import pandas as pd
import matplotlib.pyplot as plt
import numpy as np

debates = [{'debate_id': 'sess_SDA-2026-04-04-frontier-proteomics-1c3dba72', 'status': 'completed', 'rounds': 4, 'quality_score': 0.56, 'turns_with_text': 3, 'chars': 2157}, {'debate_id': 'sess_SDA-2026-04-04-frontier-proteomics-1c3dba72_20260412-115413', 'status': 'completed', 'rounds': 4, 'quality_score': 0.68, 'turns_with_text': 4, 'chars': 13378}]
df = pd.DataFrame(debates)
df

transcript_rows = [{'round': 1, 'persona': 'theorist', 'content': '', 'chars': 0}, {'round': 2, 'persona': 'skeptic', 'content': "I'd be happy to critically evaluate hypotheses for you, but I don't see any specific hypotheses provided in your message. Could you please share the hypotheses from the Theorist that you'd like me to analyze?\n\nOnce you provide them, I'll systematically evaluate each one by:\n\n1. **Identifying specific weaknesses** - Looking for logical gaps, unsupported assumptions, overgeneralizations, or methodological flaws\n2. **Citing counter-evidence** - Searching the literature for contradictory findings or alternative explanations\n3. **Proposing falsification experiments** - Designing specific tests that could disprove the hypothesis\n4. **Providing revised confidence scores** - Assessing the strength of evidence and likelihood of the hypothesis being correct\n\nPlease share the hypotheses you'd like me to evaluate, and I'll conduct a thorough critical analysis using available scientific literature and databases.", 'chars': 912}, {'round': 3, 'persona': 'domain_expert', 'content': "I notice that your message appears to be incomplete - you've provided the framework for hypothesis assessment but haven't included the actual hypotheses you'd like me to evaluate.\n\nTo provide you with a thorough druggability and feasibility assessment, I'll need you to share:\n\n1. **The specific hypotheses** you want me to analyze\n2. **The target disease/condition** (since you mentioned neurodegenerative diseases)\n3. **Any specific molecular targets or pathways** mentioned in the hypotheses\n\nOnce you provide the hypotheses, I can systematically evaluate each one using the framework you've outlined:\n\n**Critical Analysis:**\n- Identify weaknesses and gaps\n- Search for counter-evidence in the literature\n- Propose falsification experiments\n- Provide revised confidence scores\n\n**Druggability Assessment:**\n- Target tractability analysis\n- Existing therapeutic approaches\n- Competitive landscape review\n- Development timeline and cost estimates\n- Safety and regulatory considerations\n\nPlease share the hypotheses you'd like me to evaluate, and I'll conduct a comprehensive analysis using PubMed searches and gene databases to provide evidence-based assessments.", 'chars': 1164}, {'round': 4, 'persona': 'synthesizer', 'content': "[API Error: Error code: 400 - {'message': 'tools: Input should be a valid list'}]", 'chars': 81}, {'round': 1, 'persona': 'theorist', 'content': "# Mechanistic Hypotheses: Synaptic Proteomic Changes in Early Alzheimer Disease Pathophysiology\n\n---\n\n## Hypothesis 1: Cdk5-Mediated PSD-95 Phosphorylation Couples Synaptic Dysfunction to Accelerated Amyloidogenesis\n\n**Title:** PSD-95 S561 Phosphorylation Links Synaptic Failure to APP Processing\n\n**Mechanism:**\nAge-dependent activation of cyclin-dependent kinase 5 (Cdk5), likely through calpain-mediated p35 cleavage to p25, leads to pathological phosphorylation of PSD-95 at serine 561. This modification disrupts PSD-95's PDZ domain interactions with AMPA receptor subunits (GRIA1-4) and NMDA receptor subunits (GRIN2A/B), impairing activity-dependent receptor trafficking and synaptic plasticity. Simultaneously, phosphorylated PSD-95 recruits ubiquitin ligase complexes that facilitate endocytosis and lysosomal degradation of ADAM10, shifting APP processing from α- to β", 'chars': 878}, {'round': 2, 'persona': 'skeptic', 'content': "# Skeptic's Evaluation: Synaptic Proteomic Hypothesis in Early Alzheimer Disease\n\n---\n\n## Overall Framing Assessment\n\nBefore evaluating individual hypotheses, a structural concern must be raised: the research question proposes five distinct proteomic domains, but only one mechanistic hypothesis is presented. This evaluation must assess what exists. The remaining domains—synaptic vesicle proteins, scaffold interactions, RTK signaling, mitochondrial proteins, and APP processing—lack corresponding hypotheses, making the request internally inconsistent. I'll evaluate what is provided and flag what's missing.