Real-world comparison between mechanical and manual cardiopulmonary resuscitation during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has posed significant challenges to healthcare systems worldwide, including an increase in out-of-hospital cardiac arrests (OHCA). Healthcare providers are now required to use personal protective equipment (PPE) during cardiopulmonary resuscitation (CPR). Additionally, mechanical CPR devices have been introduced to reduce the number of personnel required for resuscitation. This study aimed to compare the outcomes of CPR performed with a mechanical device and the outcomes of manual CPR performed by personnel wearing PPE. METHODS: This multicenter observational study utilized data from the Korean Cardiac Arrest Research Consortium registry. The study population consisted of OHCA patients who underwent CPR in emergency departments (EDs) between March 2020 and June 2021. Patients were divided into two equal propensity score matched groups: mechanical CPR group (n = 421) and PPE-equipped manual CPR group (n = 421). Primary outcomes included survival rates and favorable neurological outcomes at discharge. Total CPR duration in the ED was also assessed. RESULTS: There were no significant between-group differences with respect to survival rate at discharge (mechanical CPR: 7.4% vs PPE-equipped manual CPR: 8.3%) or favorable neurological outcomes (3.3% vs. 3.8%, respectively). However, the mechanical CPR group had a longer duration of CPR in the ED compared to the manual CPR group. CONCLUSION: This study found no significant differences in survival rates and neurological outcomes between mechanical CPR and PPE-equipped manual CPR in the ED setting. However, a longer total CPR duration was observed in the mechanical CPR group. Further research is required to explore the impact of PPE on healthcare providers' performance and fatigue during CPR in the context of the pandemic and beyond.

Lactate Levels as a Predictor of Emergency Department Revisits in Infants With Acute Bronchiolitis.

OBJECTIVE: This study aimed to identify predictive biomarkers for unscheduled emergency department (ED) revisits within 24 hours of discharge in infants diagnosed with acute bronchiolitis (AB). METHODS: A retrospective observational study was conducted on infants diagnosed with AB who visited 3 emergency medical centers between January 2020 and December 2022. The study excluded infants with comorbidities, congenital diseases, and prematurity and infants who revisited the ED after 24 hours of discharge. Demographic data, vital signs, and laboratory results were collected from the medical records. Univariable and multivariable logistic regression analyses were performed on factors with P of less than 0.1 in univariable analysis. Receiver operator curve analysis was used to assess the accuracy of lactate measurements in predicting ED revisits within 24 hours of discharge. RESULTS: Out of 172 participants, 100 were in the revisit group and 72 in the discharge group. The revisit group was significantly younger and exhibited higher lactate levels, lower pH values, and higher pCO2 levels compared to the discharge group. Univariable logistic regression identified several factors associated with revisits. Multivariable analysis found that only lactate was a variable correlated with predicting ED revisits (odds ratio, 18.020; 95% confidence interval [CI], 5.764-56.334). The receiver operator curve analysis showed an area under the curve of 0.856, with an optimal lactate cutoff value of 2.15. CONCLUSION: Lactate value in infants diagnosed with AB were identified as a potential indicator of predicting unscheduled ED revisits within 24 hours of discharge. The predictive potential of lactate levels holds promise for enhancing prognosis prediction, reducing health care costs, and alleviating ED overcrowding. However, given the study's limitations, a more comprehensive prospective investigation is recommended to validate these findings.

The Role of Glutamine Homeostasis in Emotional and Cognitive Functions.

Glutamine (Gln), a non-essential amino acid, is synthesized de novo by glutamine synthetase (GS) in various organs. In the brain, GS is exclusively expressed in astrocytes under normal physiological conditions, producing Gln that takes part in glutamatergic neurotransmission through the glutamate (Glu)-Gln cycle. Because the Glu-Gln cycle and glutamatergic neurotransmission play a pivotal role in normal brain activity, maintaining Gln homeostasis in the brain is crucial. Recent findings indicated that a neuronal Gln deficiency in the medial prefrontal cortex in rodents led to depressive behaviors and mild cognitive impairment along with lower glutamatergic neurotransmission. In addition, exogenous Gln supplementation has been tested for its ability to overcome neuronal Gln deficiency and reverse abnormal behaviors induced by chronic immobilization stress (CIS). Although evidence is accumulating as to how Gln supplementation contributes to normalizing glutamatergic neurotransmission and the Glu-Gln cycle, there are few reviews on this. In this review, we summarize recent evidence demonstrating that Gln supplementation ameliorates CIS-induced deleterious changes, including an imbalance of the Glu-Gln cycle, suggesting that Gln homeostasis is important for emotional and cognitive functions. This is the first review of detailed mechanistic studies on the effects of Gln supplementation on emotional and cognitive functions.

