A Stromal Niche Defined by Expression of the Transcription Factor WT1 Mediates Programming and Homeostasis of Cavity-Resident Macrophages.

Tissue-resident macrophages require specific milieus for the maintenance of defining gene-expression programs. Expression of the transcription factor GATA6 is required for the homeostasis, function and localization of peritoneal cavity-resident macrophages. Gata6 expression is maintained in a non-cell autonomous manner and is elicited by the vitamin A metabolite, retinoic acid. Here, we found that the GATA6 transcriptional program is a common feature of macrophages residing in all visceral body cavities. Retinoic acid-dependent and -independent hallmark genes of GATA6+ macrophages were induced by mesothelial and fibroblastic stromal cells that express the transcription factor Wilms' Tumor 1 (WT1), which drives the expression of two rate-limiting enzymes in retinol metabolism. Depletion of Wt1+ stromal cells reduced the frequency of GATA6+ macrophages in the peritoneal, pleural and pericardial cavities. Thus, Wt1+ mesothelial and fibroblastic stromal cells constitute essential niche components supporting the tissue-specifying transcriptional landscape and homeostasis of cavity-resident macrophages.

Array programming with NumPy.

Array programming provides a powerful, compact and expressive syntax for accessing, manipulating and operating on data in vectors, matrices and higher-dimensional arrays. NumPy is the primary array programming library for the Python language. It has an essential role in research analysis pipelines in fields as diverse as physics, chemistry, astronomy, geoscience, biology, psychology, materials science, engineering, finance and economics. For example, in astronomy, NumPy was an important part of the software stack used in the discovery of gravitational waves1 and in the first imaging of a black hole2. Here we review how a few fundamental array concepts lead to a simple and powerful programming paradigm for organizing, exploring and analysing scientific data. NumPy is the foundation upon which the scientific Python ecosystem is constructed. It is so pervasive that several projects, targeting audiences with specialized needs, have developed their own NumPy-like interfaces and array objects. Owing to its central position in the ecosystem, NumPy increasingly acts as an interoperability layer between such array computation libraries and, together with its application programming interface (API), provides a flexible framework to support the next decade of scientific and industrial analysis.

Adipose tissue is a critical regulator of osteoarthritis.

Osteoarthritis (OA), the leading cause of pain and disability worldwide, disproportionally affects individuals with obesity. The mechanisms by which obesity leads to the onset and progression of OA are unclear due to the complex interactions among the metabolic, biomechanical, and inflammatory factors that accompany increased adiposity. We used a murine preclinical model of lipodystrophy (LD) to examine the direct contribution of adipose tissue to OA. Knee joints of LD mice were protected from spontaneous or posttraumatic OA, on either a chow or high-fat diet, despite similar body weight and the presence of systemic inflammation. These findings indicate that adipose tissue itself plays a critical role in the pathophysiology of OA. Susceptibility to posttraumatic OA was reintroduced into LD mice using implantation of a small adipose tissue depot derived from wild-type animals or mouse embryonic fibroblasts that undergo spontaneous adipogenesis, implicating paracrine signaling from fat, rather than body weight, as a mediator of joint degeneration.

Energy-Efficient Neuromorphic Architectures for Nuclear Radiation Detection Applications.

A comprehensive analysis and simulation of two memristor-based neuromorphic architectures for nuclear radiation detection is presented. Both scalable architectures retrofit a locally competitive algorithm to solve overcomplete sparse approximation problems by harnessing memristor crossbar execution of vector-matrix multiplications. The proposed systems demonstrate excellent accuracy and throughput while consuming minimal energy for radionuclide detection. To ensure that the simulation results of our proposed hardware are realistic, the memristor parameters are chosen from our own fabricated memristor devices. Based on these results, we conclude that memristor-based computing is the preeminent technology for a radiation detection platform.

Author Correction: SciPy 1.0: fundamental algorithms for scientific computing in Python.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

SciPy 1.0: fundamental algorithms for scientific computing in Python.

