A census of human soluble protein complexes.

Cellular processes often depend on stable physical associations between proteins. Despite recent progress, knowledge of the composition of human protein complexes remains limited. To close this gap, we applied an integrative global proteomic profiling approach, based on chromatographic separation of cultured human cell extracts into more than one thousand biochemical fractions that were subsequently analyzed by quantitative tandem mass spectrometry, to systematically identify a network of 13,993 high-confidence physical interactions among 3,006 stably associated soluble human proteins. Most of the 622 putative protein complexes we report are linked to core biological processes and encompass both candidate disease genes and unannotated proteins to inform on mechanism. Strikingly, whereas larger multiprotein assemblies tend to be more extensively annotated and evolutionarily conserved, human protein complexes with five or fewer subunits are far more likely to be functionally unannotated or restricted to vertebrates, suggesting more recent functional innovations.

The inheritance of social status: England, 1600 to 2022.

A lineage of 422,374 English people (1600 to 2022) contains correlations in social outcomes among relatives as distant as 4th cousins. These correlations show striking patterns. The first is the strong persistence of social status across family trees. Correlations decline by a factor of only 0.79 across each generation. Even fourth cousins, with a common ancestor only five generations earlier, show significant status correlations. The second remarkable feature is that the decline in correlation with genetic distance in the lineage is unchanged from 1600 to 2022. Vast social changes in England between 1600 and 2022 would have been expected to increase social mobility. Yet people in 2022 remain correlated in outcomes with their lineage relatives in exactly the same way as in preindustrial England. The third surprising feature is that the correlations parallel those of a simple model of additive genetic determination of status, with a genetic correlation in marriage of 0.57.

Treatment options for symptomatic knee osteoarthritis in adults.

ABSTRACT: Knee osteoarthritis is a common medical condition in adults, especially among older adults. The incidence and prevalence of knee osteoarthritis are increasing, and many healthcare providers manage patients with symptomatic presentations. This article reviews the most common nonsurgical and surgical treatment options for knee osteoarthritis, emphasizing evidence-based and practical therapies.

Predictors of neurosurgical intervention in complicated mild traumatic brain injury patients: a retrospective cohort study.

OBJECTIVES: To determine the predicting demographic, clinical and radiological factors for neurosurgical intervention in complicated mild traumatic brain injury (mTBI) patients. METHODS: Design: retrospective multicenter cohort study. Participants: patients aged ≥16 presenting to all level-I trauma centers in Quebec between 09/2016 and 12/2017 with mTBI(GCS 13-15) and complication on initial head CT (intracranial hemorrhage/skull fracture). Procedure: Consecutive medical records were reviewed and separated into two groups: no neurosurgical intervention and neurosurgical intervention (NSI). Main outcome: neurosurgical intervention. Analysis: multiple logistic regression model. RESULTS: Four hundred and seventy-eight patients were included and 40 underwent NSI. One patient had radiological deterioration but no clinical deterioration prior to surgery. Subdural hemorrhage ≥4 mm width (OR:3.755 [95% CI:1.290-10.928]) and midline shift (OR:7.507 [95% CI: 3.317-16.989]) increased the risk of NSI. Subarachnoid hemorrhage was associated with a lower risk of NSI (OR:0.312 [95% CI: 0.136-0.713]). All other intracranial hemorrhages were not associated with NSI. CONCLUSION: Radiological deterioration was not associated with the incidence of NSI. Subdural hemorrhage and midline shift should be predicting factors for neurosurgery. Some patients with isolated findings such as subarachnoid hemorrhage could be safely managed in their original center without being transferred to a level-I trauma center.

Do Mountain Bikers Know When They Have Had a Concussion and, Do They Know to Stop Riding?

