1. Last 7 days
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    Tumor-infiltrating plasma cell profiling after PD-1 blockade reveals tumor-specific antibodies
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    Imipramine Reverses Sorafenib Resistance in Hepatocellular Carcinoma by Targeting the BLOC1S5/FOXO1 Signaling Axis
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    Single-cell transcriptome-guided biomimetic magnetothermal hydrogel microspheres for multimodal eradication of residual glioblastoma
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    Population genomics reveals gene flow and positive selection patterns in the wine-related yeast Hanseniaspora uvarum
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    Beta-Caryophyllene Prevents Ouabain-Induced Neurodegeneration and Behavioral Alterations Through PKA/GSK-3β Pathway
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  16. www.medrxiv.org www.medrxiv.org
    Advancing Brain Health Equity after Traumatic Brain Injury: A Multi-Stakeholder Global Priority-Setting Study
    1
    1. JanLouis 30 Jul 2026

      R0:

      Reviewer #1:

      To the authors: Respected authors, the theme of your research is highly relevant and timely, particularly given the importance of equity, patient-centered care, and stakeholder engagement in health systems research. This manuscript presents a valuable and comprehensive effort to identify priorities for advancing brain health equity after traumatic brain injury by engaging multiple stakeholder groups. I particularly commend the inclusion of individuals with lived experience and the commitment to co-creation throughout the project. The integration of social determinants, stakeholder perspectives, implementation considerations, and knowledge mobilization strategies reflects a thoughtful and mature approach to equity-oriented research. It is refreshing to see a project where people with lived experience are not merely participants, but meaningful contributors to the development and prioritization process. It is also encouraging to see research that not only identifies challenges but also seeks to advance implementation and develop actionable solutions. The project is ambitious in scope, methodologically detailed, and addresses an important gap in the literature. The work demonstrates substantial effort, coordination, and dedication from the research team. Indeed, the scale of stakeholder engagement, co-creation activities, and implementation planning could easily constitute a full thesis project or multiple standalone publications. I was also encouraged to see that the work has already moved beyond priority setting and toward dissemination and action, with the outputs already generating substantial engagement and visibility. The manuscript is generally well organized and scientifically relevant. However, I have a few concerns and comments that I hope will strengthen an already valuable contribution.

      Major Comment 1: My primary concern relates to the characterization of the study as a "global" priority-setting exercise. The findings support priorities among the sampled stakeholders but do not support claims regarding global stakeholder priorities. As the authors note, the participant sample is overwhelmingly concentrated in North America and in high-income countries. According to the manuscript, 88.5% of respondents originated from North America. Consequently, many countries, health systems, cultural contexts, and populations that may experience substantially different barriers to brain health equity are not represented within the stakeholder sample. I recognize that achieving truly global representation is extraordinarily difficult and that no study can realistically capture all perspectives. I also appreciate that the authors acknowledge this limitation and have already initiated efforts to engage underrepresented populations through future grants and collaborations. Nevertheless, given the study's central focus on equity, caution is warranted when presenting these findings as global priorities. Geographic, socioeconomic, cultural, and health system contexts can substantially influence stakeholder priorities. Even within the same country, priorities may differ considerably across regions, communities, and populations. When the ultimate goal is to identify priorities and guide action, these contextual differences become especially important. For this reason, I encourage the authors to consider these options: Reframe the manuscript as a North American study, as the vast majority are from such a region, and even the Knowledge mobilization priorities and implementation tracks identified during Round Robin activity seem to be directed to such a region. Or even limiting to the Canadian context. Reframe the manuscript as a multi-country stakeholder priority-setting study rather than a global study. (which still would be taken with care and not truly appropriate) Adopt more cautious language when discussing global implications and generalizability. Clarify throughout the manuscript that the identified priorities reflect the perspectives of the stakeholder groups represented within this sample. Consider waiting for more data from additional countries, since this initiative has started, as mentioned in the limitations section. Or publishing this study as a preliminary location(s) with the aforementioned suggestions, and then expanding this initiative across a broader range of countries and regions. Engaging with more neurological associations and brain organizations, as well as local leaders across different countries and regions. Such an effort would provide an extraordinary opportunity to compare priorities across settings and strengthen the evidence base needed to support truly global recommendations. In addition, future iterations could consider region-specific analyses or parallel priority-setting exercises conducted within different geographic contexts, followed by a comparative synthesis. This approach would allow for both local relevance and broader cross-context insights, ultimately strengthening the validity and applicability of global recommendations.

      Major Comment 2: I appreciate the authors' attention to inclusivity and the deliberate involvement of diverse stakeholder groups, including Indigenous communities and individuals from different racial and ethnic backgrounds. However, the manuscript reports that more than 85% of participants identified as White. This limitation is acknowledged but warrants further discussion given the study's focus on equity and the development of priorities based on such. As highlighted, previous research has demonstrated important differences in TBI incidence, risk factors, access to care, outcomes, and long-term recovery across racialized and marginalized populations. As such, the priorities identified in this study should be interpreted with consideration of the demographic composition of the sample. The discussion and limitations sections could further acknowledge how the underrepresentation of racial and ethnic minority populations may have influenced the priorities identified. Future efforts could benefit from targeted partnerships with advocacy organizations, Indigenous communities, Black communities, Latino communities, hospitals, clinics, and community leaders serving underrepresented populations to ensure broader participation and co-leadership in future iterations of this work. I also believe that the proposed future studies will benefit from collecting a broader range of social identity variables. As well as exploring the intersections between these determinants, some of which have been assessed. Experiences of inequity are often shaped by multiple overlapping social factors rather than a single characteristic in isolation. An intersectional approach may therefore provide a richer understanding of how social determinants influence priorities, access to care, and outcomes following traumatic brain injury.

      Additional Comments by Section: 1. Title: While informative, the title may not fully reflect the breadth and complexity of the multi-phase work undertaken and places considerable emphasis on the term "global" despite the acknowledged limitations in representation. 2. Background: No major comments. The background is clear, concise, well-referenced, and effectively establishes the rationale for the study. 3. Methods: The methodology across all three objectives is sound, comprehensive, detailed, and generally well described. These are my suggestions and questions: I particularly appreciated the use of REPRISE and PROGRESS-Plus frameworks. I also suggest considering the SAGER guidelines for reporting sex and gender. And given the survey component, consideration of the CHERRIES checklist may strengthen reporting transparency.

      The manuscript states that the survey was designed to maximize accessibility and global reach. If global reach was a primary objective, was translation into additional languages beyond English considered? Additionally, regarding the knowledge dissemination materials described at the end of this objective, the manuscript emphasizes maximizing accessibility and global reach. If the intention is truly global, I would suggest translating materials into more languages beyond English and French. Otherwise, it may be more accurate to describe this as enhancing accessibility within specific linguistic regions rather than globally.

      I truly appreciated that multiple stakeholders contributed to authorship and were involved in reviewing the survey prior to dissemination, as well as the a priori effort to recruit respondents across stakeholder groups. However, it was not entirely clear how recruitment targets were determined. Were formal sample size calculations performed? Was thematic saturation considered? How were recruitment targets established for each stakeholder category?

      Additional details regarding survey dissemination would be helpful. Through which channels was the survey distributed? Were professional organizations, hospitals, rehabilitation centers, advocacy groups, social media platforms, mailing lists, or community organizations involved? What strategies were used to reach underrepresented populations? This would assist readers in evaluating representativeness and potential selection bias.

      1. Results: Overall, the results are clearly presented. Yet a few considerations: I was unsure how to interpret the following sentence: "To further explore the relevance of social parameters for brain health outcomes after TBI, we utilized ML algorithms ... to data extracted from 30 published studies..." I suggest rewording for clarity.

      I also suggest rewording the following sentence for clarity: “Taking into account the gaps in existing evidence, survey development and the following objective were intentionally designed to remain broad, enabling comprehensive capture of relevant social equity determinants without restriction.”

      Some information currently reported within the Results section appears methodological and may be better placed within the Methods section, or removed if repetitive.

      It would be easier to interpret the table if the total weighting reference (5 total) were explicitly stated within the table caption.

      I found the framing of some social determinants difficult to interpret. Certain variables appear to be presented as adverse conditions (e.g., housing insecurity), whereas others are presented as positive resources or protections (e.g., access to benefits). Could this have influenced how respondents perceived and prioritized these determinants during survey completion, or could this have affected the interpretation of the resulting weighted scores? For the display of results, for clarity, would it be appropriate to consider a more consistent framing of these variables?

      The text following Figure 2 appears somewhat disconnected from the surrounding content. Please verify whether this text belongs within the main manuscript, the figure caption, or supplementary material. This text: “The goal is to provide access and link for people with lived experience to resources across the continuum of care and reducing accessibility barriers. The content areas that were discussed at the Round Robin activity for feasibility and impact, listed in the boxes, are not exhaustive. Complete list of topics is listed in S9 File.” Additionally, the S9 File is already referenced earlier.

      Additional figures, given the large number of results and supplementary material, could be beneficial for better visualizing the findings.

      1. Discussion: Well written and engaging, however, I encourage the authors to align interpretations more closely with the study's sampling characteristics. In particular, I would avoid statements suggesting that the study demonstrates both global relevance and sensitivity to local context. The findings clearly demonstrate relevance across different stakeholder groups, but the limited geographic and social representation makes it more difficult to support broader conclusions. Another suggestion, if the authors are interested, would be to include examples of similar initiatives, implementation strategies, or policy responses proposed or adopted in other countries. Such examples could provide additional context and help strengthen the proposed calls to action.

      2. Limitations: appropriately developed but could potentially be expanded further. Additional limitations that may warrant consideration include: -> Survey availability only in English. ->Limited racial and ethnic diversity within the sample. While this is mentioned briefly, it would benefit from deeper discussion regarding implications for survey design, recruitment, interpretation of findings, and broader consequences. It would also be helpful to outline concrete steps for improving representation in future work. -> Potential selection bias associated with survey dissemination channels. -> Limited consideration of intersectionality across multiple social determinants. -> Virtual participation and Zoom-related accessibility barriers, as well as other potential accessibility limitations. -> For the systematic review component, the authors note that several important social determinants were reported infrequently across the included studies and were therefore excluded from the analysis. The implications of these missing data for subsequent analyses should be discussed further. -> I was also interested in the finding that approximately 88% of survey respondents were female, despite previous evidence suggesting that TBI disproportionately affects males. The authors may wish to discuss possible explanations for this discrepancy.

      I encourage the authors to address the comments above and resubmit the manuscript for further evaluation. I congratulate the authors on undertaking such a project. The amount of work, coordination, stakeholder engagement, and dedication required to complete a three-stage study of this nature should not be underestimated. Too often, research stops at describing problems. I appreciate the effort to move beyond, engaging stakeholders throughout the process, co-creating solutions, and beginning to translate findings into practice. It is also encouraging to see that these efforts have already generated substantial engagement and dissemination. While I have raised concerns regarding representation and interpretation, these comments stem from a shared commitment to ensuring that equity-focused research is approached with particular care and reflection. I recognize the challenges involved in conducting this type of work and appreciate the authors' transparency and aim. Overall, this is a thoughtful, well-executed, and important topic that I hope continues to grow through future collaborations and broader stakeholder engagement.

