Nerve-triggered mast cell proteases may be required for initial skin injury under heat and pressure
In innervated human skin, nerve-triggered mast cell proteases may be required for initial irreversible injury under moderate heat and pressure. Suppressing nerve activity could delay injury more than warning; unchanged cell-death onset with effects only on late inflammation would reject the hypothesis.
Stage of verification
- Hypothesis published2026-09-26
- Indirect evidenceAssessed at 4 of 10
- Direct testAwaited
Map of the hypothesis
Hover over an icon or tap it to see its name.
Where in the body
Biological function
Local release of mast-cell proteases in response to neuropeptides from sensory nerve endings during combined exposure to moderate heat and pressure.
Kind of knowledge gap
A double ring marks the main placement where a group contains several values.
Target map
Every target of every published hypothesis, each with the actions a hypothesis can propose on it. The targets and the actions of this hypothesis are drawn solid.
Enzyme
Proteases
Enzymes that break down proteins
Where this hypothesis actsExtracellular proteases released by mast cells in aged skin exposed to moderate heat and pressure
Hypotheses on this target 7
Inhibition6
Activation
Lower level1
Higher level
Replacement
Protection from degradation
Cofactor removal
Synthesis suppression
Function preservation
What is proposed
Inhibition
Selectively inhibit protease activity
With whatNot stated in the record
HowSelective inhibition of proteases while preserving neuronal activity; no specific inhibitor is stated
Possible result
Possible prevention of the first irreversible keratinocyte damage while preserving neuronal activity
From the recordСелективное торможение протеаз воспроизводит защиту при сохранённой нервной активности.
Signalling pathway
Neuronal secretion
The release of signalling substances from neurons
Where this hypothesis actsSensory nerve endings in aged skin exposed to moderate heat and pressure
Hypotheses on this target 1- Inhibition1
- Activation
Desensitisation- Function preservation
Feedback restoration
Rhythm restoration
What is proposed
Inhibition
Suppress neuronal secretion
With whatNot stated in the record
HowNot stated in the record
Possible result
Possible prevention of initial irreversible skin damage and preservation or extension of warning time
From the recordподавление нейрональной секреции предотвращает первое необратимое повреждение кератиноцитов.
All targets of the lab
Every target read from the published hypotheses, each kind around its pictogram. A larger mark means more hypotheses act on that target. Point at a mark and the actions proposed on it branch out of it.
Solid and named: the targets of this hypothesis
Explore in depth
The logic
The train of thought that ends in this hypothesis. Each stage is the reason the next exists. The master question narrows to a goal, the goal to an unknown nobody has closed, the unknown to the hypothesis proposed here. Every step below says what it rests on and what carries it.
Reducing itch may change both when skin signals danger and when damage begins. The unexpected move is that quieting nerves could delay damage more than it delays warning, leaving more time for protective action even while the irritant remains. This is a hypothesis generated by the pipeline, not a measured result.
- Combined moderate heat and pressure are proposed to engage sensory nerve endings in older skin.
- The nerve endings are proposed to release chemical messengers that trigger nearby mast cells.
- The mast cells are proposed to release protein-cutting enzymes into the space outside cells.
- Those enzymes are proposed to enable the first irreversible injury, rather than merely worsen damage that has already begun.
- Suppressing nerve activity is predicted to reduce this enzyme release while also reducing itch and delaying warning.
- Injury is predicted to be delayed more than warning, lengthening the interval available for protective action despite the remaining irritant.
Imagine an alarm wire that also switches on a damaging machine. Weakening the signal could delay the alarm yet buy more escape time if it delays the machine even longer.
Where the picture breaks: Skin has several routes to injury, and heat and pressure may cause damage without this proposed nerve-to-enzyme route. The picture does not establish that the route is necessary or that injury would be delayed more than warning.
- Master questionstep 01 of 04
A therapy is sought that would bring the functional condition of middle-aged people's skin closer to that of young people's skin.
Rests on: The goal takes youthful skin function as the desired treatment outcome, without specifying which measurements would establish that outcome.
AssumptionYouthful skin function is assumed to be a suitable treatment target; the supplied goal does not define its component functions or criteria for success.
- Goal pillarstep 02 of 04
Skin's protective responses should remain compatible when several stresses act at once.
Rests on: The broad aim of restoring skin function motivates examining protection, but does not explicitly identify compatibility under simultaneous stresses as a component of the target.
