Second, I am unclear about the question on the perceived quality of research work. Was this quality defined for researchers, as quality can mean different things (e.g. how robust their set-up was, how important their research question was)? If researchers have different definitions of what quality means, this can cause additional heterogeneity in responses. Given that the survey cannot be repeated now, maybe this can be discussed as a limitation.

I was surprised to see that discipline was considered as a moderator for some of the analyses but not for the main analysis on the acceptance and rejection rates.

I was also suppressed not to see publication charges as one of the reasons asked for not submitting to selected journals. Low and middle-income countries often have more women in science but are also less likely to support high publication charges.

Finally, academic rank was asked of respondents but was not taken as a moderator.

DOI: 10.1371/journal.pbio.3002223

Resource: RRID:ZFIN_ZDB-ALT-051025-4

Curator: @evieth

SciCrunch record: RRID:ZFIN_ZDB-ALT-051025-4

What is this?

https://kingjim.us/flatty-works<br /> Flatty Works A6 size horizontal case<br /> ~$24.00

Acquired green version 2023-04-07<br /> https://boffosocko.com/2023/04/20/review-of-king-jim-a6-size-horizontal-flatty-works-case-5460/

https://www.lochby.com/collections/frontpage/products/venture-pouch<br /> Lochby Venture Pouch<br /> $44.00

Acquired one of these in early 2023 on sale?

several internal sections including for pens. <br /> will easily fit a handful or so of 4 x 6" index cards for quick travel

https://www.rickshawbags.com/travelers-notebook-case#!/graphite/orange-420d-liner/flo-orange/no-mod/no-mod/flo-orange

Rickshaw Bags, Traveler's Notebook Case $59.00

https://www.jetpens.com/Delfonics-Carrying-Bag-M-A5-Dark-Denim/pd/37102

Delfonics Carrying Bag - M (A5) - Dark Denim<br /> $36.00

Perhaps a bit large, but could be used as a mini-portable office to hold a variety of things including 4 x 6" index cards for work on the go.

https://www.jetpens.com/Lihit-Lab-Altna-Carrying-Sleeve-Small-Gray/pd/24824<br /> Lihit Lab Altna Carrying Sleeve - Small - Gray<br /> $30.50

B6 is 4.9 x 6.9 inches, so just slightly larger than 4 x 6 inches

https://www.jetpens.com/Lihit-Lab-Smart-Fit-Carrying-Pouch-A6-Olive/pd/12378

Lihit Lab Smart Fit Carrying Pouch - A6 - Olive<br /> $21.50

https://www.jetpens.com/Delfonics-Carrying-Bag-S-A6-Dark-Blue/pd/38393<br /> Delfonics Carrying Bag - S (A6) - Dark Blue $32.00

https://www.jetpens.com/Kleid-Mesh-Carry-Pouch-Mini-Charcoal/pd/37439

Meant for A6 notebooks, but would likely fit 4 x 6" index cards. $17.00

Reviewer #3 (Public Review):

In this manuscript, the authors challenge the fundamental concept that all neurons are derived from ectoderm. Specifically, they aim to show that while the early ENS arises embryologically from neural crest (NENs), with age it is slowly replaced by mesoderm-derived neurons (MENs). This claim is based on an array of transgenic reporter mice, immunofluorescence, and transcriptomics. They further propose that the transition from NENs to MENs is regulated by a changing balance in GDNF-RET versus HGF-MET signaling, respectively.

This is a provocative and potentially paradigm-changing proposal, but the data presented and the interpretation of that data fall short of establishing it.

1) MENs share more common characteristics with fibroblasts. The authors interpret this as representing neurons with fibroblast characteristics. Why not fibroblasts with neuronal characteristics? The ability to express neurotransmitter receptors and calcium channels is common in fibroblasts, but that isn't sufficient to characterize a neuron. For example, many cell types express neurotransmitters (CGRP in ILCs, Penk in fibroblasts). Expressing one of the Hu proteins (Elavl2) probably isn't enough to call these "neurons," especially when neurons usually express Elavl3-4 (HuC/D). Including calcium imaging and showing presence of action potentials would strengthen the argument that these are in fact neurons.

2) The scRNA-seq is unconvincing. There are several technical issues and the analysis omits important information required to make an unbiased assessment.

a. One issue in the interpretation is that MENs are shown by IHC to constitute half the neuronal population, with NENs making up the other half. The authors state that they performed an unbiased approach, sequencing all cells in the muscularis. If it were truly unbiased, then why do they detect a 28-fold increase in MENs in the single cell data? This does not reflect the IHC findings and points to an issue in technique that needs to be addressed.

b. Cell populations annotated by the author are confusing. The "unknown" population expresses many genes that are epithelial markers. This is puzzling because the authors state that they only sequenced the muscularis. This leads to questions regarding the initial samples and whether they were dissected appropriately or contaminated by another population.

c. The authors report a population of ICCs at P21 which is not identified at 6-months. Closer inspection of their data shows bona fide ICC markers, Ano1 and Kit, in their SMC cluster at 6-months, with failure to identify ICC clusters, raising questions about whether they have identified a new cell type.

d. While the authors critically examine other scRNA-seq datasets and claim that those groups mislabeled their populations, the above does not instill confidence in their ability to counter the unified literature.

