Targeted protein degradation directly engaging lysosomes or proteasomes.

Targeted protein degradation (TPD) has been established as a viable alternative to attenuate the function of a specific protein of interest in both biological and clinical contexts. The unique TPD mode-of-action has allowed previously undruggable proteins to become feasible targets, expanding the landscape of "druggable" properties and "privileged" target proteins. As TPD continues to evolve, a range of innovative strategies, which do not depend on recruiting E3 ubiquitin ligases as in proteolysis-targeting chimeras (PROTACs), have emerged. Here, we present an overview of direct lysosome- and proteasome-engaging modalities and discuss their perspectives, advantages, and limitations. We outline the chemical composition, biochemical activity, and pharmaceutical characteristics of each degrader. These alternative TPD approaches not only complement the first generation of PROTACs for intracellular protein degradation but also offer unique strategies for targeting pathologic proteins located on the cell membrane and in the extracellular space.

Sadopeptins A and B, Sulfoxide- and Piperidone-Containing Cyclic Heptapeptides with Proteasome Inhibitory Activity from a Streptomyces sp.

New sulfur-bearing natural products, sadopeptins A and B (1 and 2), were discovered from Streptomyces sp. YNK18 based on a targeted search using the characteristic isotopic signature of sulfur in mass spectrometry analysis. Compounds 1 and 2 were determined to be new cyclic heptapeptides, bearing methionine sulfoxide [Met(O)] and 3-amino-6-hydroxy-2-piperidone (Ahp), based on 1D and 2D NMR spectroscopy along with IR, UV, and MS. The configurations of sadopeptins A and B (1 and 2) were established via the analysis of the ROESY NMR correlation, oxidation, Marfey's method, and circular dichroism (CD) spectroscopy. The bioinformatics analysis of the full Streptomyces sp. YNK18 genome identified a nonribosomal peptide synthetase (NRPS) biosynthetic gene cluster (BGC), and a putative biosynthetic pathway is proposed. Sadopeptins A and B displayed proteasome-inhibitory activity without affecting cellular autophagic flux.

Aggresomal sequestration and STUB1-mediated ubiquitylation during mammalian proteaphagy of inhibited proteasomes.

The 26S proteasome, a self-compartmentalized protease complex, plays a crucial role in protein quality control. Multiple levels of regulatory systems modulate proteasomal activity for substrate hydrolysis. However, the destruction mechanism of mammalian proteasomes is poorly understood. We found that inhibited proteasomes are sequestered into the insoluble aggresome via HDAC6- and dynein-mediated transport. These proteasomes colocalized with the autophagic receptor SQSTM1 and cleared through selective macroautophagy, linking aggresomal segregation to autophagic degradation. This proteaphagic pathway was counterbalanced with the recovery of proteasomal activity and was critical for reducing cellular proteasomal stress. Changes in associated proteins and polyubiquitylation on inhibited 26S proteasomes participated in the targeting mechanism to the aggresome and autophagosome. The STUB1 E3 Ub ligase specifically ubiquitylated purified human proteasomes in vitro, mainly via Lys63-linked chains. Genetic and chemical inhibition of STUB1 activity significantly impaired proteasome processing and reduced resistance to proteasomal stress. These data demonstrate that aggresomal sequestration is the crucial upstream event for proteasome quality control and overall protein homeostasis in mammals.

Harnessing the power of collective intelligence in dentistry: a pilot study in Victoria, Australia.

BACKGROUND: In many dental settings, diagnosis and treatment planning is the responsibility of a single clinician, and this process is inevitably influenced by the clinician's own heuristics and biases. Our aim was to test whether collective intelligence increases the accuracy of individual diagnoses and treatment plans, and whether such systems have potential to improve patient outcomes in a dental setting. METHODS: This pilot project was carried out to assess the feasibility of the protocol and appropriateness of the study design. We used a questionnaire survey and pre-post study design in which dental practitioners were involved in the diagnosis and treatment planning of two simulated cases. Participants were provided the opportunity to amend their original diagnosis/treatment decisions after viewing a consensus report made to simulate a collaborative setting. RESULTS: Around half (55%, n = 17) of the respondents worked in group private practices, however most practitioners (74%, n = 23) did not collaborate when planning treatment. Overall, the average practitioners' self-confidence score in managing different dental disciplines was 7.22 (s.d. 2.20) on a 1-10 scale. Practitioners tended to change their mind after viewing the consensus response, particularly for the complex case compared to the simple case (61.5% vs 38.5%, respectively). Practitioners' confidence ratings were also significantly higher (p < 0.05) after viewing the consensus for complex case. CONCLUSION: Our pilot study shows that collective intelligence in the form of peers' opinion can lead to modifications in diagnosis and treatment planning by dentists. Our results lay the foundations for larger scale investigations on whether peer collaboration can improve diagnostic accuracy, treatment planning and, ultimately, oral health outcomes.