      Reviewer #2:

      Discussion draws broad conclusions about cross-cultural consistency that are not adequately supported by the data. I suggest tempering the generalizability claims throughout the manuscript or more explicitly qualify them as reflecting primarily North American and European perspectives. Provide more explicit justification for why saturation was claimed across all stakeholder groups, particularly given the small n in the researcher and healthcare provider categories. I would more explicitly discuss how community voice was preserved and weighted during the Round Robin, particularly given that Services and Benefits themes were underrepresented in the team discussion relative to the external survey.

      This is an important topic, thank you for your efforts.

      Reviewer #3:

      This manuscript addresses an important and underexplored issue the integration of social parameters of health into traumatic brain injury (TBI) research, policy, and practice through a multi-stakeholder priority-setting process. There is strong rationale for the study as an equity issue and a timely need to address this. The study combines evidence synthesis, stakeholder engagement, and consensus development within the PROGRESS-Plus framework to develop an equity-oriented knowledge mobilization agenda. The topic aligns well with the aims of PLOS Global Public Health and has the potential to make a meaningful contribution.

      The manuscript is thoughtfully conceived and clearly reflects substantial effort from an interdisciplinary team. The commitment to stakeholder engagement, representation from those most affected by but least represented in the research about TBI, and both short- and long-term knowledge mobilization are notable strengths.

      However, several methodological and reporting issues currently limit the manuscript's impact. Most importantly, the manuscript is overly ambitious: Addressing all three objectives in one manuscript is too much for the reader to digest. There are insufficient methodological justification and/or scholarly references for several analytic decisions. For example, there is little scholarly justification for why Round Robin approach was selected over established priority-setting approaches such as Delphi Technique or Nominal Group Technique. As another example, there are no scholarly references for thematic analysis of open-ended survey answers.

      Major Areas to Address:

      1. The manuscript attempts to accomplish too many objectives. It combines evidence synthesis, machine learning meta-research, survey development, stakeholder engagement, qualitative analysis, consensus building, implementation science, and knowledge mobilization. Each component is valuable, but together they reduce the impact of each. Please clarify the primary contribution of the paper.

      2. Strengthen mixed-methods integration. Although described as a convergent parallel mixed-methods study, the three objectives function largely as sequential work packages. Consider using joint displays, explicit meta-inferences, and a clearer explanation of how qualitative and quantitative findings informed one another.

      3. Expand discussion of sampling implications. Address the implications of English-only recruitment, access to Zoom, organizational recruitment networks, volunteer bias, digital access, and limited representation from low- and middle-income settings in a manuscript that implies global priority setting

      Minor Areas to Address: • Clarify the novel contribution beyond previously published systematic reviews and protocol papers (specifically with respect to Objective 1) • Simplify Table 2 and distinguish PROGRESS-Plus domains from individual factors. • Deepen interpretation of why specific priorities emerged during the Round Robin process. • Reduce repetition of "knowledge mobilization" throughout the manuscript and shorten several lengthy paragraphs.

      Overall Assessment:

      This manuscript addresses an important gap in equity-oriented traumatic brain injury research and demonstrates impressive stakeholder engagement, and commitment to knowledge mobilization. The integration of evidence synthesis, stakeholder priorities, and implementation planning is innovative and well aligned with the aims of PLOS Global Public Health.

      The principal revisions required concern methodological clarity, analytical integration, transparency of reporting, and cautious interpretation of findings. Consider separate manuscripts for Objectives 1, 2, and 3. With these revisions, the manuscript has the potential to make a valuable contribution to the literature on equity-oriented priority setting and knowledge mobilization in traumatic brain injury research.

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  17. biz.libretexts.org biz.libretexts.org
    14.4: Import and Export Options
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    1. SavageD760 30 Jul 2026
      Importing External Data Remember that importing external data makes a copy of the data within Access and does not affect the data in the external source. After the import, no connection remains between the current database and the external source.

      importing external data

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  18. www.khanacademy.org www.khanacademy.org
    Life history strategies (article) | Ecology | Khan Academy
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  19. tkz96.github.io tkz96.github.io
    AI-Assisted Development — The AI Development Playbook
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  20. callyzer.co callyzer.co
    How to Spot Low-Quality Leads in 10 Seconds
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  22. investor.modernlao.com investor.modernlao.com
    Modern Lao Group · Account Reality
    3
    1. Gls 30 Jul 2026
      What gets paid first

      Sam I understand and yes this is all very good, I appreciate it. but the reality is it s a juke and jive game until Cameron funds and every penny needs to go where it needs to go. I will concentrate on getting more money because I cannot afford to put Nathong on full stop delay. I can delay strategic things like cabinets, and working out the water purfication system, maybe some plumbing and faucets not on yet, final coat of paint works to mid september and have it appear like we are just tidying up when they arrive in October. I have to get that stage, no options and how the money flows is based on those issues. Yes it needs to flow proper but at the moment there is no proper, its purely survival. I have to do more planning on this and will do but must find a couple of supply issues so that crew does not lose a second. By end of August that home will be 90- 95% complete and If I have to work 24 hours a day then I shall.

    2. Gls 30 Jul 2026
      When the incoming payments land

      Sam good but the reality is that there is two stages to all the money,,,,, three primary goals. 1. Sufficient work on Cameron to not cause any alarms. 2. Moving Nathong forward as follows: roof, I'm going to have to pull a trick on the roof because I do not have the 1800 to 2000 usd put toward the full roof at 200,000 kip per meter and require about 220 meteres with the foam insulation so what we will do is put on the cheaper product with out the insulation and spend approx 85,000 kip per meter on 220 or 18,700,000 kip plus 2 Million for ridge and edge cap. The house will then be covered and we can get to the finishing process with rain interfering. Then ceiling, electrical, plumbing whil;e also commencing with the tile work. The deck is 42.5 meters at 300,000 kip (won't know exactly until i get to Souvanny home store ) but close at 12,500,000 plus 10% waste so 13,750,000. Same cost for inside flooring at 72 Metere x 300,000 is 21,600,000- plus 10% waste for total of 24,200,000 but until i get to soucvanny cannot know exactly. If I log onto their webite I can see prices in the 350,000 kip per box and each box of 60 x 60 tiles represents 1.44 M2 so approx 250,000 kip per meter. three bathrooms at average of 12m per bath room including shower so 36m x 300,000, another 10,800,000 plus 10% waste , total 11,880,000 approx. Electrical wire, red black and green wire rolls run at 950,000 for 100M, will require five of each color so 15,000,000, ceiling wall board for 120M including cut and waste at 200,000 per sheet and each sheet is approx 2M so 60 for 12 Mil. Paint and primer will be 4 to 6Mil

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  23. johnkellden.medium.com johnkellden.medium.com
    Playⁿ: Mechanism Design
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  24. theright2read.org theright2read.org
    People's National Library Policy 2024
    1
    1. dhokli 30 Jul 2026
      unnatural chains of caste, class, gender, sexual orientation and disability & the Fundamental Rights enshrined within the Indian Constitution according the Right To Life, Right To Equality, Right To Rea

      Race???

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  25. www.google.com www.google.com
    "documents looks like RAG" - Google Search
    1
    1. indyweb 30 Jul 2026
      How Standard RAG Works

      contrast with Trail Blazing with IndyWikiNizerResearch

      • Save Page with /single file Browser Extension
      • add it to appropriately named IPFS folder Structure
      • using IPFS Desktop
      • pin parsonally archived web page using a Pinning Service like Pinata or web3.storage
      • annotate Saved Page
      • reflect the folder structure in a WikiTrail leading to the page
      • create a TrailPlex Page at the leaf of the blaed (folder path) trail
      • add a link to the WikiPlex Page in the annotation Page notes
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  26. openurl.ebsco.com openurl.ebsco.com
    The impact of linguistic bias upon speech-language pathologists' attitudes towards non-standard dialects of English.
    8
    1. ctriviso 30 Jul 2026
      Consequently, thepractice, values and attitudes of speech-language pathologists (SLPs) are influenced bythe lens of measurement and comparison of language against a standardised dominantlanguage or dialect, allowing little space for the language variation that is a core compo-nent of our human identity (Clyne, 2008; Goldstein & Iglesias, 2001). In contrast, thelanguage use of individuals seeking speech-language pathology services challenges thesestandardised boundaries of “correct” language use through the geographical, cultural anddiachronic variation of language and the cross-linguistic influence in an increasinglyglobalised world. Thus, it is necessary for SLPs to critique the discourses that influencetheir own language attitudes and bias to accurately distinguish true communicationdisorders from language differences that may result from variations in dialect (Lowet al., 2019; Toohill et al., 2012).

      Environment shaping voice and way we speak!

    3. ctriviso 30 Jul 2026
      In the current study, participants were aware that responses werebeing used in a study about language variation; hence, responses may reflect how partici-pants thought they should feel, rather than what they felt.

      Not fair. Responses swayed.

    4. ctriviso 30 Jul 2026
      The study alsohas some limitations. Sample bias may be present due to the location of the study and thenetworks used in the distribution of the study. A

      So can the data really be taken seriously?? Oppression? Why was sample size so small and biased???

    5. ctriviso 30 Jul 2026
      This may lead to teachers’ over-referral of children from linguistically diverse back-grounds to speech-language pathology services as their dialectal differences are perceivedas a potential communication disorder (Stow & Dodd, 2003). Although there is researchavailable both internationally and within Australia regarding language attitudes and theirimpact on school children, no studies have been published investigating SLPs’ attitudestowards non-standard dialects.

      Being 23 years later I wonder if this has changed

    6. ctriviso 30 Jul 2026
      Whilst speakers draw on dialect for expression of identity, they also hold unacknow-ledged attitudes towards others based on language and dialect. According to the socialidentity theory of intergroup behaviour (Tajfel & Turner, 1986), when encountering some-one from a different background, people do not act as individuals engaging on the basis ofinterpersonal relationships, but rather as members of a defined group.

      Rooted in oppression !

    7. ctriviso 30 Jul 2026
      In contrast, thelanguage use of individuals seeking speech-language pathology services challenges thesestandardised boundaries of “correct” language use through the geographical, cultural anddiachronic variation of language and the cross-linguistic influence in an increasinglyglobalised world.

      Another point to environment influencing ones voice and way of speaking

    8. ctriviso 30 Jul 2026
      Consequently, thepractice, values and attitudes of speech-language pathologists (SLPs) are influenced bythe lens of measurement and comparison of language against a standardised dominantlanguage or dialect, allowing little space for the language variation that is a core compo-nent of our human identity

      Standard english leaves little room for personal identity.