OBJECTIVE: To establish the prevalence of concussions in mountain bikers and to determine factors that increase their risk of concussion. Secondary objectives include determination of whether mountain bikers have undiagnosed concussions, continue to ride after experiencing concussion symptoms, and if they knowingly ride with a broken helmet. DESIGN: Retrospective survey. SETTING: Seven-day mountain bike stage race. PARTICIPANTS: Two hundred nineteen mountain bikers. MAIN OUTCOME MEASURES: Number of rider concussions diagnosed, number of riders experiencing concussion symptoms without diagnosed concussions, number of riders who continue to ride after experiencing a concussion symptom, and number of riders who rode with a broken helmet. INDEPENDENT VARIABLES: The independent variables studied included age, gender, nationality, number of times riding in past year, style of riding (cross-country, downhill, or freeride), years mountain biking, years mountain bike racing, whether they are a sponsored cyclist, and whether they also ride a road bike. RESULTS: Fifteen of 219 mountain bikers (6.9%) had a diagnosed concussion after being hit in the head while mountain biking within the past year, with older riders having a decreased risk [odds ratio (OR), 0.91; P = 0.04], and sponsored riders having a 5-fold increased risk compared with nonsponsored riders (OR, 4.20; P = 0.05). Twenty-eight riders (12.8%) experienced a concussion symptom without being diagnosed with a concussion and 67.5% of the riders who experienced a concussion symptom continued to ride afterward. Overall, 29.2% of riders reported riding with a broken helmet. CONCLUSIONS: The yearly prevalence of diagnosed concussions in mountain bikers is 6.9%. More than one-third of mountain bikers do not recognize when they have had a concussion and continue riding after experiencing concussion symptoms or with a broken helmet. These behaviors increase their risk of worsening concussion symptoms and acquiring a second injury.

Discriminability of multiple cutaneous and proprioceptive hand percepts evoked by intraneural stimulation with Utah slanted electrode arrays in human amputees.

BACKGROUND: Electrical stimulation of residual afferent nerve fibers can evoke sensations from a missing limb after amputation, and bionic arms endowed with artificial sensory feedback have been shown to confer functional and psychological benefits. Here we explore the extent to which artificial sensations can be discriminated based on location, quality, and intensity. METHODS: We implanted Utah Slanted Electrode Arrays (USEAs) in the arm nerves of three transradial amputees and delivered electrical stimulation via different electrodes and frequencies to produce sensations on the missing hand with various locations, qualities, and intensities. Participants performed blind discrimination trials to discriminate among these artificial sensations. RESULTS: Participants successfully discriminated cutaneous and proprioceptive sensations ranging in location, quality and intensity. Performance was significantly greater than chance for all discrimination tasks, including discrimination among up to ten different cutaneous location-intensity combinations (15/30 successes, p < 0.0001) and seven different proprioceptive location-intensity combinations (21/40 successes, p < 0.0001). Variations in the site of stimulation within the nerve, via electrode selection, enabled discrimination among up to five locations and qualities (35/35 successes, p < 0.0001). Variations in the stimulation frequency enabled discrimination among four different intensities at the same location (13/20 successes, p < 0.0005). One participant also discriminated among individual stimulation of two different USEA electrodes, simultaneous stimulation on both electrodes, and interleaved stimulation on both electrodes (20/24 successes, p < 0.0001). CONCLUSION: Electrode location, stimulation frequency, and stimulation pattern can be modulated to evoke functionally discriminable sensations with a range of locations, qualities, and intensities. This rich source of artificial sensory feedback may enhance functional performance and embodiment of bionic arms endowed with a sense of touch.

Activities of daily living with bionic arm improved by combination training and latching filter in prosthesis control comparison.

BACKGROUND: Advanced prostheses can restore function and improve quality of life for individuals with amputations. Unfortunately, most commercial control strategies do not fully utilize the rich control information from residual nerves and musculature. Continuous decoders can provide more intuitive prosthesis control using multi-channel neural or electromyographic recordings. Three components influence continuous decoder performance: the data used to train the algorithm, the algorithm, and smoothing filters on the algorithm's output. Individual groups often focus on a single decoder, so very few studies compare different decoders using otherwise similar experimental conditions. METHODS: We completed a two-phase, head-to-head comparison of 12 continuous decoders using activities of daily living. In phase one, we compared two training types and a smoothing filter with three algorithms (modified Kalman filter, multi-layer perceptron, and convolutional neural network) in a clothespin relocation task. We compared training types that included only individual digit and wrist movements vs. combination movements (e.g., simultaneous grasp and wrist flexion). We also compared raw vs. nonlinearly smoothed algorithm outputs. In phase two, we compared the three algorithms in fragile egg, zipping, pouring, and folding tasks using the combination training and smoothing found beneficial in phase one. In both phases, we collected objective, performance-based (e.g., success rate), and subjective, user-focused (e.g., preference) measures. RESULTS: Phase one showed that combination training improved prosthesis control accuracy and speed, and that the nonlinear smoothing improved accuracy but generally reduced speed. Phase one importantly showed simultaneous movements were used in the task, and that the modified Kalman filter and multi-layer perceptron predicted more simultaneous movements than the convolutional neural network. In phase two, user-focused metrics favored the convolutional neural network and modified Kalman filter, whereas performance-based metrics were generally similar among all algorithms. CONCLUSIONS: These results confirm that state-of-the-art algorithms, whether linear or nonlinear in nature, functionally benefit from training on more complex data and from output smoothing. These studies will be used to select a decoder for a long-term take-home trial with implanted neuromyoelectric devices. Overall, clinical considerations may favor the mKF as it is similar in performance, faster to train, and computationally less expensive than neural networks.

