Receptor-interacting protein kinase 3 (RIPK3) functions as a key regulator of necroptosis. Here, we report that the RIPK3 expression level is negatively regulated by CHIP (carboxyl terminus of ...Hsp70-interacting protein; also known as STUB1) E3 ligase-mediated ubiquitylation. Chip(-/-) mouse embryonic fibroblasts and CHIP-depleted L929 and HT-29 cells exhibited higher levels of RIPK3 expression, resulting in increased sensitivity to necroptosis induced by TNF (also known as TNFα). These phenomena are due to the CHIP-mediated ubiquitylation of RIPK3, which leads to its lysosomal degradation. Interestingly, RIPK1 expression is also negatively regulated by CHIP-mediated ubiquitylation, validating the major role of CHIP in necrosome formation and sensitivity to TNF-mediated necroptosis. Chip(-/-) mice (C57BL/6) exhibit inflammation in the thymus and massive cell death and disintegration in the small intestinal tract, and die within a few weeks after birth. These phenotypes are rescued by crossing with Ripk3(-/-) mice. These results imply that CHIP is a bona fide negative regulator of the RIPK1-RIPK3 necrosome formation leading to desensitization of TNF-mediated necroptosis.
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IJS, NUK, SBMB, UL, UM, UPUK
Given their important role in neuronal function, there has been an increasing focus on altered lipid levels in brain disorders. The effect of a high-fat (HF) diet on the lipid profiles of the cortex, ...hippocampus, hypothalamus, and olfactory bulb of the mouse brain was investigated using nanoflow ultrahigh pressure liquid chromatography-electrospray ionization-tandem mass spectrometry in the current study. For 8 weeks, two groups of 5-week-old mice were fed either an HF or normal diet (6 mice from each group analyzed as the F and N groups, respectively). The remaining mice in both groups then received a 4-week normal diet. Each group was then subdivided into two groups for another 4-week HF or normal diet. Quantitative analysis of 270 of the 359 lipids identified from brain tissue revealed that an HF diet significantly affected the brain lipidome in all brain regions that were analyzed. The HF diet significantly increased diacylglycerols, which play a role in insulin resistance in all regions that were analyzed. Although the HF diet increased most lipid species, the majority of phosphatidylserine species were decreased, while lysophosphatidylserine species, with the same acyl chain, were substantially increased. This result can be attributed to increased oxidative stress due to the HF diet. Further, weight-cycling (yo-yo effect) was found more critical for the perturbation of brain lipid profiles than weight gain without a preliminary experience of an HF diet. The present study reveals systematic alterations in brain lipid levels upon HF diet analyzed either by lipid class and molecular levels.
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•High-fat diet (HFD) significantly perturbed mouse brain lipidome (four different regions).•Diacylglycerols increased (>3-folds) in four regions of brain upon HFD.•Most phosphatidylserine decreased upon HFD, while lysophosphatidylserine with the same acyl chain substantially increased.•Weight-cycling was found more critical in brain lipid perturbation than weight-gain group.
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GEOZS, IJS, KILJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Lipids are important signaling molecules regulating biological processes under normal and diseased conditions. Although p53 mutation is well-known for causing cancer, the relationship between ...p53-related tumorigenesis and altered lipid profile is unclear. We profiled differences in lipid expressions in liver, lung, and kidney in p53 knockout (KO) mice by high-speed quantitative analysis of 320 lipids (399 species identified) using nanoflow ultrahigh performance liquid chromatography–tandem mass spectrometry (nUPLC-MS/MS). Lung tissues were most severely affected by the lack of p53 gene, as shown by significant reduction (24–44%, P < 0.05) in total phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM), diacylglycerol (DG), and triacylglycerol (TG), and significant increases (30–50%) in phosphatidylserine (PS), phosphatidylinositol (PI), and monohexosylceramide (MHC). MHC levels increased in all tissues. Dihexosylceramide (DHC) level decreased only in kidney tissue. Most PI, PS, and phosphatidic acid (PA) species showing significant increases contained a saturated acyl chain (18:0) in lung and liver tissues. Neutral glycerolipids (16:0/22:0-DG and most TGs with saturated and monounsaturated acyl chains) decreased 2–4-fold in the liver tissue. Our results suggest that the lack of p53 and altered lipid profiles are closely related, but as their changes vary from one tissue to another, the lipid alterations are tissue-specific.
