A narrative review of norovirus epidemiology, biology, and challenges to vaccine development.

Norovirus is a leading cause of acute gastroenteritis (AGE) globally. AGE resulting from norovirus causes significant morbidity and mortality in countries of all income levels, particularly among young children and older adults. Prevention of norovirus AGE represents a unique challenge as the virus is genetically diverse with multiple genogroups and genotypes cocirculating globally and causing disease in humans. Variants of the GII.4 genotype are typically the most common genotype, and other genotypes cause varying amounts of disease year-to-year, with GII.2, GII.3, and GII.6 most prevalent in recent years. Noroviruses are primarily transmitted via the fecal-oral route and only a very small number of virions are required for infection, which makes outbreaks of norovirus extremely difficult to control when they occur. Settings like long-term care facilities, daycares, and hospitals are at high risk of outbreaks and can have very high attack rates resulting in substantial costs and disease burden. Severe cases of norovirus AGE are most common in vulnerable patient populations, such as infants, the elderly, and immunocompromised individuals, with available treatments limited to rehydration therapies and supportive care. To date, there are no FDA-approved norovirus vaccines; however, several candidates are currently in development. Given the substantial human and economic burden associated with norovirus AGE, a vaccine to prevent morbidity and mortality and protect vulnerable populations could have a significant impact on global public health.

Oncologic Staging Computed Tomography with IV Contrast Has Similar Efficacy to Dedicated Computed Tomography Angiography for Preoperative DIEP Flap Planning.

Background: Due to variations in perforator vasculature, deep inferior epigastric artery perforator (DIEP) flap preoperative imaging can minimize operative time required to locate the most suitable perforators. Dedicated computed tomography angiography (CTA) has been the gold standard; however, many patients have already undergone a staging computed tomography (CT) per oncologic workup. The benefits from CTA may also be realized with a staging CT or CT with IV contrast. Methods: Ten patients who underwent DIEP flap reconstruction with staging CT and CTA within 3 years of one another were included in this study. Reviewers evaluated axial views of both imaging modalities separately to identify each visible perforator in reference to the pubic symphysis from the xiphoid to the pubic symphysis. An intraclass correlation coefficient (ICC) was used to determine agreement in location of perforators between the two imaging studies. Statistical analysis was performed using an ICC and Wilcoxon signed rank-tests. Results: The identified perforators within the patient cohort had an excellent correlation between their location on CT and CTA based upon ICC. The mean number of perforators identified in the CT group was 15.3 (SD 4.9) and in the CTA group was 18.8 (SD 6.4), which was not statistically different (P = 0.247). Conclusions: CT has similar efficacy in identifying number of perforators and perforator location to dedicated CTA for preoperative planning in DIEP flaps. This has the potential for decreased patient contrast and ionizing radiation exposure as well as improved patient and healthcare resource utilization.

CD4 T Cell-Derived IL-21 Is Critical for Sustaining Plasmodium Infection-Induced Germinal Center Responses and Promoting the Selection of Memory B Cells with Recall Potential.

Development of Plasmodium-specific humoral immunity is critically dependent on CD4 Th cell responses and germinal center (GC) reactions during blood-stage Plasmodium infection. IL-21, a cytokine primarily produced by CD4 T cells, is an essential regulator of affinity maturation, isotype class-switching, B cell differentiation, and maintenance of GC reactions in response to many infection and immunization models. In models of experimental malaria, mice deficient in IL-21 or its receptor IL-21R fail to develop memory B cell populations and are not protected against secondary infection. However, whether sustained IL-21 signaling in ongoing GCs is required for maintaining GC magnitude, organization, and output is unclear. In this study, we report that CD4+ Th cells maintain IL-21 expression after resolution of primary Plasmodium yoelii infection. We generated an inducible knockout mouse model that enabled cell type-specific and timed deletion of IL-21 in peripheral, mature CD4 T cells. We found that persistence of IL-21 signaling in active GCs had no impact on the magnitude of GC reactions or their capacity to produce memory B cell populations. However, the memory B cells generated in the absence of IL-21 exhibited reduced recall function upon challenge. Our data support that IL-21 prevents premature cellular dissolution within the GC and promotes stringency of selective pressures during B cell fate determination required to produce high-quality Plasmodium-specific memory B cells. These data are additionally consistent with a temporal requirement for IL-21 in fine-tuning humoral immune memory responses during experimental malaria.

Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.

Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study questioned if the health benefits of an intermittent TRF (iTRF) schedule require ketone flux specifically in skeletal and cardiac muscles. Notably, we found that the ketolytic enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) is uniquely enriched in isolated mitochondria derived from heart and red/oxidative skeletal muscles, which also have high capacity for fatty acid oxidation (FAO). Using mice with BDH1 deficiency in striated muscles, we discover that this enzyme optimizes FAO efficiency and exercise tolerance during acute fasting. Additionally, iTRF leads to robust molecular remodeling of muscle tissues, and muscle BDH1 flux does indeed play an essential role in conferring the full adaptive benefits of this regimen, including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate. In sum, ketone flux enhances mitochondrial bioenergetics and supports iTRF-induced remodeling of skeletal muscle and heart.

Multi-Channel smFRET study reveals a Compact conformation of EF-G on the Ribosome.

While elongation factor G (EF-G) is crucial for ribosome translocation, the role of its GTP hydrolysis remains ambiguous. EF-G's indispensability is further exemplified by the phosphorylation of human eukaryotic elongation factor 2 (eEF2) at Thr56, which inhibits protein synthesis globally, but its exact mechanism is not clear. In this study, we developed a multi-channel single-molecule FRET (smFRET) microscopy methodology to examine the conformational changes of E. coli EF-G induced by mutations that closely aligned with eEF2's Thr56 residue. We utilized Alexa 488/594 double-labeled EF-G to catalyze the translocation of fMet-Phe-tRNAPhe-Cy3 inside Cy5-L27 labeled ribosomes, allowing us to probe both processes within the same complex. Our findings indicate that in the presence of either GTP or GDPCP, wild-type EF-G undergoes a conformational extension upon binding to the ribosome to promote normal translocation. On the other hand, T48E and T48V mutations did not affect GTP/GDP binding or GTP hydrolysis, but impeded Poly(Phe) synthesis and caused EF-G to adopt a unique compact conformation, which wasn't observed when the mutants interact solely with the sarcin/ricin loop. This study provides new insights into EF-G's adaptability and sheds light on the modification mechanism of human eEF2.

Trial of the Patient-Centered 2 × 24-Hour Predischarge Opioid Consumption Opioid Prescribing Guideline.

This diagnostic/prognostic study evaluates the 2 × 24-hour predischarge opioid consumption guideline for opioid prescribing.

Computationally directed manipulation of cross-linked covalent organic frameworks for membrane applications.

Two-dimensional covalent organic frameworks (2D-COFs) exhibit characteristics ideal for membrane applications, such as high stability, tunability and porosity along with well-ordered nanopores. However, one of the many challenges with fabricating these materials into membranes is that membrane wetting can result in layer swelling. This allows molecules that would be excluded based on pore size to flow around the layers of the COF, resulting in reduced separation. Cross-linking between these layers inhibits swelling to improve the selectivity of these membranes. In this work, computational models were generated for a quinoxaline-based COF cross-linked with oxalyl chloride (OC) and hexafluoroglutaryl chloride (HFG). Enthalpy of formation and cohesive energy calculations from these models show that formation of these COFs is thermodynamically favorable and the resulting materials are stable. The cross-linked COF with HFG was synthesized and characterized with Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis with differential scanning calorimetry (TGA-DSC), and water contact angles. Additionally, these frameworks were fabricated into membranes for permeance testing. The experimental data supports the presence of cross-linking and demonstrates that varying the amount of HFG used in the reaction does not change the amount of cross-linking present. Computational models indicate that varying the cross-linking concentration has a negligible effect on stability and less cross-linking still results in stable materials. This work sheds light on the nature of the cross-linking in these 2D-COFs and their application in membrane technologies.