Grape seed powder increases gastrointestinal motility.

Grape seed is an important natural bioactive product with various health benefits. Interstitial cells of Cajal (ICCs) are pacemaker cells in the gastrointestinal (GI) tract. The present study investigated the effects of grape seed powder (GSP) on ICC properties and GI motility. GSP depolarized the pacemaker potentials of ICCs in a dose­dependent manner. Y25130 or SB269970 slightly inhibited GSP­induced effects. However, Y25130 and SB269970 together completely blocked GSP-induced effects. In the presence of inhibitors of protein kinase C, protein kinase A, or mitogen-activated protein kinase, GSP­induced ICC depolarization was inhibited. GSP increased the intestinal transit rate in normal mice and in mice with acetic acid-induced GI motility disorder. In addition, the levels of motilin and substance P were elevated after GSP dosing. These results demonstrate that GSP can regulate GI motility, and therefore, it is a potential therapeutic agent for treating GI motility disorders.

Spontaneous Formation of Highly Stable Nanoparticle Supercrystals Driven by a Covalent Bonding Interaction.

Nanoparticle supercrystals (NPSCs) are of great interest as materials with emergent properties. Different types of intermolecular forces, such as van der Waals interaction and hydrogen bonding, are present in the NPSCs fabricated to date. However, the limited structural stability of such NPSCs that results from the weakness of these intermolecular forces is a challenge. Here, we report a spontaneous formation of NPSCs driven by covalent bonding interactions, a type of intramolecular force much stronger than the above-mentioned intermolecular forces. A model solution-phase anhydride reaction is used to form covalent bonds between molecules grafted on the surface of gold nanoparticles, resulting in three-dimensional NPSCs. The NPSCs are very stable in different solvents, in dried conditions, and at temperatures as high as 160 °C. In addition to this, the large library of covalent-bond-forming reactions available and the low cost of reactants make the covalent bonding approach highly versatile and economical.

Alisma canaliculatum Extract Affects AGS Gastric Cancer Cells by Inducing Apoptosis.

The anti-cancer effects of Alisma canaliculatum extracts (ACE) were identified in AGS gastric cancer cells. Our results showed that ACE inhibited the growth of AGS cells, increased the proportion of sub-G1 phase cells, and depolarized the membrane potential of mitochondria. ACE-induced gastric cancer cell death was associated with Bcl-2, survivin and Bax level changes, and it activated caspase-3 and -9. In addition, it was involved in the activation of MAPKs and increased the reactive oxygen species (ROS). These results suggest that ACE induces apoptosis in AGS gastric cancer cells, and therefore, ACE may have the potential to treat gastric cancer.

Enhanced Soft 3D Reconstruction Method with an Iterative Matching Cost Update Using Object Surface Consensus.

In this paper, we propose a multi-view stereo matching method, EnSoft3D (Enhanced Soft 3D Reconstruction) to obtain dense and high-quality depth images. Multi-view stereo is one of the high-interest research areas and has wide applications. Motivated by the Soft3D reconstruction method, we introduce a new multi-view stereo matching scheme. The original Soft3D method is introduced for novel view synthesis, while occlusion-aware depth is also reconstructed by integrating the matching costs of the Plane Sweep Stereo (PSS) and soft visibility volumes. However, the Soft3D method has an inherent limitation because the erroneous PSS matching costs are not updated. To overcome this limitation, the proposed scheme introduces an update process of the PSS matching costs. From the object surface consensus volume, an inverse consensus kernel is derived, and the PSS matching costs are iteratively updated using the kernel. The proposed EnSoft3D method reconstructs a highly accurate 3D depth image because both the multi-view matching cost and soft visibility are updated simultaneously. The performance of the proposed method is evaluated by using structured and unstructured benchmark datasets. Disparity error is measured to verify 3D reconstruction accuracy, and both PSNR and SSIM are measured to verify the simultaneous enhancement of view synthesis.

