About

Thomas T. Joseph, MD, PhD, is an Assistant Professor of Anesthesiology and Critical Care at the Hospital of the University of Pennsylvania. He serves as an Attending Anesthesiologist at Penn Presbyterian Medical Center and The Hospital of the University of Pennsylvania. Dr. Joseph is also the Assistant Physician Lead for PennChart Anesthesia and OpTime Applications at Penn Medicine. His research expertise includes computational biophysics and molecular dynamics simulation, anesthesia, and medical informatics. His clinical expertise is in anesthesiology. Dr. Joseph has contributed to various scientific publications, focusing on topics such as anesthetic mechanisms, molecular interactions, and computational approaches in biomedical research.

Research topics

• Medicine
• Chemistry
• Surgery
• Internal medicine
• Biophysics

Selected publications

• Recommendations for disclosure of artificial intelligence in scientific writing and publishing: a regional anesthesia and pain medicine modified Delphi study

  Regional Anesthesia & Pain Medicine · 2025-09-02 · 10 citations

  articleOpen access

  Introduction The use of artificial intelligence (AI) in the scientific process is advancing at a remarkable speed, thanks to continued innovations in large language models. While AI provides widespread benefits, including editing for fluency and clarity, it also has drawbacks, including fabricated content, perpetuation of bias, and lack of accountability. The editorial board of Regional Anesthesia & Pain Medicine (RAPM) therefore sought to develop best practices for AI usage and disclosure. Methods A steering committee from the American Society of Regional Anesthesia and Pain Medicine used a modified Delphi process to address definitions, disclosure requirements, authorship standards, and editorial oversight for AI use in publishing. The committee reviewed existing publication guidelines and identified areas of ambiguity, which were translated into questions and distributed to an expert workgroup of authors, reviewers, editors, and AI researchers. Results Two survey rounds, with 91% and 87% response rates, were followed by focused discussion and clarification to identify consensus recommendations. The workgroup achieved consensus on recommendations to authors about definitions of AI, required items to report, disclosure locations, authorship stipulations, and AI use during manuscript preparation. The workgroup formulated recommendations to reviewers about monitoring and evaluating the responsible use of AI in the review process, including the endorsement of AI-detection software, identification of concerns about undisclosed AI use, situations where AI use may necessitate the rejection of a manuscript, and use of checklists in the review process. Finally, there was consensus about AI-driven work, including required and optional disclosures and the use of checklists for AI-associated research. Discussion Our modified Delphi study identified practical recommendations on AI use during the scientific writing and editorial process. The workgroup highlighted the need for transparency, human accountability, protection of patient confidentiality, editorial oversight, and the need for iterative updates. The proposed framework enables authors and editors to harness AI’s efficiencies while maintaining the fundamental principles of responsible scientific communication and may serve as an example for other journals.

  PublisherOA PDFDOI

• The cryo-EM structure and physical basis for anesthetic inhibition of the THIK1 K2P channel

  Proceedings of the National Academy of Sciences · 2025-04-03 · 4 citations

  articleOpen access

  THIK1 tandem pore domain (K2P) potassium channels regulate microglial surveillance of the central nervous system and responsiveness to inflammatory insults. With microglia recognized as critical to the pathogenesis of neurodegenerative diseases, THIK1 channels are putative therapeutic targets to control microglia dysfunction. While THIK channels can principally be distinguished from other K2Ps by their distinctive inhibitory response to volatile anesthetics (VAs), molecular details governing THIK channel gating remain largely unexplored. Here, we report a 3.2 Å cryo-electron microscopy structure of the THIK1 channel in a closed conformation. A central pore gate located directly below the THIK1 selectivity filter is formed by inward-facing TM4 helix tyrosine residues that occlude the ion conduction pathway. VA inhibition of THIK requires closure of this central pore gate. Using a combination of anesthetic photolabeling, electrophysiology, and molecular dynamics simulation, we identify a functionally critical THIK1 VA binding site positioned between the central gate and a structured section of the THIK1 TM2/TM3 loop. Our results demonstrate the molecular architecture of the THIK1 channel and elucidate critical structural features involved in regulation of THIK1 channel gating and anesthetic inhibition.