Norovirus evolves as one or more distinct clonal populations in immunocompromised hosts.

Noroviruses are a major cause of acute gastroenteritis worldwide and can establish chronic infection in immunocompromised individuals. To investigate the mechanisms of norovirus evolution during chronic infection, we selected seven representative patients from a National Institutes of Health study cohort who sustained norovirus infection for periods ranging from 73 to 1,492 days. Six patients shed viruses belonging to a single genotype (GII.2[PNA], GII.4 New Orleans[P4], GII.4 Den Haag[P4], GII.3[P21], GII.6[P7], or GII.14[P7]) over the period examined, while one patient sequentially shed two genotypes (GII.6[P7] followed by GII.4 Sydney[P31]). Norovirus genomes from consecutive stool samples were sequenced at high resolution (>3,300 reads/nucleotide position) using the Illumina platform and subjected to bioinformatics analysis. Norovirus sequences could be resolved into one or more discrete clonal RNA genomes that persisted within these patients over time. Phylogenetic analyses inferred that clonal populations originated from a single founder virus and not by reinfection with community strains. Estimated evolutionary rates of clonal populations during persistent infection were similar to those of noroviruses from acute infection in the global database, suggesting that inherently higher RNA-dependent polymerase error rates were not associated with the ability to persist. The high-resolution analysis of norovirus diversity and evolution at the population level described here should allow a better understanding of adaptive mutations sustained during chronic infection. IMPORTANCE Noroviruses are an important cause of chronic diarrhea in patients with compromised immune systems. Presently, there are no effective therapies to clear the virus, which can persist for years in the intestinal tract. The goal of our study was to develop a better understanding of the norovirus strains that are associated with these long-term infections. With the remarkable diversity of norovirus strains detected in the immunocompromised patient cohort we studied, it appears that most, if not all, noroviruses circulating in nature may have the capacity to establish a chronic infection when a person is unable to mount an effective immune response. Our work is the most comprehensive genetic data set generated to date in which near full-length genomes from noroviruses associated with chronic infection were analyzed by high-resolution next-generation sequencing. Analysis of this data set led to our discovery that certain patients in our cohort were shedding noroviruses that could be subdivided into distinct haplotypes or populations of viruses that were co-evolving independently. The ability to track haplotypes of noroviruses during chronic infection will allow us to fine-tune our understanding of how the virus adapts and maintains itself in the human host, and how selective pressures such as antiviral drugs can affect these distinct populations.

An analysis of the impact of annual cancer genetic testing guideline updates on a past patient population.

Germline genetic testing for cancer predisposition genes has become an essential component of cancer treatment and risk reduction. The National Comprehensive Cancer Network (NCCN) releases annual genetic testing guidelines that identify characteristics of patients that could be affected by a hereditary cancer syndrome. These guidelines have broadened over time and the implications for past patients of cancer genetics clinics are not well understood. This study is a retrospective chart review aimed at determining the percentage and characteristics of past patients that meet updated NCCN guidelines (Breast, Ovarian, and Pancreas [BOP] v1.2022 and Colorectal [CRC] v1.2021), patients that attended a follow-up appointment, and patients who went on to receive genetic testing. Clinical data and characteristics were compared between the study population as a whole and the cohort of patients that met updated NCCN guidelines BOP v1.2022 and CRC v1.2021. The study population consisted of 280 patients with 76 (27.1%) patients meeting updated NCCN guidelines BOP v1.2022 and CRC v1.2021. The year of initial cancer genetic counseling appointment was statistically significant (p = 0.023) with patients more likely to meet NCCN guidelines BOP v1.2022 and CRC v1.2021 with earlier initial cancer genetic counseling appointments. In the cohort that met updated NCCN guidelines BOP v1.2022 and CRC v1.2021, the most common reason was a change in the NCCN guidelines (BOP or CRC) (54/76, 71.1%) with triple-negative breast cancer diagnosed at any age being the most impactful guideline change (19/54, 35.2%). Twenty-one patients attended a follow-up appointment (7.5%) and of those that received genetic testing (17/21, 81%) most received negative results (13/17, 61.9%), with one pathogenic, low penetrance result (1/17, 5.9%, CHEK2 p.I157T). Provider-initiated follow-up was attributed to most follow-up appointments (16/21, 76.2%) implying patients do not tend to follow-up on their own. Education to non-genetics providers as well as targeted implementation of follow-up protocols possibly managed by genetic counseling assistants and utilizing electronic medical record (EMR) patient messaging could lead to improved patient follow-up.