[What knows a frail swiss population about chronic obstructive pulmonary disease?] / Que sait une population suisse fragilisée de la bronchopneumopathie chronique obstructive ?

COPD affects nearly 400 000 people in Switzerland. It remains under-diagnosed and patients know little about it. This survey study aimed to measure this knowledge in a population receiving home care in the canton of Neuchâtel. Knowledge of the terms « COPD ¼ and « emphysema ¼ was not related to gender, the fact that patients had already had spirometry or the COPD risk group to which they belonged. Patients treated with inhaled drugs, smokers and ex-smokers were more familiar with the term « COPD ¼. The treatment of people with COPD requires careful monitoring of those diagnosed with the disease, but also increased attention to the disease itself and its symptoms among patients, caregivers and physicians.

La bronchopneumopathie chronique obstructive (BPCO) atteint près de 400 000 personnes en Suisse. Elle reste sous-diagnostiquée et les patients la connaissent peu. Cette étude sous forme d'enquête visait à mesurer ces connaissances dans une population qui reçoit des soins à domicile dans le canton de Neuchâtel. La connaissance des termes « BPCO ¼ et « emphysème ¼ n'avait pas de relation avec le sexe, le fait que les patients aient déjà eu une spirométrie ou le groupe de risque de BPCO auquel ils appartenaient. Les patients traités par médicaments inhalés, les fumeurs et les ex-fumeurs étaient plus familiers avec le terme « BPCO ¼. Le traitement des personnes atteintes de BPCO passe par un suivi attentif de celles chez qui on a diagnostiqué la maladie, mais aussi par une attention accrue à la maladie elle-même et à ses symptômes chez les patients, les soignants et les médecins.

Seasonal Dynamics and Interannual Variability in Mercury Concentrations and Loads through a Three-Reservoir Complex.

The Hells Canyon Complex (HCC) along the Snake River (Idaho-Oregon border, U.S.A.) encompasses three successive reservoirs that seasonally stratify, creating anoxic conditions in the hypolimnion that promote methylmercury (MeHg) production. This study quantified seasonal dynamics and interannual variability in mercury concentrations (inorganic divalent mercury (IHg) and MeHg) and loads at four reservoir inflow and outflow locations through the HCC (2014-2017). We observed (1) that the HCC is a net sink for both IHg and MeHg, (2) interannual variability in IHg and MeHg loads largely reflecting streamflow conditions, and (3) seasonal variability in particulate IHg loading at the inflow (greatest from February to April) and MeHg export from the outflow (greatest from September to December) of the HCC. Seasonal export of MeHg was evidenced by increases in monthly mean concentrations of unfiltered MeHg (approximately 2-fold) and the percentage of total mercury (THg) as MeHg (≥4-fold) coincident with reservoir destratification. Despite evidence of seasonal export of MeHg from the HCC, annual loads indicate a 42% decrease in unfiltered MeHg from HCC inflow to outflow. Results from this study improve the understanding of seasonal variability in mercury transport through and transformation within a reservoir complex.

Twins Support the Absence of Parity-Dependent Fertility Control in Pretransition Populations.