AssumptionCompatibility between protective responses under simultaneous stresses is taken as one component of the youthful function being sought.
- Gap questionstep 03 of 04
Equally effective itch relief might preserve warning of increasing heat and pressure only when the tissue irritant is removed, while reducing nerves' responsiveness might permit greater exposure at the cost of unnoticed injury.
Rests on: The preceding stage supplies the concern about interacting protective responses. It does not supply the proposed distinction between removing an irritant and quieting nerves.
LeapThe missing basis is evidence or an explicit prior argument that, at equal itch relief, removing the irritant uniquely preserves warning while quieting nerves allows hidden damage.
- Hypothesisstep 04 of 04
Moderate heat and pressure together may cause the first irreversible skin injury only after sensory nerve endings release neuropeptides, small protein-like chemical messengers, that prompt local mast cells to release proteases. Quieting the nerves could therefore delay injury more than warning, increasing the time available for protection despite a persisting irritant.S2S8
Rests on: The gap supplies the comparison between warning and injury timing; the hypothesis supplies a different possible relationship between them. The abstract of S2, in Allergology International in 2022, describes regulation of mast cells by nerve-derived messengers, but does not establish enzyme-dependent injury under heat and pressure. S8, in the Journal of Immunology in 2014, reports mast-cell release before disruption of seals between skin cells in a mouse scald model producing second-degree burns; that sequence does not establish that nerve-triggered enzymes are necessary for the first irreversible injury in older human skin under moderate heat and pressure.
Supported by literature
What is carried, and what is not. The supplied screened material speaks to two component links: nerve signals acting on mast cells, and mast-cell enzymes contributing to skin injury. These are partial supports from different settings; none of the supplied sources establishes the full sequence from combined moderate heat and pressure through nerve-triggered enzyme release to a longer warning-to-injury interval in older human skin.
Where the reasoning is carried by something unstated · 3
- Master question. Youthful skin function is assumed to be a suitable treatment target; the supplied goal does not define its component functions or criteria for success.
- Goal pillar. Compatibility between protective responses under simultaneous stresses is taken as one component of the youthful function being sought.
- Gap question. The missing basis is evidence or an explicit prior argument that, at equal itch relief, removing the irritant uniquely preserves warning while quieting nerves allows hidden damage. Establish the missing link before relying on this step.
How a result here could mislead · 3
- Damage returning after active enzymes are added could be read as restoration of the proposed natural route even if the added enzymes independently injure skin at an exposure the original challenge would never produce. What closes it: The added enzyme activity, location and timing must be measured against those produced by the unblocked challenge. The specified inactive-enzyme comparison must be accompanied by a comparison establishing whether active enzymes cause injury without the combined challenge; the supplied design does not specify that comparison.
- Less late inflammation could be mistaken for prevention of the first irreversible injury. Conversely, unchanged injury could be mistaken for a failed hypothesis when the model lacks the required nerve–mast-cell connection or the intervention fails to block it. What closes it: A criterion for the first irreversible injury must be fixed before testing and measured over time alongside nerve-messenger release and enzyme activity outside cells. The supplied requirement to confirm the model's relevant connections must be met, and successful blockade must be demonstrated; late inflammation alone cannot decide the claim.
- A larger warning-to-injury interval among people selected for equal itch improvement could reflect selection after treatment rather than protection caused by quieting nerves. The injury boundary would also be estimated from work outside the body, rather than directly observed in those people. What closes it: The comparison must be specified before treatment and retain participants independently of their achieved itch relief, with starting sensory function and skin damage recorded. Any estimated human interval must state how the outside-body injury boundary is transferred and its uncertainty; the supplied material does not establish that transfer.
What would make this wrong. The necessity claim would fail if the first irreversible injury began at the same time under matched internal tissue temperature, pressure, oxygen availability and exposure duration after verified selective inhibition of the relevant proteases in a model with the required cellular connections intact. Changes confined to later inflammation would not rescue the claim. Separately, if nerve suppression delayed warning as much as or more than injury, the proposed increase in protective time would fail even if the enzyme route contributed to damage.