3) MENs are identified based on genes that could be related to neurons, including calcium channels, neurotransmitter receptors, etc. It is worth noting that mesenchymal cells, ICCs, and smooth muscle also possess these characteristics. Therefore, it hard to justify why these MENs are considered "neurons." The authors should perform an analysis to examine homology between clusters in order to show which clusters the MENs are more similar to, neurons or otherwise.

4) Several issues raise questions about the quality of the scRNA-seq data, making interpretations very difficult:

a. MENs are identified to have higher UMI counts than other cells, which the authors interpret as the cells being bigger than others. If this is the case, why is this only observed in the P21 dataset and not at 6 months. Notably, high UMIs are also a sign of doublet contamination.

b. Authors include data from RBCs. As they do not have a nucleus, RNA abundance is low as expected. However, markers for RBCs include smooth muscle specific markers, MYH11 (an MEN marker) and Acta2. The presence of these markers can indicate high levels of "ambient RNA" which enters droplets from other cells lysed during digestion. Interestingly, MENs appear to cluster close to RBCs.

c. In light of the above possible evidence of doublet contamination and high levels of ambient RNA, the markers of MENs need to be reconsidered. MENs are stated to express markers that were previously (up until this manuscript) accepted markers of intestinal mesothelium (Ukp3b Krt19, WT1), smooth muscle cells (Myh11), and fibroblasts (Dcn, C3, Col6a1), raising the possibility that MENs are an erroneous cluster containing RNA from all these cell types.

5) The MEN population appears to be the largest cell population in the gut, which is unprecedented. The authors compare their scRNA-seq data to several other studies that have not made similar observations. Such analysis of other datasets is used to inform on the new data being generated. In the current manuscript, however, this takes the reverse approach and the authors analyze other data based on the assumption that they all mislabeled the MEN population.

a. In their assessment of Drokhlyansky et al., the authors claim that their mesothelium annotation is wrong despite expressing known mesothelial markers. This includes the gene Upk3b which is a bona fide mesothelial marker in the gut but is also expressed by "MENs." They proceed to analyze the Elmentaite et al. dataset and state that their "transitional fibroblast" population are actually MENs. That paper also has a population of Upk3b+ mesothelial cells and it is unclear why those are not actually MENs like in the Drokhlyansky et al. study.

b. The authors often refer to the study of May-Zhang et al. and their cluster annotated as "mesenchymal neurons" in the gut. It should be known that the original authors never made this claim. Rather, they acknowledge that the clusters in their study with poor correlation to neuronal profiles exhibit strong predictions for mesenchymal and vascular/immune cell types. They state: "We considered the possibility that these clusters might be non-neuronal." If these are "mesenchymal neurons" then the same logic would indicate that there are vascular neurons and immune cell neurons, and therefore this does not make a very compelling case.

6) A weakness of this study is that a lot of the data relies on reporter gene expression. The authors need to acknowledge several weaknesses of this approach. First, Wnt1-tdT recombination may be incomplete or one can have "Cre mosaicism" and therefore the lack of tdT is not sufficient evidence to say that those neurons are not neural crest-derived. Second, one can have off-target or leaky Cre expression, leading to low-level tdT expression, as seen in many of the images in this study. Third, Cre can exhibit toxicity and this may be more problematic in older mice given the long-term continuous expression of Cre (He et al, Am J Pathology, 2014;184:1660; Loonstra et al, PNAS, 2001;98:9209; Forni et al, J Neurosci, 2006;26:9593; Rehmani et al, Molecules, 2019;24:1189; Gillet et al, Sci Rep, 2019;9:19422; Stifter and Greter, Eur J Immunol, 2020;50:338).

• four mitigating factors that make power appear to corrupt when something else is actually going on.
  • dirty hands
    • people in power often are faced with no good alternatives and your hands will appear dirty, even when you choose the lesser of the evils
  • the idea of learning
    • authoritarian leaders are new to the job in the beginning and they have to learn to be good at being bad. Their leadership may appear to get worse but they are just learning how to be more effectively ruthless - on-the-job training
  • the problem of opportunity
    • a scaling effect. A leader of a country has far more people they can harm with his/her decision than a janitor.
  • the problem of scrutiny
    • people in power get more scrutiny
    • if you are not in power, you could be committing a crime but never get caught because you are not scrutinized to the same degree - think Donald Trump

• four main arguments about power
  • 1. worse people get power, corruptible people seek power
  • 1. power makes people worse, power corrupts
  • 3 we are drawn to the wrong kinds of leaders for all the wrong reasons
  • 4 we can design systems to make better people end up in power

Reviewer #4 (Public Review):

This is potentially a landmark study with far-reaching consequences for archaeology, palaeoanthropology, and more widely. The antiquity of intentional human mark marking is a hot topic but this study – understood as initial – has as yet incomplete sources of evidence and methods; and it will be interesting to follow how the study develops in subsequent studies.

Strengths and points to build on:

* Heuristic potential: As knowledge advances it poses a risk to accepted knowledge – and we should accept that one such risk is moving on from long-held disciplinary tenets. In this case, there has been a growing quantum of evidence – all hotly debated – for the deep antiquity of mark-making and even symbolism by species other than ourselves. Most researchers now accept Neanderthal symbolic capacity actualised in burials, intentional mark-making and the like. The evidence here presented is not unequivocal but is very suggestive and an ideal test case for applying multi-disciplinary techniques of analysis and interpretation beyond the expertise of the listed authors *see comments in 'weaknesses'). This work by itself may be equivocal but when taken together with other such work, points to a 'human' sensu lato past that is as complex as it is long. This work then helps all researchers to at least be alive to the possibility of things like anthropic marks and residues in a context not normally thought to have it.