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    openurl.ebsco.com/contentitem/doi:10.1080/02699206.2020.1803405
  27. theright2read.org theright2read.org
    History of Public Library System and Policy in India
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  28. techgues.net techgues.net
    How Different Industries Use Telecalling to Increase Revenue - Techgues.Com
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  29. openurl.ebsco.com openurl.ebsco.com
    The Colour of Language: Accent, Devaluation and Resistance in Latin American Immigrant Lives in Canada.
    9
    1. ctriviso 30 Jul 2026
      Acker, Joan. 1997. My Life as a Feminist Sociologist; or, Getting the Man out of My Head. In Feminist Sociology: Life Histories of a Movement, ed. Barbara Laslett and Barrie Thorne, 28-47. New Brunswick, NJ: Rutgers University Press.

      This one I need to read! Could be helpful for research paper

    2. ctriviso 30 Jul 2026
      The moment the young waitress heard my request uttered in my accented English, my ESL-ness blocked her ability to understand; she seemed to have become deaf. As I spoke, the expression of her face turned more and more hopeless. After I repeated my request a couple of times while the waitress kept saying "pardon me," "pardon me," my student intervened to "interpret."

      Right away wanted to write her off based on an accent.

    3. ctriviso 30 Jul 2026
      Class, gender and politics are closely connected to the character and outcomes of immigrants' encounters with the language of the society of settlement.

      Environment shapes you, and your language.

    4. ctriviso 30 Jul 2026
      Language, in particular the accents of those who have learned to speak the dominant English language as adults, is one of the most important markers of Otherness and "difference," and of devaluation.

      The assimilation that was forced.

    5. ctriviso 30 Jul 2026
      represents a threat to whiteness and Standard English. Hence, in the dominant discourse, bilingualism is constructed as inadequacy, impoliteness, and transgression, and is harshly disapproved; it is for the non-native speaker of English to be bilingual, not for the native speaker

      A THREAT! RE: my point on standard english rooted in oppression.

    6. ctriviso 30 Jul 2026
      We had dared to challenge the supremacy of Standard English, but at the cost of our child's marginalization in the classroom.

      THIS! comes with a stigma. Diversity isn't always what it seems

    7. ctriviso 30 Jul 2026
      She knew that the education her daughter Gloria had achieved was of little value unless she spoke "un-accented" English:

      A pain I know all too well, my grandparents not wanting to teach my dad spanish for the same reason, so I never learned either.

    8. ctriviso 30 Jul 2026
      While through Lemert's influence I integrate my life experience into my teaching and research, through Acker's metaphor of "getting the man out of [one's] head," I have been encouraged to get the power of Standard English and whiteness out of my head to be able to reflect and write on the connections between Standard English, colonialism, whiteness, and the ESL immigrant experience.

      I like this, "getting the man out of one's head". Look into this reference.

    9. ctriviso 30 Jul 2026
      Probing the connections between Standard English, colonialism, whiteness and the immigrant experience, this piece moves from an educator's autobiography to the analysis of other immigrant lives to understand the production of a dominant discourse that reaffirms whiteness and the native speaker of English over the identity of the speaker of English as second language.

      The 'right' vs. 'wrong' idea of english language being rooted in oppression. Thesis of essay

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    openurl.ebsco.com/contentitem/doi:10.1353/ces.2013.0018
  30. www.biorxiv.org www.biorxiv.org
    Demonstrating the ability of GABAergic cells in the zona incerta to modulate motivation
    4
    1. Public_Reviews 30 Jul 2026

      eLife Assessment

      This set of studies provides important knowledge for the role of zona incerta neurons in motivation and food-seeking in mice. The evidence supporting the findings is convincing, with the use of multiple approaches and nice behavioral procedures to provide converging lines of evidence. Additional analyses and data from the current studies would further strengthen the evidence. This work will be of interest to those interested in motivation and its brain substrates.

      Summary
    2. Public_Reviews 30 Jul 2026

      Reviewer #1 (Public review):<br /> <br /> Summary:

      This manuscript by Laura Korobkova and Brian Dias describes an interesting study of the role of GABAergic neurons in the zona incerta (ZI) in incentive motivation for reward.

      The authors report that DREADD inhibition of ZI neurons reduced the effort breakpoint in a progressive ratio task, which measures the intensity of incentive motivation to obtain food rewards. In other tests, chemogenetic inhibition did not alter food consumption or memory.

      Conversely, DREADD excitation of ZI neurons increased incentive motivation in the progressive ratio task, expressed as a higher breakpoint for food rewards.

      Korobkova and Dias report that prior stress exposure to a series of stressors (e.g., forced swim & water submersion, restraint, mild footshock) by itself reduced the breakpoint for food reward under vehicle, though it did not impair the ability to learn an instrumental response. However, DREADD excitation of ZI neurons in previously stressed mice increased the breakpoint to normal levels equivalent to the never-stressed group. This important finding indicates the ability of ZI stimulation to rescue the incentive motivational deficit induced by prior stress.

      In fiber photometry studies using vGAT-CRE mice to specifically identify GABA neurons, Korobkova and Dias report that ZI GABA neurons are excited by sensory signals, including neutral cues. However, after reward conditioning, ZI GABA neurons increase their activation to the CS+ cue that predicts reward, but not to the CS- cue that doesn't. ZI neurons also respond in an instrumental reward task during both lever press and reward delivery. The authors conclude that ZI neurons respond to sensory stimuli, but specifically code the motivational significance of reward-related stimuli.

      In optogenetic studies, the authors find that ZI GABA neuron stimulation during a reward CS+ enhances motivated responding to obtain reward, particularly in females, but not stimulation outside the CS+. This suggests the ZI stimulation in females may specifically enhance the incentive salience of the CS+, namely the cue's ability to trigger an increase in 'wanting' for the reward. However, that effect was not found here in males.

      Altogether, this is a fine contribution to the literature, and the authors deserve congratulations on their study and manuscript.

      Strengths:

      This is a powerful and creative set of studies that clarifies the roles of ZI neurons in sensory processing and especially in incentive motivation for rewards. The use of multiple methods and test situations to triangulate on reward motivation functions gives a well-rounded perspective on ZI function. The discovery of incentive motivation roles for ZI neurons is intriguing and improves understanding of ZI, which traditionally has been a relatively understudied brain structure. The finding that ZI stimulation may rescue stress-induced deficits in motivation is especially notable and may have therapeutic implications.

      Weaknesses:

      Minor: This version of the manuscript focuses the introduction and discussion specifically on ZI GABA neurons. The ZI may be primarily GABAergic, but also contains other neurons, and DREADD studies may have used the hSyn promoter, which would impact all types of ZI neurons. Other studies here did more specifically target GABA neurons using vGAT Cre mice and specific targeting. The manuscript might be slightly improved by distinguishing in the discussion a bit more clearly which effects implicate GABA neurons specifically, and which effects might include other neurons too, to more clearly parse out the relative roles of GABA vs broader neuronal populations in ZI.

      Review 1
    3. Public_Reviews 30 Jul 2026

      Reviewer #2 (Public review):

      Summary:

      This paper describes a study that uses a combination of observational and experimental techniques to investigate the hypothesis that the zona incerta is a neural loci where sensory information is integrated to interpret the motivational value of reward-associated cues. They show that manipulation of GABAergic neurons in this region bidirectionally modulates responding during a progressive ratio test, that activating these neurons recovers motivational deficits incurred by chronic stress, and that they fire in response to reward-associated visual or auditory cues. They also showed that activity in these neurons is not necessary for incentive salience of reward-associated cues, because inactivating them did not prevent Pavlovian-instrumental transfer. However, activating them did enhance responding during the presentation of reward-associated cues in females but not in males.

      Strengths:

      The study has a very systematic and elegant approach to assess how this region responds first to intrinsic motivation and then to motivation-enhancing effects of reward-associated cues.

      Weaknesses:

      Males and females are used throughout, but sample sizes are generally too small to make a meaningful interpretation of sex differences (which is not the focus of the study, but is worth bearing in mind). In the last experiment, the lack of discrimination between CS+ and CS- conditions across training for males confounds any interpretation of sex-differences in the outcomes.

      The ZI is known to be a region where there is notable convergence of neural inputs from a diverse and heterogenous range of sensory and other cortical inputs. To my knowledge, this is the first study that has directly tested whether it may serve to encode motivational/incentive properties of reward-associated cues. The outcomes are not definitive - it appears that they are sufficient but not necessary. However, this study represents an important first step - the ZI also has notable heterogeneity in the genetic identity of neurons, and properly dissecting the function of ZI microcircuits will likely require characterising function based on more than one molecular marker. This is addressed by the authors in the discussion.

      In summary, this study will have a significant impact on our understanding of how motivation is calculated based on complex environmental signals.

      Review 2
    4. Public_Reviews 30 Jul 2026

      Reviewer #3 (Public review):

      Summary:

      The authors investigated the role of the zona incerta in motivation and cue-reward associations. Using chemogenetic and optogenetic manipulations of the ZI, they altered motivation in cued and uncued variants of the progressive ratio task and rescued deficits in motivation induced by chronic stress. They further use fiber photometry to demonstrate that the ZI tracks the formation of cue-reward associations.

      Strengths:

      (1) The authors fill an important gap in the literature linking sensory input to motivation via the zona incerta.

      (2) The authors demonstrate that ZI tracks cue value rather than just tracking sensory input.

      (3) The authors demonstrate that the ZI excitation rescues stress-induced suppression of motivation.

      (4) The authors perform several important control tasks, demonstrating that their findings are not a result of alterations in locomotor activity, food consumption, or memory.

      Weaknesses:

      In Figure 1D and E (inhibitory vs excitatory DREADDS), the control groups in the Gi group appear to have more elevated breakpoints than the control groups in the Gq group, although a statistical comparison between the two is not reported. It is not clear if this is because the two groups were given a different reinforcement schedule, this should be made clearer.

      In Figure 1E, it is important to note that although the authors found a significant planned comparison between Gq VEH and Gq CNO, the interaction was not significant, nor were comparisons to mice injected with control virus. Thus, activation of ZI GABA neurons appears to be a relatively weak effect.

      In Figure 5, the authors see what is likely a significant difference in lever presses during acclimation between the Gi and GFP groups, which they state is an expected difference. However, it is difficult to see why this would be expected. While Gi:CNO manipulation yielded lower breakpoints in Figure 1D, it did not yield lower FR1 responding for food in Fig S3 (although this was FR1 for food dispenser visits rather than lever press). One reason I ask is that the authors highlight the differences in CS+/CS- between groups, but the biggest difference between groups appears to be in acclimation, which may be driving the group x block interaction.

      In Figure 6, the authors demonstrate that optogenetic stimulation during cue light increases the breakpoint in females, but not in males. They suggest that this may be because the males did not sufficiently discriminate the cue light before optogenetic manipulation began. If this were the case, then the authors would need to use "cue discrimination" as a factor to determine if it is a better predictor than sex.

      The authors' work demonstrates that chemogenetic inhibition of GABAergic ZI cells reduces uncued motivation for reward but enhances cued responses under extinction. The authors state that this is a paradoxical finding that suggests that the ZI operates within a redundant motivation network. However, a critical difference between the two tasks is that one measures motivation for food while the other measures persistent responding under food extinction, which are not the same process. Thus, a simpler explanation is that ZI inhibition reduces motivation and impairs extinction.