What it would change. If the mechanism held, improving middle-aged skin's protective function could involve blocking an injury-producing nerve-to-enzyme route while retaining enough warning for action. Warning timing would have to be assessed relative to actual tissue vulnerability, because a later warning would not by itself establish poorer protection. That result would not establish restoration of youthful skin function or a successful therapy. Testing people aged 40–60 is restricted in the proposal to exposures below established injury limits, so a longer interval to actual human injury would remain unestablished; the functional outcome called SPV_7 is also not defined in the supplied material.
Sources read · 7
Skin neurogenic inflammation. · Seminars in immunopathology · 2018
Does not settle: This retrieved passage is a reference list. It does not establish whether mast-cell proteases are required for initial heat-and-pressure skin injury, whether neuropeptides trigger such release in aged skin, or whether neural or protease inhibition changes injury timing, itch, or SPV_7.
Neuro-allergology: Mast cell-nerve cross-talk. · Allergology international : official journal of the Japanese Society of Allergology · 2022
“Moreover, MCs are positive for a large number of receptors for classical neurotransmitters (e.g., acetylcholine and corticotropin-releasing hormone) and neuropeptides (e.g., substance P, calcitonin gene-related peptides and hemokinin), and MC's functions are regulated by those nerve-derived factors.”
Does not settle: Источник не устанавливает, что при сочетании умеренного тепла и давления протеазы тучных клеток необходимы для первого необратимого повреждения возрастной кожи. Не описаны давление, температура, длительность воздействия, возрастная кожа, подавление нервной активности, задержка повреждения, функциональный результат SPV_7 или причинная роль внеклеточной протеолитической активности.
House dust mites activate nociceptor-mast cell clusters to drive type 2 skin inflammation. · Nature immunology · 2019
“the data presented suggest that, under the conditions studied, D. farinae + SEB-induced cutaneous inflammation required TRPV1 + nociceptors and the release of SP, which then activated skin mast cells.”
Does not settle: Источник не устанавливает роль протеаз тучных клеток при тепле и давлении, начальном необратимом повреждении возрастной кожи, временных пределах повреждения, подавлении нервной активности или результате SPV_7.
Mast cell-neuron axis as a core mechanism in chronic pruritus of atopic dermatitis: from mechanistic insights to therapeutic targets. · Frontiers in immunology · 2025
“SP released from activated intraepidermal nerve fibers binds to MRGPRX2 on MCs, triggering non-IgE-mediated degranulation and initiating a positive neuroimmune feedback loop ( , ).”
Does not settle: Источник не устанавливает необходимость протеаз тучных клеток для начального необратимого повреждения возрастной кожи при сочетании умеренного тепла и давления. Он также не определяет влияние подавления нервной активности на повреждение, зуд, время предупреждения или результат SPV_7.
Mouse mast cell proteases 4 and 5 mediate epidermal injury through disruption of tight junctions. · Journal of immunology (Baltimore, Md. : 1950) · 2014
“In summary, we show that thermal challenge sufficient for a second-degree burn to the skin causes immediate non-cytotoxic MC zonal degranulation at 30 s with expansion of this secretory process at 120 s. That MC activation in the dermis and hypodermis precedes the disruption of the TJs suggests an initiating role for the MC in the early loss of claudin 4 and appearance of epidermal edema”
Does not settle: This source describes a mouse scald model of second-degree thermal injury. It does not establish effects of combined moderate heat and pressure, aged skin, sensory-neuropeptide triggering, nerve suppression, itch or warning timing, or the stated SPV_7 functional result.
IL-33 promotes food anaphylaxis in epicutaneously sensitized mice by targeting mast cells. · The Journal of allergy and clinical immunology · 2016
“We demonstrate that IL-33 is released locally and systemically following mechanical skin injury, enhances IgE-mediated MC degranulation in vitro , and promotes oral anaphylaxis following EC sensitization by targeting MCs.”
Does not settle: Источник описывает механическое повреждение кожи и дегрануляцию тучных клеток в модели аллергической анафилаксии у мышей. Он не устанавливает роль нейропептидов чувствительных окончаний, протеаз тучных клеток, сочетания умеренного тепла и давления, возрастной кожи, первого необратимого повреждения или влияния подавления нервной активности.
The role of mouse mast cell proteases in the proliferative phase of wound healing in microdeformational wound therapy. · Plastic and reconstructive surgery · 2014
“Results suggest that mouse mast cell proteases 4, 5, and 6 are mediators of the critical role mast cells play in microdeformational wound therapy in the proliferative phase of healing.”