* Decentering speciesism: As per the above comment, I appreciate empirical studies that erode speciesism – in particular studies that open up our minds to the possibility that multiple members of the Genus Homo were capable of intentional mark-making and even 'symbolic' behaviour, though this latter term is not well understood or uniformly used. This is probably because of continuous unconscious bias on our part as currently the only exemplar of our genus living - in contrast to most of the past in which different species and genera co-existed - if not on the same landscape and/or at exactly the same time, then with enough overlap that people would have realised 'others' were about either by sight and/or by encountering their physical remains and artefacts.

* Problematising 'firsts' and deep time: A strength – but which needs to be developed in this manuscript – is our understanding of time and change. We have a plethora of dating techniques but relatively few substantive monographs, articles, and think tanks on time – and especially on how change comes about and what causes it. This leads us to privilege 'firsts' and the 'oldest' finds in 'deep' time above those that are more recent and in 'shallow' time. I would suggest in addition to the claims for the oldest of the reported marks, the authors develop nascent remarks on the possibility the suite of marks may have been made over time. This will help counter criticism that these marks – if established to be anthropic – were not just a singularity, but part of patterned behaviour, which would move it towards the realm of 'symbolic' cognitive behaviour. And indeed, it would be good to hear more about why in this place, these marks were made to establish a replicable model for identifying early anthropic marks.

Ultimately, this manuscript presents evidence that those who are pro the deep antiquity of intentional mark-making by Homo (and possibly even other genera) will find enough evidence to support; while those sceptical of such claims will find enough methodological flaws and evidential limits to refute those claims. The next decade of work will likely be definitive and this article makes a key contribution to the debate.

Weaknesses and points to attend to:

* Definitions: The term 'rock engraving' is used rather uncritically and also the term 'etching' – and it would be useful to have a short definition of how the authors understand the term. Rock art scholars regularly debate these terms and whether they are or are not 'rock art' with its overwhelmingly visual bias; which this discovery may usefully help overthrow and advance.

* Dating: There is no evidence provided for dating the marks found in the cave system. They could, for example, have been made more recently than the dates claimed – and by another species (if we accept their anthropogenic authorship). This is a perennial problem of much rock art research – especially when it comes to understanding the wider archaeological/palaeoanthropological context. More crucially, accurate dating allows a more reliable understanding of authorship and who/what was responsible for a particular artefact or feature. This has not been demonstrated in this case, though we do have fossil evidence of Homo naledi in the cave system. The article title is this incorrect / and unsupported claim as the marks, if they are anthropic, have not been dated and are of unknown age. The authors allow that there may have been multiple episodes, but not that the marks can belong to a time other than they posit – either earlier, later, or distributed over a long period as the authors allow for in their concluding remarks.

* Authorship: The study does not utilise either a geoscientist as one of the authorial team, or a rock art specialist. These are key oversights as the former would help better contextualise the dating of the marks reported on, as well as explore alternative non-anthropogenic agents that may have created the marks reported on. For example, the marks and 'pitting' etc may be the result of water bringing abrasive agents during times of flooding, hitting prominent rock features in the cave system. Some explanation is given from lines 114-124, but are uncited. The overlying 'sediment' may be similar to the mondmilch found in cave systems and which is of natural origin. It may be that these non-anthropogenic causes are easy to discount; but the arguments do need to be made. Or, that the polishing was made by Homo naledi brushing against the surfaces as they moved in the cave system, independent of any mark-making. A Table showing the pros and cons of intentional anthropic versus natural authorship would be very effective - as well as showing some of the natural linear marks in the cave system to avoid any confirmation or similar bias. FTIR analysis of the panel A-C would be more than useful to determine whether an additional layer of material has been added. This is mentioned for future work, but this seems a rather post-hoc research programme.

* Use-wear analysis: If the marks are anthropic in origin; they are likely to have been made by a stone tool, which would leave characteristic marks, directionality and sequencing, distinct from natural causes. It is vital this work – such as was done on the Blombos engraved ochre – is done here – for example, linking to the chert and other tools described on lines 152-158. Note Figure 19, of such a tool, is very hard to make out. The Blombos – and Klasies River Mouth engraved ochres (curiously not referenced) – have very similar geometric markings and there is a real opportunity to compare these in securely dated contexts of 70-120 kya –which could support the argument made here for Homo naledi's cognitive capacity. On figure 16 it would be good to know on what basis some marks were selected as anthropic – and why others were not; this would help demonstrate the methodology and ability to distinguish between the two kinds of marks.

* Viewshed: The rock art specialist would have added essential expertise on how to study anthropic marks. For example, the images of the marks shown are all of individual or small collections of motifs rather than showing each panel as well as all panels together, to help understand the iconographic context as an ensemble – a 'feature' rather than isolated 'artefacts' or 'motifs'. Line 60 mentions being able to see these as a 'triptych' but the reader is not able to have this view in this manuscript. From the cave map, it is not clear whether all three 'panels' (an unfortunate art historical term that suggests a framed entity - better to use a term like 'cluster') can be viewed simultaneously or in sequence. The view shed in relation to the area where the bodies were recovered is vaguely stated as 'only a few metres away' and is worth developing. I understand 3D scans have been made so it would be useful to have a version showing the marks in relation to where the bodies were recovered and as a 3-cluster ensemble.

