Dermacentor ticks are widespread in eastern Washington and are known vectors of bacterial pathogens and harborers of endosymbionts belonging to the genera Francisella and Rickettsia. Some Dermacentor species can become infected with Ehrlichia chaffeensis Anderson et al. (Rickettsiales: Ehrlichiaceae); it remains unclear if any are competent vectors for this bacterial pathogen. This study reports the abundance of Dermacentor species and prevalence of select tick-borne bacterial pathogens collected from two conservation areas popular among hikers in Spokane County, Washington. In total, DNA from 599 adult ticks was analyzed using PCR; 87.8% (526/599) were identified as Dermacentor andersoni Stiles and 12.2% (73/599) as D. similis Lado, Glon and Klompen (Ixodida: Ixodidae). Ticks were also screened for the presence of bacterial DNA using genus- or species-specific primers targeting Rickettsia spp., Francisella spp., and E. chaffeensis. Rickettsia endosymbionts, R. peacockii Niebylski et al. or R. rhipicephali (Burgdorfer et al.) Weiss and Moulder (Rickettsiales: Rickettsiaceae), were found in 4.0% (21/526) of D. andersoni. Francisella-like endosymbionts were detected in 65.9% (395/599) of all ticks. No species known to be pathogenic belonging to either Rickettsia or Francisella were detected. However, E. chaffeensis was detected in 15.3% (12/73) of D. similis, which to our knowledge is the first report of ticks harboring this species of bacteria in Washington state. These findings contribute to understanding the microbial ecology of ticks in the Inland Northwest.
The gut microbiome plays an important role in mammalian host health and ability to adapt to environmental conditions. While the gut microbiome is often considered fairly stable over short periods of time in the absence of a dramatic stressor, relatively little is known about the actual time scale of microbiome shifts, particularly in wildlife species. Most existing temporal studies utilize captive subjects, while here we employ the Western deer mouse, Peromyscus sonoriensis, in a field-based study to assess short-term microbiome dynamics (less than 2 days) in the wild. Mice were live-trapped at several urban and rural parks over a two-night trapping period in and around Spokane, WA, USA in May of 2024. We collected fecal samples from 43 different individuals, capturing two to four time points per individual, and bacterial community composition was determined via 16S profiling with Nanopore sequencing. Genus-level profiles were compared across time points for each individual, showing relative consistency in types of taxa present for most mice, but some marked shifts in Ligilactobacillus in some mice. Calculation of intraclass correlation coefficients, however, showed low stability in alpha diversity (Shannon index) over time, suggesting greater variability than initially anticipated. Analysis with respect to site urbanization, sex, and age showed a significant effect of age when accounting for homogeneity of variance, with additional exploration of urbanization and sex needed in future work. These results provide important insight into the understudied area of host microbiome dynamics and highlight the complex nature of relationships between microbiome, health, and environment.
Developing a skilled workforce pipeline is crucial to scaling operations and ensuring the highest standards of quality and safety. To address this challenge, we propose a dual framework that incorporates both internal employee training to maximize personnel resources, as well as external outreach and workforce development programs.Our Spokane manufacturing site undertook a major workforce transformation by adopting a shared resource model and cross-training existing team members to perform multiple roles. This initiative enabled continuous 24-hour operations, improved flexibility, and allowed for more efficient deployment of technicians across production lines in preparation to scale operations.In addition to internal development, we collaborate with local academic institutions and economic development organizations to drive interest in biomanufacturing careers. Most notability, our investment in future talent through a partnership with the local community college to create a biotech manufacturing certification course prepares potential workforce members with the foundational skills needed to succeed in the growing pharma manufacturing industry.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors slow diabetic kidney disease progression, but their intrarenal mechanisms remain incompletely understood, particularly in type 1 diabetes (T1D), where kidney protection has not been definitively established. ATTEMPT (NCT04333823) was a placebo-controlled trial in which 98 youth (ages 12 to 21) with T1D and hyperfiltration were randomized 1:1 to dapagliflozin (5 milligrams) or placebo for 16 weeks. Participants underwent sequential kidney biopsies, multiparametric kidney MRI, and plasma and urine proteomics. The sequential research kidney biopsies were performed on adults 18 years or older at one of three sites (baseline n = 16, follow-up n = 11). Single-cell RNA sequencing of 214,415 cells across 27 biopsies revealed coordinated transcriptional shifts across nephron, vascular, and immune compartments. In the proximal tubule, the primary site of SGLT2 expression, dapagliflozin down-regulated glycolysis, gluconeogenesis, and oxidative stress markers. Endothelial cells showed reduced profibrotic and inflammatory gene expression with increased protective factors. Podocytes demonstrated enhanced cytoskeletal reinforcement and suppressed interferon signaling. These molecular changes paralleled clinical improvements, including attenuation of hyperfiltration, improved glycemic control, and normalization of medullary oxygenation. Trajectory analyses revealed dapagliflozin shifted tubular cells from injury-prone toward healthier phenotypes. Cross-cohort comparison against healthy controls showed that more than 55% of dapagliflozin-responsive genes shifted toward healthy control expression patterns. Urine proteomics mirrored tissue changes with decreased injury markers and increased protective proteins. These convergent molecular mechanisms, metabolic reprogramming, dampened inflammation, and normalized oxygen handling provide hypothesis-generating mechanistic insights into potential kidney-protective mechanisms of SGLT2 inhibitor therapy in youth with T1D.