      Review 3
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    biorxiv.org/content/10.64898/2026.05.10.724142v1
  31. www.biorxiv.org www.biorxiv.org
    Glycolipid MPIase is essential for the TAT (Twin-Arginine Translocation) pathway
    3
    1. Public_Reviews 30 Jul 2026

      eLife Assessment

      This study demonstrates a critical role of the glycolipid membrane protein insertase (MPIase) in the twin-arginine translocation (Tat) pathway, a protein translocation system that is conserved across all domains of life. The successful reconstitution of the bacterial Tat system in both bacteria-derived and artificial liposomes provides solid experimental evidence that MPIase has a broader role in membrane protein translocation than previously recognized. By revealing the essential function of a nonproteinaceous membrane component in catalyzing a core cellular process, this work offers fundamental insights into the molecular mechanisms of protein translocation.

      Summary
    2. Public_Reviews 30 Jul 2026

      Reviewer #1 (Public review):

      Hanako and colleagues demonstrated that glycolipid MPIase is essential for the TAT system, and they successfully reconstituted the TAT system in vitro for the first time. This will facilitate the understanding of the mechanism of the TAT system.

      My major points are listed below for the authors to consider:

      (1) The authors successfully reconstituted the TAT system using the purified TatA/B/C, but the translocation efficiency was much lower than that of native INV. The authors partly attributed this to the reason that "MPIase recovery would be too low to detect the TAT activity" in the Discussion part. So, what would happen to the translocation efficiency if you added more MPIase to the reconstituted system? How about the abundance of MPIase from the INV and reconstituted proteoliposomes?

      (2) Why were only TatC levels measured in Figure 2C, whereas the expression levels of TatA were not detected? Also, from my observation, the amount of TatC in the third lane is lower than that in the previous two lanes.

      (3) The authors should explain why the TatA/B/C ratios in Figure 3C (1:1:1) and Figure 3D (10:1:1) are inconsistent.

      (4) ~30% of the fluorescence was recovered in the membrane fraction (Figure 4A) both in the functional TAT signal sequence (RR) and in the inactivating mutant signal sequence (KK), which suggests that MPIase acts as a relatively broad recognition factor. Given that MPIase does not discriminate between RR and KK, why do un-translocated substrates remain in the cytoplasm rather than non-specifically adhering to the membrane when MPIase is depleted in vivo?

      Review 1
    3. Public_Reviews 30 Jul 2026

      Reviewer #2 (Public review):

      Summary:

      In this manuscript, the authors investigated the relationship between the Tat system and MPIase, a glycolipid that facilitates protein integration into the bacterial cell membrane. The TAT (twin-arginine translocation) system is a unique membrane transport machinery that exports fully folded proteins containing a twin-arginine signal peptide. Using both in vivo and in vitro approaches, the authors demonstrated that a sufficient amount of MPIase is required for Tat-dependent protein translocation. Furthermore, the authors successfully reconstituted the Tat transport system by combining recombinant TatA, TatB, TatC, MPIase, and FoF1-ATP synthase.

      Strengths:

      The reconstituted system clearly demonstrated the requirement for each component, as substrate translocation occurred only when all components were present. Based on these findings, the authors proposed a mechanistic role for MPIase in facilitating Tat-mediated membrane translocation. Previous studies have shown that MPIase is involved in Sec-dependent protein translocation and membrane protein integration, as well as YidC-dependent membrane insertion. The present study further demonstrated that MPIase also plays an essential role in the Tat translocation pathway. Overall, this work highlights the central importance of MPIase in bacterial membrane protein biogenesis and provides new insights into the molecular mechanism of Tat-dependent protein transport.

      Weaknesses:

      (1) To show the importance of the Tat system in bacterial cells, it would be good to describe in the introduction how many proteins are translocated via the Tat system.

      (2) Figure 2B and D show that a sufficient amount of MPIase is important in SufI translocation. However, the reason why MPIase level was upregulated in the BL21 strain but not in the KS46 strain remains unexplained. The authors should address this point.

      (3) In Figures 4A and B, the authors explain that MPIase first works as a receptor of TorA-GFP without recognizing the RR motif. This conclusion is based on the results of the fractionation assays, where "sup" indicates the cytoplasmic and periplasmic fractions, and "ppt" indicates the membrane fraction. In Figure 4B, under the TatABC+++, (RR), +MPIase condition, the substrate is secreted most efficiently via the Tat pathway and should therefore be recovered in the periplasm fraction (sup). However, the authors point out that efficiently processed substrate was recovered in the ppt fraction rather than the sup fraction. The authors should explain why this occurred.

      Review 2
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    biorxiv.org/content/10.64898/2026.06.05.730299v2
  32. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Double hyperautofluorescent ring on fundus autofluorescence in ABCA4
    1
    1. Vibhor 30 Jul 2026
      ABCA4

      Case#: 1 male, 6 years old, from Taiwanese and Korean decent.

      DiseaseAssertion: ABCA4-related retinopathy Stargardt disease

      FamilyInfo: Single affected individual. Paternal uncle presented with Stargart disease previously, and Taiwanese and Korean descent underwent genetic testing to identify two pathogenic variants in the ABCA4 gene. One of the variants found was the same ABCA4 variant from the originally affected individual. No additional family information is provided in text.

      CasePresentingHPOs: HP:0000529 - progressive visual loss, HP:0025010 - Foveal atrophy, HP:0000603 - Central scotoma, HP:0007663 - Decreased visual acuity, HP:0030602 - Abnormal fundus autofluorescence imaging, HP:0007984 - ERG: Reduced dark-adapted b-wave amplitude, HP:0000512 - Abnormal electroretinogram, HP:0020032 - Hyperreflective retinal dots on OCT

      CaseHPOFreeText: peripapillary sparing was observed on fundus autofluorescence imaging.

      CaseNotHPOs: HP:0012045 - Retinal flecks

      CaseNotHPOFreeText: N/A

      Genotyping Method: Genetic testing was used and after sequencing two variants were found on the ABCA4 gene.

      PreviouslyPublished: N/A

      Variant: NM_000350.3(ABCA4):c.3523-2A>G

      Variant: NM_000350.3(ABCA4):c.2249T>C (p.Leu750Pro)

      ClinVar: Variation ID: 866764

      ClinVar: Variation ID: 417984

      CAID: N/A

      SupplementalData: N/A

      Gene:ABCA4 HGNC:34 InheritancePattern:AutosomalRecessive DiseaseEntity:STGD1 AlleleOrigin:Germline Zygosity:CompoundHeterozygous ClinVarID:417984 ClinVarID:866764 MultipleGeneVariants FundusAutofluorescence PeripapillarySparing DecreasedERGResponses MacularAtrophy DecreasedCentralVA Scotoma PreviousTesting FamilyInfo automated_hgnc:34 automated_hgnc_source:hgnc_tag ClinGen ABCA4 Annotations
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    pmc.ncbi.nlm.nih.gov/articles/PMC5950710/
  33. Local file Local file
    Untitled document
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  34. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    Whole exome sequencing analysis identifies novel Stargardt disease-related gene mutations in Chinese Stargardt disease and retinitis pigmentosa patients
    1
    1. Vibhor 30 Jul 2026
      STGD-4F30ABCA4c.4555delAp.T1519Rfs*5HeteroARN/AN/AN/AN/AYABCA4c.6397T>Cp.C2133RHeteroD1D2D322.80Y

      Case#: Sporadic Patient #4, female, Chinese, 30yo at report

      DiseaseAssertion: STGD

      FamilyInfo: n/a, sporadic case

      CasePresentingHPOs:

      CaseHPOFreeText:

      CaseNotHPOs:

      CaseNotHPOFreeText:

      GenotypingMethod: WES with Sanger sequencing confirmation

      PreviouslyPublished: no

      Variant: c.4555delA p.(T1519Rfs*5); c.6397T>C p.(C2133R)

      ClinVar: 2021273; 2733921

      CAID: CA341277387; CA645372203

      SupplementalData:

      ClinVarID: 2021273 CA341277387 CaseInfo Individual ClinVarID: 2733921 CA645372203 automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    ncbi.nlm.nih.gov/pmc/articles/PMC8956586/
  35. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare ABCA4 Variant in a Child with Early-Onset Stargardt Disease
    1
    1. Vibhor 30 Jul 2026
      10-year-old girl

      Case#: Patient female, 10y, ethnicity not reported

      DiseaseAssertion: Stargardt disease (STGD1), early onset

      FamilyInfo: autosomal recessive inheritance; co-segregation of variants in parents (each heterozygous). Pedigree shown in Figure 1A. One unaffected sibling reported.

      CasePresentingHPOs: HP:0007663, HP:0007754, HP:0002587, HP:0030636, HP:0000548

      CaseHPOFreeText: early-onset visual decline (age 7), symmetric disease in both eyes, hyperautofluorescent ring surrounding macular atrophy, lipofuscin accumulation, photoreceptor degeneration.

      CaseNotHPOs: HP:0007707

      CaseNotHPOFreeText: normal anterior segment on slit lamp exam; no external ocular abnormalities reported.

      Genotyping Method: Sanger sequencing confirmation; variant identification likely via next-generation sequencing (not explicitly stated).

      PreviouslyPublished: n/a

      Variant: ABCA4 NM_000350.2: c.6817-713A>G; c.3259G>A (p.Glu1087Lys)

      ClinVar: n/a

      CAID: CA2837995439, CA227097

      SupplementalData: phenotype and validation data in Figures 1–5 and Supplemental Figures S1–S5

      InheritancePattern:AutosomalRecessive DiseaseEntity:STGD1 AlleleOrigin:Germline Zygosity:CompoundHeterozygous CAID:2837995439 CAID:227097 DecreasedCentralVA MacularAtrophy FundusAutofluorescence Scotoma automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    pmc.ncbi.nlm.nih.gov/articles/PMC11011354/
  36. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    PERIPAPILLARY ATROPHY IN STARGARDT DISEASE
    1
    1. Vibhor 30 Jul 2026
      Case 1A 55-year-old male was examined for long-standing central visual impairment since age 18. Family history was not significant for ocular disease. His best-corrected visual acuity of 20/350 OD and 20/200 OS was consistent with measurements over the last 20 years. Spherical refractive error measured −3.5 OD and −2.0 OS. Anterior segment examination was unremarkable and applanation tonometry measured 17 mmHg OD and 14 mmHg OS. Posterior segment examination and autofluorescence imaging were significant for sharply demarcated central and peripapillary zones of atrophy and the absence of fleck lesions (Figure 1, A–D). Humphrey visual fields demonstrated bilateral central scotomas with eccentric fixation at the inferior border. ERG examination was subnormal and similar to results obtained 22 years ago.Open in a separate windowFig. 1Case 1. STGD with peripapillary atrophy and mutations P1380L and IVS40 + 5G>A. A, Autofluorescence OD. B, Color Photo OD. C, Autofluorescence OS. D, Color Photo OS. All show marked peripapillary and macular atrophy with a sharply demarcated zone of sparing between them. These characteristics caused initial diagnostic confusion with choroidal sclerosis.Genetic testing was employed for further diagnostic information and two heterozygous ABCA4 mutations, P1380L and IVS40 + 5G>A, were identified and classified as disease-causing alleles, thereby confirming the diagnosis of STGD.