* Image enhancements: Also, in addition to polarised images, have colour enhancement tools like DStretch been tried to see if, for example, attempts at colouring with different coloured sands were made? Similarly, a 3D scan of the motif and panel – (Metashape is mentioned but not shown) – might assist in understanding how the marks and the rock they are on might relate to each other- as research in European upper Palaeolithic contexts has shown. Here, experimenting with different kinds of lighting - or in the absence of lighting, of tactility and how these marks and their rock support may have been experienced by those who may have made and interacted with them? As a note, it would be useful to have a scale in each image of the 'engravings' and it is a pity the one in situ photograph with the scale is not a standard rock art colour-corrected scale as is commonly used in rock art research.

Reviewer #4 (Public Review):

Berger et al. 2023a argues that Homo naledi intentionally buried their dead within the Rising Star cave system by digging pits and covering the bodies with infilled sediment. The authors identified two burials: Dinaledi Feature 1 from the Dinaledi Chamber, and the Hill Antechamber Feature from the Hill Antechamber. The evolutionary and behavioral implications for such behavior are highly significant and would be the first instance of a relatively small-brained hominin engaging is complex behavior that is often found in association with Homo sapiens and Homo neanderthalensis. Thus, the scientific rigor to validate these findings should be of the highest quality, and thus, provide clear documentation of intentional burial. In an attempt to meet these standards, the authors stated a series of tests that would support their hypothesis of intentional burials in the Rising Star Cave system:

"The key observations are (1) the difference in sediment composition within the feature compared to surrounding sediment; (2) the disruption of stratigraphy; (3) the anatomical coherence of the skeletal remains; (4) the matrix-supported position of some skeletal elements; and (5) the compatibility of non-articulated material with decomposition and subsequent collapse." (page 5)

To find support for the first (1) test, the authors collected sediment samples from various locations within the Rising Star Cave system, including sediment from within and outside Dinaledi Feature 1. However:

• The authors did not select sediment samples from within the Hill Antechamber Feature, so this test was only used to assess Dinaledi Feature 1.

• The sediment samples were analyzed using x-ray diffraction (XRD) and x-ray fluorescence (XRF) to test the mineralogy and chemistry of the samples from within and outside the feature. The XRF results were presented as weighted percentages (not intensities) with no control source reported. The weighted percentages were analyzed using a principal components analysis (PCA) while the particle-size distribution was analyzed using GRADISTAT statistics package and the Folk and Ward Method to summarize "mean grain size, sorting, skewness and kurtosis in addition to the percentages of clay, silt and sand in each sample." (page 28).

• The PCA results were reported solely as a biplot without showing the PC scores projected into the loading space, which is unusual and does not present the data accurately. Instead, the authors present the scores of a single component (PC2, figure 3) because the authors interpreted this component as "distinctly delineates fossil-bearing sediments from sterile sediments based on the positive loadings of P and S" (Page 6). However, the supplementary table that reports XRF bulk chemistry results as a weighted percentage of minerals within each sample (SI Table 1) shows mostly an absence of data for both Na and S. Since Na is at the lower end of detection limits for the method, and S seems to just be absent from the list, the intentions of the authors for showing the inclusion of these elements in their PCA results is unclear. Given that this is the author's primary method for demonstrating a burial, this issue is particularly concerning and requires additional attention.

• Regardless of the missing data, this reviewer attempted to replicate the XRF PCA results using the data provided in SI Table 1 and was unsuccessful. The samples that were collected from within the feature (SB) cluster with samples collected from sterile sediments and other locations around the cave system. Thus, these results are not replicable as currently reported.

• Visual comparisons of sediment grain size, shape, and composition were qualitatively summarized. Grain size was plotted as a line graph and is buried as supplemental Figure S13 showing sample by color and area, but these results do not distinguish samples from WITHIN the burial compared to OUTSIDE the burial as the authors state in the methods as a primary goal.

To test the second (2) aim, the "stratigraphy" was primarily described in text.

• For Dinaledi Feature 1, the authors state that the layer around Feature 1 "is continuous in the profile immediately to the east of the feature; it is disrupted in the sediment profile at the southern extent of the feature (fig. 3b)." Upon examination of figure 3b, the image shows an incredibly small depiction of the south (?) profile view with an extremely large black box overlaying a large portion of the photograph containing a small 5 cm scale. Visually, there is no difference in the profile that would suggest a disruption in the form of a pit. The LORM (orange-red mud layer) does seem to become fragmentary, but no micromorphological analysis was conducted on this section to provide an evaluation of stratigraphic composition. Also, by only excavating a portion of the feature, the authors were unable to adequately demonstrate the full extent of this feature.