The Saving Kidneys, Hearts, and Lives workshop in March 2025, hosted by the American Society of Nephrology, brought together diverse stakeholders in the care of patients with cardiovascular-kidney-metabolic (CKM) syndrome, including multispecialty health care professionals, patients, and researchers from academic and community-based backgrounds. The CKM syndrome encompasses multidirectional interactions among kidney diseases, cardiovascular diseases, diabetes, and obesity. Highly efficacious therapies are presently available to reduce risks of adverse kidney and cardiovascular events as well as all-cause mortality. The goal of the Saving Kidneys, Hearts, and Lives workshop was to gain insights into and make recommendations for the role of nephrology in CKM care. Following a series of plenary talks about the current state, interactive discussions among participants focused on developing tangible strategies and opportunities for nephrology in addressing CKM syndrome. Participants noted that nephrology spans internal medicine, with special expertise in managing kidney diseases, BP, and CKM risk factors along with training that emphasizes interactions among complex chronic conditions. Participants highlighted the importance of screening and implementation of CKM syndrome diagnostic and therapeutic strategies earlier than when patients have been typically referred to nephrology specialty care. In addition, participants explored the contributions of nephrologists to upstream care, beyond their conventional focus on high-risk, rare, or advanced kidney diseases. Participants recognized barriers, including payment structures that provide relatively modest resources for complex chronic care before KRT and gaps in nephrology training to manage CKM syndrome. Ongoing strategies by the American Society of Nephrology will focus on collaborations and crossing traditional specialty boundaries of nephrology, cardiology, and metabolic diseases to promote overall CKM health.
To analyze concordance between pharmacist evaluators and paid actor standardized patient (SP) evaluators when grading student pharmacists' performance in a simulated mental health patient interaction. A mental health telehealth simulation was developed for second-year student pharmacists. Performance was concurrently assessed by an SP and a pharmacist evaluator. Differences in rubric-based assessments between the two evaluator types were subsequently analyzed as paired samples using the McNemar test. All fifty-nine enrolled students completed the simulation. There was strong agreement between SP and pharmacist evaluations for communication and professionalism metrics across the cohort. Discrepancies were observed on 8.6% of the rubric items and occurred most frequently on rubric items that required clinical judgment such as "recommended appropriate over-the-counter (OTC) options for the patient" (27% disagreement) or "no/limited use of medical jargon" (22% disagreement). Significant differences were seen with SP's reporting that the student did not complete some tasks, while the pharmacist evaluators reported the task as completed, such as "asked about duration of symptoms," and "recommended appropriate OTC/nonpharmacologic options for the patient". This study found strong concordance between SP and pharmacist evaluators for assessing observable communication behaviors and professionalism but identified significant differences in ratings for items requiring clinical judgment.
