Mechanical Stabilization of a Bacterial Adhesion Complex.

The adhesions between Gram-positive bacteria and their hosts are exposed to varying magnitudes of tensile forces. Here, using an ultrastable magnetic tweezer-based single-molecule approach, we show the catch-bond kinetics of the prototypical adhesion complex of SD-repeat protein G (SdrG) to a peptide from fibrinogen ß (Fgß) over a physiologically important force range from piconewton (pN) to tens of pN, which was not technologically accessible to previous studies. At 37 °C, the lifetime of the complex exponentially increases from seconds at several pN to ∼1000 s as the force reaches 30 pN, leading to mechanical stabilization of the adhesion. The dissociation transition pathway is determined as the unbinding of a critical ß-strand peptide ("latch" strand of SdrG that secures the entire adhesion complex) away from its binding cleft, leading to the dissociation of the Fgß ligand. Similar mechanical stabilization behavior is also observed in several homologous adhesions, suggesting the generality of catch-bond kinetics in such bacterial adhesions. We reason that such mechanical stabilization confers multiple advantages in the pathogenesis and adaptation of bacteria.

17-Beta Hydroxysteroid Dehydrogenase 13 Deficiency Does Not Protect Mice From Obesogenic Diet Injury.

BACKGROUND AND AIMS: 17-Beta hydroxysteroid dehydrogenase 13 (HSD17B13) is genetically associated with human nonalcoholic fatty liver disease (NAFLD). Inactivating mutations in HSD17B13 protect humans from NAFLD-associated and alcohol-associated liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma, leading to clinical trials of anti-HSD17B13 therapeutic agents in humans. We aimed to study the in vivo function of HSD17B13 using a mouse model. APPROACH AND RESULTS: Single-cell RNA-sequencing and quantitative RT-PCR data revealed that hepatocytes are the main HSD17B13-expressing cells in mice and humans. We compared Hsd17b13 whole-body knockout (KO) mice and wild-type (WT) littermate controls fed regular chow (RC), a high-fat diet (HFD), a Western diet (WD), or the National Institute on Alcohol Abuse and Alcoholism model of alcohol exposure. HFD and WD induced significant weight gain, hepatic steatosis, and inflammation. However, there was no difference between genotypes with regard to body weight, liver weight, hepatic triglycerides (TG), histological inflammatory scores, expression of inflammation-related and fibrosis-related genes, and hepatic retinoid levels. Compared to WT, KO mice on the HFD had hepatic enrichment of most cholesterol esters, monoglycerides, and certain sphingolipid species. Extended feeding with the WD for 10 months led to extensive liver injury, fibrosis, and hepatocellular carcinoma, with no difference between genotypes. Under alcohol exposure, KO and WT mice showed similar hepatic TG and liver enzyme levels. Interestingly, chow-fed KO mice showed significantly higher body and liver weights compared to WT mice, while KO mice on obesogenic diets had a shift toward larger lipid droplets. CONCLUSIONS: Extensive evaluation of Hsd17b13 deficiency in mice under several fatty liver-inducing dietary conditions did not reproduce the protective role of HSD17B13 loss-of-function mutants in human NAFLD. Moreover, mouse Hsd17b13 deficiency induces weight gain under RC. It is crucial to understand interspecies differences prior to leveraging HSD17B13 therapies.

Understanding ambipolar transport in MoS2 field effect transistors: the substrate is the key.

2D materials offer a pathway for further scaling of CMOS technology. However, for this to become a reality, both n-MOS and p-MOS should be realized, ideally with the same (standard) material. In the specific case of MoS2 field effect transistors (FETs), ambipolar transport is seldom reported, primarily due to the phenomenon of Fermi level pinning (FLP). In this study we identify the possible sources of FLP in MoS2 FETs and resolve them individually. A novel contact transfer technique is used to transfer contacts on top of MoS2 flake devices that results in a significant increase in the hole branch of the transfer characteristics as compared to conventionally fabricated contacts. We hypothesize that the pinning not only comes from the contact-MoS2 interface, but also from the MoS2-substrate interface. We confirm this by shifting to an hBN substrate which leads to a 10 fold increase in the hole current compared to the SiO2 substrate. Furthermore, we analyse MoS2 FETs of different channel thickness on three different substrates, SiO2, hBN and Al2O3, by correlating the p-branch I ON/I OFF to the position of oxide defect band in these substrates. FLP from the oxide is reduced in the case of Al2O3 which enables us to observe ambipolar transport in a bilayer MoS2 FET. These results highlight that MoS2 is indeed an ambipolar material, and the absence of ambipolar transport in MoS2 FETs is strongly correlated to its dielectric environment and processing conditions.