A conclusion of the European Fertility Project in 1986 was that pretransition populations mostly displayed natural fertility, where parity-dependent birth control was absent. This conclusion has recently been challenged for England by new empirical results and has also been widely rejected by theorists of long-run economic growth, where pre-industrial fertility control is integral to most models. In this study, we use the accident of twin births to show that for three Western European-derived pre-industrial populations-namely, England (1730-1879), France (1670-1788), and Québec (1621-1835)-we find no evidence for parity-dependent control of marital fertility. If a twin was born in any of these populations, family size increased by 1 compared with families with a singleton birth at the same parity and mother age, with no reduction of subsequent fertility. Numbers of children surviving to age 14 also increased. Twin births also show no differential effect on fertility when they occurred at high parities; this finding is in contrast to populations where fertility is known to have been controlled by at least some families, such as in England, 1900-1949, where a twin birth increased average births per family by significantly less than 1.

Randomness in the Bedroom: There Is No Evidence for Fertility Control in Pre-Industrial England.

Overturning a generation of research, Cinnirella et al. Demography, 54, 413-436 (2017) found strong parity-dependent fertility control in pre-Industrial England 1540-1850. We show that their result is an unfortunate artifact of their statistical method, relying on mother fixed effects, which contradicts basic biological possibilities for fecundity. These impossible parity effects also appear with simulated fertility data that by design have no parity control. We conclude that estimating parity control using mother fixed effects is in no way feasible. We also show, using the Cambridge Group data that Cinnirella et al. used, that there is no sign of parity-dependent fertility control in English marriages before 1850.

Selective Decrease in Allodynia With High-Frequency Neuromodulation via High-Electrode-Count Intrafascicular Peripheral Nerve Interface After Brachial Plexus Injury.

OBJECTIVES: Kilohertz high-frequency alternating current (KHFAC) electrical nerve stimulation produces a reversible nerve block in peripheral nerves in human patients with chronic pain pathologies. Although this stimulation methodology has been verified with nonselective extrafascicular electrodes, the effectiveness of producing a selective nerve block with more-selective intrafascicular electrodes has not been well documented. The objective of this study was to examine whether intrafascicular electrodes can block painful stimuli while preserving conduction of other neural activity within the implanted nerve. MATERIALS AND METHODS: We analyzed the effects of various stimulation waveforms delivered through Utah Slanted Electrode Arrays (USEAs) implanted in the median nerve of a male human subject with a left brachial plexus injury. We compared KHFAC stimulation with a sham control. RESULTS: KHFAC stimulation through USEA electrodes produced a reduction in pain sensitivity in the palmar aspect of the left middle finger. KHFAC had limited effects on the patient's ability to feel tactile probing in the same area or move the digits of his left hand. Other tested stimulation parameters either increased or showed no reduction in pain. CONCLUSIONS: KHFAC stimulation in peripheral nerves through intrafascicular electrodes demonstrated a selective reduction in pain sensitivity while preserving other nerve functions. This treatment may benefit patient populations who have chronic pain originating from peripheral nerves, but who do not want to block whole-nerve function in order to preserve sensory and motor function reliant on the implanted nerve. Furthermore, KHFAC may benefit patients who respond negatively to other forms of peripheral nerve stimulation therapy.

Assessing Lift-Off Times for a Hospital-Based Helicopter Transport Program.

OBJECTIVE: Hospital-based helicopter transport programs must define and track their own lift-off times (LOTs). The goal of this quality improvement study was to evaluate LOTs, identify factors influencing LOTs, and implement changes to improve LOTs without compromising safety. METHODS: A retrospective evaluation of 248 flights during 2016 was completed using recorded times from our dispatch center. Actual LOTs were compared with policy LOT goals. Tasks for flight departure were identified, timed, and sorted into those that should not be pressured and those amenable to process change. RESULTS: Five tasks were identified as being amenable to process change. The average LOT for scene calls was 10.56 minutes (range, 1-22 minutes) and met our 10-minute policy goal 59% of the time. The average LOT for interfacility flights was 13.2 minutes (range, 4-76 minutes) and met the policy goal of 15 minutes 76.5% of the time. CONCLUSION: We identified tasks amenable to safe process change to decrease LOTs. The data supported LOT policy change to a single LOT goal of 13 minutes for all flights. This change represents an acceptable goal for all LOTs without compromising safety to our patients and teams.

Restoration of motor control and proprioceptive and cutaneous sensation in humans with prior upper-limb amputation via multiple Utah Slanted Electrode Arrays (USEAs) implanted in residual peripheral arm nerves.