Does not settle: This source does not establish whether mast-cell proteases are required for the initial irreversible injury caused by combined moderate heat and pressure, whether sensory-neuropeptide signaling triggers their release, or effects in aged skin, humans, symptoms, neural suppression, or protection time.
The gap this hypothesis explains
What is measured here stands in for what matters, and may not track it.
At equal itch relief, does removing irritation preserve heat and pressure warnings while calming nerves conceals injury?
Original wording · exactly as the pipeline generated it
При одинаковом уменьшении зуда сохраняется ли предупреждение о нарастающем тепле и давлении только после устранения тканевого раздражителя, тогда как снижение нервной возбудимости увеличивает переносимую нагрузку ценой скрытого повреждения?
What this question is asking
The question concerns whether equally effective itch relief can have different consequences for the skin’s ability to warn of injury. It compares removing a tissue irritant with reducing nerve excitability, meaning how readily nerves produce electrical signals, while holding the reduction in itch equal. The proposed distinction is that removing irritation preserves warning sensations during increasing heat and pressure, whereas reducing nerve activity allows greater exposure before discomfort stops it, potentially concealing injury. The intended comparison concerns middle-aged human skin, with warnings occurring seconds or minutes before damage and within a young-adult reference range; these are proposed requirements, not results established by the supplied sources.
- Tissue irritant
- Something that provokes irritation in skin tissue. The input does not identify a particular irritant or establish that removing it repairs existing injury.
- Nerve excitability
- How readily a nerve cell produces electrical signals in response to stimulation. It is a variable property, not a simple on-or-off state; reducing it does not by itself establish which sensations will change.
- Sensory nerve cells
- Nerve cells that carry information about bodily conditions or external stimulation. Their electrical responsiveness is measured in S8, but the supplied finding does not measure warning time before skin injury.
- Sodium channel Nav1.7
- A voltage-gated sodium channel, subtype 1.7: a protein through which sodium passes across a nerve cell’s outer membrane to contribute to electrical signaling. S8 links loss of its electrical current to reduced nerve excitability in mice.
- Protective warning and warning time
- Here, a protective warning means a sensation that signals potentially damaging exposure early enough for action. Warning time is the interval between that sensation and the beginning of injury; neither the required interval nor its preservation is demonstrated in the supplied sources.
- Tolerated exposure
- The amount or duration of heat or pressure endured before exposure stops. This is distinct from the amount that tissue can withstand without injury.
- Hidden injury
- Tissue damage that occurs without a sufficient warning sensation. It is a proposed outcome in the question, not a reported finding in the supplied evidence.
- Heat-pain detection threshold
- The point during heat stimulation at which pain is first detected. It measures perception and does not, by itself, identify when tissue damage begins.
- Sensitive skin
- The skin condition used to describe the people discussed in S3. The supplied material does not give its defining criteria or establish that this group represents middle-aged skin generally.
- Inflamed tissue
- Tissue undergoing an inflammation response. S1 discusses increased itch and pain sensitivity in this setting without establishing the treatment comparison in the question.
- Spinal cord
- The part of the nervous system within the spine that helps transmit and process sensory signals. S1 identifies it as another location where related patterns of increased itch and pain sensitivity occur.
- Young-adult reference range
- A comparison range intended to describe warning times in younger adults. The input specifies this as a desired benchmark but supplies no measurements or age boundaries defining it.
Removing a tissue irritant preserves protective warnings about increasing heat and pressure, whereas reducing nerve excitability increases tolerated exposure at the cost of hidden injury, even when itch relief is equal.
A tissue irritant is something that provokes irritation in the skin, while nerve excitability describes how readily nerves send electrical signals. The assumption is that removing the irritant leaves danger signals intact, but making nerves less responsive suppresses those signals without preventing damage. If established, this distinction would explain why the same improvement in itch could represent either safer skin function or concealed injury.
S8 supports a narrower mechanism: loss of sodium channel Nav1.7 current reduced the excitability of sensory nerve cells in mice. It does not establish delayed warnings, greater tolerated exposure, hidden injury, or a comparison with irritant removal at equal itch relief. S3 reports a changed heat-pain detection threshold in people with sensitive skin, but the supplied quote gives neither its direction nor its relationship to injury. The supplied reading is too indirect to establish or refute the proposed contrast.S8S3
The same question asked without the part nothing read establishes:
- At equal itch relief, how do removing a skin irritant and reducing nerve excitability differ in warning time before heat and pressure cause injury?