Validation of an Analytical Method of 3',4',5-Trihydroxy-3-Methoxy-6,7-Methylenedioxyflavone 4'-Glucuronide for Standardization of Spinacia oleracea.

Spinach (Spinacia oleracea) is one of the most famous vegetables worldwide, rich in essential metabolites for various health benefits. It is a valuable plant source that has the potential to be a nutraceutical. This study aimed to evaluate the single characteristic marker compound to establish the validation of HPLC-DAD methods applied to the development of a nutraceutical using spinach samples. Six metabolites (1-6) were identified from the spinach samples such as freeze-dried spinach (FDS) and spinach extract concentrate (SEC) by LC-Q-TOF/MS analysis. Among the six metabolites, 3',4',5-trihydroxy-3-methoxy-6,7-methylenedioxyflavone 4'-glucuronide (TMG) was selected as a marker compound due to its highest abundance and high selectivity. The specificity, accuracy, linearity, precision, repeatability, limit of detection (LOD), and limit of quantification (LOQ) of TMG in the spinach samples (FDS and SEC) were validated according to AOAC international guideline. The specificity was confirmed by monitoring the well separation of the marker compound from other compounds of spinach samples in the base peak intensity (BPI) and ultraviolet (UV) chromatogram. The calibration curve of TMG (15.625~500 µg/mL) had reasonable linearity (R2 = 0.999) considered with LOD and LOQ values, respectively. Recovery rate of TMG was 93-101% for FDS and 90-95% for SEC. The precision was less than 3 and 6% in the intraday and interday. As a result, the HPLC-DAD validation method of TMG in the spinach samples (FDS and SEC) was first established with AOAC and KFDA regulations for approving functional ingredients in functional foods.

FAK Activation Promotes SMC Dedifferentiation via Increased DNA Methylation in Contractile Genes.

RATIONALE: Vascular smooth muscle cells (SMCs) exhibit remarkable plasticity and can undergo dedifferentiation upon pathological stimuli associated with disease and interventions. OBJECTIVE: Although epigenetic changes are critical in SMC phenotype switching, a fundamental regulator that governs the epigenetic machineries regulating the fate of SMC phenotype has not been elucidated. METHODS AND RESULTS: Using SMCs, mouse models, and human atherosclerosis specimens, we found that FAK (focal adhesion kinase) activation elicits SMC dedifferentiation by stabilizing DNMT3A (DNA methyltransferase 3A). FAK in SMCs is activated in the cytoplasm upon serum stimulation in vitro or vessel injury and active FAK prevents DNMT3A from nuclear FAK-mediated degradation. However, pharmacological or genetic FAK catalytic inhibition forced FAK nuclear localization, which reduced DNMT3A protein via enhanced ubiquitination and proteasomal degradation. Reduced DNMT3A protein led to DNA hypomethylation in contractile gene promoters, which increased SMC contractile protein expression. RNA-sequencing identified SMC contractile genes as a foremost upregulated group by FAK inhibition from injured femoral artery samples compared with vehicle group. DNMT3A knockdown in injured arteries reduced DNA methylation and enhanced contractile gene expression supports the notion that nuclear FAK-mediated DNMT3A degradation via E3 ligase TRAF6 (TNF [tumor necrosis factor] receptor-associated factor 6) drives differentiation of SMCs. Furthermore, we observed that SMCs of human atherosclerotic lesions exhibited decreased nuclear FAK, which was associated with increased DNMT3A levels and decreased contractile gene expression. CONCLUSIONS: This study reveals that nuclear FAK induced by FAK catalytic inhibition specifically suppresses DNMT3A expression in injured vessels resulting in maintaining SMC differentiation by promoting the contractile gene expression. Thus, FAK inhibitors may provide a new treatment option to block SMC phenotypic switching during vascular remodeling and atherosclerosis.