      Case#: Hwang Case 1, US, male, 55yo at report, 18yo at onset

      DiseaseAssertion: Stargardt disease

      FamilyInfo: Family history was not significant for ocular disease

      CasePresentingHPOs: HP:0007663, HP:0500087, HP:0000603, HP:0000512

      CaseHPOFreeText: BCVA of 20/350 OD and 20/200 OS. Spherical refractive error measured −3.5 OD and −2.0 OS. Posterior segment examination and autofluorescence imaging were significant for sharply demarcated central and peripapillary zones of atrophy and the absence of fleck lesions (Figure 1, A–D). Humphrey visual fields demonstrated bilateral central scotomas with eccentric fixation at the inferior border.

      CaseNotHPOs:

      CaseNotHPOFreeText:

      GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.

      PreviouslyPublished: n/a

      Variant: P1380L and IVS40 + 5G>A

      ClinVar: 7904

      CAID: CA129033

      SupplementalData: n/a

      CA129033 CaseInfo Individual ClinVarID: 7904 automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    ncbi.nlm.nih.gov/pmc/articles/PMC2743754/
  37. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Partial paternal uniparental disomy (UPD) of chromosome 1 in a patient with Stargardt disease
    1
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    pmc.ncbi.nlm.nih.gov/articles/PMC2553007/
  38. www.sciencedirect.com www.sciencedirect.com
    A novel mutation in the ABCR gene in four patients with autosomal recessive Stargardt disease
    1
    1. Vibhor 30 Jul 2026
      Patient 3, a 37-year-old Caucasian woman, presented in July 1998 with a gradual decline in visual acuity that began at the age of 12.

      Case#: Patient 3, 37-year-old female

      PMID: 10612508

      DiseaseAssertion: STGD1

      FamilyInfo: Affected sibling in autosomal recessive family.

      CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

      CaseHPOFreeText: Gradual visual decline beginning at age 12. Visual acuity 20/400 in both eyes. Fundus examination revealed bilateral macular atrophy with pigment deposits and numerous yellow flecks in the posterior pole and midperiphery. Fluorescein angiography showed large hypofluorescent regions with surrounding hyperfluorescence and peripheral dark choroid.

      CaseNotHPOs: Not reported

      CaseNotHPOFreeText: Not reported

      GenotypingMethod: PCR and direct sequencing of ABCA4

      PreviouslyPublished: Yes

      Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

      ClinVar: Not reported

      CAID: Not reported

      SupplementalData: Segregation and sequencing data (Figures 1, 4)

      CaseInfo Individual DecreasedCentralVA FundusAbnormality DiseaseEntity: STGD1 InheritancePattern: AutosomalRecessive Zygosity: CompoundHeterozygous SegregationData SupplementalData Gene:ABCA4 automated_hgnc:34 automated_hgnc_source:Gene_Name ClinGen ABCA4 Annotations
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    sciencedirect.com/science/article/pii/S0002939499002366
  39. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
    Molecular analysis of the ABCA4 gene for reliable detection of allelic variations in Spanish patients: identification of 21 novel variants
    1
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    pubmed.ncbi.nlm.nih.gov/19028736/
  40. www.ajo.com www.ajo.com
    mmc1.pdf
    1
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    ajo.com/cms/10.1016/j.ajo.2020.06.027/attachment/2c3c8baa-ae3a-4cb6-a3ad-ae429569a986/mmc1.pdf
  41. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    Personalized genetic counseling for Stargardt disease: Offspring risk estimates based on variant severity
    2
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    ncbi.nlm.nih.gov/pmc/articles/PMC8948157/
  42. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
    A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)
    1
    1. Vibhor 30 Jul 2026
      A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

      PMID: 31456290

      Gene: ABCA4

      HGNCID: HGNC:34

      SupplementalData: as applicable Table S2. Variant found in cohort of 2,420 families including 3,413 individuals with inherited retinal diseases in Israel. Likely, this is the same family reported in PMID 29706639.

      Total number of families: 1; phenotype/s: CRD; NM_000350.2:c.4895dup, p.(Asn1632Lysfs*14)

      General PMID:31456290 Gene:ABCA4 automated_hgnc:34 automated_hgnc_source:Gene_Name ClinGen ABCA4 Annotations
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    pubmed.ncbi.nlm.nih.gov/31456290/
  43. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis
    1
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    pmc.ncbi.nlm.nih.gov/articles/PMC2660377/
  44. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    Genotypes Predispose Phenotypes—Clinical Features and Genetic Spectrum of ABCA4-Associated Retinal Dystrophies
    1
    1. Vibhor 30 Jul 2026
      Panel-based NGS testing was performed for all recruited patients for the identification of disease-causing variants. All patients recruited in this present cohort had two allele disease-causing ABCA4 variants confirmed according to the American College of Medical Genetics and Genomics guidelines (Supplementary Table S2).

      Case#: Family F23 Patient P26, 42yo

      DiseaseAssertion: MD-C

      FamilyInfo: family f23

      CasePresentingHPOs:

      CaseHPOFreeText:

      CaseNotHPOs:

      CaseNotHPOFreeText:

      GenotypingMethod: capture-based next-generation sequencing (NGS) testing

      PreviouslyPublished: n/a

      Variant: c.4555del(;)6119G>A genotype b (a patient harboring a severe/null variant and a missense or in-frame insertion/deletion variant)

      CAID: CA232815

      SupplementalData: table s2

      SupplementalTable CaseInfo Individual CAID:CA232815 automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    pmc.ncbi.nlm.nih.gov/articles/PMC7759801/
  45. oce-ovid-com.libproxy.lib.unc.edu oce-ovid-com.libproxy.lib.unc.edu
    PROGRESSION OF ABCA4 -RELATED RETINOPATHY: Prognostic value of demographic, functional, genetic, and imaging parameters
    1
    1. Vibhor 30 Jul 2026
      Seventy eyes (38 patients), of which 46 (66%) were female and 24 (34%) male, with RPE atrophy secondary to ABCA4 -related retinopathy (age [years], 45.51 ± 16.70; range 14–78) were included in the study ( Table 1 and see Table, Supplemental Digital Content 2 , http://links.lww.com/IAE/B170 , which shows the individual baseline and progression data of all included eyes).

      Case#: Patient #32, male, 60yo at baseline visit, "late" age of onset

      DiseaseAssertion: ABCA4-related retinopathy with secondary RPE atrophy

      FamilyInfo: n/a

      CasePresentingHPOs:

      CaseHPOFreeText: Inclusion criteria were defined as 1) presence of at least one mutated allele in ABCA4 (NM_000350.2) in Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing 2) a compatible phenotype with flecks at the level of the RPE consistent with ABCA4 -related Stargardt disease 3) presence of RPE atrophy, and 4) serial examinations with an interval of at least 6 months. RPE atrophy to the end-stage (i.e., demarcated lesions with ≥90% darkness of the optic disc under short-wavelength excitation light, DDAF) that previously showed highest interreader agreement.7 The size of DDAF has to be at least 0.05 mm 2 (each single atrophic area in cases of multifocality), and the entire lesion must be completely visualized on the AF image at each visit to be advanced for analysis. Self-reported symptom onset into early-onset (≤10 years), intermediate-onset (11–44 years), and late-onset (≥45 years). ff-ERG based Category: Group 1 contained eyes with normal scotopic and photopic responses; Group 2, eyes with normal scotopic responses, but reduced (over 2 SDs) photopic B-wave and 30-Hz flicker amplitudes; and Group 3, eyes with impairment of both rod- and cone-driven responses. BCVA: OD=0, OS=0 [LogMAR] .

      CaseNotHPOs:

      CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting image quality led to exclusion from the study

      GenotypingMethod: Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing

      PreviouslyPublished: n/a

      Variant: allele 1: c.52C>T/p.(Arg18Trp) // c.1715G>A/p.(Arg572Gln) // c.2828G>A/p.(Arg943Gln) allele 2: c.1588G>A/p.(Gly863Ala) // c.5603A>T/p.(Asn1868Ile)

      ClinVar: 7900

      CAID: CA226918

      SupplementalData: The supplemental table linked here contains genotype and phenotype information.

      CaseInfo Individual SupplementalTable ClinVarID:7900 CAID:CA226918 automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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  46. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort—Impact of Selected Deep Intronic Variants and Common SNPs
    1
    1. Vibhor 30 Jul 2026
      Supplement 4Click here for additional data file.(480K, pdf)Supplement 5Click here for additional data file.(460K, pdf)

      This variant was found in 92 of the 670 alleles in this cohort (Supplement 4). Supplement 5 has the individuals listed with their genotypes, but only mentions variants that were classified as VUS/LP/P, so it is unknown which individuals specifically had this variant or which other variants they also had.

      InsufficientEvidence CA285825 SupplementalTable automated_hgnc:34 automated_hgnc_source:CAID ClinGen ABCA4 Annotations
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    ncbi.nlm.nih.gov/pmc/articles/PMC5270621/
  47. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration
    1
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    ncbi.nlm.nih.gov/pmc/articles/PMC7796138/
  48. www.gimjournal.org www.gimjournal.org
    Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics
    1
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    gimjournal.org/article/S1098-3600(21)01183-7/fulltext
  49. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
    Clinical and genetic characteristics of Stargardt disease in a large Western China cohort: Report 1
    1
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    pubmed.ncbi.nlm.nih.gov/32845068/
  50. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
    ABCA4 Gene Screening by Next-Generation Sequencing in a British Cohort
    1
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    pmc.ncbi.nlm.nih.gov/articles/PMC3796939/
  51. www.biorxiv.org www.biorxiv.org
    Quantitative multi-scale morphodynamic analysis reveals ratchet-like collective DVE migration and epiblast retrograde cell flow during anterior patterning in the mouse embryo
    4
    1. Public_Reviews 30 Jul 2026

      eLife Assessment

      The authors provide convincing evidence that, during early mouse embryogenesis, distal visceral endoderm cells migrate in a coordinated, intermittent start-and-stop manner along an axis that correlates with the asymmetric morphology of the ectoplacental cone. This fundamental finding is supported by high-quality live imaging and quantitative image analysis, while computational modelling suggests that the observed intermittent behavior may be explained by the movement of a cohesive cell group through a viscoelastic tissue, rather than by fluctuations in DVE migration velocity itself.