Rural adults (those residing in nonmetropolitan counties) face persistent barriers to brain-health assessment that may help prevent or delay cognitive decline. This study reports protocol and pilot feasibility findings from year 1 of a 3-year longitudinal project evaluating Building a Rural Aging and Intervention Network: Factors that Impact Trajectories (BRAIN-FIT), a community-embedded program to improve access to multidomain screening and awareness of modifiable dementia risk factors. Using a mixed-methods design, 119 adults aged 45 or older completed a single-day interdisciplinary screening incorporating clinical-standard measures (cardiovascular, physical, lifestyle, social-emotional, sensory, cognitive, and speech-language health), followed by individualized-results review. 63 participants completed a 4-week post-event behavior change evaluation. BRAIN-FIT, delivered across 7 community sites in 3 cities through 18 events, enrolled 163 adults (aged 46-95; M = 67.5) with socioeconomic and clinical heterogeneity. Engagement was strong: 119 consented to longitudinal participation, 95% completed all stations and rated the program highly feasible (3.7-4.4 out of 5). Screening identified prevalent modifiable risk factors: elevated cardiometabolic indicators, reduced physical endurance, sleep disturbance, and sensory impairment. Cognitive and language performance remained largely within functional limits, suggesting engagement during a preventive window. Community-embedded multimodal screening appears to be a viable program for identifying actionable brain-health risk prior to substantial decline. By reaching diverse adults outside traditional care pathways, BRAIN-FIT advances a pragmatic population-health approach to dementia prevention. Longitudinal follow-up will evaluate sustained behavior change, strengthen referral integration, and inform hybrid effectiveness-implementation trials to promote healthier aging trajectories.
The olfactory system is pivotal for insects to detect external chemical signals and regulate essential life processes. Dendroctonus valens, an invasive forest pest, displays strong chemotaxis toward the plant kairomone (+)-3-carene. To unravel the molecular mechanism underlying olfactory recognition, we identified 28 odorant-binding proteins (OBPs) from D. valens via transcriptome sequencing and identified DvalOBP6 and DvalOBP18 as potential key candidates for this host kairomone component using qRT-PCR. Tissue expression analysis revealed that these two Minus-C OBPs are predominantly expressed in olfactory-related tissues (antennae, legs, and wings) with distinct sexual dimorphism. Homology modeling and molecular docking showed that both proteins adopt a typical six-α-helix fold, and bind (+)-3-carene primarily via hydrophobic interactions with binding energies of -5.53 kcal/mol and -4.96 kcal/mol, respectively. RNA interference of DvalOBP6 or DvalOBP18 significantly abolished the olfactory preference of D. valens adults for (+)-3-carene. Collectively, our findings demonstrate that DvalOBP6 and DvalOBP18 play critical roles in (+)-3-carene perception, providing a theoretical basis for the development of green pest control technologies targeting insect olfactory communication.
This study aimed to describe contemporary neonatal therapy practice in the neonatal intensive care unit (NICU). This Institutional Review Board (IRB)-approved research, conducted in 2024, surveyed occupational therapists (OTs), physical therapists (PTs), and speech-language pathologists (SLPs) who worked in the NICU within the past 5 years. There were 1,095 clinicians from 728 hospitals who responded: 459 (42%) OTs, 328 (30%) PTs, and 308 (28%) SLPs. Among respondents, 517 (55%) practiced in Level III NICUs, 385 (41%) in Level IV NICUs, and 48 (5%) in Level II units. Additionally, 581 (62%) were Certified Neonatal Therapists (CNTs). Most respondents reported the presence of OTs (765, 95%), SLPs (697, 86%), and PTs (691, 85%) in their NICU, and 723 (81%) had standing therapy orders. Most (513; 58%) reported having all three disciplines in their NICU. Common neurobehavioral assessments included the Test of Infant Motor Performance, General Movement Assessment, Infant Positioning Assessment Tool, and Hammersmith Neonatal Neurological Assessment. Frequently used feeding assessments were the Early Feeding Skills Assessment, Neonatal Eating Outcome Assessment, and Neonatal Oral Motor Assessment Scale. Therapists commonly treated infants requiring ventilatory support, supported skin-to-skin care, facilitated breastfeeding transitions, and worked with extremely low birth weight, late preterm, and substance-exposed infants. Regarding care philosophy, 211 (62%) reported using the Supporting and Enhancing NICU Sensory Experiences (SENSE) program, 123 (36%) Trauma-Informed Care, 97 (28%) the Newborn Individualized Developmental Care and Assessment program (NIDCAP), 95 (28%) Neonatal Integrative Developmental Care Model, and 68 (20%) Family Integrated Care. Over the past 5 years, therapists described shifts toward evidence-based practice, stronger interdisciplinary collaboration, development of structured small-baby team approaches, and implementation of interventions such as the SENSE and Infant-Driven Feeding programs. There is greater integration of neonatal therapists to identify developmental risks and provide targeted interventions in the NICU. · Neonatal therapy is increasingly specialized, with more CNTs.. · There are rapid changes occurring in neonatal therapy practice.. · Neonatal therapists have increased use of standardized assessment and specialized programming.. · Multidisciplinary teams in the NICU are on the rise.. · Neonatal therapists report more evidence-based practice and involvement in research..