  PublisherOA PDFDOI

• Nitrous oxide activates layer 5 prefrontal neurons via SK2 channel inhibition for antidepressant effect

  Nature Communications · 2025-04-03 · 11 citations

  articleOpen access

  Abstract Nitrous oxide (N 2 O) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N 2 O induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions. N 2 O-induced L5 activation rescues a stress-associated hypoactivity state, persists following exposure, and is necessary for its antidepressant-like activity. Although NMDA-receptor antagonism is believed to be a primary mechanism of action for N 2 O, L5 neurons activate even when NMDA-receptor function is attenuated through both pharmacological and genetic approaches. By examining different molecular and circuit targets, we identify N 2 O-induced inhibition of calcium-sensitive potassium (SK2) channels as a key molecular interaction responsible for driving specific L5 activity along with ensuing antidepressant-like effects. These results suggest that N 2 O-induced L5 activation is crucial for its fast antidepressant action and this effect involves novel and specific molecular actions in distinct cortical cell types.

  PublisherOA PDFDOI

• BPS2025 - Allosteric modulation of ELIC by POPG and POPE, and distinguishing overlapping phospholipid binding modes using SAFEP

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• A vein bypass first <i>versus</i> a best endovascular treatment first revascularization strategy for patients with chronic limb-threatening ischaemia who require an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularization procedure to restore limb perfusion: the BASIL-2 within-trial health economic analysis

  British journal of surgery · 2025-05-31 · 1 citations

  articleOpen access

  BACKGROUND: Chronic limb-threatening ischaemia (CLTI) places a considerable socioeconomic burden health and social care systems worldwide. The objective of this health economic analysis was to investigate the cost-effectiveness (CEA) and cost-utility (CUA) of a vein bypass (VB) first versus a best endovascular treatment (BET) first revascularization strategy in patients with CLTI who require an infra-popliteal revascularization procedure to restore limb perfusion. METHODS: CEA and CUA analyses were conducted from the perspective of the UK National Health Service. Patient-level resource use and health outcomes data collected from the BASIL-2 trial over 2-7 years of follow-up were utilized to estimate incremental cost-effectiveness ratios expressed as cost per amputation-free life year (AFLY) and cost per quality-adjusted life year (QALY). EQ-5D-5L was used to generate participant QALYs at 2 and 3 years. RESULTS: At two years, the mean(s.d.) discounted hospital cost was £15 742.59(16 182.60) and £13 273.66(15 446.92) in the VB-first and BET-first revascularization strategy groups respectively. The lower costs (-£2524.23, 95% c.i., -£5844.93 to £1131.52) in the BET-first group were mainly due to the reduced number of days in hospital and lower procedural costs. BET-first was also more effective leading to additional AFLYs (0.429, 95% c.i., 0.03 to 0.88) at 7 years and discounted QALYs (0.016, 95% c.i., -0.08 to 0.12) at 2 years. CONCLUSION: A best endovascular first revascularization strategy dominated a vein bypass first strategy in the cost-effectiveness and cost-utility analyses. The findings were robust across different scenarios and prespecified subgroups.

  PublisherOA PDFDOI

• Functionalization of 1,3-Diisopropylbenzene to Probe the Antagonism of Propofol Anesthesia