      Summary
    2. Public_Reviews 30 Jul 2026

      Reviewer #1 (Public review):

      Summary:

      The authors study how the migration of distal visceral endoderm (DVE) cells in early mouse embryos becomes channeled towards one direction and the corresponding movement of the epiblast on which the DVE cells migrate. To this end, they develop an analysis pipeline of an in toto live data set previously obtained by the authors, which includes superpixel motion tracking of the visceral endoderm surface and subregions thereof. They find that a morphological asymmetry of the ectoplacental cone is indicative of anterior-posterior axis orientation. Even during the phases prior to and after collective migration, DVE cell speed was larger than in the surrounding tissue. The crossover from the pre-migratory to the migratory phase relies on the alignment of DVE cell motion. During the migration phase, counter-rotating vortices appeared in the emVE as expected when a rigid body moves through an incompressible fluid. Furthermore, DVE migration exhibits what the authors term a ratchet-like behavior, where the cells alternate between bursts of collective migration and periods of essentially no net motion. This behavior could be reproduced in vertex-model simulations, where DVE cells were subjected to a constant external force in an otherwise passive environment of cells. The observed intermittent behavior results from building up stress in the surrounding tissue that is released through cell rearrangements involving T1 transitions. These findings are in line with experimental results, although in embryos, T1 transitions are not as abundant as in the simulations and are largely confined to the region ahead of the DVE. Finally, the authors report a distally directed planar motion in the anterior epiblast underlying the visceral endoderm and thus opposite to the motion of the DVE. Cell migration in the posterior epiblast was slower and more random than in the anterior.

      Strengths:

      The authors provide a detailed analysis of the cell migration patterns in the embryo and show through vertex-model simulations that some of the observed features are really consequences of the properties of incompressible fluids.

      Weaknesses:

      Naming the intermittent dynamics of DVE cells as ratchet-like seems inappropriate, as it is rather reminiscent of stick-slip dynamics.. Quantitatively, the simulations do not provide much more insight beyond providing the flow profile of the (complex) fluid behavior of the tissue surrounding the DVE. It would be interesting to identify mechanisms that underlie migration alignment of DVE cells and to study in detail the T1 transitions - why are they confined to certain regions of the tissue? Furthermore, the theoretical analysis should be extended so that it also considers the dynamics of epiblast cells.

      Review 1
    3. Public_Reviews 30 Jul 2026

      Reviewer #2 (Public review):

      Summary:

      The work provides mechanistic insights into the establishment of the anterior-posterior axis of the mouse embryo by quantifying multiple cellular and tissular parameters from high-quality live imaging data. It shows that the direction of the axis is predetermined by the embryo geometry, that the cells whose migration defines the direction of the axis (the anterior visceral endoderm) have a ratchet-like movement probably depending on transient relaxation events of the epithelial cells lying in their way, and that the adjacent cell layer (the epiblast) moves in the opposite direction.

      Strengths:

      The dataset is large, with multiple embryos from relevant reporter lines integrally imaged at high resolution for long periods of time, and the analysis tools are novel, original and powerful.

      Weaknesses:

      Since all data are obtained from wild-type unchallenged embryos, the direct causality between events may not be fully guaranteed.

      Review 2
    4. Public_Reviews 30 Jul 2026

      Reviewer #3 (Public review):

      Summary:

      In this manuscript, the authors investigate the dynamics of distal visceral endoderm (DVE) migration during early anterior-posterior axis formation in the mouse embryo. Using long-term light-sheet imaging combined with geodesic projections and quantitative motion analysis, they characterize DVE migration at both the cellular and tissue levels. The study identifies three distinct phases of DVE migration, describes the intermittent "stop-and-go" nature of DVE movement, and quantifies coordinated tissue behaviors within the visceral endoderm. The authors further report a previously unrecognized posterior movement of the underlying epiblast that occurs concomitantly with anterior DVE migration. Finally, they develop a two-dimensional vertex model to investigate the mechanical basis of the observed intermittent migration, proposing that cycles of stress accumulation and T1-mediated stress relaxation within the surrounding visceral endoderm account for the observed dynamics

      Strengths:

      Overall, this is a very interesting study combining state-of-the-art live imaging with an impressive quantitative image analysis framework. The imaging quality is excellent, and the authors provide one of the most detailed quantitative descriptions of visceral endoderm (VE) dynamics to date. In particular, the combination of whole-embryo light-sheet imaging, geodesic projections and quantitative analysis provides a rich dataset that will undoubtedly be valuable for the community. The model is also informative and provides a mechanistic hypothesis for the start and stop motion of the VE.

      Weaknesses:

      (1) Clarification of the Superpixel-based image analysis

      The image analysis pipeline is impressive but could be explained more clearly for readers unfamiliar with the authors' previous work. In particular, the manuscript relies extensively on superpixel tracking, but it remains unclear what advantages this approach offers over more conventional Lagrangian particle image velocimetry (PIV). Since this paper should be self-contained, it would be helpful if the authors briefly explained the rationale for choosing superpixel tracking rather than referring readers to their previous eLife publication.

      Related to this point, the manuscript appears to use two different levels of coarse-graining. Motion is initially estimated from thousands of superpixels (1000-5000 according to the Methods), whereas the quantitative analyses are ultimately averaged over only 32 spatial sectors. The relationship between these two levels of representation is not entirely clear and would benefit from clarification. Why use such a dense superpixel seeding, which seems oversampled, if the intent is to eventually bin the result?

      Relatedly, how was the number of superpixels chosen? What is their effective size relative to the size of a VE or epiblast cell? This information is important because the analysis appears to be oversampled. This is particularly evident in Movie S14/Figure 7, where numerous superpixels appear to span a single epiblast cell. At this spatial scale, the measured motion is likely to include intracellular or subcellular movements, such as interkinetic nuclear migration or transient cell-shape changes, rather than pure tissue displacement. This may be somewhat misleading, as the visual impression is that the tissue itself is moving, whereas in some instances this reflects cellular/subcellular fluctuations. A discussion of the spatial scale of the superpixel analysis, together with a demonstration that the conclusions are robust to the degree of coarse-graining, would greatly strengthen the manuscript, especially regarding he movement of the epiblast (see point 4).

      (2) Use of the term "ratchet-like"

      We would recommend avoiding the term ratchet-like and instead using start-stop or stop-and-go migration throughout the manuscript. While these terms describe the same observed behavior, ratchet-like implicitly suggests an irreversible mechanism underlying the motion, whereas the present study primarily documents an intermittent migration pattern. In my opinion, stop-and-go is a more descriptive and mechanistically neutral terminology, leaving the mechanistic interpretation to the modelling section.

      (3) Mechanistic interpretation of the stop-and-go behavior

      The vertex model constitutes the principal mechanistic component of the study and provides an interesting explanation for intermittent DVE migration through stress accumulation followed by T1-mediated stress relaxation. However, the comparison between the model and the experimental data reveals an important discrepancy. As acknowledged by the authors, the model predicts a broader distribution of T1 transitions than observed experimentally, whereas in vivo T1 events appear largely confined to the embryonic visceral endoderm ahead of the migrating DVE.

      This discrepancy suggests that an important aspect of junctional mechanics may be missing from the current formulation. Have the authors considered whether an asymmetric constitutive description, in which junctions remodel more readily under compression than under tension, could better account for the observed spatial restriction of T1 events? Such constitutive asymmetry may provide a more biologically realistic mechanism for intermittent migration while preserving the overall framework proposed here.

      Overall, we find the modelling direction promising, but at present the model appears somewhat premature or overly simplified relative to the experimental observations. The simulations convincingly demonstrate that T1-mediated stress relaxation can generate intermittent migration, but they do not yet quantitatively, if not qualitatively, reproduce the spatial distribution of T1 events observed in vivo. Since the authors have segmented some samples, could all the cells then provide a movie with T1 annotated? That would be helpful to get an intuition on the level of performance of the model compared to experimental data.

      Related to this point, the stop-and-go behavior shown in Figure S7 is not immediately obvious. It would be helpful to display the instantaneous DVE velocity together with the timing of T1 transitions, allowing the proposed correlation to be appreciated more directly. In addition, in Figure 5E, the lower panel appears to be labelled "DVE position", whereas the text suggests that DVE velocity is intended. This should be clarified.

      (4) Motion of the epiblast

      The observation of coordinated epiblast motion is intriguing. However, it would be helpful if the authors quantified the magnitude of the net displacement. From the movies, the overall displacement appears relatively modest, perhaps on the order of one cell diameter. Is this indeed the case?

      More generally, we have some concerns regarding the quantification and representation of epiblast motion. As discussed above, the superpixel analysis appears to operate at a subcellular scale, with many superpixels spanning the apico-basal extent of individual epiblast cells. Consequently, the measured motion may partly reflect transient cell deformations, for example during mitosis or interkinetic nuclear migration, rather than displacement of the tissue itself. Finally, we wonder whether the flattened representation is the most appropriate way to present the epiblast data. Such projections are clearly helpful for analyzing the whole VE motion over a curved epithelial surface. However, the epiblast motion described here is essentially linear, and it is therefore less obvious how the flattening affects the apparent displacement. It would be helpful if the authors could also present the epiblast movement in the original, non-flattened imaging data (e.g. using an optical transverse section through the embryo). At present, the motion is only shown either as a geodesic projection or as a flattened transverse view, such that the reader never directly observes the movement in its native three-dimensional geometry.

      Review 3
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  52. www.biorxiv.org www.biorxiv.org
    A hierarchical coordinate system for sequence memory in human entorhinal cortex
    4
    1. Public_Reviews 30 Jul 2026

      eLife Assessment

      This valuable study provides fMRI evidence for a hierarchical representation of sequence, arranged along the anterior-posterior axis of the entorhinal cortex, as well as evidence from human single-unit recordings for sequence position coding in the hippocampus and entorhinal cortex. Weaknesses include tenuous links between the single-unit and fMRI datasets, incomplete evidence for some claims, lack of discussion of relevant hippocampal literature, and potential over-interpretation of the findings in relation to rodent grid coding. This work will be of interest to researchers studying memory, sequence representations, and spatial coding in the medial temporal lobe.

      Summary
    2. Public_Reviews 30 Jul 2026

      Reviewer #1 (Public review):

      Summary:

      Shpektor et al. propose a link between how humans learn abstract and hierarchical structures to support memory (for example, remembering the event of the first landing on the moon) and the medial temporal lobe (MTL) and grid cells in particular. Given that there is solid work on how grid cells in different modules jointly encode position in rodents, providing evidence for the existence of a similar code in humans in the non-spatial domain and in relation to memory formation, would constitute a valuable finding.

      The authors first examine a small human intracranial dataset to demonstrate that sequence position is decodable in MTL population codes. They then examine behavioral data from two larger groups of participants who passively viewed content presented in a hierarchical sequence and show that errors in recall of positions within that sequence qualitatively match hierarchical predictions. The task design enabled distinct signatures of memory representations at different levels of hierarchy. While there were no multivariate patterns in MTL or any brain region that matched these patterns reliably, a follow-up analysis in MTL revealed a gradient along the anterior-posterior axis, such that lower levels of the hierarchy tended to have representational peaks in more anterior regions of the MTL, which was consistent across the two fMRI datasets.

      Major strengths of the study include the novelty of the experimental paradigm and data.

      In particular, single cell recording in MTL from a small number of human participants during sequence learning and testing a larger group of human participants on a sequence amenable to hierarchical structure learning, and collecting fMRI data during retrieval.

      Furthermore, the paper tackles an important question and does so from both directions, using inspirations from both biology and computational science to navigate it.

      The primary weaknesses of the paper are a lack of compelling support for the overarching claim about hierarchical representation and a lack of clarity and consistency about exactly what those hierarchical representations should and do look like. My concerns regarding these weaknesses are described below, and I believe that most, if not all, of them could be addressed through additional analysis and paper revisions.