• The authors attempt to describe "a bowl-shaped concave layer of clasts and sediment-free voids make up the bottom of the feature" (page 13) and refer to figures and supplementary information that do not depict any stratigraphic profile. Moreover, the authors state that "the leg, foot, and adjacent [skeletal?] material cut across stratigraphy" indicating that the skeleton is orientated on a flat plane against the surrounding stratigraphy that is "30{degree sign} slope of floor and underlying strata" (page 51, fig. 10c captions). There is no mention of infilled sediment from a pit and how this relates to the skeleton or the slope of the floor. It is therefore extremely unclear what the authors are meaning to describe without any visual or micromorphological supplementation to demonstrate a "bowl-shaped concave layer".

The third (3) test was to evaluate the anatomical coherence of the skeletal remains using macro- and micro-CT (computed tomography) of the Hill Antechamber Feature that was removed during excavation. To visually assess the anatomy of the Dinaledi Feature 1 burial, the authors describe the spatial relationship of skeletal elements as they were being excavated but halted partway through the excavation.

• The authors do not provide any documentation (piece-plotting, 3D rendering of stages of excavation, etc.) of the elements that were removed from the Dinaledi Feature. Figure 4 and SI Fig. S22 show the spatial relationship between identifiable skeletal elements that remain in the Feature. However, in Fig. 4, it is unclear why the authors chose to plot 2023-2014 excavated material along with material reported here, and it's even more difficult to understand the anatomical positioning of the elements given their color and point size choices. Although, the authors do provide a 3D rendering of the unexcavated remains showing some skeletal cohesion, apart from the mandible and teeth being re-located near the pelvis (Fig. 9). That said, it is very difficult to visually confirm the elements from this model or understand the original placement of the skeleton.

• 3D renderings of the Hill Antechamber feature skeletal material is clearly shown in SI Fig. S26. Contrary to what the authors state in text, there is a rather wide dispersal and rearrangement of elements for a "burial" that is theoretically protected from scavengers and other agents that would aid in dispersing bone from the surface. The authors do not offer any alternatives to explain disturbance, such as human activity, which clearly took place.

• Moreover, there does not appear to be any intentional arrangement of limbs that may suggest symbolic orientation of the dead (another line of evidence often used to support intentional burial but omitted by the authors). Thus, skeletal cohesion is not enough evidence to support the hypothesis of an intentional burial.

The fourth (4) test was attempted by evaluating whether some elements were vertically aligned from 3D reconstructed models of Hill Antechamber Feature and a photogrammetric model of the Dinaledi Feature 1. The authors state that "the spatial arrangement of the skeletal remains is consistent with primary burial of the fleshed body" (page 8 in reference to Dinaledi Feature 1) without providing any evidence, qualitative or quantitative, that this is the case for either burial.

Since this reviewer was unable to understand the fifth (5) test as it was written by the authors, I am unable to comment on the evidence to support this test and will default to the other reviewers for evaluation of this claim.

In addition to a lack of evidence to support the claims of intentional burial, this paper was also written extremely poorly. For example, the authors often overused 'persuasive communication devices' (see eLife article, https://elifesciences.org/articles/88654) to mislead readers:

"During this excavation, we recognized that the developing evidence was suggestive of a burial, due to the spatial configuration of the feature and the evidence that the excavated material seemed to come from a single body." (page 5)

As an opening statement to introduce Dinaledi Feature 1, the authors state the interpretation and working hypothesis as fact before the authors present any evidence. This is known as "HARKing" and "gives the impression that a hypothesis was formulated before data were collected" (Corneille et al. 2023). This type of writing is pervasive throughout the manuscript and requires extensive editing. I recommend that the authors review the article provided by eLife (https://elifesciences.org/articles/88654) and carefully review the manuscript. Moreover, as this text demonstrates, the authors’ word choice is indicative of storytelling for a popular news article instead of a scientific paper. I highly suggest that the authors review the manuscript carefully and present the data prior to giving conclusions in a clear and concise manner.

Moreover, the writing structure is inconsistent. Information that should be included in results is included in the methods, text in the results should be in discussions, and so forth. This inconsistency is pervasive throughout the entire manuscript, making it incredibly difficult to adequately understand what the authors had done and how the results were interpreted.

Finally, the "artifact" that was described and visualized using CT models is just that - a digitally colored model. The object in question has not been analyzed. Until this object is removed from the dirt and physically analyzed, this information needs to be removed from the manuscript as there is nothing to report before the object is physically examined.

Overall, there is not enough evidence to support the claim that Homo naledi intentionally buried their dead inside the Rising Star Cave system. Unfortunately, the manuscript in its current condition is deemed incomplete and inadequate, and should not be viewed as finalized scholarship.

reply to u/taurusnoises (Bob Doto) at tk

Yep, for almost a full year now on 4x6" index cards. (Receipts for the kids: https://boffosocko.com/wp-content/uploads/2023/07/wp-1688411021709-scaled.jpg)

Previously I'd used a Hobonichi Cousin (page per day) journal for this. (Perhaps I should have stayed with the A6 size instead of the larger A5 for consistency?) Decades ago (around 1988ish?) I had started using a 2 page per day DayTimer pocket planners (essentially pre-printed/timed index cards spiral bound into monthly booklets which they actually shipped in index card-like plastic boxes for storage/archival purposes). Technically I've been doing a version of this for a really long time in one form or another.

It generally includes a schedule, to do lists (bullet journal style), and various fleeting notes/journaling similar to the older Memindex format, just done on larger cards for extra space. I generally either fold them in half for pocket storage for the day or carry about in groups for the coming week(s) when I'm away from my desk for extended periods (also with custom blank index card notebooks/pads).