SciPy is an open-source scientific computing library for the Python programming language. Since its initial release in 2001, SciPy has become a de facto standard for leveraging scientific algorithms in Python, with over 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repositories and millions of downloads per year. In this work, we provide an overview of the capabilities and development practices of SciPy 1.0 and highlight some recent technical developments.

Leptin mediates the regulation of muscle mass and strength by adipose tissue.

Adipose tissue secretes numerous cytokines (termed 'adipokines') that have known or hypothesized actions on skeletal muscle. The majority of adipokines have been implicated in the pathological link between excess adipose and muscle insulin resistance, but approximately half also have documented in vitro effects on myogenesis and/or hypertrophy. This complexity suggests a potential dual role for adipokines in the regulation of muscle mass in homeostasis and the development of pathology. In this study, we used lipodystrophic 'fat-free' mice to demonstrate that adipose tissue is indeed necessary for the development of normal muscle mass and strength. Fat-free mice had significantly reduced mass (∼15%) and peak contractile tension (∼20%) of fast-twitch muscles, a slowing of contractile dynamics and decreased cross-sectional area of fast twitch fibres compared to wild-type littermates. These deficits in mass and contractile tension were fully rescued by reconstitution of ∼10% of normal adipose mass, indicating that this phenotype is the direct consequence of absent adipose. We then showed that the rescue is solely mediated by the adipokine leptin, as similar reconstitution of adipose from leptin-knockout mice fails to rescue mass or strength. Together, these data indicate that the development of muscle mass and strength in wild-type mice is dependent on adipose-secreted leptin. This finding extends our current understanding of the multiple roles of adipokines in physiology as well as disease pathophysiology to include a critical role for the adipokine leptin in muscle homeostasis. KEY POINTS: Adipose-derived cytokines (adipokines) have long been implicated in the pathogenesis of insulin resistance in obesity but likely have other under-appreciated roles in muscle physiology. Here we use a fat-free mouse to show that adipose tissue is necessary for the normal development of muscle mass and strength. Through add-back of genetically modified adipose tissue we show that leptin is the key adipokine mediating this regulation. This expands our understanding of leptin's role in adipose-muscle signalling to include development and homeostasis and adds the surprising finding that leptin is the sole mediator of the maintenance of muscle mass and strength by adipose tissue.

Congenital lipodystrophy induces severe osteosclerosis.

Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated "fat-free" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals. FF mice, like Berardinelli-Seip patients, are diabetic but normalization of glucose tolerance and significant reduction in circulating insulin fails to alter their skeletal phenotype. Importantly, the skeletal phenotype of FF mice is completely rescued by transplantation of adipocyte precursors or white or brown fat depots, indicating that adipocyte derived products regulate bone mass. Confirming such is the case, transplantation of fat derived from adiponectin and leptin double knockout mice, unlike that obtained from their WT counterparts, fails to normalize FF bone. These observations suggest a paucity of leptin and adiponectin may contribute to the increased bone mass of Berardinelli-Seip patients.

Epithelial-adipocyte interactions are required for mammary gland development, but not for milk production or fertility.

To investigate the role of adipose tissue in reproductive function and mammary gland development and function, we have examined lipodystrophic (LD) mice. LD mice of both sexes are sterile, but fertility can be restored with leptin injections. Mammary glands from lipodystrophic mice were rudimentary and lacked terminal end buds. Leptin-injected LD mice were able to become pregnant, showed normal pregnancy-associated glandular proliferation despite a smaller glandular area, were able to produce a small amount of milk that had grossly normal content of milk proteins and neutral lipids, but could not sustain pups to weaning. In order to separate the individual requirements for 1) adipokines such as leptin, 2) estradiol, and 3) physical epithelial-adipocyte interactions, we performed a series of experiments with both lipodystrophic mice and ob (obese mice with a mutation in the lep gene encoding the adipokine leptin) mice that received either estradiol treatment or preadipocyte transplant. The resulting fat pad did not rescue the defect in mammary gland development in lipodystrophic mice. The defect also could not be rescued with estradiol pellets. Ob/ob mice, like LD mice, lack leptin and estradiol, but retain adipose tissue. Ob mice have defective mammary gland development. However, in striking contrast to what was observed in lipodystrophic mice, reconstitution of a WT fat pad in ob mice rescued the defect in mammary gland development. Estradiol treatment did not rescue mammary gland development in ob mice. Therefore direct interaction between mammary gland epithelia and adipocytes is a requirement for full invasion and expansion of the gland, but is not required for glandular proliferation during pregnancy and milk production.