- At equal itch relief in middle-aged adults, do either of these approaches preserve warning time before skin injury within a young-adult reference range?
- Only irritant removal preserves warnings If reducing nerve activity delays warnings while injury begins at the same exposure, the interval available for protective action would shrink. Greater tolerated exposure would then conceal vulnerability, whereas irritant removal would provide itch relief with warning function preserved.
- Both approaches preserve warnings If both approaches leave sufficient time between warning and injury, reducing nerve activity would not necessarily sacrifice this protective function. Equal itch relief could then coexist with preserved warnings through either route, weakening the proposed exclusive advantage of irritant removal.
- Neither approach preserves warnings If warnings remain too late after both approaches, removing the irritant would not by itself establish recovery of protective sensation. Symptom improvement through either route could therefore overstate restoration of skin function.
- Only reduced nerve activity preserves warnings If reducing nerve activity preserves warning time while irritant removal does not, the proposed ordering would be reversed. Removing irritation would then be insufficient evidence of preserved protection, and reduced nerve activity would not imply concealed injury.
The question treats an unpleasant sensation as a possible warning that allows exposure to heat or pressure to stop before tissue is injured. If itch relief also delays that warning, greater tolerated exposure could reflect weaker sensation rather than greater resistance to injury. If removing irritation relieves itch while preserving warning time, symptom relief and protection could instead coexist. Mistaking either pattern for the other would make itch reduction or tolerated exposure an unreliable measure of restored skin function; these are conditional consequences of the question’s proposed mechanism.
Подавление Nav1.7 RL-2 может ослаблять защитную боль; уменьшение контактного раздражения RL-3 не устанавливает сохранность предупреждения при сочетанной нагрузке.
При приемлемом зуде предупреждающее ощущение должно возникать за секунды или минуты до повреждения, в пределах молодого эталона.
Одинаковое снижение симптомов не различает восстановление ткани и маскировку опасной нагрузки; требуется измерение времени для защитного действия.
The mechanism it proposes
The engine's own statement of the hypothesis, in full.
При сочетании умеренного тепла и давления первое необратимое повреждение возрастной кожи может требовать местного выброса протеаз тучных клеток, запускаемого нейропептидами чувствительных окончаний. Предполагается, что этот ферментативный этап необходим уже для возникновения повреждения в исследуемом диапазоне нагрузок. Поэтому подавление нервной активности способно одновременно уменьшить зуд, отсрочить предупреждение и ещё сильнее отсрочить повреждение. Тканевой раздражитель при этом сохраняется, а запас времени для защитного действия увеличивается. Причинный субстрат представляет собой внеклеточная протеолитическая активность. Её ограничение должно поддерживать функциональный результат SPV_7 при приемлемых симптомах.
Testing and possible results
The prediction that would tell it apart
A hypothesis that predicts what its rivals predict is not worth running an experiment over. This is the observation on which this one differs.
В иннервированной модели человеческой кожи при одинаковых температуре внутри ткани, давлении, оксигенации и длительности воздействия подавление нейрональной секреции предотвращает первое необратимое повреждение кератиноцитов. Добавление активных протеаз тучных клеток возвращает повреждение при сохранённом подавлении нейронов; каталитически неактивные протеазы такого эффекта не дают. Селективное торможение протеаз воспроизводит защиту при сохранённой нервной активности. Гипотеза отвергается, если вмешательства меняют только позднее воспаление, а начало гибели клеток остаётся прежним. У людей ожидается сохранение или увеличение расчётного времени между предупреждением и повреждением даже после уменьшения нервной возбудимости.
States a measurable outcome; comparing rivals needs more conditions. The prediction specifies observable prevention and restoration of damage, an active versus inactive protease comparison, and an explicit rejection condition involving unchanged cell-death onset. No rival prediction was supplied. Only a bench experiment would settle it.
What testing it would take
The engine's own read on whether this is testable with methods that already exist.
Активность протеаз, гибель клеток и нейропептидную секрецию можно измерять в органных культурах и совместных культурах кожи, сенсорных нейронов и тучных клеток. Сохранность соответствующих связей в модели требуется подтвердить. У людей 40-60 лет допустимы только пробы ниже установленных пределов повреждения; экспериментальное определение момента повреждения проводится вне организма.