Metformin is the first-line treatment for type 2 diabetes mellitus in pediatric patients and it's prescriptions in children have increased for off-label indications. However, interindividual variability of metformin pharmacokinetics in children is not well studied. Metformin is a cation that requires multiple transporters for its absorption, distribution and elimination, including organic cation transporters (OCTs) and multidrug and toxin extrusion (MATE) transporters. We conducted a 12 h clinical pharmacokinetic study in 36 pediatric patients (age, 7-21 years) treated with metformin and analyzed the data using non-compartmental and population pharmacokinetic models to describe metformin pharmacokinetics and associated covariates. The association of OCT and MATE genetic variants on metformin absorption and elimination was investigated. The dose-normalized plasma exposure of metformin varied by 3.3-fold among children. Renal clearance was higher in children compared to the reported data in healthy adults or adults with diabetes. Total body weight (TBW) and estimated glomerular filtration rate (eGFR) significantly affected metformin oral clearance. OCT2 c.390 G > T (p.Thr130 = , rs624249) was associated with metformin oral clearance and secretary clearance, whereas OCT3 c.-29G > A (rs555754) and c.360 C > T (p.Arg120 = , rs668871) were significantly associated with the absorption rate constant and oral clearance. Metformin dosing in children can be optimized based on TBW, eGFR, and OCT2/3 genetic variants to improve its safety and efficacy. Metformin pharmacokinetics is highly variable, and limited data are available on the pediatric population. Total body weight and estimated glomerular filtration rate are associated with metformin oral clearance. OCT2/3 genetic variants can influence the elimination and absorption of metformin. Consideration of population factors associated with metformin pharmacokinetics in dose selection can improve its safety and efficacy.
There is a need for improved glycemia monitoring tools for people with type 2 diabetes (T2D) and end-stage kidney failure (ESKF). This prospective, randomized, crossover trial compared the efficacy of real-time continuous glucose monitoring (rtCGM) with capillary blood glucose (CBG) testing in adults with T2D and ESKF undergoing hemodialysis. The primary outcome was percentage of time below range (%TBR) <70 mg/dL. The %TBR <70 mg/dL was not significantly different between groups (mean 1.17% ± 1.8 vs. 1.29% ± 2.7; P = 0.28). Compared with CBG testing, percentage time in range (%TIR) was higher (63.4% ± 24 vs. 54.5% ± 23) and mean glucose lower (173.6 ± 37 vs. 187.7 ± 38 mg/dL) after the rtCGM intervention, while percentage time above range (%TAR) >180 mg/dL (35.3% ± 25 vs. 44.3% ± 23) and >250 mg/dL decreased (12.3% ± 15 vs. 18.8% ± 19) (all P ≤ 0.01). In adults with T2D and ESKF undergoing hemodialysis, TBR was minimal and not influenced by rtCGM use. Compared with CBG testing, %TIR and %TAR improved during the rtCGM intervention. Future studies are needed to confirm the benefits of rtCGM in this population.
Body mass index (BMI) fluctuation has adverse health consequences, yet its determinants remain poorly understood. We examined genetic and environmental influences on BMI fluctuation and its associations with BMI trajectories. Data from 14 longitudinal twin cohorts, including 58 311 individuals (54% women) and 22 714 complete twin pairs (9761 monozygotic), were pooled. BMI trajectories from ages 18 to 99 years were estimated using linear mixed-effects models. BMI fluctuation was defined as the average squared residual between observed and expected BMI around individual trajectories. Genetic and environmental contributions to BMI fluctuation and its associations with baseline BMI and BMI change were assessed using structural equation modelling. Additive genetic effects explained a moderate proportion of variance in BMI fluctuation (a2 = 0.20 in men, 0.29 in women), with the remainder attributable to unique environmental effects (e2 = 0.80 and 0.71). No evidence of sex-specific genetic effects was found. Genetic contributions varied across life stages, peaking in men at ages 31-50 (a2 = 0.36) and in women at 51-65 (a2 = 0.36). Higher baseline BMI was associated with greater fluctuation, whereas greater directional BMI change was associated with less fluctuation. Higher BMI at ages 18-30 was associated with greater subsequent BMI fluctuation across later adulthood stages. Previous associations were driven by both genetic and unique environmental factors. BMI fluctuation was predominantly explained by unique environmental effects, with moderate heritability that varied across life stages with no evidence of sex-specific genetic effects. Genetic and environmental factors contribute to how BMI fluctuation is associated with BMI change.