I won't go into the fact that in the 90's I had a 5,000+ person rolodex... or an index card (in the entertainment they called them buck slips) with the phone numbers and names of \~100 people I dealt with regularly when early brick cell phones didn't have great (or any) storage/functionality.

Reviewer #4 (Public Review):

This work aims at analyzing the impact of histone variants and histone modifications on chromatin states of the Arabidopsis genome. Authors claim that histone variants are as significant as histone modifications in determining chromatin states. They also study the effect of mutations in the DDM1 gene on the exchange of H2A.Z to H2A.W, which convert the silent state of transposons into a chromatin state normally found on protein coding genes.

This is an interesting and well done study on the organization of the Arabidopsis genome in different chromatin states, adding to the previous reports on this issue.

severe, or showing disapproval 嚴厲的，苛刻的

(of a bird or animal) to lose feathers, skin, or hair as a natural process at a particular time of year so that new feathers, skin, or hair can grow （鳥或動物）脫毛；褪皮；換羽

a large feather 羽毛，翎

gas or extremely small drops of liquid that result from the heating of a liquid or solid 蒸氣；霧氣

the best or most successful point or time 頂峰；鼎盛時期

the appearance or expression of someone's face 面容；臉色；面部表情

happily or brightly 歡樂地，喜氣洋洋地；閃亮地，明亮地

covered with areas of different colours that do not form a regular pattern 雜色的；斑駁的

If time elapses, it goes past.（時間）流逝，過去

to go into or through something, making a hole in it using a sharp point 刺穿，刺透，刺破

sleep

Reviewer #4 (Public Review):

A combination of optogenetic behavioral experiments and functional imaging are employed to identify the role of mechanosensory neurons in food swallowing in adult Drosophila. While some of the findings are intriguing and the overall goal of mapping a sensory to motor circuit for this rhythmic movement are admirable, the data presented could be improved.

The circuit proposed (and supported by GRASP contact data) shows these multi-dendritic neurons connecting to pharyngeal motor neurons. This is pretty direct - there is no evidence that they affect the hypothetical central pattern generator - just the execution of its rhythm. The optogenetic activation and inhibition experiments are constitutive, not patterned light, and they seem to disrupt the timing of pumping, not impose a new one. A slight slowing of the rhythm is not consistent with the proposed function.

The mechanosensory channel mutants nompC, piezo, and TMC have a range of defects. The role of these channels in swallowing may not be sufficiently specific to support the interpretation presented. Their other defects are not described here and their overall locomotor function is not measured. If the flies have trouble consuming sufficient food throughout their development, how healthy are they at the time of assay? The level of starvation or water deprivation can affect different properties of feeding - meal size and frequency. There is no description of how starvation state was standardized or measured in these experiments.

The brain is likely to move considerably during swallow, so the GCaMP signal change may be a motion artifact. Sometimes this can be calculated by comparing GCaMP signal to that of a co-expressed fluorescent protein, but there is no mention that this is done here. Therefore, the GAaMP data cannot be interpreted.

At 9¢/card these are very expensive in comparison to bulk cards which usually can be found for 1-2¢/card. The difference however is in the luxuriousness of the silky smooth texture. Whether you're writing with your favorite fountain pen or a carefully chosen pencil. I don't know if these are the same brand of Bristol cards that Vladimir Nabokov used for his writing, but one could easily image him using such lovely material.

These provide a very smooth writing experience for fountain pens, gel pens and pencils. I particularly love the way my Tennessee Reds and Blackwing 602s glide over their surface. In comparison to some Japanese stationery, I'd put these cards somewhere between tsuru tsuru (slippery) and sara sara (smooth). If you're looking for a toothier paper, you'll definitely want to look elsewhere. They take fountain pens pretty well with no feathering or ghosting. My juiciest fountain pen dries in about 15 seconds, while a drier extra fine is dry in about 7 seconds, so it may take some care not to smear ink if you're on the messier end of the spectrum.

Pencil erases reasonably well, though there may be some minimal residual ghosting here. At 205 gsm, they've got a satisfying thickness unseen in most index cards and one is unlikely to rip or crinkle them when erasing. They're also thick enough that the wettest Sharpie won't bleed much less ghost through. You have to hold a card up to a backlight to see the appearance of any ghosting through it and even then, not well.

For the sticklers used to using standard 4 x 6" index cards, one should take note that the dimensions of these are slightly shorter in both dimensions—they're closer to 3.94" x 5.91". This means that you might have to take some care that while flipping through mixed company of cards your Exacompta can potentially hide between larger imperial sized cards. They're also close to, but not quite A6 in size either (105 x 148.5 mm or 4.1 x 5.8 inches).

Reviewer #4 (Public Review):

The authors have collected an impressive array of physiological data and provided some beautiful 3D images of SBCs with dendrites. These are clearly strengths. The computational models for mechanisms of SBC responses, however, are made to fit what may be inadequate anatomical data. Instead of conclusions, perhaps they need to reword their discussions to refer to the anatomy as hypothetical substrates.

https://docdrop.org/pdf/Bergonzi1992Melodic_Structures-4edv1_ocr.pdf/?src=ocr

Melodic Structures (Vol 1) Bergonzi, J 1994

Reviewer #4 (Public Review):

In this manuscript, Clary and colleagues use two-photon imaging to visualize the dynamics of Merkel cells and their innervating sensory axons using a combination of transgenic lines, where these parts of the mechanosensory organs of the skin are labelled with distinct fluorescent proteins. It is noteworthy that this study does not stand alone, but should be compared to prior published work cited by the authors, such as Wright et al., Developmental Biology 422 (2017) 4-13.