Computed Tomography for Pediatric Pelvic Fractures in Pediatric Versus Adult Trauma Centers.

BACKGROUND: Pediatric pelvic fractures are a significant source of morbidity for children in the United States. In the era of specialized care, the relationship between trauma center designation and outcomes remains unknown. We hypothesized that there would be no difference in patient outcomes when treated at adult trauma centers (ATCs), pediatric trauma centers (PTCs), or dual trauma centers (DTCs). MATERIALS AND METHODS: We used the National Trauma Data Bank to identify pediatric (≤14 y) patients suffering pelvic fractures in 2013-2015. DTCs were defined as centers with level I or II trauma designation for both pediatric and adult care. Primary outcomes included mortality, complications, and computed tomography (CT) utilization. RESULTS: There were 4260 patients who met study criteria. Of these, 1290 (22%) were treated at ATCs, 1332 (30%) at PTCs, and 2120 (48%) at DTCs. Pediatric patients treated at ATCs were more likely to suffer a complication or receive a CT scan. On multivariate analysis, patients treated at PTCs and DTCs were significantly less likely to have a recorded complication or receive head, thoracic, or whole-body CT scans compared with ATCs. DTCs, but not PTCs, used fewer abdominal CT scans. Mortality rates were not predicted by center designation. CONCLUSIONS: For pediatric pelvic fractures, centers with pediatric trauma designation (PTCs and DTCs) appear to have better outcomes despite significantly less use of CT scans. Further studies are needed to determine optimal management of pediatric pelvic fractures while minimizing exposure to ionizing radiation. LEVEL OF EVIDENCE: Level III Retrospective.

Infiltration of intramuscular adipose tissue impairs skeletal muscle contraction.

KEY POINTS: Muscle infiltration with adipose tissue (IMAT) is common and associated with loss of skeletal muscle strength and physical function across a diverse set of pathologies. Whether the association between IMAT and muscle weakness is causative or simply correlative remains an open question that needs to be addressed to effectively guide muscle strengthening interventions in people with increased IMAT. In the present studies, we demonstrate that IMAT deposition causes decreased muscle strength using mouse models. These findings indicate IMAT is a novel therapeutic target for muscle dysfunction. ABSTRACT: Intramuscular adipose tissue (IMAT) is associated with deficits in strength and physical function across a wide array of conditions, from injury to ageing to metabolic disease. Due to the diverse aetiologies of the primary disorders involving IMAT and the strength of the associations, it has long been proposed that IMAT directly contributes to this muscle dysfunction. However, infiltration of IMAT and reduced strength could both be driven by muscle disuse, injury and systemic disease, making IMAT simply an 'innocent bystander.' Here, we utilize novel mouse models to evaluate the direct effect of IMAT on muscle contraction. First, we utilize intramuscular glycerol injection in wild-type mice to evaluate IMAT in the absence of systemic disease. In this model we find that, in isolation from the neuromuscular and circulatory systems, there remains a muscle-intrinsic association between increased IMAT volume and decreased contractile tension (r2  > 0.5, P < 0.01) that cannot be explained by reduction in contractile material. Second, we utilize a lipodystrophic mouse model which cannot generate adipocytes to 'rescue' the deficits. We demonstrate that without IMAT infiltration, glycerol treatment does not reduce contractile force (P > 0.8). Taken together, this indicates that IMAT is not an inert feature of muscle pathology but rather has a direct impact on muscle contraction. This finding suggests that novel strategies targeting IMAT may improve muscle strength and function in a number of populations.

The Association of Payer Status and Injury Patterns in Pediatric Bicycle Injuries.