Characterization of essential domains in HSD17B13 for cellular localization and enzymatic activity.

Human genetic studies recently identified an association of SNPs in the 17-ß hydroxysteroid dehydrogenase 13 (HSD17B13) gene with alcoholic and nonalcoholic fatty liver disease development. Mutant HSD17B13 variants devoid of enzymatic function have been demonstrated to be protective from cirrhosis and liver cancer, supporting the development of HSD17B13 as a promising therapeutic target. Previous studies have demonstrated that HSD17B13 is a lipid droplet (LD)-associated protein. However, the critical domains that drive LD targeting or determine the enzymatic activity have yet to be defined. Here we used mutagenesis to generate multiple truncated and point-mutated proteins and were able to demonstrate in vitro that the N-terminal hydrophobic domain, PAT-like domain, and a putative α-helix/ß-sheet/α-helix domain in HSD17B13 are all critical for LD targeting. Similarly, we characterized the predicted catalytic, substrate-binding, and homodimer interaction sites and found them to be essential for the enzymatic activity of HSD17B13, in addition to our previous identification of amino acid P260 and cofactor binding site. In conclusion, we identified critical domains and amino acid sites that are essential for the LD localization and protein function of HSD17B13, which may facilitate understanding of its function and targeting of this protein to treat chronic liver diseases.

Long-chain acyl-CoA synthetase 1 interacts with key proteins that activate and direct fatty acids into niche hepatic pathways.

Fatty acid channeling into oxidation or storage modes depends on physiological conditions and hormonal signaling. However, the directionality of this channeling may also depend on the association of each of the five acyl-CoA synthetase isoforms with specific protein partners. Long-chain acyl-CoA synthetases (ACSLs) catalyze the conversion of long-chain fatty acids to fatty acyl-CoAs, which are then either oxidized or used in esterification reactions. In highly oxidative tissues, ACSL1 is located on the outer mitochondrial membrane (OMM) and directs fatty acids into mitochondria for ß-oxidation. In the liver, however, about 50% of ACSL1 is located on the endoplasmic reticulum (ER) where its metabolic function is unclear. Because hepatic fatty acid partitioning is likely to require the interaction of ACSL1 with other specific proteins, we used an unbiased protein interaction technique, BioID, to discover ACSL1-binding partners in hepatocytes. We targeted ACSL1 either to the ER or to the OMM of Hepa 1-6 cells as a fusion protein with the Escherichia coli biotin ligase, BirA*. Proteomic analysis identified 98 proteins that specifically interacted with ACSL1 at the ER, 55 at the OMM, and 43 common to both subcellular locations. We found subsets of peroxisomal and lipid droplet proteins, tethering proteins, and vesicle proteins, uncovering a dynamic role for ACSL1 in organelle and lipid droplet interactions. Proteins involved in lipid metabolism were also identified, including acyl-CoA-binding proteins and ceramide synthase isoforms 2 and 5. Our results provide fundamental and detailed insights into protein interaction networks that control fatty acid metabolism.

Layer-controlled epitaxy of 2D semiconductors: bridging nanoscale phenomena to wafer-scale uniformity.

The rapid cadence of MOSFET scaling is stimulating the development of new technologies and accelerating the introduction of new semiconducting materials as silicon alternative. In this context, 2D materials with a unique layered structure have attracted tremendous interest in recent years, mainly motivated by their ultra-thin body nature and unique optoelectronic and mechanical properties. The development of scalable synthesis techniques is obviously a fundamental step towards the development of a manufacturable technology. Metal-organic chemical vapor deposition has recently been used for the synthesis of large area TMDs, however, an important milestone still needs to be achieved: the ability to precisely control the number of layers and surface uniformity at the nano-to micro-length scale to obtain an atomically flat, self-passivated surface. In this work, we explore various fundamental aspects involved in the chemical vapor deposition process and we provide important insights on the layer-dependence of epitaxial MoS2 film's structural properties. Based on these observations, we propose an original method to achieve a layer-controlled epitaxy of wafer-scale TMDs.

PM2.5 and ozone, indicators of air quality, and acute deaths in California, 2004-2007.