In recent decades, life expectancy among people with type 1 diabetes has improved substantially in many high-income countries and well resourced health-care settings, highlighting persistent global inequities in survival for people with type 1 diabetes living in low-income and middle-income countries. Simultaneously, the growing proportion of individuals living into older adulthood in some settings highlights the need to look beyond insulin and glucose to consider the global health systems and wider determinants of health that shape health and longevity in the setting of type 1 diabetes. The goal of this Review is to integrate the psychosocial, environmental, and societal challenges associated with ageing and type 1 diabetes including disease burden, health system and organisational responses, self-care, and caregiver support. Additionally, we identify key research gaps for the future, considering the life course of people with type 1 diabetes in the context of where they live.
As experts in communication, palliative care clinicians know to avoid not only well-recognized verbal pitfalls (such as describing a patient as "non-compliant" or a "poor historian") but also more subtle ones that colleagues in other specialties might still use (such as "withdrawing care"). Yet despite our training and experience, we, too, are prone to mis-speaking. This Special Report identifies some less obvious verbal missteps that can interfere with the provision of holistic, goal-concordant care. While they may initially seem innocuous, we have repeatedly witnessed the unintended detrimental effects on patients and families. Words, indeed, are a primary instrument in palliative care; we have the responsibility to wield them prudently.
Supervised deep learning (DL) receives great interest for automated analysis of microscopic images with an increasing body of literature supporting its potential. The development and testing of those DL models rely heavily on the availability of high-quality, large-scale data sets. However, creating such data sets is a complex and resource-intensive process, often hindered by challenges such as time constraints, domain variability, and risks of bias in image collection and label creation. This review provides a comprehensive guide to the critical steps in data set creation, including (1) image acquisition, (2) selection of annotation software, and (3) annotation creation. For image acquisition, besides ensuring a sufficiently large number, it is important to address sources of image variability (domain shifts), such as those related to slide preparation and digitization, that could lead to algorithmic errors if not adequately represented in the training data. For annotations, key quality criteria are the 3 "C"s: correctness, consistency, and completeness. For mitigation of annotation bias of a single annotator, this review explores advanced annotation methods (eg, computer-assisted annotations). To support data set creators, a standard operating procedure is provided as supplemental material, summarizing all important considerations for data set creation. Furthermore, this article underscores the importance of open data sets in driving innovation and enhancing reproducibility of DL research. By addressing the challenges and offering practical recommendations, this review aims to advance the creation and availability of high-quality, large-scale data sets, ultimately contributing to the development of generalizable and robust DL models for pathology applications.
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with an urgent need for reliable, noninvasive biomarkers that can serve as reasonably likely surrogate endpoints, as diagnosis remains limited by the invasiveness of liver biopsy and the inaccuracy of existing noninvasive tests. MASH disrupts hepatic and renal transporter expression and function, leading to increased systemic retention of drug substrates. Because ezetimibe-glucuronide (EZEG) is a substrate of transporters altered in MASH, we evaluated whether EZEG could serve as a noninvasive, mechanism-based exogenous diagnostic function test. Plasma and urine EZEG concentrations were quantified by liquid chromatography-tandem mass spectrometry in biopsy-confirmed patients with nonalcoholic fatty liver disease activity scores (NAS) of 0-5 after administration of a 1 mg subtherapeutic dose of ezetimibe. Patients with MASH (NAS = 5, n = 8) exhibited approximately 4.5-fold higher plasma EZEG concentrations than non-MASH individuals (NAS 0-4, n = 45), demonstrating excellent discrimination with an area under the receiver operating characteristic curve of 0.92 (95% CI, 0.79-1.00) using the 60-minute postdose concentration. Plasma EZEG was strongly associated with hepatocyte ballooning, the U.S. Food and Drug Administration-defining and most difficult-to-detect histologic feature of MASH, supporting mechanistic specificity. In contrast, urinary EZEG excretion showed only modest increases and poor diagnostic discrimination. These findings indicate that MASH-associated transporter dysfunction leads to systemic EZEG accumulation, supporting its use as a mechanism-based diagnostic function test and a promising noninvasive strategy for early detection and disease stratification. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatohepatitis (MASH) lacks reliable noninvasive tests for diagnosis and therapeutic development. This study demonstrates that plasma ezetimibe-glucuronide, measured after a subtherapeutic ezetimibe dose, sensitively detects MASH-associated transporter dysfunction and strongly correlates with hepatocyte ballooning, the defining histologic feature of MASH. This mechanism-based probe-drug approach provides a highly discriminative, noninvasive strategy to support early disease detection and patient stratification.