BACKGROUND: Bicycle injuries continue to cause significant morbidity in the United States. How insurance status affects outcomes in children with bicycle injuries has not been defined. We hypothesized that payer status would not impact injury patterns or outcomes in pediatric bicycle-related accidents. METHODS: The National Trauma Data Bank was used to identify pediatric (≤18 y) patients involved in bicycle-related crashes admitted in year 2016. Patients with private insurance were compared with all others (uninsured, Medicaid, and Medicare). RESULTS: There were 5619 patients that met study criteria. Of these, 2500 (44%) had private insurance. Privately insured were older (12 y versus 11, P < 0.001), more likely to be white (77% versus 56%, P < 0.001), and more likely to wear a helmet (26% versus 9%, P < 0.001). On multivariate analysis, factors associated with traumatic brain injury included age (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.06-1.08; P < 0.001) and helmet use (OR, 0.64; 95% CI, 0.55-0.74; P < 0.001). Patients without private insurance were significantly less likely to wear a helmet (OR, 0.52; 95% CI, 0.44-0.63; P < 0.001). Uninsured patients had significantly higher odds of a fatal injury (OR, 4.43; 95% CI, 1.52-12.92; P = 0.006). CONCLUSIONS: Uninsured children that present to a trauma center after a bicycle accident are more likely to die. Although helmet use reduced the odds of traumatic brain injury, minorities and children without private insurance were less likely to be helmeted. Public health interventions should increase helmet access to children without private insurance, especially uninsured children.

Did the Affordable Care Act Reach Penetrating Trauma Patients?

BACKGROUND: The benefits of the Affordable Care Act (ACA) for trauma patients have been well established. However, the ACA's impact on penetrating trauma patients (PTPs), a population that is historically young and uninsured, has not been defined. We hypothesized that PTPs in the post-ACA era would have better outcomes. MATERIAL AND METHODS: The National Trauma Data Bank (NTDB) was queried for all PTPs from 2009 (pre-ACA) and 2011-2014 (post-ACA). Subset analysis was performed in patients aged 19-25 y, as this group was eligible for the ACA's dependent care provision (DCP). RESULTS: There were 9,714,471 patients in the study, with 2,053,501 (21.1%) pre-ACA and 7,660,970 (78.9%) post-ACA. When compared to pre-ACA, patients in the post-ACA cohort were more likely to have commercial/private insurance, less likely to have Medicaid, and more likely to be uninsured. On logistic regression, the pre-ACA era was associated with mortality (HR: 1.02, 95% CI: 1.01-1.04, P = 0.004). Being uninsured was associated with mortality (HR: 1.89, 95% CI: 1.87-1.92, P < 0.001). On subset analysis of the DCP age group, post-ACA patients were more likely to be uninsured (24.1% versus 17.6%; P < 0.001). In addition, for the DCP age group, pre-ACA era was not associated with mortality (HR: 1.03, 95% CI: 0.99-1.06, P = 0.20). CONCLUSIONS: Although the ACA provided a survival benefit to PTPs overall, it did not increase insurance coverage for this population. In addition, the DCP of the ACA did not improve insurance access for PTP in the eligible age group. Further efforts are needed to extend insurance access to this population.

Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy.

Factor D (FD) is an essential component of the complement alternative pathway (AP). It is an attractive pharmaceutical target because it is an AP-specific protease circulating in blood. Most components of the complement activation pathways are produced by the liver, but FD is highly expressed by adipose tissue. Two critical questions are: 1) to what degree does adipose tissue contribute to circulating FD levels and 2) what quantity of FD is sufficient to maintain a functional AP? To address these issues, we studied a novel mouse strain with complete lipodystrophy (LD), the fld mouse with partial LD, an FD-deficient mouse, and samples from lipodystrophic patients. FD was undetectable in the serum of LD mice, which also showed minimal AP function. Reconstitution with purified FD, serum mixing experiments, and studies of partial LD mice all demonstrated that a low level of serum FD is sufficient for normal AP activity in the mouse system. This conclusion was further supported by experiments in which wild-type adipose precursors were transplanted into LD mice. Our results indicate that almost all FD in mouse serum is derived from adipose tissue. In contrast, FD levels were reduced ∼50% in the sera of patients with congenital generalized LD. Our studies further demonstrate that a relatively small amount of serum FD is sufficient to facilitate significant time-dependent AP activity in humans and in mice. Furthermore, this observation highlights the potential importance of obtaining nearly complete inhibition of FD in treating alternative complement activation in various autoimmune and inflammatory human diseases.