Usage of Natural Volatile Organic Compounds as Biological Modulators of Disease.

Plants produce a wide variety of natural volatile organic compounds (NVOCs), many of which are unique to each species. These compounds serve many purposes, such as fending off herbivores and adapting to changes in temperature and water supply. Interestingly, although NVOCs are synthesized to deter herbivores, many of these compounds have been found to possess several therapeutic qualities, such as promoting nerve stability, enhancing sleep, and suppressing hyperresponsiveness, in addition to acting as antioxidants and anti-inflammatory agents. Therefore, many NVOCs are promising drug candidates for disease treatment and prevention. Given their volatile nature, these compounds can be administered to patients through inhalation, which is often more comfortable and convenient than other administration routes. However, the development of NVOC-based drug candidates requires a careful evaluation of the molecular mechanisms that drive their therapeutic properties to avoid potential adverse effects. Furthermore, even compounds that appear generally safe might have toxic effects depending on their dose, and therefore their toxicological assessment is also critical. In order to enhance the usage of NVOCs this short review focuses not only on the biological activities and therapeutic mode of action of representative NVOCs but also their toxic effects.

Proteasomal adaptations underlying carfilzomib-resistance in human bone marrow plasma cells.

Donor-specific antibodies (DSAs) have a deleterious effect on allografts and remain a major immunologic barrier in transplantation. Current therapies to eliminate DSAs are ineffective in highly HLA-sensitized patients. Proteasome inhibitors have been employed as a strategy to target bone marrow plasma cells (BMPCs), the source of long-term antibody production; however, their efficacy has been limited by poorly defined drug-resistance mechanisms. Here, we performed transcriptomic profiling of CD138+ BMPCs that survived in vivo desensitization therapy with the proteasome inhibitor carfilzomib to identify mechanisms of drug resistance. The results revealed a genomic signature that included increased expression of the immunoproteasome, a highly specialized proteasomal variant. Western blotting and functional studies demonstrated that catalytically active immunoproteasomes and the immunoproteasome activator PA28 were upregulated in carfilzomib-resistant BMPCs. Carfilzomib-resistant BMPCs displayed reduced sensitivity to the proteasome inhibitors carfilzomib, bortezomib, and ixazomib, but enhanced sensitivity to an immunoproteasome-specific inhibitor ONX-0914. Finally, in vitro carfilzomib treatment of BMPCs from HLA-sensitized patients increased levels of the immunoproteasome ß5i (PSMB8) catalytic subunit suggesting that carfilzomib therapy directly induces an adaptive immunoproteasome response. Taken together, our results indicate that carfilzomib induces structural changes in proteasomes and immunoproteasome formation.

Ternary Polypeptide Nanoparticles with Improved Encapsulation, Sustained Release, and Enhanced In Vitro Efficacy of Carfilzomib.

PURPOSE: To develop a new nanoparticle formulation for a proteasome inhibitor Carfilzomib (CFZ) to improve its stability and efficacy for future in vivo applications. METHODS: CFZ-loaded ternary polypeptide nanoparticles (CFZ/tPNPs) were prepared by using heptakis(6-amino-6-deoxy)-ß-cyclodextrin(hepta-hydrochloride) (HaßCD) and azido-poly(ethylene glycol)-block-poly(L-glutamic acid sodium salt) (N3-PEG-PLE). The process involved ternary (hydrophobic/ionic/supramolecular) interactions in three steps: 1) CFZ was entrapped in the cavity of HaßCD by hydrophobic interaction, 2) the drug-cyclodextrin inclusion complexes were mixed with N3-PEG-PLE to form polyion complex nanoparticles, and 3) the nanoparticles were modified with fluorescent dyes (AFDye 647) for imaging and/or epithelial cell adhesion molecule (EpCAM) antibodies for cancer cell targeting. CFZ/tPNPs were characterized for particle size, surface charge, drug release, stability, intracellular uptake, proteasome inhibition, and in vitro cytotoxicity. RESULTS: tPNPs maintained an average particle size of 50 nm after CFZ entrapment, EpCAM conjugation, and freeze drying. tPNPs achieved high aqueous solubility of CFZ (>1 mg/mL), sustained drug release (t1/2 = 6.46 h), and EpCAM-mediated cell targeting, which resulted in increased intracellular drug accumulation, prolonged proteasome inhibition, and enhanced cytotoxicity of CFZ in drug-resistant DLD-1 colorectal cancer cells. CONCLUSIONS: tPNPs improved stability and efficacy of CFZ in vitro, and these results potentiate effective cancer treatment using CFZ/tPNPs in future vivo studies.