Evaluation of optimal scene time interval for out-of-hospital cardiac arrest using a deep neural network.

AIM: This study aims to develop a cardiac arrest prediction model using deep learning (CAPD) algorithm and to validate the developed algorithm by evaluating the change in out-of-hospital cardiac arrest patient prognosis according to the increase in scene time interval (STI). METHODS: We conducted a retrospective cohort study using smart advanced life support trial data collected by the National Emergency Center from January 2016 to December 2019. The smart advanced life support data were randomly partitioned into derivation and validation datasets. The performance of the CAPD model using the patient's age, sex, event witness, bystander cardiopulmonary resuscitation (CPR), administration of epinephrine, initial shockable rhythm, prehospital defibrillation, provision of advanced life support, response time interval, and STI as prediction variables for prediction of a patient's prognosis was compared with conventional machine learning methods. After fixing other values of the input data, the changes in prognosis of the patient with respect to the increase in STI was observed. RESULTS: A total of 16,992 patients were included in this study. The area under the receiver operating characteristic curve values for predicting prehospital return of spontaneous circulation (ROSC) and favorable neurological outcomes were 0.828 (95% confidence interval 0.826-0.830) and 0.907 (0.914-0.910), respectively. Our algorithm significantly outperformed other artificial intelligence algorithms and conventional methods. The neurological recovery rate was predicted to decrease to 1/3 of that at the beginning of cardiopulmonary resuscitation when the STI was 28 min, and the prehospital ROSC was predicted to decrease to 1/2 of its initial level when the STI was 30 min. CONCLUSION: The CAPD exhibits potential and effectiveness in identifying patients with ROSC and favorable neurological outcomes for prehospital resuscitation.

Acutely increased ß-hydroxybutyrate plays a role in the prefrontal cortex to escape stressful conditions during the acute stress response.

Ketone bodies can be increased in the blood under certain physiological conditions, but their role under such conditions remains to be clarified. In the present study, we found the increment and usage of ß-hydroxybutyrate (BHB) in the prefrontal cortex (PFC) during acute stress. BHB levels increased in the blood and PFC after 30-min acute immobilization stress, and BHB dehydrogenase 1 increased in the PFC simultaneously, but not in the hippocampus. Moreover, increased levels of acetyl-CoA, pyruvate carboxylase, and glutamate dehydrogenase 1 were found in the PFC, implicating the metabolism of increased BHB in the brain. Thus, we checked the levels of glutamate, glutamine, and GABA and found increased levels of glutamate and glutamine in the stressed group compared with that in the control group in the PFC. Exogenous administration of BHB enhanced struggling behaviors under stressful conditions. Our results suggest that the metabolism of BHB from peripheral blood in the PFC may contribute to acute stress responses to escape stressful conditions.

Dipeptide YA is Responsible for the Positive Effect of Oyster Hydrolysates on Alcohol Metabolism in Single Ethanol Binge Rodent Models.

Accumulative alcohol hangovers cause liver damage through oxidative and inflammatory stress. Numerous antioxidant and anti-inflammatory reagents have been developed to reduce alcohol hangovers, but these reagents are still insignificant and have limitations in that they can cause liver toxicity. Oyster hydrolysate (OH), another reagent that has antioxidant and anti-inflammatory activity, is a product extracted through an enzymatic hydrolysis process from oysters (Crassostrea gigas), which can be easily eaten in meals. This study was aimed at determining the effects of OH on alcohol metabolism, using a single high dose of ethanol (EtOH) administered to rodents, by monitoring alcohol metabolic enzymes, oxidative stress signals, and inflammatory mediators. The effect of tyrosine-alanine (YA) peptide, a main component of OH, on EtOH metabolism was also identified. In vitro experiments showed that OH pretreatment inhibited EtOH-induced cell death, oxidative stress, and inflammation in liver cells and macrophages. In vivo experiments showed that OH and YA pre-administration increased alcohol dehydrogenase, aldehyde dehydrogenase, and catalase activity in EtOH binge treatment. In addition, OH pre-administration alleviated CYP2E1 activity, ROS production, apoptotic signals, and inflammatory mediators in liver tissues. These results showed that OH and YA enhanced EtOH metabolism and had a protective effect against acute alcohol liver damage. Our findings offer new insights into a single high dose of EtOH drinking and suggest that OH and YA could be used as potential marine functional foods to prevent acute alcohol-induced liver damage.