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IJS, KILJ, NUK, PNG, UL, UM
Tumour suppressor p53 is known to be associated with the maintenance of mitochondrial functional properties in the skeletal muscles. As deactivation or mutation of p53 can affect the synthesis of ...lipids, investigating the relationship between p53-related energy generation metabolism and perturbation of lipid profile is critical. In this study, 329 lipid species (among 412 identified species) in two different skeletal muscle tissues (the gastrocnemius and soleus) from p53 knockout (KO) mice were quantitatively analysed using nanoflow ultrahigh performance liquid chromatography tandem mass spectrometry (nUPLC-MS/MS). Overall, lipids from the soleus tissues were more affected by p53 KO than those from the gastrocnemius in most lipid profiles. In p53 KO, lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), phosphatidic acid (PA), sphingomyelin (SM), and triacylglycerol (TAG), including 6 TAG (44:2, 46:0, 58:5, 58:8, 58:9, and 50:0), were significantly increased (p < 0.05) by 1.4-2-fold only in the soleus tissue. Overall monohexosylceramide (MHC) levels, including those of 3 MHC species (d18:0/24:0, d18:1/22:0, and d18:1/24:0), were significantly increased (p < 0.05) by 2-4 fold, only in the gastrocnemius tissue. The results suggest that lipid profiles are significantly altered by the lack of p53 in muscle tissues.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Effective lung isolation prevents lung-to-lung aspiration during thoracotomy for the management of hemoptysis. Double-lumen endobronchial tubes (DLT) and bronchial blockers are commonly used for lung ...separation during thoracic surgery. In this study, the fluid-sealing characteristics of the endobronchial cuffs of three different commercially available DLTs (Broncho-Cath with a polyvinylchloride cuff, Broncho-Cath with a polyurethane cuff, and Human Broncho with a silicone cuff) and two different bronchial blockers (Arndt and Coopdech bronchial blockers) were evaluated using a benchtop model. The lateral decubitus position for the surgical management of bleeding from the right lung was simulated. The artificial tracheobronchial tree was placed horizontally, with the left bronchus in the dependent position and the right bronchus in the non-dependent position. In the DLT experiments, the tracheobronchial tree was intubated with left-sided DLTs, and the endobronchial cuff was inflated to maintain the intracuff pressure at 25 cmH
O. In the experiments with bronchial blockers, each bronchial blocker was inserted into the right bronchus, and the endobronchial cuff was inflated to seal the main bronchus. A fluid leakage test around the endobronchial cuff was performed using three different types of DLT (size 35, 37, and 41 Fr, each) and two different types of bronchial blockers (9 Fr). The 5 mL of colored water was poured into the right bronchus to simulate the blood flow from the operative side, and the times to the first and 100% leakage around the endobronchial cuff were recorded. Each bronchial blocker showed significantly less leakage over time than the other DLTs (P < 0.05). Fluid was not fully leaked around the cuffs for 24 h with either bronchial blocker. The times to first and 100% leakage were not significantly different among different types of DLTs. The times to first and 100% leakage did not also differ among the three different sizes of each type DLT. There was no significant difference in the time to first leakage around the endobronchial cuffs between Arndt and Coopdech bronchial blockers. Bronchial blockers provided a more effective seal against lung-to-lung aspiration than DLTs in the lateral decubitus position for thoracotomy in the benchtop model.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cellular senescence is a complex stress response implicated in aging. Autophagy can suppress senescence but is counterintuitively necessary for full senescence. Although its anti-senescence role is ...well described, to what extent autophagy contributes to senescence establishment and the underlying mechanisms is poorly understood. Here, we show that selective autophagy of multiple regulatory components coordinates the homeostatic state of senescence. We combined a proteomic analysis of autophagy components with protein stability profiling, identifying autophagy substrate proteins involved in several senescence-related processes. Selective autophagy of KEAP1 promoted redox homeostasis during senescence. Furthermore, selective autophagy limited translational machinery components to ameliorate senescence-associated proteotoxic stress. Lastly, selective autophagy of TNIP1 enhanced senescence-associated inflammation. These selective autophagy networks appear to operate in vivo senescence during human osteoarthritis. Our data highlight a caretaker role of autophagy in the stress support network of senescence through regulated protein stability and unravel the intertwined relationship between two important age-related processes.