Longitudinal associations between depressive symptoms and clinical factors in ankylosing spondylitis patients: analysis from an observational cohort.

OBJECTIVES: Although cross-sectional studies have shown that ankylosing spondylitis-specific factors correlate with depressive symptom severity, the association of these factors over time is unresolved. We examined the demographic and clinical factors associated with longitudinal depressive symptom severity in AS patients. METHODS: We analyzed sociodemographic, clinical, behavioral and medication data from 991 patients from the Prospective Study of Outcomes in Ankylosing spondylitis cohort, and measured depression severity with the Center for Epidemiological Studies Depression (CES-D) Scale administered at approximately 6-month visit intervals. Multivariable longitudinal negative binomial regression models were conducted using generalized estimating equation modeling to assess the demographic, clinical, and medication-related factors associated with depression severity by CES-D scores over time. RESULTS: The median baseline CES-D score (possible range 0-60) was 10.0 (interquartile range = 5, 17). In longitudinal multivariable analyses, higher CES-D scores were associated with longitudinal smoking, greater functional impairment, greater disease activity, self-reported depression, and poor global health scores. Marital status (e.g., being married) was associated with lower CES-D. Adjusted mean CES-D scores in our model decreased over time, with a significant interaction between time and gender observed. CONCLUSION: This study identified longitudinal clinical factors such as greater disease activity, greater functional impairment, and poor global health to be associated with longitudinal depression severity. These factors are potentially modifiable and may help manage depressive symptoms in AS.

Micelle-Assisted Formation of Nanoparticle Superlattices and Thermally Reversible Symmetry Transitions.

Nanoparticle superlattices (NPSLs) are of great interest as materials with designed emerging properties depending on the lattice symmetry as well as composition. The symmetry transition of NPSLs depending on environmental conditions can be an excellent ground for making new stimuli-responsive functional materials. Here, we report a spherical micelle-assisted method to form exceptionally ordered NPSLs which are inherently sensitive to environmental conditions. Upon mixing functionalized gold nanoparticles (AuNPs) with a nonionic surfactant spherical micellar solution, NPSLs of different symmetries such as NaZn13, MgZn2, and AlB2-type are formed depending on the size ratio between micelles and functionalized AuNPs and composition. The NPSLs formed by the spherical micelle-assisted method show thermally reversible order-order (NaZn13-AlB2) and order-disorder (MgZn2-isotropic) symmetry transitions, which are consistent with the Gibbs free energy calculations for binary hard-sphere model. This approach may open up new possibilities for NPSLs as stimuli-responsive functional materials.

Acidiphilamides A-E, Modified Peptides as Autophagy Inhibitors from an Acidophilic Actinobacterium, Streptacidiphilus rugosus.

Five new tripeptides, acidiphilamides A-E (1-5), were discovered along with two previously reported compounds, l-isoleucinamide (6) and l-valinamide (7), from Streptacidiphilus rugosus AM-16, an acidophilic actinobacterial strain isolated from acidic forest soil. The structures of 1-5 were elucidated as modified tripeptides bearing phenylalaninol or methioninol fragments with C3-C5 acyl chains based mainly on NMR and mass spectroscopic data. The absolute configurations of the amine units were established by advanced Marfey's method and GITC (2,3,4,6-tetra- O-acetyl-ß-d-glucopyranosyl isothiocyanate) derivatization followed by LC/MS analysis. Acidiphilamides A and B (1 and 2), the first secondary metabolites isolated from the rare actinobacterial genus Streptacidiphilus, significantly inhibited autophagic flux but not proteasome activity in HeLa cells. These compounds appeared to block mainly the autophagosome-lysosome fusion step in the late stage of cellular autophagy.

Preparation and Characterization of High Functional Ophthalmic Lens Material Containing Acrylic Formation Isocyanate Group with Carbon Nanoparticles.