Transient changes in paretic and non-paretic isometric force control during bimanual submaximal and maximal contractions.

PURPOSE: The purpose of this study was to investigate transient bimanual effects on the force control capabilities of the paretic and non-paretic arms in individuals post stroke across submaximal and maximal force control tasks. METHODS: Fourteen chronic stroke patients (mean age = 63.8 ± 15.9; stroke duration = 38.7 ± 45.2 months) completed two isometric force control tasks: (a) submaximal control and (b) maximal sustained force production. Participants executed both tasks with their wrist and fingers extending across unimanual (paretic and non-paretic arms) and bimanual conditions. Mean force, force variability using coefficient of variation, force regularity using sample entropy were calculated for each condition. RESULTS: During the submaximal force control tasks (i.e., 5, 25, and 50% of maximum voluntary contraction), the asymmetrical mean force between the paretic and non-paretic arms decreased from unimanual to bimanual conditions. The asymmetry of force variability and regularity between the two arms while executing unimanual force control tended to decrease in the bimanual condition because of greater increases in the force variability and regularity for the non-paretic arm than those for the paretic arm. During the maximal sustained force production tasks (i.e., 100% of maximum voluntary contraction), the paretic arm increased maximal forces and decreased force variability in the bimanual condition, whereas the non-paretic arm reduced maximal forces and elevated force variability from unimanual to bimanual conditions. CONCLUSIONS: The current findings support a proposition that repetitive bimanual isometric training with higher execution intensity may facilitate progress toward stroke motor recovery.

Allergic contact dermatitis of both eyes caused by alcaftadine 0.25%: a case report.

BACKGROUND: To report the first case of allergic contact dermatitis (ACD) associated with alcaftadine 0.25% ophthalmic solution. CASE PRESENTATION: The patient was a 51-year-old woman with no previous history of side effects to ophthalmic antihistamine agents. She had been prescribed alcaftadine 0.25% for allergic conjunctivitis. On first application of the medication, she did not experience any cutaneous reaction. One day later, after the second alcaftadine 0.25% application, both eyelids became swollen, and erythematous changes were evident. On slit-lamp examination, conjunctival injection was noted in the absence of conjunctival swelling or any other findings. Fundus examination was unremarkable. To evaluate the cause of ACD, a patch test was performed and 48 h later was noted to be positive for alcaftadine 0.25%. Based on the positive patch test, the patient was diagnosed with ACD caused by alcaftadine 0.25%. After 9 days of treatment, the swelling and erythema completely resolved. CONCLUSIONS: Although there have been no previous reports of alcaftadine 0.25%-associated ACD, it should be suspected in patients with swelling and erythematous change of both eyes after using alcaftadine 0.25%.

Operational and environmental conditions regulate the frictional behavior of two-dimensional materials.