      In the first part of the paper, the authors provide single-cell recordings in MTL, and they report the existence of cells that are sensitive to position (more so than to picture). However, they don't elaborate on this result with a model for an abstract sequence code. This is an issue because one possible explanation for the sequential position decoding is that neurons just fire at the presentation of the first image and decay at different rates, or ramp up toward action or feedback. One might be able to decode the position in sequence from these cells' activity, but can hardly call this an abstract code of position in a sequence. However, the authors don't provide further investigation into what the single-cell result might suggest and move on to a completely different fMRI experiment in the second part of the paper. Being able to decode sequence position does not, in my view, necessarily imply an abstract positional code - and I felt that further analysis of the single unit data would be required to identify what representations gave rise to that decoding ability.

      The most compelling evidence that participants were encoding temporal order hierarchically came from behavioral data in the second part of the paper. However, these results were not presented clearly enough to evaluate their reliability and specificity. Figure 2i shows histograms of errors across participants with arrows pointing to bars that apparently correspond to errors of different levels of hierarchy. There are three colored bars, corresponding to errors of one unit at the first, second, or third levels of hierarchy. The first level is not diagnostic of hierarchy, but the other two colored bars appear higher than the colors nearby them. However, my understanding is that these bars correspond to situations with the same tone - which seems like an obvious reason that two positions might be confused, which in my view would weaken the argument for hierarchical encoding. Furthermore, there is no display of variability in the plot or indication of individual differences, so it is hard to tell whether the histogram is dominated by a few participants who made a lot of errors or is reflective of a general tendency across participants.

      The fMRI analyses, while creative, raise questions regarding interpretability. The authors report no representations of hierarchical position at any level, either in MTL or across the whole brain, which would typically be taken as a lack of evidence for the representations existing. Follow-up analyses revealed that what shadows of representations do exist seem to line up along the anterior-posterior gradient. But what does that mean if we can't be sure that the representations are really there? Typically, we tally up evidence supporting an overarching claim by testing multiple predictions that are all consistent with the same story - but in this case, it seems that not all such test results are consistent.

      In many cases, it was difficult to judge the strength of evidence due to somewhat minimal reporting on the exact hypotheses tested and test statistics.

      On a high level, I found the overarching story linking the two datasets together to be somewhat tenuous. While I understand that science rarely rolls out as a coherent story, presenting the authors' valuable experiments in this fashion makes it harder for the reader to digest the information and reach a conclusion. The relevance of the first section of the paper to the second is not immediately apparent. Each section provides somewhat incomplete evidence for a set of claims on its own - but my view was that combining the two studies led to more questions than answers - since the paradigms and measurements are so different.

      In conclusion, the authors propose an interesting account of how memories are formed in the human brain, by building an abstract and hierarchical code. The paper identifies a few separate findings that are suggestive of hierarchical abstract memory encoding in the MTL - yet I believe that more work would need to be done to irrefutably support that claim.

      Review 1
    3. Public_Reviews 30 Jul 2026

      Reviewer #2 (Public review):

      Overall, I think these are exciting results that make a very nice contribution to the literature. I thought the picture-tagging of sequence locations in the fMRI study was clever, and the across-sequence RSA results were especially compelling. But there are several aspects of the presentation of the results that reduced my confidence and enthusiasm.

      (1) This is an unusual paper in that there is one human intracranial study and two fMRI studies. The paradigm for the intracranial study is very different than the fMRI paradigm. The key differences are that the fMRI paradigm is hierarchical, while the intracranial is flat, with no sequence learning component, and the fMRI is auditory, while the intracranial is auditory. The justification for the switch from intracranial to fMRI was that intracranial does not allow anterior-posterior axis analysis, but there are so many differences between the studies that this feels like an awkward transition and justification. Also, anterior-posterior analysis in the MTL may not be feasible in EC with intracranial data, but it can be feasible in the hippocampus, and indeed this could be very worthwhile and relevant to pursue (see point 2).

      While the two independent fMRI datasets is a strength, the replications would have been much more compelling had the analysis for the second dataset been preregistered.

      (2) The intracranial results are pitched as a novel "abstract coordinate representation" but there is a substantial prior literature on MTL "ordinal position codes", which I believe is the same thing in this paradigm. Most of this literature is in the hippocampus, which is, of course, very relevant given the hippocampal findings here, but there is also evidence for this kind of information in EC, e.g., https://elifesciences.org/articles/45333.

      (3) Given the intracranial results in the hippocampus as well as the prior relevant literature on position coding, it was not clear why the hippocampus was not an ROI in the fMRI studies.

      (4) It wasn't until reading the Methods section carefully that I understood that the results do not hold for the right EC, only the left. This deserves more acknowledgment.

      (5) The use of one-sided t-tests with an alpha of .05 reduced my confidence in the robustness of the results.

      Review 2
    4. Public_Reviews 30 Jul 2026

      Reviewer #3 (Public review):

      Summary:

      Shpektor et al. investigate how hierarchical sequence structure is represented in the entorhinal cortex (EC) and medial temporal lobe (MTL) using a combination of single-unit recordings and fMRI. In the single-unit recordings, they find abstract representations of ordinal position within short sequences in both the EC and the hippocampus. Next, they use two fMRI datasets to examine representations of hierarchical sequence structure in EC. They find that these representations (1) are organized along a posterior-to-anterior hierarchy, with finer sequence structure represented in posterior EC and coarser structure in anterior EC, and (2) generalize across sensory features, suggesting an abstract representation of sequence position. The authors take these findings as evidence of a non-spatial hierarchical coordinate system in the human EC, analogous to grid cells in rodents.

      Strengths:

      The methodological approach presented in this study is commendable, combining single-unit recordings in the MTL with two fMRI datasets. The finding of hierarchical and abstract sequence representations in the EC is compelling and is replicated across these datasets and modalities. The manuscript addresses important questions about how the MTL abstracts across experiences that share hierarchical structure, a topic of considerable current interest. As such, the work is likely to be of broad interest to researchers studying these processes in both rodents and humans.

      Weaknesses:

      In my view, the main weaknesses concern the interpretation of the results, as well as several areas where additional analyses and methodological clarification would strengthen the manuscript. My point-by-point comments are as follows:

      (1) I found the evidence for hierarchical and abstract sequence-position representations interesting. However, I am less convinced by the stronger claim that these findings demonstrate a coordinate system analogous to grid-cell coding. The current results appear to provide stronger support for abstract sequence-position coding than for grid-like coding per se. In particular, it is not clear to me that hierarchical sequence representations necessarily imply a grid-like representational format or a coordinate system. Many neural systems exhibit gradients of representational scale along the anterior-posterior axis, both within and across brain regions, without being considered grid-like. I would encourage the authors to clarify why it should be interpreted specifically in terms of a coordinate system rather than more general hierarchical sequence representations. The manuscript would benefit either from a more explicit justification of this link to grid-cell coding or from a more cautious framing of the conclusions.

      (2) Relatedly, the emphasis on grid-cell-like coding naturally centers the story on entorhinal cortex (EC). Yet, the single-neuron results indicate that the hippocampus contained a comparable number of position-selective cells. In addition, a large body of literature has implicated the hippocampus in hierarchical representations of memories, sequences, and relational structure. For completeness, I encourage the authors to repeat the key fMRI analyses within the hippocampus, rather than focusing exclusively on EC.

      (3) I have some concerns regarding the amount of information available to distinguish representations at different levels of the sequence hierarchy. As I understand the design, each 113-tone sequence was associated with only eight images, meaning there were approximately 14 tones between successive image events. It would be helpful to provide additional detail regarding how image coordinates were assigned and selected, how many observations contributed to each hierarchical level, and how much statistical power was available to distinguish representations at different scales.

      (4) I was also uncertain about the potential influence of visual similarity in Dataset 1. My understanding is that the images were not entirely unique but instead consisted of rotated versions of the same images. If so, this visual similarity could potentially complicate the interpretation of representational structure. It would therefore be useful to clarify whether repeated images occurred within the same or different locations in the hierarchy and to provide analyses demonstrating that the reported effects cannot be explained by visual similarity. This seems particularly important given that the corresponding effects in Dataset 2 were weaker.

      (5) The rationale for using a custom orderness metric could be explained more clearly. It would be helpful to understand why a custom metric was preferred over rank-order measures such as Kendall's tau or Spearman's rho. I would be interested in seeing whether the orderness results replicate using one of these more conventional metrics.

      (6) I had difficulty reconciling the finding that sequence representation effects are stronger across rather than within sequences. Intuitively, I would have expected representations within a sequence to reflect both shared hierarchical position and sensory experience, thus yielding stronger within-sequence effects than across sequences. The opposite pattern seems somewhat counterintuitive. I would appreciate additional discussion of this pattern and what it implies about the nature of the underlying representation. It would also be informative to know whether similar effects are observed elsewhere in the brain, and why EC might preferentially express a purely abstract representation more strongly than representations that additionally share sensory features.

      (7) The authors' theory is that hierarchical representations of sequences in EC are used as a scaffold for memory, yet the current paper does not link their behavioural results to their neural ones. I think making such a link would greatly strengthen the results presented here. For example, is displacement error or sequence memory related to ordered representations of the sequence structure?

      (8) I thought the manuscript would benefit from a broader discussion of prior work on (1) sequence representations and (2) hierarchical representations in the hippocampus and related regions. As it stands, the manuscript does a good job of situating its findings within the literature on grid cells in the EC but gives comparatively little attention to the literature on sequence representations in the hippocampus. Placing the current findings within this broader body of work would help clarify which aspects of the results are specific to a grid-like interpretation and which may instead reflect more general principles of hierarchical representation in the MTL or across the brain.

      Review 3
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  53. access.infobase.com access.infobase.com
    Article: African-American Vernacular English (AAVE; aka Black English, Negro Dialect, Ebonics) 1619-present
    4
    1. Jeraldin 30 Jul 2026
      For another, these writers needed to write in a manner that was directly comprehensible to their prospective European- American readers, as well as to literate fellow African Americans.

      Northern African Americans had to write in a way for their audience to understand what they were trying to convey or prove a point.

    2. Jeraldin 30 Jul 2026
      Even among native speakers of AAVE, most African-American writers use SE in their formal writing (e.g., for publication or for business audiences), whether or not they do so in their informal writing (e.g., when texting, tweeting, e-mailing, or corresponding with family or friends).

      African Americans use translanguaging between speaking and writing in SE and AAVE.

    3. Jeraldin 30 Jul 2026
      Though they needed to communicate clearly with European Americans so that they could understand and be understood by European Americans, they nonetheless had an opportunity to develop their own distinctive AAVE.

      By African Americans developing their own AAVE. They developed an English language that both their community and the European Americans can understand.

    4. Jeraldin 30 Jul 2026
      Their rich literature was passed along from person to person and generation to generation through the oral tradition.

      I think this is how Ebonics was developed into what the language is now.