This research was conducted to produce the high functional hydrogel ophthalmic lens containing iso-cyanate group and nanoparticles. IsoMA (2-Isocyanatoethyl methacrylate) and carbon nanoparticles were used as additives for the basic combination including HEMA (2-hydroxyethyl methacrylate), MA (methacrylic acid), and MMA (methyl methacrylate). And also, the materials were copolymerized with EGDMA (ethylene glycol dimethacrylate) as the cross-linking agent and AIBN (azobisisobutyronitrile) as the initiator. Measurement of the physical characteristics of the produced material showed that the refractive index was 1.4027~1.4446, water content 31.13~44.01%, contact angle 43.99~65.67°, visible light transmittance 26.17~92.13%, and tensile strength 0.0652~0.2528 kgf. The breaking strength were in the range of 0.0872~0.1851 kgf. These results showed the decrease of contact angle and increase of water content by the addition of IsoMA and carbon nanoparticles and that showing both additives made synergy effect of wettability. As a result of the absorbance measurement, no significant difference was observed in all the samples, so it can be judged that the stabilization of nanoparticles in the polymer was maintained. Therefore, these materials considered to satisfy the basic requirements of ophthalmic lenses with high performance of tensile strength, breaking strength and wettability.

Study on the High Functional Contact Lens Material with Superior Oxygen Transmissibility and Antibacterial Properties.

The silicone monomer (SiH2) used in this study contains acrylate monomer, DMA (n,n-dimethylacrylamide). For the polymerization, PtOEP (platinum octaethylporphyrin) was added to the synthesized silicone, DMA (n,n-dimethyl acrylamide), HPMA (hydroxy propyl methacrylate), PEGMEMA [poly(ethylene glycol) methyl ether methylacrylate], EGDMA (ethylene glycol dimethacrylate) and the initiator AIBN (azobisisobutyronitrile) with various concentrations. Using the polymer produced through the thermal polymerization process, the optical and physical characteristics of high performance silicone hydrogel lenses were measured. The water content of sample containing PtOEP was in the range of 65.21∼66.56%. And also, oxygen permeability (Dk) of sample containing PtOEP was in the range of 30.20∼30.85 × 10-11 cm²/sec × mlO2/ml × mmHg. In case of the sample with nanoparticle, the oxygen permeability was higher than that of Ref. sample without nanoparticle. Silicone hydrogel monomer containing PtOEP was expected to be used usefully as a material for red tinted chromagen optical lens with high oxygen permeability for color amblyopia.

Preparation and Characterization of Functional Ophthalmic Polymer Containing Nanoparticles Using Heat Treatment Method After Polymerization.

The functional hydrogel lens containing HEMA (2-hydroxyethylmethacrylate) was manufactured by thermal polymerization and heat treatment method after room temperature polymerization, respectively. In this study, HEMA, EGDMA (ethylene glycol dimethacrylate) and the initiator AIBN (azobisisobutyronitrile) were used for thermal copolymerization and the mixture was heated at 100 °C for 1 hour. And also, HEMA, EGDMA, the initiator and distilled water were used for heat treatment method after room temperature copolymerization and the mixture was heated 80 °C for 1 hour and then treated at 100 °C for 1 hour to produce the hydrogel ophthalmic lens by cast mold method. To make the functional hydrogel lens, ZnPC and platinum octaethyl porphyrin were used as additives. The measurements of the physical characteristics of the copolymerized material showed that refractive index and contact angle of sample was in the range of 1.4010∼1.4585 and 21.46∼87.28°, respectively. In case of heat treatment method after room temperature copolymerization, the refractive index and wettability of sample was higher than that of thermal polymerization. And also, the addition of ZnPC nanoparticles allowed the hydrogel lens to block UV-light. The absorbance value of solution in which the lens prepared by the heat treatment method was immersed were much lower than that of thermal polymerization, so it can be judged that the stabilization of produced polymer maintained well. Based on the results of this study, the produced optical lens can be considered to satisfy the basic requirements of optical lens and can be used effectively as an additive for functional ophthalmic lens material with high refractive index and wettability.

Validation of the MCNP6 code for SFR shielding design analysis.