  ACS Chemical Neuroscience · 2025-12-03

  articleOpen access

  General anesthetics like propofol are widely used, but their molecular mechanisms remain poorly understood, limiting the rational design of novel anesthetics or antagonists to enhance safety. We evaluated nine propofol derivatives for their ability to immobilize, or modulate propofol-induced immobilization, in larval zebrafish, using spontaneous and elicited movement as distinct endpoints. We hypothesized that compounds unable to act as hydrogen-bond donors would antagonize immobilization─evidenced by rightward EC50 shifts─while hydrogen-bond-capable derivatives would retain immobilizing effects. Results confirmed that nondonor analogues antagonized propofol’s effects, whereas donor molecules had sedative activity, and a hydrocarbon control did not shift the EC50 curve. Quantum-mechanical calculations of hydrogen-bond acidity were correlated to behavioral outcomes, supporting their predictive potential. Notably, a tertiary amine analogue (PEARL 6, N,N-dimethyl-2,6-diisopropylaniline) antagonized most strongly (25.6-fold increase in propofol’s EC50 for spontaneous movement and a 1.86-fold increase for elicited movement) without causing excitation when administered alone. These findings identify structural features that distinguish sedative from antagonistic activity and provide characterization of a key feature of propofol derivatives.

  PublisherDOI

• Free energies of lipid binding: A comparison of estimates from coarse-grained and atomistic molecular dynamics

  Biophysical Journal · 2024-02-01

  article
  PublisherDOI

• Nitrous Oxide activates layer 5 prefrontal cortical neurons via SK2 channel inhibition for antidepressant effect

  Research Square · 2024-01-25 · 1 citations

  preprintOpen access
  PublisherOA PDFDOI

• alchemlyb: the simple alchemistry library

  The Journal of Open Source Software · 2024-09-26 · 28 citations

  articleOpen access

  effectively.

  PublisherDOI

• Propofol directly binds and inhibits skeletal muscle ryanodine receptor 1 (RyR1)

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-01-12 · 2 citations

  preprintOpen access1st authorCorresponding

  Abstract As the primary Ca 2+ release channel in skeletal muscle sarcoplasmic reticulum (SR), mutations in the type 1 ryanodine receptor (RyR1) or its binding partners underlie a constellation of muscle disorders, including malignant hyperthermia (MH). In patients with MH mutations, exposure to triggering drugs such as the halogenated volatile anesthetics biases RyR1 to an open state, resulting in uncontrolled Ca 2+ release, sarcomere tension and heat production. Restoration of Ca 2+ into the SR also consumes ATP, generating a further untenable metabolic load. When anesthetizing patients with known MH mutations, the non-triggering intravenous general anesthetic propofol is commonly substituted for triggering anesthetics. Evidence of direct binding of anesthetic agents to RyR1 or its binding partners is scant, and the atomic-level interactions of propofol with RyR1 are entirely unknown. Here, we show that propofol decreases RyR1 opening in heavy SR vesicles and planar lipid bilayers, and that it inhibits activator-induced Ca 2+ release from SR in human skeletal muscle. In addition to confirming direct binding, photoaffinity labeling using m- azipropofol (AziP m ) revealed several putative propofol binding sites on RyR1. Prediction of binding affinity by molecular dynamics simulation suggests that propofol binds at least one of these sites at clinical concentrations. These findings invite the hypothesis that in addition to propofol not triggering MH, it may also be protective against MH by inhibiting induced Ca 2+ flux through RyR1.

  PublisherOA PDFDOI

Frequent coauthors

• Jérôme Hénin

  Centre National de la Recherche Scientifique

  24 shared

• Grace Brannigan

  Rutgers, The State University of New Jersey

  18 shared

• Richard Bulbulia

  15 shared

• Roderic G. Eckenhoff

  University of Pennsylvania

  12 shared

• Alison Halliday

  10 shared

• Weiming Bu

  University of Pennsylvania

  8 shared

• Roman Osman

  Icahn School of Medicine at Mount Sinai

  8 shared

• Judy R. Mangion

  8 shared

Labs

• Thomas T. Joseph LabPI

Education

• Residency, Anesthesiology

  Mount Sinai Hospital

  2016

• MD

  Icahn School of Medicine at Mount Sinai

  2012

• PhD

  Icahn School of Medicine at Mount Sinai

  2010

• BS

  Washington University in St. Louis

  2003