Multicenter Validation of the Revised Assessment of Bleeding and Transfusion (RABT) Score for Predicting Massive Transfusion.

BACKGROUND: Massive transfusion (MT) is a lifesaving treatment for hemorrhaging patients. Predicting the need for MT is crucial to improve survival. The aim of our study was to validate the Revised Assessment of Bleeding and Transfusion (RABT) score to predict MT in a multicenter cohort of trauma patients. METHODS: We performed a (2015-2017) analysis of adult (age ≥ 18 year) trauma patients who had a high-level trauma team activation at three Level I trauma centers. The RABT was calculated using the 4-point score [blunt (0)/penetrating trauma (1), shock index ≥ 1 (1), pelvic fracture (1), and FAST positive (1)]. A RABT score of ≥ 2 was used to predict MT (≥ 10 units of packed red blood cells within 24 h). The area under the receiver operating characteristic curve (AUROC) was calculated to assess the score's predictive power compared to the Assessment of Blood Consumption (ABC) score. RESULTS: We analyzed 1018 patients: 216 (facility I), 363 (facility II), and 439 (facility III). The mean age was 41 ± 19 year, and the injury severity score (ISS) was 29 [22-36]. The overall MT rate was 19%. The overall AUROC of RABT ≥ 2 was 0.89. The sensitivity of the RABT ≥ 2 was 78%, and the specificity was 91%. The RABT score had a higher sensitivity (78% vs. 69%) and specificity (91% vs. 82%) than the ABC score. CONCLUSION: The RABT score is a valid tool to predict MT in severely injured trauma patients. It is an objective score that aids clinicians in predicting the need for MT to mobilize blood products and minimize the waste of resources.

Terahertz Detection with Perfectly-Absorbing Photoconductive Metasurface.

Terahertz (THz) photoconductive devices are used for generation, detection, and modulation of THz waves, and they rely on the ability to switch electrical conductivity on a subpicosecond time scale using optical pulses. However, fast and efficient conductivity switching with high contrast has been a challenge, because the majority of photoexcited charge carriers in the switch do not contribute to the photocurrent due to fast recombination. Here, we improve efficiency of electrical conductivity switching using a network of electrically connected nanoscale GaAs resonators, which form a perfectly absorbing photoconductive metasurface. We achieve perfect absorption without incorporating metallic elements, by breaking the symmetry of cubic Mie resonators. As a result, the metasurface can be switched between conductive and resistive states with extremely high contrast using an unprecedentedly low level of optical excitation. We integrate this metasurface with a THz antenna to produce an efficient photoconductive THz detector. The perfectly absorbing photoconductive metasurface opens paths for developing a wide range of efficient optoelectronic devices, where required optical and electronic properties are achieved through nanostructuring the resonator network.

Cost Burden and Mortality in Rural Emergency General Surgery Transfer Patients.