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Creating and sustaining healthy academic work environments is an ethical and professional imperative for all nursing programs. Using the Pathway for Fostering Organizational Civility as a theoretical framework, this article shares pre- and postassessment results from one nursing program's positive cultural transformation. The Healthy Work Environment Inventory was used to measure perceptions of the workplace culture, resulting in marked improvements in mission alignment, teamwork, psychological safety, communication, and trust. Critical strategies for fostering and sustaining a healthy academic work environment included leadership support, culture assessment, team formation, implementing a data-driven action plan, policy development, and celebrating successes.
Rhodoquinone (RQ) is a crucial electron carrier involved in anaerobic metabolism across select bacteria, protists, and animal species. Its biosynthesis is catalyzed by the rhodoquinone biosynthesis enzyme (RquA), a methyltransferase-like enzyme that uses S-adenosyl-L-methionine to transfer an amino group, converting ubiquinone (UQ) into RQ. The activity of RquA in vitro is enhanced by the presence of divalent metal cations. To probe the metal dependence of RquA, we characterized its interactions with Mn(II), Co(II), and Zn(II). We found that these metal cations bind to RquA with a 1:1 stoichiometry and that Mn(II) and Co(II) exhibited sub-micromolar binding affinities to RquA. Using Mn(II) as a spectroscopic probe, continuous‑wave electron paramagnetic resonance (EPR) revealed a single Mn(II) species with zero‑field splitting parameters |D| = 540(30) MHz and E/D = 0.30(3). Pulse EPR experiments on natural‑abundance and 15N‑labeled samples further identified a weakly‑to‑moderately coupled nitrogen ligand, with an isotropic hyperfine coupling constant |aiso(15N)| = 2.7(1) MHz. Integrating these data with an AlphaFold3‑derived structural model, we propose a putative binding site for the catalytically required divalent metal cation, providing new insight into the structural basis of RquA function.
To examine the effect of chronic alcohol exposure on the activity of CYP3A enzymes in human liver, we studied the metabolism of CYP3A-specific substrates 7-benzyloxyquinoline (7-BQ) and ivermectin in 23 preparations of human liver microsomes (HLM) obtained from donors with documented alcohol exposure, from non-drinkers to heavy alcoholics. All HLM samples were characterized for the composition of the cytochrome P450 pool by global proteomics. Our studies revealed a significant increase in the activities of CYP3A enzymes by alcohol exposure. This effect is not associated with CYP3A enzyme levels, which do not correlate with alcohol exposure. Instead, the rates of 7-BQ and ivermectin metabolism correlate with the content of alcohol-inducible CYP2E1. However, this enzyme does not metabolize ivermectin, and its activity with 7-BQ is negligible. A significant increase in the rate of ivermectin demethylation was also observed in CYP3A4-containing Supersomes® and pooled HLM upon incorporation of purified CYP2E1 into their membrane. These results suggest that the reported acceleration of the elimination of drugs metabolized by CYP3A enzymes by alcohol exposure is due to functional effects of the interaction between CYP3A and CYP2E1. To elucidate the potential mechanism of this effect, we studied the formation of CYP2E1-CYP3A4 complexes in CYP3A4-containing Supersomes with co-incorporated CYP2E1 using tag-transfer chemical crosslinking mass spectrometry (CX-MS). These experiments confirmed physical interactions between the proteins and allowed the identification of CYP3A4 residues at the sites of contact. This information was used to build structural models of the CYP2E1-CYP3A4 complex and to propose possible mechanisms for the observed effects.