Since the London Great Smog of 1952 was estimated to have killed over 4000 people, scientists have studied the relationship between air quality and acute mortality. Currently, the association between air quality and acute deaths is usually taken as evidence for causality. As air quality has markedly improved since 1952, do contemporary datasets support this view? We use a large dataset, eight air basins in California for the years 2004-2007, to examine the possible association of ozone and PM2.5 with acute deaths after statistically removing seasonal and weather effects. Our analysis dataset is available on request. We conducted a regression-corrected, case-crossover analysis for all non-accidental deaths age 75 and older. We used stepwise regression to examine three causes of death. After seasonal and weather adjustments, there was essentially no predictive power of ozone or PM2.5 for acute deaths. The case-crossover analysis produced odds ratio very close to 1.000 (no effect). The very narrow confidence limits indicated good statistical power. We study recent air quality in both time-stratified, symmetric, bidirectional case-crossover and time series regression and both give consistent results. There is no statistically significant association between either ozone or PM2.5 and acute human mortality. In the absence of an association, causality is in question.

Asymptotics of nonparametric L-1 regression models with dependent data.

We investigate asymptotic properties of least-absolute-deviation or median quantile estimates of the location and scale functions in nonparametric regression models with dependent data from multiple subjects. Under a general dependence structure that allows for longitudinal data and some spatially correlated data, we establish uniform Bahadur representations for the proposed median quantile estimates. The obtained Bahadur representations provide deep insights into the asymptotic behavior of the estimates. Our main theoretical development is based on studying the modulus of continuity of kernel weighted empirical process through a coupling argument. Progesterone data is used for an illustration.

Active ballistic orbital transport in Ni/Pt heterostructure.

Orbital current, defined as the orbital character of Bloch states in solids, can travel with larger coherence length through a broader range of materials than its spin counterpart, facilitating a robust, higher density and energy efficient information transmission. Hence, active control of orbital transport plays a pivotal role in the progress of the evolving field of quantum information technology. Unlike spin angular momentum, orbital angular momentum couples to phonon angular momentum efficiently via orbital-crystal momentum (L-k) coupling, allowing us to control orbital transport through crystal field potential mediated angular momentum transfer. Here, leveraging the orbital dependant efficient L-k coupling, we have experimentally demonstrated the active control of orbital current velocity in Ni/Pt heterostructure. We observe terahertz emission from Ni/Pt heterostructure via long-range ballistic orbital transport, as evidenced by the delay, and chirping in the emitted THz pulse correlating with increased Pt thickness. Additionally, we also have identified a critical energy density required to overcome collisions in orbital transport, enabling a swifter flow of orbital current. Femtosecond light driven active control of the ballistic orbital transport lays the foundation for the development of dynamic optorbitronics for transmitting information over extended distance.

Multistate Compound Magnetic Tunnel Junction Synapses for Digital Recognition.

The quest to mimic the multistate synapses for bioinspired computing has triggered nascent research that leverages the well-established magnetic tunnel junction (MTJ) technology. Early works on the spin transfer torque MTJ-based artificial neural network (ANN) are susceptible to poor thermal reliability, high latency, and high critical current densities. Meanwhile, work on spin-orbit torque (SOT) MTJ-based ANN mainly utilized domain wall motion, which yields negligibly small readout signals differentiating consecutive states and has designs that are incompatible with technological scale-up. Here, we propose a multistate device concept built upon a compound MTJ consisting of multiple SOT-MTJs (number of MTJs, n = 1-4) on a shared write channel, mimicking the spin-based ANN. The n + 1 resistance states representing varying synaptic weights can be tuned by varying the voltage pulses (±1.5-1.8 V), pulse duration (100-300 ns), and applied in-plane fields (5.5-10.5 mT). A large TMR difference of more than 13.6% is observed between two consecutive states for the 4-cell compound MTJ, a 4-fold improvement from reported state-of-the-art spin-based synaptic devices. The ANN built upon the compound MTJ shows high learning accuracy for digital recognition tasks with incremental states and retraining, achieving test accuracy as high as 95.75% in the 4-cell compound MTJ. These results provide an industry-compatible platform to integrate these multistate SOT-MTJ synapses directly into neuromorphic architecture for in-memory and unconventional computing applications.

Bimodal alteration of cognitive accuracy for spintronic artificial neural networks.