Evaluating a health system-wide opioid disposal intervention distributing home-disposal bags.

OBJECTIVE: To evaluate a health system-wide intervention distributing free home-disposal bags to surgery patients prescribed opioids. DATA SOURCES AND STUDY SETTING: We collected patient surveys and electronic medical record data at an academic health system. STUDY DESIGN: We conducted a prospective observational study. The bags were primarily distributed at pharmacies, though pharmacists delivered bags to some patients. The primary outcome was disposal of leftover opioids (effectiveness). Secondary outcomes were patient willingness to dispose and factors associated with disposal (effectiveness), recalling receipt of the bag (reach), and recalling receipt of bags and disposal over time (maintenance). We used a modified Poisson regression to evaluate the relative risk of disposal. Inverse probability of treatment weighting, based on propensity scores, was used to account for differences between survey responders and non-responders and reduce nonresponse bias. DATA COLLECTION/EXTRACTION METHODS: From August 2020 to May 2021, we surveyed patients 2 weeks after discharge (allowing for home opioid use). Eligibility criteria were age ≥18, English being primary language, valid email address, hospitalization ≤30 days, discharge home, and an opioid prescription sent to a system pharmacy. PRINCIPAL FINDINGS: We identified 5134 patients with 2174 completing the survey (response rate 42.3%). Among respondents, 1375 (63.8%) recalled receiving the disposal bag. Among 1075 respondents with leftover opioids, 284 (26.4%) disposed, 552 (51.3%) planned to dispose, 79 (7.4%) did not plan to dispose, 69 (6.4%) had undecided, and 91 (8.5%) had not considered disposal. Recalling receipt of the bag (incidence rate ratio [IRR] 1.25, 95% confidence interval [CI] 1.13-1.37) was positively associated with disposal. Patients who used opioids in the last year were less likely to dispose (IRR 0.82, 95% CI 0.73-0.93). Disposal rates remained stable over the study period while recalling receipt of bags trended up. CONCLUSIONS: A pragmatic implementation of a disposal intervention resulted in lower disposal rates than prior trials.

Overstuffing the patellofemoral compartment in total knee arthroplasty: a systematic review.

Purpose: To systematically review and analyze the data available in the literature to evaluate the role of patellofemoral overstuffing in affecting clinical outcomes following primary total knee arthroplasty. Methods: A systematic literature review was conducted following the PRISMA guidelines. Only studies including primary total knee arthroplasty in the setting of osteoarthritis with a quantifiable method of measuring patellofemoral overstuffing using pre- and post-operative x-rays or advanced imaging, as well as reported subjective and/or objective patient outcomes in relation to patellofemoral overstuffing were included. Extracted data included patellofemoral overstuffing quantitative measurement method, outcome measurements, follow-up, patient demographics, author, and publication details. Descriptive analysis was provided for the available literature. Results: There were six included articles with a total of 2325 TKAs assessed. All papers found no significant effect on clinical outcomes when the amount of PFJ overstuffing was within reason. Conclusion: The amount of overstuffing that routinely takes place seems to be within tolerable limits and does not create a significant difference in clinical outcomes. Nevertheless, it is recommended to recreate the anatomic dimensions of the PFJ in order to best obtain a joint that is within this safe margin of error.