In this paper, the uncertainty of the Monte Carlo code MCNP6 for the sodium-cooled fast reactor (SFR) shielding design is studied. Shielding analysis, which ensures the radiation safety of the core design, is challenging for the Monte Carlo modeling because it is associated with large uncertainties. In order to evaluate the performance of the MCNP6 relative to the shielding design of the SFR, four SFR shielding benchmarks from the Shielding Integral Benchmark Archive Database benchmark suite, i.e. JANUS Phase VIII, SDT12, EURAC_Na and HARMO_Na were selected and analysed. In this research, the weight window variance-reduction technique and the neutron data library ENDF/B-VII.1 were used in the modeling of the benchmark problems. The results and the validation of the MCNP6 models with the available measurement data are presented in this paper. These results contribute to the assessment of radiological protection and shielding design of the Korean Prototype Gen-IV Sodium-cooled Fast Reactor.

Inactivation of USP14 Perturbs Ubiquitin Homeostasis and Delays the Cell Cycle in Mouse Embryonic Fibroblasts and in Fruit Fly Drosophila.

BACKGROUND/AIMS: The 26S proteasome is the key proteolytic complex for recognition and degradation of polyubiquitinated target substrates in eukaryotes. Among numerous proteasome-associated proteins, a deubiquitinating enzyme (DUB) USP14 has been identified as an endogenous inhibitor of the proteasome. Here, we explored the complex regulatory functions of USP14 that involve ubiquitin (Ub) homeostasis and substrate degradation in flies and mammals. METHODS: USP14-null primary and immortalized mouse embryonic fibroblasts (MEFs) and USP14 knocked-down Drosophila were analyzed in this study. We measured proteasome and DUB activities using fluorogenic reporter substrates and adduct-forming probes. To examine the levels of ubiquitin, we performed immunoblotting and immunohistochemistry. Mass spectrometry (MS) was used to examine polyUb chain linkages and USP14-interacing proteins. Cell cycle was analyzed by flow cytometry, BrdU labeling, and phospho-histone H3 staining. RESULTS: The homeostasis of Ub in USP14-/-MEFs was markedly perturbed because of facilitated clearance of Ub. This phenomenon was recapitulated in muscles of USP14-deficient Drosophila with old ages. Absolute quantitation using MS also revealed that USP14-/- MEFs contained significantly increased amounts of Ub, compared with wild-type. The key phenotype of USP14-/- MEFs was their delayed proliferation originated from prolonged interphase possibly through aberrant degradation of cyclins A and B1. We found that knocking down USP14 in Drosophila resulted in delayed eye development associated with reduced mitotic activity. CONCLUSION: Our study identifies novel cellular functions of USP14 not only in cellular Ub hometostasis but also in cell cycle progression. USP14 was also essential for proper Drosophila eye development. These results strongly suggest that the USP14-mediated proteasome activity regulation may be directly related to various human diseases including cancer.

Roles of Exosome-Like Vesicles Released from Inflammatory C2C12 Myotubes: Regulation of Myocyte Differentiation and Myokine Expression.

BACKGROUND/AIMS: The complicated differentiation processes of cells in skeletal muscle against inflammation that induce muscle atrophy are not fully elucidated. Given that skeletal muscle is a secretory organ, we evaluated the effects of inflammation on myogenic signals and myokine expression, and the roles of inflammatory exosomes released by myotubes in myogenic differentiation. METHODS: Inflammation was induced by treatment of fully differentiated C2C12 myotubes with a cytokine mixture of TNF-α and INF-γ. Exosome-like vesicles (ELVs) were isolated from conditioned media of control or inflamed myotubes and incubated with myoblasts. The expression of molecular switches that contribute to myogenic differentiation, including several kinases, their downstream targets, and myokines, were evaluated using immunoblot analysis in inflamed myotubes and in myoblasts treated with ELVs. RESULTS: Inflammation activated molecular mechanisms contributing to muscle atrophy, including AMPK, p-38 MAPK and JNK, while inhibiting Akt-mediated myogenic signals. In addition, inflammation induced myostatin expression with suppression of a myostatin-counteracting myokine, decorin. Well-characterized ELVs released from inflamed myotubes induced myoblast inflammation and inhibited myogenic mechanisms while stimulating atrophic signals. CONCLUSION: Inflammation of skeletal muscle induces muscle atrophy via multiple mechanisms, including the regulation of myokines and kinases. Inflammatory ELVs are likely to contribute to inflammation-induced muscle atrophy.