BACKGROUND: Recent articles have suggested regionalization of some emergency general surgery (EGS) problems to tertiary referral centers. We sought to characterize the clinical and cost burden of such transfers to our tertiary referral center. MATERIALS AND METHODS: Data were collected retrospectively for nine EGS diagnoses for patients admitted to the EGS service during calendar years 2015 and 2016. Patients were grouped as inpatient transfers (IPTs), Emergency Department transfers (EDTs), or local admissions (LAs). Demographic data, length of stay at originating site, insurance status, Charlson Comorbidity Index, and all relevant financial data were obtained. RESULTS: Six hundred sixty-three patients were reviewed: 93 IPTs, 343 EDTs, and 227 LAs. IPTs required longer lengths of stay (7.0 d compared to 4.0 d for EDTs and 3.0 d for LAs), higher median direct costs, and higher case mix index, which produced a higher median revenue but averaged a median net loss (-$264 compared to +$2436 for EDTs and +$3125 for LAs). The IPTs had higher median comorbidities (Charlson Comorbidity Index 3.5 versus 2.9 for EDTs and 2.0 for LAs), age (62 y versus 58 for EDTs and 52 for LAs), and mortality rate (7.5% versus 2.3% for EDTs and 0.4% for LAs). CONCLUSIONS: Patients who present to a tertiary care EGS service as an IPT from another hospital have more comorbidities, higher mortality rate, and result in a financial loss. These data suggest the need for adequate risk adjustment in quality assessment of tertiary referral center outcomes and the need for increased financial reimbursement for the care of these patients.

Spectroscopic elucidation of energy transfer in hybrid inorganic-biological organisms for solar-to-chemical production.

The rise of inorganic-biological hybrid organisms for solar-to-chemical production has spurred mechanistic investigations into the dynamics of the biotic-abiotic interface to drive the development of next-generation systems. The model system, Moorella thermoacetica-cadmium sulfide (CdS), combines an inorganic semiconductor nanoparticle light harvester with an acetogenic bacterium to drive the photosynthetic reduction of CO2 to acetic acid with high efficiency. In this work, we report insights into this unique electrotrophic behavior and propose a charge-transfer mechanism from CdS to M. thermoacetica Transient absorption (TA) spectroscopy revealed that photoexcited electron transfer rates increase with increasing hydrogenase (H2ase) enzyme activity. On the same time scale as the TA spectroscopy, time-resolved infrared (TRIR) spectroscopy showed spectral changes in the 1,700-1,900-cm-1 spectral region. The quantum efficiency of this system for photosynthetic acetic acid generation also increased with increasing H2ase activity and shorter carrier lifetimes when averaged over the first 24 h of photosynthesis. However, within the initial 3 h of photosynthesis, the rate followed an opposite trend: The bacteria with the lowest H2ase activity photosynthesized acetic acid the fastest. These results suggest a two-pathway mechanism: a high quantum efficiency charge-transfer pathway to H2ase generating H2 as a molecular intermediate that dominates at long time scales (24 h), and a direct energy-transducing enzymatic pathway responsible for acetic acid production at short time scales (3 h). This work represents a promising platform to utilize conventional spectroscopic methodology to extract insights from more complex biotic-abiotic hybrid systems.

Use of Plasma-Based Trauma Transfusion Protocols at Level IV Trauma Centers.

Early initiation of a high ratio massive transfusion can lower trauma patient mortality by 80%. Long transport times from rural Level IV trauma centers therefore require that damage control resuscitation begin before patient transfer. This study evaluates the current use of fresh frozen plasma (FFP) at Level IV trauma centers and the feasibility of implementing trauma transfusion protocols at these centers. Demographic and clinical data were collected for trauma patients at all state Level IV trauma centers who would have met criteria for massive transfusion protocol (MTP) activation based on the Assessment of Blood Consumption (ABC) score. All state Level IV trauma centers were also surveyed to determine availability of blood bank plasma resources. A total of 760 adult trauma patients presented to a Level IV trauma center during the study period. Three hundred sixty-eight patients (48.4%) were transferred to a higher level of care. Because FAST (Focused Assessment with Sonography for Trauma) results were not available in the state registry data, we included all blunt trauma patients with an ABC score of 1 as "potential ABC-positive patients." Forty-two (5.5%) patients were potentially ABC positive. Fifteen of 22 Level IV centers responded to our survey. Seventy-three percent of respondents have FFP available. Mean time to FFP availability was 63.1 min. Median total length of stay from registration to emergency department discharge for potentially ABC-positive patients was 2 hr. Because most Level IV trauma centers have FFP and thaw times are such that administration would not delay transport to a higher level of care, we recommend implementation of MTPs at Level IV trauma centers to reduce hemorrhage-associated mortality.

SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.

Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.