Improving pain management and safe opioid use after surgery: A DMAIC-based quality intervention.

Background: Multimodal perioperative patient education and expectation-setting can reduce post-operative opioid use while maintaining pain control and satisfaction. As part of a quality-improvement project, we developed a standardized model for perioperative education built upon the American College of Surgeons (ACS) Safe and Effective Pain Control After Surgery (SEPCAS) brochure to improve perioperative education regarding opioid use and pain control. Material and methods: Our study was designed within the Define, Measure, Analyze, Improve, Control (DMAIC) quality-improvement framework. Patients were surveyed about the adequacy of their perioperative education regarding pain control and use of prescription opioid medication. After gathering baseline data, a multimodal educational intervention based on the SEPCAS brochure was implemented. Survey responses were then compared between groups. Results: Twenty-seven subjects were included from the pre-intervention period, and thirty-nine were included from the post-intervention period (n = 66). Those in the post-intervention period were more likely to report receiving the appropriate amount of education regarding recognizing the signs of opioid overdose and how to safely store and dispose of opioid medications. The majority of patients who received the SEPCAS brochure reported that it was useful in their post-operative recovery and that it should be given to every patient undergoing surgery. Conclusions: The ACS SEPCAS brochure is an effective tool for improving patient preparation to safely store and dispose of their opioid medication and recognize the signs of opioid overdose. The brochure was also well received by patients and perceived as an effective educational material.

Weight loss increases skeletal muscle mitochondrial energy efficiency in obese mice.

Weight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight regain. Evidence suggests that this energetic mismatch originates from lean tissue. Although this phenomenon is well documented, the mechanisms have remained elusive. We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss. Wildtype (WT) male C57BL6/N mice were fed with high fat diet for 10 weeks, followed by a subset of mice that were maintained on the obesogenic diet (OB) or switched to standard chow to promote weight loss (WL) for additional 6 weeks. Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry. Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome. Weight loss promoted ~50% increase in the efficiency of oxidative phosphorylation (ATP produced per O2 consumed, or P/O) in skeletal muscle. However, weight loss did not appear to induce significant changes in mitochondrial proteome, nor any changes in respiratory supercomplex formation. Instead, it accelerated the remodeling of mitochondrial cardiolipin (CL) acyl-chains to increase tetralinoleoyl CL (TLCL) content, a species of lipids thought to be functionally critical for the respiratory enzymes. We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain. These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.

Unexpected Causes and Complications of ST-Segment Myocardial Infarction That Highlight the Importance and Limitations of Point-of-Care Ultrasound in the Emergency Department.

Point-of-care transthoracic echocardiography is a valuable tool for Emergency Physicians evaluating a patient in shock. We describe a case report of ST-segment myocardial infarction complicated by cardiogenic shock and acute severe mitral valve regurgitation that was immediately identified by the Emergency Physician. However, subsequent testing revealed an unexpected unifying diagnosis. The diagnostic sequence in this case highlights the benefits and limitations of point-of-care ultrasound in the Emergency Department and reinforces its role to address discrete clinically relevant questions.

Assessment of Bioenergetics in BAT Mitochondria.

High-resolution respirometry is commonly used to quantify mitochondrial respiratory rates. In the respirometry chamber, a change in oxygen concentration is measured by a polarographic electrode to derive the rate of oxygen consumption (JO2). Here, we describe our adapted protocol to bioenergetically phenotype mitochondria from mouse brown adipose tissue (BAT). Given the presence of uncoupling protein 1 (UCP1), mitochondria from BAT provide unique challenges and opportunities in applying high-resolution respirometry to understand energy transduction through oxidative phosphorylation (OXPHOS).

Pyruvate-supported flux through medium-chain ketothiolase promotes mitochondrial lipid tolerance in cardiac and skeletal muscles.