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•Systematic identification of autophagy substrate proteins in cellular senescence•Selective autophagy shapes the senescent state through regulated protein stability•Selective autophagy promotes redox homeostasis, proteostasis, and inflammation•Selective autophagy networks appear to operate in vivo senescence during human OA
Lee et al. present an integrative approach combining quantitative proteomics with protein stability profiling to allow for systematic identification of autophagy substrate proteins. The authors show that during cellular senescence, autophagy plays a caretaker role in the stress support network by regulating protein stability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Prior to the advent of the next-generation heater for wearable/on-body electronic devices, various properties are required, including conductivity, transparency, mechanical reliability, and ...conformability. Expansion to two-dimensional (2D) structure of metallic nanowires based on network- and mesh-type geometries has been widely exploited for realizing these heaters. However, the routes led to many drawbacks such as the low-density cross-bar linking, self-aggregation of wire, and high junction resistance. Although 2D carbon nanomaterials such as graphene and reduced graphene oxide (rGO) have shown their potentials for the purpose, CVD-grown graphene with sufficiently high conductivity was limited due to its poor processability for large-area applications, while rGO fabricated with a complex reduction process involving the use of toxic chemicals suffered from a low electrical conductivity. In this study, we demonstrate a simple and robust process, utilizing electrostatic assembling of negatively charged MXene flakes on a positively treated surface of substrate, for fabricating a metal-like 2D MXene thin film heater (TFH). Our TFH showed a high optical property (>65%), low sheet resistance (215 Ω/sq), fast electrothermal response (within dozens of seconds) with an intrinsically high electrical conductivity, and mechanical flexibility (up to 180° bending). Its capability for forming a firm and stable ionic-type interface with a counterpart surface allows us to develop a shape-adaptable and patchable thread heater (TH) that can be shaped on diverse substrates even under harsh conditions of conventional sewing or weaving processes. This work suggests that our shape-adaptable MXene heaters are potentially suitable not only for wearable devices for local heating and defrosting but also for a variety of emerging applications of soft actuators and wearable/flexible healthcare monitoring and thermotherapy.
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IJS, KILJ, NUK, PNG, UL, UM
e23005 Background: Novel clinical trial designs are conducted in the precision medicine era. This study aimed to evaluate biomarker-driven, adaptive phase II trials in precision oncology, focusing on ...infrastructure, efficacy, and safety. Methods: We systematically reviewed and analyzed the target studies. EMBASE and PubMed searches from 2015 to 2023 generated 29 eligible trials. Data extraction included infrastructure, biomarker screening methodologies, efficacy, and safety profiles. Results: Government agencies, cancer hospitals, and academic societies with accumulated experiences led investigator-initiated precision oncology clinical trials (IIPOCTs), which later guided sponsor-initiated precision oncology clinical trials (SIPOCTs). Most SIPOCTs were international studies with basket design. IIPOCTs primarily used the central laboratory for biomarker screening, but SIPOCTs used both central and local laboratories. Most of the studies adapted next-generation sequencing and/or immunohistochemistry for biomarker screening. Fifteen studies included an independent central review committee for outcome investigation. Efficacy assessments predominantly featured objective response rate as the primary endpoint, with varying results. Nine eligible studies contributed to the United States Food and Drug Administration’s marketing authorization. Safety monitoring was rigorous, but reporting formats lacked uniformity. Health-related quality of life and patient-reported outcomes were described in some protocols but rarely reported. Table. Precision Oncology Trials led to the FDA approval. Conclusions: Our results reveal that precision oncology trials with adaptive design rapidly and efficiently evaluate anticancer drugs’ efficacy and safety, particularly in specified biomarker-driven cohorts. The evolution from IIPOCT to SIPOCT has facilitated fast regulatory approval, providing valuable insights into the precision oncology landscape. Table: see text
With the aging of the population, the number of people with age-related memory complaints has also increased. The purpose of this study was to develop a cognitive rehabilitation program based on ...mnemonic skills and memory compensatory strategies (CRM) and to investigate the effects of CRM in community-dwelling older adults without dementia.
This study was an open-label, single-arm, pilot study. We developed a CRM program comprising 8 weekly sessions. The study participants consisted of older adults with normal cognitive function and mild cognitive impairment (MCI). They were recruited from eight dementia counseling centers and one senior welfare center. To assess the effects of CRM, we administered the following tests at baseline and after completion of the program: Subjective Memory Complaints Questionnaire, the Short form of Geriatric Depression Scale, the Euro Quality of life-5 Dimension, and the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery.
Thirty-two participants completed the study. Among older adults with normal cognitive function, CRM showed significant improvement in verbal memory function. Among the older adults with MCI, CRM showed significant improvements in language ability, verbal recognition memory, nonverbal memory, attention, and processing speed.
CRM improved cognitive function in two distinct populations, older adults with normal cognitive function and older adults with MCI. Additionally, our preliminary findings suggest that older adults with MCI show cognitive improvement in both the trained and non-trained cognitive domains.
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