The friction characteristics of single-layer h-BN, MoS2, and graphene were systematically investigated via friction force microscopy measurements at various operational (e.g., normal force and sliding speed) and environmental (e.g., relative humidity and thermal annealing) conditions. The low friction characteristics of these single-layer materials were clearly observed from the normal force-dependent friction results, and their interfacial shear strengths were further estimated using a Hertz-plus-offset model. In addition, speed-dependent friction characteristics clearly demonstrated two regimes of friction as a function of sliding speed - the first is the logarithmic increase in friction with sliding speed regime at sliding speeds smaller than the critical speed and the second is the friction plateau regime at sliding speeds greater than the critical speed. Fundamental parameters such as effective shape of the interaction potential and its corrugation amplitude for these single-layer materials were characterized using the thermally-activated Prandtl-Tomlinson model. Moreover, friction of single-layer h-BN, MoS2, and graphene was found to increase with relative humidity and decrease with thermal annealing; these trends were attributed to the diffusion of water molecules to the interface between the single-layer materials and their substrates, which leads to an increase in the puckering effect at the tip-material interface and interaction potential corrugation. The enhanced puckering effect was verified via molecular dynamics simulations. Overall, the findings enable a comprehensive understanding of friction characteristics for several classes of two-dimensional materials, which is important to elucidate the feasibility of using these materials as protective and solid-lubricant coating layers for nanoscale devices.

Alpha-lipoic acid reduces retinal cell death in diabetic mice.

Oxidative stress plays an important role in the development of diabetic retinopathy. Here, we examined whether α-lipoic acid (α-LA), a natural antioxidant, attenuated retinal injury in diabetic mice. The α-LA was orally administered to control mice or mice with streptozotocin-induced diabetes. We found that α-LA reduced oxidative stress, decreased and increased retinal 4-hydroxy-2-nonenal and glutathione peroxidase, respectively, and inhibited retinal cell death. Concomitantly, α-LA reversed the decreased activation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, and increased the levels of peroxisome proliferator-activated receptor delta and sirtuin3 in diabetic mouse retinas, similar to results shown after metformin treatment of retinal pigment epithelial cells (RPE) exposed to high glucose. Moreover, α-LA lowered the levels of O-linked ß-N-acetylglucosamine transferase (OGT) and thioredoxin-interacting protein (TXNIP) in diabetic retinas that were more pronounced after metformin treatment of RPE cells. Importantly, α-LA lowered interactions between AMPK and OGT as shown by co-immunoprecipitation analyses, and this was accompanied by less cell death as measured by double immunofluorescence staining by terminal deoxynucleotide transferase-mediated dUTP nick-end labelling and OGT or TXNIP in retinal ganglion cells. Consistently, α-LA lowered the levels of cleaved poly(ADP-ribose) polymerase and pro-apoptotic marker cleaved caspase-3 in diabetic retinas. Our results indicated that α-LA reduced retinal cell death partly through AMPK activation or OGT inhibition in diabetic mice.

Microsphere-Based Nanoindentation for the Monitoring of Cellular Cortical Stiffness Regulated by MT1-MMP.

Biophysical properties are intimately connected to metastatic functions and aggressiveness in cancers. Especially, cellular stiffness is regarded as a biomarker for the understanding of metastatic potential and drug sensitivity. Here, protease-mediated changes of cortical stiffness are identified due to the deformation of cytoskeleton alignment at a cortex. For the past few decades, membrane type 1-matrix metalloproteinase (MT1-MMP) has been well known as a kernel protease enriched in podosomes during metastasis for extracellular matrix degradation. However, the biophysical significance of MT1-MMP expressing cancer cells is still unknown. Therefore, the nanomechanics of cancer cells is analyzed by a nanoindentation using a microsphere-attached cantilever of atomic force microscopy (AFM). In conclusion, the results suggest that MT1-MMP has contributed as a key regulator in cytoskeletal deformation related with cancer metastasis. Particularly, the AFM-based nanoindentation system for the monitoring of cortical nanomechanics will be crucial to understand molecular networks in cancers.

Moiré-free fingerprint sensors based on multilayer oxide-metal-oxide electrodes.

The display quality of touchscreen devices with on-screen fingerprint sensors is reduced by moiré patterns, interference phenomena caused by an overlap between the pixel pattern of the display, and the electrode pattern of the fingerprint sensor. A promising strategy for resolving this issue is to reduce the visibility of the moiré pattern, by including a filling layer with a transmittance similar to that of the electrodes, between the different patterns. We propose a moiré-free fingerprint sensor that uses an oxide-metal-oxide (IZO/Ag/IZO) multilayer as a highly transparent electrode. To verify the moiré reduction effect, we conducted a two-dimensional spectral analysis to calculate the spatial frequencies of the superimposed image of the display and the sensor patterns, and demonstrated experimentally that the proposed electrode greatly reduces the undesirable moiré phenomenon.