The study demonstrates a comparably high degree of remodelling, with a large fraction of Merkel cells (50% in three weeks) and a similar fraction of elaborated (cup-like) axons endings disappearing. It appears by timing and correlation that changes in Merkel cells can clearly drive axonal remodelling, while axons can still remodel even if the Merkel cells remain stable by the parameters measured here. Moreover, changes in Merkel cells partially relate to the hair growth cycle.

The imaging approach chosen is straightforward and clearly suited in principle to reveal the dynamism of the studied cellular structures. To co-visualize two synaptic partners in a vertebrate sensory organ in vivo - while not unprecedented - certainly remains quite challenging, and represents a strength of the paper. Similarly, understanding how stable structures in the nervous system are under homeostatic (rather than developmental) conditions, remains an understudied topic. I also found some of the correlative analysis in the later parts of the study quite interesting, albeit not always straightforward to interpret.

My central concern is the very high disappearance rate of Merkel cells. This, in my view is not compatible with a steady state situation in an adult animal - and not with the prior literature (especially the similar study by Wright et al. cited above). Obviously, if this rate were to continue, Merkel cells would all be lost in early adulthood in mice. Whether this is the case in the specific anatomical location was not examined in the study - but it would also imply that the study really addresses a dynamic developmental remodelling situation and should be written up accordingly. I am more suspicious of the depilation agent (plus the shaving). As Wright et al. already show that shaving causes some changes in Merkel cell dynamics (but, as far as I can tell, did not chemically depilate), I would not be surprised that we see an artificially high remodelling rate. Such skin treatment-related biology is probably less relevant in the context of neurobiology (albeit probably quite interesting to other audiences). So, my recommendation to the authors would be to invest some energy to find out, what causes the swift Merkel cell loss.

Another technical point that warrants discussion is the axonal labelling - first, I do not find the innervation patterns always easy to discern in the images provided, so I am not always sure how reliable this part is. Any artefact here creates the impression of dynamics, as during in vivo imaging stability is more reassuring than change. There are many ways not to see or recognize something, while there are few options to explain by an artefact why something did not change. Additionally, it might be good to explicitly mention that the TrkC mice are knock-in/knock-out (this is how I understood the JAX entry) - so the observations were made under reduced TrkC expression. It would help to explain, why this cannot affect axonal dynamics or Merkel cell-axon interactions.

Overall, while I feel that the authors performed an interesting in vivo imaging study, I think technical aspects make it difficult to conclude with confidence, whether we are watching a normal and physiological process here or dynamics that are induced by specific interventions. While these interventions might represent conditions that can occur also outside the laboratory, it would be important to clarify how the reader should contextualize this study.

Il s'agit à nouveau d'une opinion de l'auteur et d'un jugement. Premièrement, il suppose que les gens ont de mauvaises expériences et, deuxièmement, qu'ils disposent d'options pour rencontrer de nouvelles personnes.

C'est l'avis de l'auteur sur la base de son expérience des personnes qu'il a rencontrées. Il s'agit d'une extrapolation d'un comportement qu'il ne peut pas prédire.

Schubert Piano Sonata No. 1 in D.137 in E II Andante

Overall measurements for Steelmaster Index Card file for 4 x 6" index cards are 16” deep x 12.25” wide x 5.25” tall.

https://www.ebay.com/itm/125930697280

Reviewer #4 (Public Review):

This work aims at analyzing the impact of histone variants and histone modifications on chromatin states of the Arabidopsis genome. Authors claim that histone variants are as significant as histone modifications in determining chromatin states. They also study the effect of mutations in the DDM1 gene on the exchange of H2A.Z to H2A.W, which convert the silent state of transposons into a chromatin state normally found on protein coding genes.

This is an interesting and well done study on the organization of the Arabidopsis genome in different chromatin states, adding to the previous reports on this issue.

Reviewer #4 (Public Review):

This is an admirable piece of work. The authors build on a previous dataset they assembled, but expand it to include all stages of early development in the nematode Caenorhabditis elegans. Cell collection was done manually, which is very impressive, and is clearly far better than pooled unidentified cells. I will not comment on the specific sequencing and analysis, since this is not my expertise, but will comment on the general conclusions and comparative framework in which the authors place their results.

While the Introduction and Discussion sections are actually fairly short, much of the presentation of the results is based on a certain comparative framework, which is explicitly a comparison between C. elegans and Drosophila melanogaster. This is an important perspective, but I feel the authors' interpretation is in some places exaggerated and in other places almost trivial.