BACKGROUND: Despite advances in sophisticated robotic hands, intuitive control of and sensory feedback from these prostheses has been limited to only 3-degrees-of-freedom (DOF) with 2 sensory percepts in closed-loop control. A Utah Slanted Electrode Array (USEA) has been used in the past to provide up to 81 sensory percepts for human amputees. Here, we report on the advanced capabilities of multiple USEAs implanted in the residual peripheral arm nerves of human amputees for restoring control of 5 DOF and sensation of up to 131 proprioceptive and cutaneous hand sensory percepts. We also demonstrate that USEA-restored sensory percepts provide a useful source of feedback during closed-loop virtual prosthetic hand control. METHODS: Two 100-channel USEAs were implanted for 4-5 weeks, one each in the median and ulnar arm nerves of two human subjects with prior long-duration upper-arm amputations. Intended finger and wrist positions were decoded from neuronal firing patterns via a modified Kalman filter, allowing subjects to control many movements of a virtual prosthetic hand. Additionally, USEA microstimulation was used to evoke numerous sensory percepts spanning the phantom hand. Closed-loop control was achieved by stimulating via an electrode of the ulnar-nerve USEA while recording and decoding movement via the median-nerve USEA. RESULTS: Subjects controlled up to 12 degrees-of-freedom during informal, 'freeform' online movement decode sessions, and experienced up to 131 USEA-evoked proprioceptive and cutaneous sensations spanning the phantom hand. Independent control was achieved for a 5-DOF real-time decode that included flexion/extension of the thumb, index, middle, and ring fingers, and the wrist. Proportional control was achieved for a 4-DOF real-time decode. One subject used a USEA-evoked hand sensation as feedback to complete a 1-DOF closed-loop virtual-hand movement task. There were no observed long-term functional deficits due to the USEA implants. CONCLUSIONS: Implantation of high-channel-count USEAs enables multi-degree-of-freedom control of virtual prosthetic hand movement and restoration of a rich selection of both proprioceptive and cutaneous sensory percepts spanning the hand during the short 4-5 week post-implant period. Future USEA use in longer-term implants and in closed-loop may enable restoration of many of the capabilities of an intact hand while contributing to a meaningful embodiment of the prosthesis.

Coevolution reveals a network of human proteins originating with multicellularity.

Protein interaction networks play central roles in biological systems, from simple metabolic pathways through complex programs permitting the development of organisms. Multicellularity could only have arisen from a careful orchestration of cellular and molecular roles and responsibilities, all properly controlled and regulated. Disease reflects a breakdown of this organismal homeostasis. To better understand the evolution of interactions whose dysfunction may be contributing factors to disease, we derived the human protein coevolution network using our MatrixMatchMaker algorithm and using the Orthologous MAtrix project (OMA) database as a source for protein orthologs from 103 eukaryotic genomes. We annotated the coevolution network using protein-protein interaction data, many functional data sources, and we explored the evolutionary rates and dates of emergence of the proteins in our data set. Strikingly, clustering based only on the topology of the coevolution network partitions it into two subnetworks, one generally representing ancient eukaryotic functions and the other functions more recently acquired during animal evolution. That latter subnetwork is enriched for proteins with roles in cell-cell communication, the control of cell division, and related multicellular functions. Further annotation using data from genetic disease databases and cancer genome sequences strongly implicates these proteins in both ciliopathies and cancer. The enrichment for such disease markers in the animal network suggests a functional link between these coevolving proteins. Genetic validation corroborates the recruitment of ancient cilia in the evolution of multicellularity.

How did the European Marriage Pattern persist? Social versus familial inheritance: England and Quebec, 1650-1850.

The European Marriage Pattern (EMP), in place in NW Europe for perhaps 500 years, substantially limited fertility. But how could such limitation persist when some individuals who deviated from the EMP norm had more children? If their children inherited their deviant behaviors, their descendants would quickly become the majority of later generations. This puzzle has two possible solutions. The first is that all those that deviated actually had lower net fertility over multiple generations. We show, however, no fertility penalty to future generations from higher initial fertility. Instead the EMP survived because even though the EMP persisted at the social level, children did not inherit their parents' individual fertility choices. In the paper we show evidence consistent with lateral, as opposed to vertical, transmission of EMP fertility behaviors.

Validity and Impact of Methods for Collecting Training Data for Myoelectric Prosthetic Control Algorithms.