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  54. scalar.lafayette.edu scalar.lafayette.edu
    Hydronarratives: Agricultural Runoff in Midwest America: Slow Violence through Agricultural Runoff
    5
    1. kimela 30 Jul 2026
      People who work with pesticides, live near farmland, or rely on private wells all carry more of the risk.

      Andreotti, Gabriella, Laura E Beane Freeman, Joseph J Shearer, Catherine C Lerro, Stella Koutros, Christine G Parks, Aaron Blair, et al. “Occupational Pesticide Use and Risk of Renal Cell Carcinoma in the Agricultural Health Study.” Environmental health perspectives, June 2020. ‌Richards, R. Peter, David B. Baker, Nancy L. Creamer, John W. Kramer, David E. Ewing, Bruce J. Merryfield, and Larry K. Wallrabenstein. “Well Water Quality, Well Vulnerability, and Agricultural Contamination in the Midwestern United States.” Journal of Environmental Quality 25 (1996): 389–402 Moses, Marion, E. Spencer Johnson, W. Kent Anger, et al. “Environmental Equity and Pesticide Exposure.” Toxicology and Industrial Health 9, no. 5 (1993): 913–959

    2. kimela 30 Jul 2026
      Pesticide runoff is an environmental justice problem due to this fact.

      Moses, Marion, E. Spencer Johnson, W. Kent Anger, et al. “Environmental Equity and Pesticide Exposure.” Toxicology and Industrial Health 9, no. 5 (1993): 913–959

    3. kimela 30 Jul 2026
      Pollution then enters ordinary life all without anyone even noticing its there.

      Nixon, Rob. 2011. Slow Violence and the Environmentalism of the Poor. Cambridge, MA: Harvard University Press.

    4. kimela 30 Jul 2026
      Chemicals may leave a field during a storm and after a long process, reappear through contaminated drinking water.

      Richards, R. Peter, David B. Baker, Nancy L. Creamer, John W. Kramer, David E. Ewing, Bruce J. Merryfield, and Larry K. Wallrabenstein. “Well Water Quality, Well Vulnerability, and Agricultural Contamination in the Midwestern United States.” Journal of Environmental Quality 25 (1996): 389–402

    5. kimela 30 Jul 2026
      Rob Nixon’s definition of slow violence as a violence that occurs over time, out of sight, and is dispersed across space fits the violence we see taking place in the river basin.

      Nixon, Rob. 2011. Slow Violence and the Environmentalism of the Poor. Cambridge, MA: Harvard University Press.

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  55. www.eltngl.com www.eltngl.com
    rex_l1_u3.pdf
    1
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    eltngl.com/assets/downloads/rex3e_pro0000009087/rex_l1_u3.pdf
  56. www.biorxiv.org www.biorxiv.org
    From prehistory to present-day: How isolation shaped the distinct genomic makeup of Italian Alpine valleys
    1
    1. kevin_alan_brook 30 Jul 2026

      Page 2 of Text S1 includes a sentence reading: "In contrast, subclade H5t is exclusively detected in the Ledro Valley and includes a newly proposed subclade, H5t1, defined by the A8053G transition, highlighting a local diversification process within Ledro Valley." YFull MTree and FamilyTreeDNA's Mitotree already named a branch H5t1 based on different mutations. Meanwhile, Mitotree's H5t5 does fit the mutational definition of "H5t1" used in this preprint. (This is visible in Family Tree DNA's Classic Mitotree View for H5t5 where two people from Italy, including one from Trentino, are put into it as of July 29, 2026.) I suggest that the authors mention that their H5t samples fit into Mitotree's branch H5t5 rather than trying to name it something new.

      As they might have noticed, since it's listed in Dataset S3, there is one current GenBank sample that belongs to this branch: GQ983098 from northern Italy from a 2010 study by A. Santoro et al. I am glad that the authors deposited additional sequences belonging to this branch to GenBank to be released when the final version of the paper is published.

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    biorxiv.org/content/10.64898/2026.07.16.738935v1
  57. scalar.lafayette.edu scalar.lafayette.edu
    Hydronarratives: Agricultural Runoff in Midwest America: Water Contamination → Health Concern
    6
    1. kimela 30 Jul 2026
      A chemical may be washed up on a field and resurface as a health concern later on

      Richards, R. Peter, David B. Baker, Nancy L. Creamer, John W. Kramer, David E. Ewing, Bruce J. Merryfield, and Larry K. Wallrabenstein. “Well Water Quality, Well Vulnerability, and Agricultural Contamination in the Midwestern United States.” Journal of Environmental Quality 25 (1996): 389–402

    2. kimela 30 Jul 2026
      its delayed effects that only reveal themselves with time

      Nixon, Rob. 2011. Slow Violence and the Environmentalism of the Poor. Cambridge, MA: Harvard University Press.

    3. kimela 30 Jul 2026
      occupational exposure too.

      Andreotti, Gabriella, Laura E Beane Freeman, Joseph J Shearer, Catherine C Lerro, Stella Koutros, Christine G Parks, Aaron Blair, et al. “Occupational Pesticide Use and Risk of Renal Cell Carcinoma in the Agricultural Health Study.” Environmental health perspectives, June 2020.

    4. kimela 30 Jul 2026
      This study looked at women in rural Wisconsin that were exposed to atrazine through well water.

      Mcelroy, Jane A., Ronald E. Gangnon, Polly A. Newcomb, Marty S. Kanarek, Henry A. Anderson, Jim Vanden Brook, A. M. Y. Trentham-Dietz, and Patrick L. Remington. 2007. “Risk of Breast Cancer for Women Living in Rural Areas from Adult Exposure to Atrazine from Well Water in Wisconsin.” Journal of Exposure Science & Environmental Epidemiology 17 (2): 207–14.

    5. kimela 30 Jul 2026
      runoff becomes part of slow violence when environmental exposure is linked to health risks.

      Nixon, Rob. 2011. Slow Violence and the Environmentalism of the Poor. Cambridge, MA: Harvard University Press.

    6. kimela 30 Jul 2026
      cancer risks, endocrine disruption, occupational exposure, and child health concerns over extended periods of time.

      Hendryx, Michael, Jamison Conley, Evan Fedorko, Juhua Luo, and Matthew Armistead. 2012. “Permitted Water Pollution Discharges and Population Cancer and Non-Cancer Mortality: Toxicity Weights and Upstream Discharge Effects in US Rural-Urban Areas.” International Journal of Health Geographics 11 (1): 9. , Mcelroy, Jane A., Ronald E. Gangnon, Polly A. Newcomb, Marty S. Kanarek, Henry A. Anderson, Jim Vanden Brook, A. M. Y. Trentham-Dietz, and Patrick L. Remington. 2007. “Risk of Breast Cancer for Women Living in Rural Areas from Adult Exposure to Atrazine from Well Water in Wisconsin.” Journal of Exposure Science & Environmental Epidemiology 17 (2): 207–14. , New-Aaron, Moses, Zaeema Naveed, and Eleanor G. Rogan. 2021. “Estrogen Disrupting Pesticides in Nebraska Groundwater: Trends between Pesticide-Contaminated Water and Estrogen-Related Cancers in an Ecological Observational Study.” Water 13 (6): 790.

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    scalar.lafayette.edu/hydronarratives/agricultural-runoff-in-the-midwest-water-contamination--health-concern
  58. scalar.lafayette.edu scalar.lafayette.edu
    Hydronarratives: Agricultural Runoff and Slow Violence in Midwest America
    7
    1. kimela 30 Jul 2026
      large region it is connected to via interconnected streams, rivers, groundwater, and wells.

      ‌Richards, R. Peter, David B. Baker, Nancy L. Creamer, John W. Kramer, David E. Ewing, Bruce J. Merryfield, and Larry K. Wallrabenstein. “Well Water Quality, Well Vulnerability, and Agricultural Contamination in the Midwestern United States.” Journal of Environmental Quality 25 (1996): 389–402

    2. kimela 30 Jul 2026
      Once chemicals enter water systems, they will travel and in a manner that is difficult to trace as it is not damage that is visible to the naked eye

      ‌Richards, R. Peter, David B. Baker, Nancy L. Creamer, John W. Kramer, David E. Ewing, Bruce J. Merryfield, and Larry K. Wallrabenstein. “Well Water Quality, Well Vulnerability, and Agricultural Contamination in the Midwestern United States.” Journal of Environmental Quality 25 (1996): 389–402

    3. kimela 30 Jul 2026
      ider regional water system

      Bussan, Derek D., Clifford A. Ochs, Colin R. Jackson, Tarun Anumol, Shane A. Snyder, and James V. Cizdziel. 2017. “Concentrations of Select Dissolved Trace Elements and Anthropogenic Organic Compounds in the Mississippi River and Major Tributaries during the Summer of 2012 and 2013.” Environmental Monitoring and Assessment 189 (2)

    6. kimela 30 Jul 2026
      water carries them off through agricultural runoff.

      Richards, R. Peter, David B. Baker, Nancy L. Creamer, John W. Kramer, David E. Ewing, Bruce J. Merryfield, and Larry K. Wallrabenstein. “Well Water Quality, Well Vulnerability, and Agricultural Contamination in the Midwestern United States.” Journal of Environmental Quality 25 (1996): 389–402

    7. kimela 30 Jul 2026
      Agricultural runoff is the result of water running over fields,

      Richards, R. Peter, David B. Baker, Nancy L. Creamer, John W. Kramer, David E. Ewing, Bruce J. Merryfield, and Larry K. Wallrabenstein. “Well Water Quality, Well Vulnerability, and Agricultural Contamination in the Midwestern United States.” Journal of Environmental Quality 25 (1996): 389–402

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    scalar.lafayette.edu/hydronarratives/agricultural-runoff-and-slow-violence-in-midwest-america
  59. access.infobase.com access.infobase.com
    Article: African American Speech and Language
    5
    1. Jeraldin 30 Jul 2026
      Like jazz, which Ebonics has influenced along with hip-hop, blues, and other musical styles, however, Ebonics has its own particular take on the conventional American wisdom and it is a vital means for subverting that wisdom.

      Ebonics will continue to be spoken and taught within the African American community.

    2. Jeraldin 30 Jul 2026
      Leon W. Todd, Jr., states, Ebonics is a politically correct term for dysfunctional speech. Legitimizing poor language habits will not help children find a job nor take control of their affairs later in life.

      Scholars like Leon Todd may believe that SAE is the professional and correct English language that should be taught to students.

    3. Jeraldin 30 Jul 2026
      He notes that the current reality is that Standard American English (SAE) is the money language. Black English is identified with poverty and, therefore, holds a great stigma.

      By making ebonics a second language this may diminish the poverty stigma that it encloses.

    4. Jeraldin 30 Jul 2026
      African American parents hold that their children suffer from linguistic problems deriving from structural differences in their spoken language just as Latino children do.

      By African American children having the option of using Ebonics as a second language they have the opportunity to understand and comprehend Standard American English profoundly.

    5. Jeraldin 30 Jul 2026
      Teachers wish to use Ebonics to teach African American students so that they will perform better academically.

      Educators using ebonics may allow student to significantly improve in their academics.

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    access.infobase.com/article/2224153-african-american-speech-and-language