Drosophila and C. elegans are two of the main models for developmental biology. However, it has been clear for over two decades that both species are highly derived and specialized and therefore, treating them as representative for their taxa is problematic. Much of the authors' discussion hinges on the question of comparing syncytial and lineage-dependent development. The syncytial early development of Drosophila is very specific and is clearly a recent innovation within a restricted group of flies. The canonical Drosophila segmentation cascade is mostly a novelty and most elements within the cascade are recent (the authors are invited to browse my 2020 review in Curr. Top. Dev. Biol.) Specifically, the expression of gap genes in regional stripes is not found very broadly. Conversely, the polarizing role of Caudal is very ancient and is probably found in all Bilateria. When making comparisons with a distantly related species, it is important to keep this in mind. Not as much is known about development of other nematodes, but the little that is known indicates that C. elegans is also unusual, and specifically, the eutelic development (conserved cell lineages in development) is not found in all nematodes.

The authors suggest that regional expression of transcription factors in stripes is a conserved characteristic of development. This is true for Hox genes and has been known for decades. The regional expression they show for other genes is not convincing as "stripes". It is no surprise that developmental transcription factors are regionalized, but linking this to the stripes of Drosophila gap genes and even more so to Drosophila pair-rule and segment-polarity genes is a bit far-fetched. Yes, many genes are expressed in restricted domains along the A-P axis, but that is all that can be said based on the data. Calling them "Drosophila-like" is unfounded.

Beyond these broad homology statements, the rest of the presentation is fine and I have no major comments.

"an act of contention" 爭吵

"to express deep sorrow for usually by wailing and lamentation" 悲嘆

"to feel regret or contrition" 懺悔

"feeling or showing anger because of something unjust or unworthy" 憤慨

"moderation in action, thought, or feeling" 節制

"eagerness and ardent interest in pursuit of something" 熱誠

"excessive or insatiable desire for wealth or gain : GREEDINESS, CUPIDITY" 貪心、貪婪

"to bend the body or a part of the body forward and downward sometimes simultaneously bending the knees" 彎腰

"to charge or entreat earnestly or solemnly" 懇求

"long strenuous fatiguing labor" 勞苦

"the authority of a sovereign power to govern or legislate"; 管轄範圍

"a unit of weight formerly used by apothecaries, equivalent to 60 grains or one eighth of an ounce." 德拉克馬

"punishment inflicted in retaliation for an injury or offense" 報仇

"to feel joy or great delight" 開心

"a condition of deep suffering from misfortune, affliction, or grief" 悲痛

"to approve openly" 認可

"an ecclesiastical agent: such as: a Church of England incumbent receiving a stipend but not the tithes of a parish" 牧師

"precipitation in the form of small balls or lumps usually consisting of concentric layers of clear ice and compact snow" 冰雹

"any of a genus (Linum of the family Linaceae, the flax family) of herbs especially : a slender erect annual (L. usitatissimum) with blue flowers commonly cultivated for its bast fiber and seed" 亞麻

"generous or more than adequate in size, scope, or capacity" 寬闊

"plural of BROTHER" 弟兄們

"a timely benefit" 福利

"to put out the light or fire of" 熄滅

"not moving; stationary" 不動

"to attack violently" 攻擊

"moisture condensed upon the surfaces of cool bodies especially at night" 露水

"to make a hole through"; 穿過

"the seed of a vetch" 稗子

"a place of deep mud or mire" 泥沼

"the quality or state of being negligent" 忽略、忽視

"lagging or tending to lag : slow especially compared to others of the same kind" 遲緩的、落後的

"behavior marked by polished manners or respect for others"; 禮節、禮儀

"showing kindness and gentleness" 良性

"an act of violence or brutality" 暴行

"violation of allegiance or of faith and confidence"; 叛變

"to cease to proceed or act" 斷念

"without pause or delay"; 猛然地

"a feeling of great surprise and wonder" 驚愕

"one who travels to a shrine or holy place as a devotee" 朝聖

"eyebrow" 眉毛

"being out of the ordinary : RARE, UNUSUAL" 非習常的

"marked by ready ability to move with quick easy grace" 俐落

"open dislike and disrespect or mockery often mixed with indignation" 鄙視、蔑視

"to constrain or strain to tension by curving" 彎曲

"to enfold or enclose with or as if with a covering"; 包裹住

"to move slowly" 逗、留

"an expression of rebuke or disapproval"; 批評的話語

"a vivid reddish orange" 珠

"to lie or fall in a slant : INCLINE" 傾斜

"an astronomical transit instrument having its vertical circle very accurately graduated for precise measurements of declination" 經絡圈

"to have an inward conviction of (something, such as a coming ill or misfortune)"; 預示、預感

“a long sharp tooth”; 獠牙

"to make slow or difficult the progress of";妨礙

"to suffuse with color" 弄髒

"to overcome in battle : subdue completely" 擊敗、征服

"a soft deposit (as of mud, slime, or shells) on the bottom of a body of water" 爛泥

“evil reputation brought about by something grossly criminal, shocking, or brutal”; 醜惡的、聲名狼藉的

"the back of the neck";頸背

to rest or lie 休息；憩息；臥眠

Doing nothing is also a sin. Dante thinks you should stand up for your ideal.

from that or from there; from a thing or place that has been previously mentioned 由此；從那裡；從那一點

Dante gives sinners a second chance, kind of humanism.

on the thing that has been mentioned 關於那，就該事

He still not understand that God is justice itself.

This imply that lust is the most difficult one for humans to overcome.

Why does Dante choose Virgil?

This is also Dante reminding himself.

Now Dante fully accepted the fact that God is justice. Those people deserve to be punished like this.