Other explanations
Every other hypothesis the engine wrote for the same gap, and the observation that would separate the two.
В иннервированной модели человеческой кожи при одинаковых температуре внутри ткани, давлении, оксигенации и длительности воздействия подавление нейрональной секреции предотвращает первое необратимое повреждение кератиноцитов. Добавление активных протеаз тучных клеток возвращает повреждение при сохранённом подавлении нейронов; каталитически неактивные протеазы такого эффекта не дают. Селективное торможение протеаз воспроизводит защиту при сохранённой нервной активности. Гипотеза отвергается, если вмешательства меняют только позднее воспаление, а начало гибели клеток остаётся прежним. У людей ожидается сохранение или увеличение расчётного времени между предупреждением и повреждением даже после уменьшения нервной возбудимости.
- Rival 01 of 02What would separate them
Poor coupling of energy use to protein repair may shorten skin’s warning time before damage predicts: При одинаковых тканевой нагрузке, нервной активности и активности протеаз изменение соотношения кофакторов Hsp70 меняет время до повреждения. Восстановление продуктивного цикла увеличивает этот интервал без сдвига сенсорного порога; ускорение гидролиза АТФ без улучшения восстановления белков защиты не даёт. В бесклеточной системе тот же дефект воспроизводится при фиксированных концентрациях АТФ и Hsp70. Отсутствие эффекта после подтверждённого восстановления работы шаперона отвергает гипотезу как основное объяснение данного расхождения.
- What would separate them
Selection by itch relief may create the apparent benefit of removing skin irritants predicts: В исследовании с распределением вмешательств до лечения и анализом всех включённых участников различие в моменте предупреждения и расчётном защитном запасе укладывается в заранее заданные границы эквивалентности. Повторный анализ только участников с одинаковым снижением зуда воспроизводит исходное различие. Его величина меняется при изменении правил отбора. В лабораторном сравнении тканей при фиксированной нагрузке ни протеазная активность, ни продуктивность Hsp70 не объясняют устойчивого различия между вмешательствами. Сохранение причинного эффекта в полном рандомизированном анализе отвергает эту гипотезу.
Why this is not the mainstream account
The engine is asked to say what its hypothesis would overturn and what would surprise a specialist. This is its answer.
В эксперименте на мышах отсутствие отдельных протеаз тучных клеток, mMCP-4 или mMCP-5, существенно ограничивало прогрессирование ожогового повреждения после одинакового ошпаривания. Это основание проверять ферментативную причинность, но исследование не доказывает обязательность нейронального запуска или переносимость результата на умеренную нагрузку у человека. [Исследование роли протеаз тучных клеток](https://pmc.ncbi.nlm.nih.gov/articles/PMC3058366/).
Патофизиология термического и контактного повреждения, учебная глава «Повреждение и гибель клеток при физических воздействиях». Пересмотра потребовало бы положение о достаточности прямого физического воздействия для начала повреждения в данном диапазоне: обязательным промежуточным этапом оказался бы нейронально запускаемый протеолиз.
При неизменной физической нагрузке подавление чувствительных нейронов увеличивает интервал до повреждения настолько, что запас времени для защиты возрастает, несмотря на более позднее предупреждение. Активная протеаза устраняет эту защиту без восстановления нейрональной активности.
Известная роль нейрогенного воспаления сама по себе не является еретической. Радикальное утверждение здесь состоит в обязательности протеолиза для самого первого необратимого повреждения при умеренной сочетанной нагрузке и в увеличении защитного временного запаса после подавления нейронов. В выполненном ограниченном поиске точная формулировка не обнаружена. Отсутствие всех соответствующих обзоров доказать нельзя; прохождение теста новизны остаётся предварительным.
What stands behind it
Which of the figures above have a study behind them, which are the engine's own, and what it would take to refute the hypothesis. This audit never judges the idea.
This hypothesis states no figure and cites no study, so there is nothing here to trace.
What it would take to refute it. Nothing already retrieved carries the prediction’s terms and it names no measurement this layer can route to a public dataset, so the bench is the residual — not a finding against it.
0 citation handles extracted; 1 Europe PMC search run; 0 records examined; 0 sources stored for enrichment, 0 with full text. A citation that did not resolve is a bibliographic failure, not proof that no such paper exists, and no hypothesis is blocked by this audit.