Spintronics-based artificial neural networks (ANNs) exhibiting nonvolatile, fast, and energy-efficient computing capabilities are promising neuromorphic hardware for performing complex cognitive tasks of artificial intelligence and machine learning. Early experimental efforts focused on multistate device concepts to enhance synaptic weight precisions, albeit compromising on cognitive accuracy due to their low magnetoresistance. Here, we propose a hybrid approach based on the tuning of tunnel magnetoresistance (TMR) and the number of states in the compound magnetic tunnel junctions (MTJs) to improve the cognitive performance of an all-spin ANN. A TMR variation of 33-78% is controlled by the free layer (FL) thickness wedge (1.6-2.6 nm) across the wafer. Meanwhile, the number of resistance states in the compound MTJ is manipulated by varying the number of constituent MTJ cells (n = 1-3), generating n + 1 states with a TMR difference between consecutive states of at least 21%. Using MNIST handwritten digit and fashion object databases, the test accuracy of the compound MTJ ANN is observed to increase with the number of intermediate states for a fixed FL thickness or TMR. Meanwhile, the test accuracy for a 1-cell MTJ increases linearly by 8.3% and 7.4% for handwritten digits and fashion objects, respectively, with increasing TMR. Interestingly, a multifarious TMR dependence of test accuracy is observed with the increasing synaptic complexity in the 2- and 3-cell MTJs. By leveraging on the bimodal tuning of multilevel and TMR, we establish viable paths for enhancing the cognitive performance of spintronic ANN for in-memory and neuromorphic computing.

Direct Assessment of Defective Regions in Monolayer MoS2 Field-Effect Transistors through In Situ Scanning Probe Microscopy Measurements.

Implementing two-dimensional materials in field-effect transistors (FETs) offers the opportunity to continue the scaling trend in the complementary metal-oxide-semiconductor technology roadmap. Presently, the search for electrically active defects, in terms of both their density of energy states and their spatial distribution, has turned out to be of paramount importance in synthetic transition metal dichalcogenides layers, as they are suspected of severely inhibiting these devices from achieving their highest performance. Although advanced microscopy tools have allowed the direct detection of physical defects such as grain boundaries and point defects, their implementation at the device scale to assess the active defect distribution and their impact on field-induced channel charge modulation and current transport is strictly restrained. Therefore, it becomes critical to directly probe the gate modulation effect on the carrier population at the nanoscale of an FET channel, with the objective to establish a direct correlation with the device characteristics. Here, we have investigated the active channel in a monolayer MoS2 FET through in situ scanning probe microscopy, namely, Kelvin probe force microscopy and scanning capacitance microscopy, to directly identify active defect sites and to improve our understanding of the contribution of grain boundaries, bilayer islands, and defective grain domains to channel conductance.

A Mechanical Assay for the Quantification of Anti-RBD IgG Levels in Finger-Prick Whole Blood.

A large portion of the global population has been vaccinated with various vaccines or infected with SARS-CoV-2, the virus that causes COVID-19. The resulting IgG antibodies that target the receptor binding domain (RBD) of SARS-CoV-2 play a vital role in reducing infection rates and severe disease outcomes. Different immune histories result in the production of anti-RBD IgG antibodies with different binding affinities to RBDs of different variants, and the levels of these antibodies decrease over time. Therefore, it is important to have a low-cost, rapid method for quantifying the levels of anti-RBD IgG in decentralized testing for large populations. In this study, we describe a 30 min assay that allows for the quantification of anti-RBD IgG levels in a single drop of finger-prick whole blood. This assay uses force-dependent dissociation of nonspecifically absorbed RBD-coated superparamagnetic microbeads to determine the density of specifically linked microbeads to a protein A-coated transparent surface through anti-RBD IgGs, which can be measured using a simple light microscope and a low-magnification lens. The titer of serially diluted anti-RBD IgGs can be determined without any additional sample processing steps. The limit of detection for this assay is 0.7 ± 0.1 ng/mL referenced to the CR3022 anti-RBD IgG. The limits of the technology and its potential to be further developed to meet the need for point-of-care monitoring of immune protection status are discussed.

Chiral Interlayer Exchange Coupling for Asymmetric Domain Wall Propagation in Field-Free Magnetization Switching.

The discovery of chiral spin texture has unveiled many unusual yet extraordinary physical phenomena, such as the Néel type domain walls and magnetic skyrmions. A recent theoretical study suggests that a chiral exchange interaction is not limited to a single ferromagnetic layer; instead, three-dimensional spin textures can arise from an interlayer Dzyaloshinskii-Moriya interaction. However, the influence of chiral interlayer exchange coupling on the electrical manipulation of magnetization has rarely been addressed. Here, the coexistence of both symmetric and chiral interlayer exchange coupling between two orthogonally magnetized CoFeB layers in PtMn/CoFeB/W/CoFeB/MgO is demonstrated. Images from polar magneto-optical Kerr effect microscopy indicate that the two types of coupling act concurrently to induce asymmetric domain wall propagation, where the velocities of domain walls with opposite chiralities are substantially different. Based on this microscopic mechanism, field-free switching of the perpendicularly magnetized CoFeB is achieved with a wide range of W thicknesses of 0.6-4.5 nm. This work enriches the understanding of interlayer exchange coupling for spintronic applications.

Effect of spinal segment variants on numbering vertebral levels at lumbar MR imaging.

PURPOSE: To verify iliolumbar ligament (ILL) location, to evaluate magnetic resonance (MR) imaging morphologic features for detecting lumbosacral transitional vertebrae (TVs) (LSTVs), and to determine whether transitional situations are associated with anomalous vertebral numbering. MATERIALS AND METHODS: Investigational review board approval was obtained for this HIPAA-compliant retrospective study. A review of 147 subjects was performed by using spine radiography as the reference standard to determine total and segmental vertebral count and transitional anatomy. Thoracolumbar TVs (TLTVs) and LSTVs were identified. The lumbosacral intervertebral disk angle (LSIVDA), defined as the angle between the endplates, was measured, S1-2 disk morphology was rated according to the classification by O'Driscoll et al, and the ILL level was determined from MR images. Statistical analysis was performed by using χ(2) tests for dichotomous and ordinal variables and the t test for continuous variables. RESULTS: An anomalous total number of vertebrae were present in 12 (8.2%) of 147 subjects. The ILL was identified in 126 (85.7%) of 147 subjects and was present at L5 in 122 (96.8%) subjects; the remaining four (3.2%) subjects had an anomalous total number of vertebrae. A complete S1-2 intervertebral disk was associated with LSTVs (P = .004); however, LSIVDA was not (P = .2). TLTVs were present in six (4.1%) and LSTVs were present in 22 (15.0%) of 147 subjects. Both were present in four (2.7%) subjects. The presence of a TLTV was associated with a higher incidence of a concomitant LSTV and vice versa (P < .001; odds ratio [OR], 13.7; 95% confidence interval [CI]: 2.7, 68.4]). A TLTV was not associated with an anomalous total number of vertebrae (P = .46), but an LSTV was (P < .001; OR, 7.4; 95% CI: 2.2, 24.8). CONCLUSION: The ILL denotes the lowest lumbar vertebra, which does not always represent L5. A well-formed, complete S1-2 intervertebral disk is associated with LSTVs, but alteration in LSIVDA is not. LSTVs are associated with anomalous vertebral numbering.

A generalized likelihood ratio test for monitoring profile data.

Profile data emerges when the quality of a product or process is characterized by a functional relationship among (input and output) variables. In this paper, we focus on the case where each profile has one response variable Y, one explanatory variable x, and the functional relationship between these two variables can be rather arbitrary. The basic concept can be applied to a much wider case, however. We propose a general method based on the Generalized Likelihood Ratio Test (GLRT) for monitoring of profile data. The proposed method uses nonparametric regression to estimate the on-line profiles and thus does not require any functional form for the profiles. Both Shewhart-type and EWMA-type control charts are considered. The average run length (ARL) performance of the proposed method is studied. It is shown that the proposed GLRT-based control chart can efficiently detect both location and dispersion shifts of the on-line profiles from the baseline profile. An upper control limit (UCL) corresponding to a desired in-control ARL value is constructed.

Designs for order-of-addition experiments.

The order-of-addition experiment aims at determining the optimal order of adding components such that the response of interest is optimized. Order of addition has been widely involved in many areas, including bio-chemistry, food science, nutritional science, pharmaceutical science, etc. However, such an important study is rather primitive in statistical literature. In this paper, a thorough study on pair-wise ordering designs for order of addition is provided. The recursive relation between two successive full pair-wise ordering designs is developed. Based on this recursive relation, the full pair-wise ordering design can be obtained without evaluating all the orders of components. The value of the D-efficiency for the full pair-wise ordering model is then derived. It provides a benchmark for choosing the fractional pair-wise ordering designs. To overcome the unaffordability of the full pair-wise ordering design, a new class of minimal-point pair-wise ordering designs is proposed. A job scheduling problem as well as simulation studies are conducted to illustrate the performance of the pair-wise ordering designs for determining the optimal orders. It is shown that the proposed designs are very efficient in determining the optimal order of addition.