Intuitive regression control of prostheses relies on training algorithms to correlate biological recordings to motor intent. The quality of the training dataset is critical to run-time regression performance, but accurately labeling intended hand kinematics after hand amputation is challenging. In this study, we quantified the accuracy and precision of labeling hand kinematics using two common training paradigms: 1) mimic training, where participants mimic predetermined motions of a prosthesis, and 2) mirror training, where participants mirror their contralateral intact hand during synchronized bilateral movements. We first explored this question in healthy non-amputee individuals where the ground-truth kinematics could be readily determined using motion capture. Kinematic data showed that mimic training fails to account for biomechanical coupling and temporal changes in hand posture. Additionally, mirror training exhibited significantly higher accuracy and precision in labeling hand kinematics. These findings suggest that the mirror training approach generates a more faithful, albeit more complex, dataset. Accordingly, mirror training resulted in significantly better offline regression performance when using a large amount of training data and a non-linear neural network. Next, we explored these different training paradigms online, with a cohort of unilateral transradial amputees actively controlling a prosthesis in real-time to complete a functional task. Overall, we found that mirror training resulted in significantly faster task completion speeds and similar subjective workload. These results demonstrate that mirror training can potentially provide more dexterous control through the utilization of task-specific, user-selected training data. Consequently, these findings serve as a valuable guide for the next generation of myoelectric and neuroprostheses leveraging machine learning to provide more dexterous and intuitive control.

Intrafascicular stimulation of monkey arm nerves evokes coordinated grasp and sensory responses.

High-count microelectrode arrays implanted in peripheral nerves could restore motor function after spinal cord injury or sensory function after limb loss. In this study, we implanted Utah Slanted Electrode Arrays (USEAs) intrafascicularly at the elbow or shoulder in arm nerves of rhesus monkeys (n = 4) under isoflurane anesthesia. Input-output curves indicated that pulse-width-modulated single-electrode stimulation in each arm nerve could recruit single muscles with little or no recruitment of other muscles. Stimulus trains evoked specific, natural, hand movements, which could be combined via multielectrode stimulation to elicit coordinated power or pinch grasp. Stimulation also elicited short-latency evoked potentials (EPs) in primary somatosensory cortex, which might be used to provide sensory feedback from a prosthetic limb. These results demonstrate a high-resolution, high-channel-count interface to the peripheral nervous system for restoring hand function after neural injury or disruption or for examining nerve structure.

RNA-seq analysis identifies potential modulators of gravity response in spores of Ceratopteris (Parkeriaceae): evidence for modulation by calcium pumps and apyrase activity.

PREMISE OF THE STUDY: Gravity regulates the magnitude and direction of a trans-cell calcium current in germinating spores of Ceratopteris richardii. Blocking this current with nifedipine blocks the spore's downward polarity alignment, a polarization that is fixed by gravity ∼10 h after light induces the spores to germinate. RNA-seq analysis at 10 h was used to identify genes potentially important for the gravity response. The data set will be valuable for other developmental and phylogenetic studies. METHODS: De novo Newbler assembly of 958 527 reads from Roche 454 sequencing was executed. The sequences were identified and analyzed using in silico methods. The roles of endomembrane Ca(2+)-ATPase pumps and apyrases in the gravity response were further tested using pharmacological agents. KEY RESULTS: Transcripts related to calcium signaling and ethylene biosynthesis were identified as notable constituents of the transcriptome. Inhibiting the activity of endomembrane Ca(2+)-ATPase pumps with 2,5-di-(t-butyl)-1,4-hydroquinone diminished the trans-cell current, but increased the orientation of the polar axis to gravity. The effects of applied nucleotides and purinoceptor antagonists gave novel evidence implicating extracellular nucleotides as regulators of the gravity response in these fern spores. CONCLUSIONS: In addition to revealing general features of the transcriptome of germinating spores, the results highlight a number of calcium-responsive and light-receptive transcripts. Pharmacologic assays indicate endomembrane Ca(2+)-ATPases and extracellular nucleotides may play regulatory roles in the gravity response of Ceratopteris spores.

Leptin therapy in insulin-deficient type I diabetes.

In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids (tricarboxylic acid cycle intermediates), amino acids, and acyl CoAs. In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes.