Induction of SOCS-3 is insufficient to confer IRS-1 protein degradation in 3T3-L1 adipocytes

Insulin receptor substrate (IRS)-1 is a key protein in insulin signaling. Several studies have shown that the expression of IRS-1 can be modulated by protein degradation via the proteasome and the degradation of IRS-1 can be related to insulin-resistant states. The degradation of IRS-1 has been shown to be induced by SOCS-1 and SOCS-3 via the ubiquitin pathway. The goal of our study was to determine if the induction of SOCS-3 correlated with increased IRS-1 degradation in cultured 3T3-L1 adipocytes. Interestingly, our studies have shown that there is little correlation between the induction in SOCS-3 expression and the degradation of IRS-1 in mature 3T3-L1 adipocytes. Our results clearly demonstrate that treatment with leukemia inhibitory factor (LIF) or cardiotrophin (CT)-1 strongly induces the expression of SOCS-3 in mature 3T3-L1 adipocytes, but does not affect the degradation of IRS-1. On the contrary, tumor necrosis factor (TNF) α and insulin, which very weakly induce SOCS-3 expression, have profound effects on IRS-1 degradation. In summary, our results indicate that the expression of SOCS-3 does not correlate with the degradation of IRS-1 proteins in fat cells. © 2006 Elsevier Inc. All rights reserved

Mutations in the _SC4MOL_ gene encoding a novel methyl sterol oxidase cause autosomal recessive psoriasisiform dermatitis, microcephaly and developmental delay

Disorders of cholesterol biosynthesis have clinical manifestations involving skeleton, eyes, neurologic development, and skin. We describe a patient with congenital cataracts, developmental delay, microcephaly, and low serum cholesterol who developed severe psoriasiform dermatitis and arthralgias beginning at age 3. Her brain MRI indicatedminor gliosis. Quantitative sterol analysis of patient plasma and skin showed marked elevation of 4alpha-methyl- and 4, 4'-dimethylsterols, indicating a deficiency in the first step of sterol C4 demethylation in cholesterol biosynthesis. Molecular studies showed mutations in _SC4MOL_, a gene predicted to encode a sterol C4 methyl oxidase. Thus, our patient has a previously undescribed inborn error of cholesterol biosynthesis. Cellular studies with patient-derived fibroblasts showed higher mitotic rate than control cells in cholesterol-depleted medium, in which _de novo_ cholesterol biosynthesis was increased with the accumulation of methylsterol. Immunologic analyses showed dysregulation of immune-related receptors in the patient and her father. Inhibition of sterol C4 methyl oxidase in human transformed lymphoblasts or in fresh leukocytes induced activation of cell cycle, and immune receptor dysregulation. These findings suggest that methylsterols influence mitotic capacity and immune function. _SC4MOL_ is situated within the psoriasis susceptibility locus _PSORS9_, and is likely a genetic risk factor for common psoriasis

Challenges in Context-Aware Neural Machine Translation

Context-aware neural machine translation involves leveraging information beyond sentence-level context to resolve inter-sentential discourse dependencies and improve document-level translation quality, and has given rise to a number of recent techniques. However, despite well-reasoned intuitions, most context-aware translation models show only modest improvements over sentence-level systems. In this work, we investigate several challenges that impede progress within this field, relating to discourse phenomena, context usage, model architectures, and document-level evaluation. To address these problems, we propose a more realistic setting for document-level translation, called paragraph-to-paragraph (para2para) translation, and collect a new dataset of Chinese-English novels to promote future research

MABEL: Attenuating Gender Bias using Textual Entailment Data

Pre-trained language models encode undesirable social biases, which are further exacerbated in downstream use. To this end, we propose MABEL (a Method for Attenuating Gender Bias using Entailment Labels), an intermediate pre-training approach for mitigating gender bias in contextualized representations. Key to our approach is the use of a contrastive learning objective on counterfactually augmented, gender-balanced entailment pairs from natural language inference (NLI) datasets. We also introduce an alignment regularizer that pulls identical entailment pairs along opposite gender directions closer. We extensively evaluate our approach on intrinsic and extrinsic metrics, and show that MABEL outperforms previous task-agnostic debiasing approaches in terms of fairness. It also preserves task performance after fine-tuning on downstream tasks. Together, these findings demonstrate the suitability of NLI data as an effective means of bias mitigation, as opposed to only using unlabeled sentences in the literature. Finally, we identify that existing approaches often use evaluation settings that are insufficient or inconsistent. We make an effort to reproduce and compare previous methods, and call for unifying the evaluation settings across gender debiasing methods for better future comparison.Comment: Accepted to EMNLP 2022. Code and models are publicly available at https://github.com/princeton-nlp/mabe

Primary Motor Cortex Excitability Is Modulated during the Mental Simulation of Hand Movement

Special issue: Motor cognitio

Distinction of disorder, classical and quantum vibrational contributions to atomic mean-square amplitudes in dielectric pentachloronitrobenzene

The solid-state molecular disorder of pentachloronitrobenzene (PCNB) and its role in causing anomalous dielectric properties are investigated. Normal coordinate analysis (NCA) of atomic mean-square displacement parameters (ADPs) is employed to distinguish disorder contributions from classical and quantum-mechanical vibrational contributions. The analysis relies on multitemperature (5-295 K) single-crystal neutron-diffraction data. Vibrational frequencies extracted from the temperature dependence of the ADPs are in good agreement with THz spectroscopic data. Aspects of the static disorder revealed by this work, primarily tilting and displacement of the molecules, are compared with corresponding results from previous, much more in-depth and time-consuming Monte Carlo simulations; their salient findings are reproduced by this work, demonstrating that the faster NCA approach provides reliable constraints for the interpretation of diffuse scattering. The dielectric properties of PCNB can thus be rationalized by an interpretation of the temperature-dependent ADPs in terms of thermal motion and molecular disorder. The use of atomic displacement parameters in the NCA approach is nonetheless hostage to reliable neutron data. The success of this study demonstrates that state-of-the-art single-crystal Laue neutron diffraction affords sufficiently fast the accurate data for this type of study. In general terms, the validation of this work opens up the field for numerous studies of solid-state molecular disorder in organic materials.Comment: Now published in Physical Review

Hubble Space Telescope Metallized Teflon(registered trademark) FEP Thermal Control Materials: On-Orbit Degradation and Post-Retrieval Analysis

During the Hubble Space Telescope (HST) Second Servicing Mission (SM2), degradation of unsupported Teflon(Registered Trademark) FEP (fluorinated ethylene propylene), used as the outer layer of the multilayer insulation (MLI) blankets, was evident as large cracks on the telescope light shield. A sample of the degraded outer layer was retrieved during the mission and returned to Earth for ground testing and evaluation. The results of the Teflon(Registered Trademark) FEP sample evaluation and additional testing of pristine Teflon(Registered Trademark) FEP led the investigative team to theorize that the HST damage was caused by thermal cycling with deep-layer damage from electron and proton radiation which allowed the propagation of cracks along stress concentrations , and that the damage increased with the combined total dose of electrons, protons, UV and x-rays along with thermal cycling. This paper discusses the testing and evaluation of the retrieved Teflon(Registered Trademark) FEP

Neuroprotective Ferulic Acid (FA)-Glycol Chitosan (GC) Nanoparticles for Functional Restoration of Traumatically Injured Spinal Cord

An urgent unmet need exists for early-stage treatment of spinal cord injury (SCI). Currently methylprednisolone is the only therapeutic agent used in clinics, for which the efficacy is controversial and the side effect is well-known. We demonstrated functional restoration of injured spinal cord by self-assembled nanoparticles composed of ferulic acid modified glycol chitosan (FA-GC). Chitosan and ferulic acid are strong neuroprotective agents but their systemic delivery is difficult. Our data has shown a prolonged circulation time of the FA-GC nanoparticles allowing for effective delivery of both chitosan and ferulic acid to the injured site. Furthermore, the nanoparticles were found both in the gray matter and white matter. The in vitro tests demonstrated that nanoparticles protected primary neurons from glutamate-induced excitotoxicity. Using a spinal cord contusion injury model, significant recovery in locomotor function was observed in rats that were intravenously administered nanoparticles at 2 h post injury, as compared to non-improvement by methylprednisolone administration. Histological analysis revealed that FA-GC treatment significantly preserved axons and myelin and also reduced cavity volume, astrogliosis, and inflammatory response at the lesion site. No obvious adverse effects of nanoparticles to other organs were found. The restorative effect of FA-GC presents a promising potential for treating human SCIs

Teflon FEP Analyzed After Retrieval From the Hubble Space Telescope

During the Hubble Space Telescope (HST) Second Servicing Mission, 6.8 years after the telescope was deployed in low Earth orbit, degradation of unsupported Teflon FEP (DuPont; fluorinated ethylene propylene), used as the outer layer of the multilayer insulation (MLI) blankets, was evident as large cracks on the telescope light shield. A sample of the degraded outer layer (see the photograph) was retrieved during the second servicing mission and returned to Earth for ground testing and evaluation. Also retrieved was a Teflon FEP radiator surface from a cryogen vent cover that was exposed to the space environment on the aft bulkhead of the HST. NASA Goddard Space Flight Center directed the efforts of the Hubble Space Telescope MLI Failure Review Board, whose goals included determining the FEP degradation mechanisms. As part of the investigations into the degradation mechanisms, specimens retrieved from the first and second HST servicing missions, 3.6 and 6.8 years after launch, respectively, were characterized through exhaustive mechanical, optical, and chemical testing. Testing led by Goddard included scanning electron microscopy, optical microscopy, tensile testing, solar absorptance measurements, time-of-flight secondary ion mass spectroscopy (TOF-SIMS), Fourier transform infrared microscopy (m-FTIR), attenuated total reflectance infrared microscopy (ATR/FTIR), and x-ray diffraction (XRD). The NASA Lewis Research Center contributed significantly to the analysis of the retrieved HST materials by leading efforts and providing results of bend testing, surface microhardness measurements, x-ray photoelectron spectroscopy, solid-state nuclear magnetic resonance spectroscopy, and density measurements. Other testing was conducted by Nano Instruments, Inc., and the University of Akron