\n\n---\n\n## Critical Evaluation: Hypothesis 1\n\n### Mechanistic Claim Summary\nCdk5/p25 activation → PSD-95 S561 phosphorylation → disrupted PDZ interactions → recruitment of ubiquitin ligases → ADAM10 degradation → shift from α- to β-secretase APP processing.\n\n---\n\n### 1. Strongest Specific Weakness: Missing Link Between PSD-95 Phosphorylation and ADAM10 Degradation\n\nThe hypothesis proposes a four-step chain from phosphorylated PSD-95 to ADAM10 loss. This is the most mechanistically vulnerable segment. PSD-95 is a synaptic scaffold; for it to directly facilitate ADAM10 degradation would require formation of a ternary complex (phospho-PSD-95 / E3 ligase / ADAM10) that has not been demonstrated in the literature.\n\n**The mechanistic gap:**\n- PSD-95 itself is ubiquitinated by E3 ligases including Mdm2 (via Dmdu-mdm2 in Drosophila) and UBE2A/NAE, but this targets PSD-95 for degradation, not ADAM10.\n- ADAM10 is a transmembrane protease with complex trafficking through the ER, Golgi, and plasma membrane. Its degradation is typically lysosomal or proteasomal and regulated by its own substrates and interacting proteins (e.g., TIP60, LRP1).\n- For PSD-95 S561 phosphorylation to drive ADAM10 degradation, one must explain how a postsynaptic density protein physically interacts with and directs E3 ligase activity toward a presynaptic/perisynaptic membrane protease with no confirmed PSD-95 binding motif.\n\nThe spatial compartmentalization is particularly problematic: ADAM10 processing of APP occurs primarily at the plasma membrane and in the trans-Golgi network, while PSD-95 S561 is presumably postsynaptic. Physical proximity is not established.\n\n---\n\n### 2. Counter-Evidence and Known Complications\n\n**a. Cdk5 activity in early AD is more complex than presented.**\nLiterature suggests Cdk5 activity is dysregulated in AD, but the directionality is context-dependent. In some hAPP/J20 models, Cdk5 activity is actually suppressed early in disease, with p25 accumulation correlating with later stages. Aβ itself can transiently inhibit Cdk5 through calpain activation and p35 cleavage—this creates a negative feedback loop rather than unidirectional activation. The hypothesis assumes Cdk5 hyperactivity drives synaptic dysfunction, but the temporal kinetics in human tissue remain unclear.\n\n**b. PSD-95 S561 is not a well-established pathological phosphorylation site.**\nMost literature on PSD-95 phosphorylation focuses on S295 (CaMKII site) and S397 (PKA/Cdk5). While S561 has been identified in phosphoproteomic screens, its functional validation as a Cdk5 target with pathology-specific significance is limited. A recent phosphoproteomic study of AD human tissue (Wingo et al., 202", 'chars': 3305}, {'round': 3, 'persona': 'domain_expert', 'content': "# Domain Expert Evaluation: Synaptic Proteomic Hypotheses in Early Alzheimer Disease\n\n## Executive Summary\n\nThe research question addresses a critical and underexplored frontier in Alzheimer's disease (AD) pathophysiology: the proteomic architecture of the aging synapse as a proximal driver of early AD neurodegeneration. I will evaluate the presented hypothesis, construct interpretable frameworks for the four missing domains, identify the highest-translational opportunities, address the Skeptic's mechanistically sound critique, and propose an underappreciated mechanism worthy of investigation.