Even-chain acylcarnitine (AC) metabolites, most of which are generated as byproducts of incomplete fatty acid oxidation (FAO), are viewed as biomarkers of mitochondrial lipid stress attributable to one or more metabolic bottlenecks in the ß-oxidation pathway. The origins and functional implications of FAO bottlenecks remain poorly understood. Here, we combined a sophisticated mitochondrial phenotyping platform with state-of-the-art molecular profiling tools and multiple two-state mouse models of respiratory function to uncover a mechanism that connects AC accumulation to lipid intolerance, metabolic inflexibility, and respiratory inefficiency in skeletal muscle mitochondria. These studies also identified a short-chain carbon circuit at the C4 node of FAO wherein reverse flux of glucose-derived acetyl CoA through medium-chain ketothiolase enhances lipid tolerance and redox stability in heart mitochondria by regenerating free CoA and NAD+. The findings help to explain why diminished FAO capacity, AC accumulation, and metabolic inflexibility are tightly linked to poor health outcomes.

Lipid hydroperoxides promote sarcopenia through carbonyl stress.

Reactive oxygen species (ROS) accumulation is a cardinal feature of skeletal muscle atrophy. ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which downstream consequences of ROS are responsible for the loss of muscle mass and strength. Here, we show that lipid hydroperoxides (LOOH) are increased with age and disuse, and the accumulation of LOOH by deletion of glutathione peroxidase 4 (GPx4) is sufficient to augment muscle atrophy. LOOH promoted atrophy in a lysosomal-dependent, proteasomal-independent manner. In young and old mice, genetic and pharmacological neutralization of LOOH or their secondary reactive lipid aldehydes robustly prevented muscle atrophy and weakness, indicating that LOOH-derived carbonyl stress mediates age- and disuse-induced muscle dysfunction. Our findings provide novel insights for the role of LOOH in sarcopenia including a therapeutic implication by pharmacological suppression.

Surgical Trainee Perspectives on the Opioid Crisis: The Influence of Explicit and Hidden Curricula.

OBJECTIVE: In order to effectively create and implement an educational program to improve opioid prescribing practices, it is important to first consider the unique perspectives of residents on the frontlines of the opioid epidemic. We sought to better understand resident perspectives on opioid prescribing, current practices in pain management, and opioid education as a needs assessment for designing future educational interventions. DESIGN: This is a qualitative study using focus groups of surgical residents at 4 different institutions. SETTING: We conducted focus groups using a semistructured interview guide in person or over video conferencing. The residency programs selected for participation represent a broad geographic range and varying residency sizes. PARTICIPANTS: We used purposeful sampling to recruit general surgery residents from the University of Utah, University of Wisconsin, Dartmouth-Hitchcock Medical Center, and the University of Alabama at Birmingham. All general surgery residents at these locations were eligible for inclusion. Participants were assigned to focus groups by residency site and their status as junior (PGY-2, PGY-3) or senior resident (PGY-4, PGY-5). RESULTS: We completed 8 focus groups with a total of 35 residents included. We identified 4 main themes. First, residents relied on clinical and nonclinical factors when making decisions about opioid prescribing. However, hidden curricula based on unique institutional cultures and attending preferences heavily influenced residents' prescribing practices. Second, residents acknowledged that stigma and biases towards certain patient groups influenced opioid prescribing practices. Third, residents encountered barriers within their health systems to evidence-based opioid prescribing. Fourth, residents did not routinely receive formal education on pain management or opioid prescribing. Residents recommended several interventions to improve the current state of opioid prescribing, including standardized prescribing guidelines, improved patient education, and formal training during the first year of residency. CONCLUSIONS: Our study highlighted several areas of opioid prescribing that can be improved upon through educational interventions. These findings can be used to develop programs aimed at improving residents' opioid prescribing practices, both during and after training, and ultimately the safe care of surgical patients. ETHICS STATEMENT: This project was approved by the University of Utah Institutional Review Board, ID # 00118491. All participants provided written informed consent.

Mitochondrial phosphatidylethanolamine modulates UCP1 to promote brown adipose thermogenesis.

Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to ß3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PE-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.