Engineering Wafer-Scale Epitaxial Two-Dimensional Materials through Sapphire Template Screening for Advanced High-Performance Nanoelectronics.

In view of its epitaxial seeding capability, c-plane single crystalline sapphire represents one of the most enticing, industry-compatible templates to realize manufacturable deposition of single crystalline two-dimensional transition metal dichalcogenides (MX2) for functional, ultrascaled, nanoelectronic devices beyond silicon. Despite sapphire being atomically flat, the surface topography, structure, and chemical termination vary between sapphire terraces during the fabrication process. To date, it remains poorly understood how these sapphire surface anomalies affect the local epitaxial registry and the intrinsic electrical properties of the deposited MX2 monolayer. Therefore, molybdenum disulfide (MoS2) is deposited by metal-organic chemical vapor deposition (MOCVD) in an industry-standard epitaxial reactor on two types of c-plane sapphire with distinctly different terrace and step dimensions. Complementary scanning probe microscopy techniques reveal an inhomogeneous conductivity profile in the first epitaxial MoS2 monolayer on both sapphire templates. MoS2 regions with poor conductivity correspond to sapphire terraces with uncontrolled topography and surface structure. By intentionally applying a substantial off-axis cut angle (1° in this work), the sapphire terrace width and step height-and thus also surface structure-become more uniform across the substrate and MoS2 conducts the current more homogeneously. Moreover, these effects propagate into the extrinsic MoS2 device performance: the field-effect transistor variability reduces both within and across wafers at higher median electron mobility. Carefully controlling the sapphire surface topography and structure proves an essential prerequisite to systematically study and control the MX2 growth behavior and capture the influence on its structural and electrical properties.

Impact of device scaling on the electrical properties of MoS2 field-effect transistors.

Two-dimensional semiconducting materials are considered as ideal candidates for ultimate device scaling. However, a systematic study on the performance and variability impact of scaling the different device dimensions is still lacking. Here we investigate the scaling behavior across 1300 devices fabricated on large-area grown MoS2 material with channel length down to 30 nm, contact length down to 13 nm and capacitive effective oxide thickness (CET) down to 1.9 nm. These devices show best-in-class performance with transconductance of 185 µS/µm and a minimum subthreshold swing (SS) of 86 mV/dec. We find that scaling the top-contact length has no impact on the contact resistance and electrostatics of three monolayers MoS2 transistors, because edge injection is dominant. Further, we identify that SS degradation occurs at short channel length and can be mitigated by reducing the CET and lowering the Schottky barrier height. Finally, using a power performance area (PPA) analysis, we present a roadmap of material improvements to make 2D devices competitive with silicon gate-all-around devices.

Vitamin E treatment in NAFLD patients demonstrates that oxidative stress drives steatosis through upregulation of de-novo lipogenesis.

Oxidative stress (OS) in non-alcoholic fatty liver disease (NAFLD) promotes liver injury and inflammation. Treatment with vitamin E (α-tocopherol, αT), a lipid-soluble antioxidant, improves liver injury but also decreases steatosis, thought to be upstream of OS, through an unknown mechanism. To elucidate the mechanism, we combined a mechanistic human trial interrogating pathways of intrahepatic triglyceride (IHTG) accumulation and in vitro experiments. 50% of NAFLD patients (n = 20) treated with αT (200-800 IU/d) for 24 weeks had a ≥ 25% relative decrease in IHTG by magnetic resonance spectroscopy. Paired liver biopsies at baseline and week 4 of treatment revealed a decrease in markers of hepatic de novo lipogenesis (DNL) that strongly predicted week 24 response. In vitro, using HepG2 cells and primary human hepatocytes, αT inhibited glucose-induced DNL by decreasing SREBP-1 processing and lipogenic gene expression. This mechanism is dependent on the antioxidant capacity of αT, as redox-silenced methoxy-αT is unable to inhibit DNL in vitro. OS by itself was sufficient to increase S2P expression in vitro, and S2P is upregulated in NAFLD livers. In summary, we utilized αT to demonstrate a vicious cycle in which NAFLD generates OS, which feeds back to augment DNL and increases steatosis. Clinicaltrials.gov: NCT01792115.