\n\n---\n\n## 1. Hypotheses with Highest Translational Potential\n\n### Hypothesis 1 (Presented): Cdk5/p25-Mediated Synaptic Dysfunction\n**Translational Rank: 2 of 5**\n\n**Clinical Landscape:**\nCdk5/p25 dysregulation is one of the most consistently observed pathological signatures in AD brain tissue, with elevated p25/p35 ratios reported in post-mortem studies across multiple cohorts (Tseng et al., 2022; Shukla et al., 2012). However, direct Cdk5 inhibitors have failed in clinical development due to the enzyme's ubiquitous roles in neuronal survival, metabolism, and cell cycle regulation—raising serious safety concerns. **Roscovitine (seliciclib)** advanced to Phase II trials for neurodegenerative indications but failed due to off-target toxicity, establishing a cautionary precedent.\n\n**Why rank 2:** The downstream node of synaptic failure driving amyloidogenesis is mechanistically compelling but undruggable at the kinase level. The more actionable insight is the *consequence* of Cdk5 activation (synaptic scaffold disruption) rather than Cdk5 itself.\n\n---\n\n### Domain 3: Receptor Tyrosine Kinase (RTK) Signaling Dysregulation\n**Translational Rank: 1 of 5 — Highest Priority**\n\n**Mechanism Reconstruction:**\nSynaptic tyrosine kinase signaling, particularly through TrkB (brain-derived neurotrophic factor receptor) and IGF-1R, declines sharply with age at the synapse. This is not merely correlative—key downstream cascades are compromised:\n\n- **TrkB signaling → PI3K/AKT → mTORC1:** Dysregulated in early AD, leads to impaired local protein synthesis at dendritic spines\n- **TrkB/IGF-1R → Ras/ERK/MAPK:** Critical for activity-dependent synaptic consolidation and memory stabilization\n- **RTK cross-talk with NMDA receptor phosphorylation:** Altered downstream kinase cascades affect NMDA receptor function at the synapse\n\n**Clinical Evidence:**\n- **BDNF (TrkB agonist) delivery** is in Phase I/II trials (intranasal BDNF, gene therapy approaches like AAV-BDNF)\n- **IGF-1 signaling** restoration shows efficacy in animal models; IGF-1 itself is in trials for AD (NCT01970056)\n- **mTOR modulation** via rapamycin has been explored, though systemic mTOR inhibition has metabolic downsides; selective synaptic mTOR targeting is a newer strategy\n\n**Patient Population Fit:**\nRTK signaling decline is observable in prodromal AD and even in MCI, making this a window for early intervention. This is mechanistically upstream of irreversible neurodegeneration—the synapse remains structurally intact and could respond to trophic support.\n\n**Safety Considerations:**\nRTK agonism carries theoretical risks of promoting oncogenesis (particularly IGF-1R, which is implicated in multiple cancers) and inducing seizures (TrkB activation can lower seizure threshold). However, localized CNS delivery (intranasal, AAV-mediated) substantially reduces systemic exposure. **BMS-986116** (TrkB partial agonist) showed acceptable safety in Phase I, though efficacy in AD remains unproven.\n\n**Why highest translational potential:**\nThis mechanism has a **direct therapeutic ligand strategy** (BDNF mimetics, IGF-1 analogs, TrkB agonists), a **clear biomarker readout** (phospho-TrkB in CSF, AKT activation markers), and addresses **synaptic dysfunction upstream** of both amyloid and tau pathology.\n\n---\n\n### Domain 5: APP Processing at the Synapse (Extended from Hypothesis 1)\n**Translational Rank: 3 of 5**\n\n**Mechanism Reconstruction:**\nThe Theorist's framework focuses on how synaptic scaffold disruption shifts APP processing", 'chars': 4117}, {'round': 4, 'persona': 'synthesizer', 'content': '{\n  "ranked_hypotheses": [\n    {\n      "rank": 1,\n      "title": "Cdk5/p25-PSD-95 Phosphorylation Disrupts Synaptic Scaffolding and Shifts APP Processing",\n      "mechanism": "Age-dependent p35-to-p25 cleavage activates Cdk5, which phosphorylates PSD-95 S561, disrupting AMPA/NMDA receptor anchoring and recruiting ubiquitin ligases that degrade ADAM10, thereby redirecting APP processing toward amyloidogenic β-secretase cleavage.",\n      "target_gene": "PSD-95 (DLG4)",\n      "confidence_score": 0.75,\n      "novelty_score": 0.55,\n      "feasibility_score": 0.70,\n      "impact_score": 0.85,\n      "composite_score": 0.72,\n      "testable_prediction": "Conditional knockout of p25 in excitatory neurons of 5xFAD mice will reduce PSD-95 S561 phosphorylation, restore surface AMPA/NMDA ratios, and decrease Aβ42/40 ratios in synaptoneurosomes without affecting amyloid plaque load.",\n      "skeptic_concern": "Causal directionality remains uncertain; amyloid may drive Cdk5 activation rather than vice versa, requiring temporal-specific perturbation experiments to establish primacy."\n    },\n    {\n      "rank": 2,\n      "title": "Synaptic Mitochondrial Proteostasis Collapse Disrupts ATP-Demand Coupling at Active Zones",\n      "mechanism": "Age-dependent oxidation and deamidation of synaptic mitochondrial proteins (including VDAC1, CypD/PPID, and MICOS complex members) impairs calcium handling and ATP generation, creating a chronic energy deficit that uncouples synaptic vesicle release probability from activity demands and triggers compensatory synaptic loss.",\n      "target_gene": "PPID (Cyclophilin D)",\n      "confidence_score": 0.60,\n      "novelty_score": 0.70,\n      "feasibility_score": 0.55,\n      "impact_score": 0.75,\n      "composite_score": 0.66,\n      "testable_prediction": "Targeted proteomics of synaptic versus nonsynaptic mitochondria from human AD prefrontal cortex will reveal oxidized MICOS subunits and CypD translocation exclusively at synaptic compartments, correlating with reduced mitochondrial calcium uptake capacity.",\n      "skeptic_concern": "Mitochondrial dysfunction may represent a downstream consequence of calcium dysregulation from NMDAR overactivation rather than an initiating event."\n    },\n    {\n      "rank": 3,\n      "title": "Synaptic Vesicle Protein Phosphorylation Reprograms Release Probability and Interacts with APP Processing",\n      "mechanism": "Synaptic activity-dependent phosphorylation of synapsin-1 by CamKII and calcineurin dynamically regulates vesicle mobilization, while Cdk5-mediated phosphorylation of synaptophysin and SV2A facilitates interaction with APP in presynaptic terminals, creating a hub where impaired neurotransmitter release converges with local Aβ secretion.",\n      "target_gene": "SYN1 (Synapsin-1)",\n      "confidence_score": 0.55,\n      "novelty_score": 0.65,\n      "feasibility_score": 0.65,\n      "impact_score": 0.70,\n      "composite_score": 0.63,\n      "testable_prediction": "Phosphoproteomics of synaptosomes from early AD cases (Braak III-IV) will show coordinated hypophosphorylation of synapsin-1 and SV2A, which correlates with reduced frequency of miniature excitatory postsynaptic currents in autologous neuronal cultures.",\n      "skeptic_concern": "Presynaptic changes are harder to measure in human tissue and may be confounded by terminal loss; requires complementary iPSC-derived neuron studies for causality."\n    }\n  ],\n  "consensus_points": [\n    "Synaptic dysfunction represents a proximal, quantifiable driver of early AD rather than a secondary consequence of amyloid deposition",\n    "Post-translational modifications—particularly phosphorylation and ubiquitination—are master regulators of synaptic proteome remodeling in prodromal AD",\n    "Cdk5/p25 activation emerges as a convergent node across multiple synaptic domains, warranting investigation as a therapeutic target"\n  ],\n  "dissent_points": [\n    "Temporal primacy remains contested: whether synaptic proteome changes initiate amyloidogenesis or are initiated by soluble Aβ oligomers is unresolved and may represent a bidirectional vicious cycle",\n    "The Skeptic correctly notes that only one of five requested domains was formally hypothesized, leaving synaptic vesicle dynamics, RTK signaling, and scaffold interaction networks inadequately formalized"\n  ],\n  "debate_summary": "The debate converges on Cdk5/p25-PSD-95 signaling as the highest-confidence mechanistic hypothesis linking synaptic scaffold disruption to amyloidogenic APP processing, though its causal primacy versus correlation with amyloid remains contested. Synaptic mitochondrial proteostasis collapse represents the highest-novelty hypothesis with substantial translational potential for metabolic intervention, while synaptic vesicle phosphoproteome remodeling offers an underappreciated presynaptic dimension of early AD pathophysiology. The Skeptic\'s structural critique is valid: a comprehensive model requires formal hypotheses for RTK/insulin signaling cascades and the remaining domains to achieve internal consistency."\n}', 'chars': 5078}]
turns = pd.DataFrame(transcript_rows)
if len(turns):
    summary = turns.groupby('persona').agg(turns=('round','count'), chars=('chars','sum')).sort_values('chars', ascending=False)
    display(summary)
else:
    print('No transcript turns with parseable structure')

if len(turns):
    persona_counts = turns.groupby('persona')['chars'].sum().sort_values()
    fig, ax = plt.subplots(figsize=(8, 4))
    persona_counts.plot(kind='barh', ax=ax, color='#607d8b')
    ax.set_xlabel('Transcript characters')
    ax.set_title('Debate contribution volume by persona')
    ax.grid(axis='x', alpha=0.25)
    plt.tight_layout(); plt.show()
else:
    print('No transcript text available for plotting')

excerpts = [{'round': 2, 'persona': 'skeptic', 'excerpt': "I'd be happy to critically evaluate hypotheses for you, but I don't see any specific hypotheses provided in your message. Could you please share the hypotheses from the Theorist that you'd like me to analyze?  Once you provide them, I'll systematically evaluate each one by:  1. **Identifying specific weaknesses** - Looking for logical gaps, unsupported assumptions, overgeneralizations, or methodological flaws 2. **Ci", 'chars': 912}, {'round': 3, 'persona': 'domain_expert', 'excerpt': "I notice that your message appears to be incomplete - you've provided the framework for hypothesis assessment but haven't included the actual hypotheses you'd like me to evaluate.  To provide you with a thorough druggability and feasibility assessment, I'll need you to share:  1. **The specific hypotheses** you want me to analyze 2. **The target disease/condition** (since you mentioned neurodegenerative diseases) 3. ", 'chars': 1164}, {'round': 4, 'persona': 'synthesizer', 'excerpt': "[API Error: Error code: 400 - {'message': 'tools: Input should be a valid list'}]", 'chars': 81}, {'round': 1, 'persona': 'theorist', 'excerpt': '# Mechanistic Hypotheses: Synaptic Proteomic Changes in Early Alzheimer Disease Pathophysiology  ---  ## Hypothesis 1: Cdk5-Mediated PSD-95 Phosphorylation Couples Synaptic Dysfunction to Accelerated Amyloidogenesis  **Title:** PSD-95 S561 Phosphorylation Links Synaptic Failure to APP Processing  **Mechanism:** Age-dependent activation of cyclin-dependent kinase 5 (Cdk5), likely through calpain-mediated p35 cleavage ', 'chars': 878}, {'round': 2, 'persona': 'skeptic', 'excerpt': "# Skeptic's Evaluation: Synaptic Proteomic Hypothesis in Early Alzheimer Disease  ---  ## Overall Framing Assessment  Before evaluating individual hypotheses, a structural concern must be raised: the research question proposes five distinct proteomic domains, but only one mechanistic hypothesis is presented. This evaluation must assess what exists. The remaining domains—synaptic vesicle proteins, scaffold interaction", 'chars': 3305}, {'round': 3, 'persona': 'domain_expert', 'excerpt': "# Domain Expert Evaluation: Synaptic Proteomic Hypotheses in Early Alzheimer Disease  ## Executive Summary  The research question addresses a critical and underexplored frontier in Alzheimer's disease (AD) pathophysiology: the proteomic architecture of the aging synapse as a proximal driver of early AD neurodegeneration. I will evaluate the presented hypothesis, construct interpretable frameworks for the four missing", 'chars': 4117}, {'round': 4, 'persona': 'synthesizer', 'excerpt': '{   "ranked_hypotheses": [     {       "rank": 1,       "title": "Cdk5/p25-PSD-95 Phosphorylation Disrupts Synaptic Scaffolding and Shifts APP Processing",       "mechanism": "Age-dependent p35-to-p25 cleavage activates Cdk5, which phosphorylates PSD-95 S561, disrupting AMPA/NMDA receptor anchoring and recruiting ubiquitin ligases that degrade ADAM10, thereby redirecting APP processing toward amyloidogenic β-secretas', 'chars': 5078}]
pd.DataFrame(excerpts)

literature = []
if literature:
    pd.DataFrame(literature)
else:
    print('No PubMed results returned for this debate question')

edges = []
if edges:
    pd.DataFrame(edges)
else:
    print('No knowledge graph edges were recorded for this debate-only analysis')