Metformin protects against retinal cell death in diabetic mice.

Retinal degeneration is an early feature of diabetic retinopathy, the major cause of blindness in the developed world. Here we investigated how the widely used antidiabetic drug metformin reduces retinal injury in diabetic mice. Metformin was orally administered to control mice or mice with streptozotocin-induced diabetes. Western blot analysis showed that levels of O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) and other related proteins such as carbohydrate-responsive element-binding protein (ChREBP) and thioredoxin-interacting protein (TXNIP) were significantly increased, and nuclear factor kappaB (NF-κB) and poly (ADP-ribose) polymerase (PARP) were activated in the diabetic retinas or retinal pigment epithelial (RPE) cells exposed to high glucose compared to controls. More importantly, RPE cells exposed to high glucose and treated with thiamet-G had higher levels of those proteins, demonstrating the role of elevated O-GlcNAcylation. Double immunofluorescence analysis revealed increased co-localization of terminal deoxynucleotide transferase-mediated dUTP nick-end labelling (TUNEL)-positive ganglion cells and OGT, ChREBP, TXNIP, or NF-κB in diabetic retinas compared to control retinas. Co-immunoprecipitation analysis showed that interaction between OGT and ChREBP or NF-κB was increased in diabetic retinas compared to control retinas, and this was accompanied by more cell death. Notably, metformin attenuated the increases in protein levels; reduced co-localization of TUNEL-positive ganglion cells and OGT, ChREBP, TXNIP, or NF-κB; and reduced interaction between OGT and ChREBP or NF-κB. Our results indicate that OGT inhibition might be one of the mechanisms by which metformin decreases retinal cell death.

O-linked-N-acetylglucosamine transferase is associated with metastatic spread of human papillomavirus E6 and E7 oncoproteins to the lungs of mice.

High-risk human papilloma virus (HPV) 16/18 infections are often found in lung cancer. The cellular mechanisms involved in the metastatic spread of HPV-infected cervical cancer cells remain largely elusive. High O-linked-N-acetylglucosamine (O-GlcNAc) modification has also been observed in lung cancer. In the present study, we assessed the relationship between O-GlcNAc transferase (OGT) and HPV 16/18 E6/E7, or C-X-C chemokine receptor type 4 (CXCR4), in HeLa cells and in lungs of xenografted mice. Depleting OGT with an OGT-specific shRNA significantly decreased levels of E6 and E7 oncoproteins in HeLa cells and xenograft tumors, and reduced tumor formation in vivo. Western blotting and immunofluorescence analysis showed significantly decreased expression levels of E6, E7, and HCF-1 in the lungs of xenografted mice treated with an OGT-specific shRNA compared to those treated with non-targeting shRNA. Additionally, levels of E7 or OGT co-localized with Ki-67 were significantly decreased in the lungs of xenografted mice treated with OGT-specific shRNA compared to those treated with non-targeting shRNA. Moreover, levels of CXCR4 were significantly decreased in HeLa cells and in the lungs of xenografted mice treated with OGT-specific shRNA compared to those treated with non-targeting shRNA; this may be related to reduced adhesion or invasion of circulating HPV-positive tumor cells. These findings provide novel evidence that OGT functions in metastatic spread of HPV E6/E7-positive tumor cells to the lungs through E6/E7, HCF-1 and CXCR4, suggesting OGT might be a therapeutic target for HPV-positive lung cancer.

Decreased levels of RGS4 in the paraventricular nucleus facilitate GABAergic inhibition during the acute stress response.

A healthy acute stress response requires both rapid increase and rapid clearance of blood corticosteroids. We previously showed that regulators of G-protein signaling 4 (RGS4), which decreases in the paraventricular nucleus (PVN) during acute stress, forms a complex with the GABAB receptor. In the present study, we show that this decrease in RGS4 levels in the PVN during an acute stress response facilitates the return of blood corticosteroids to basal levels. Moreover, the effect of RGS4 decrease is attenuated by a GABAB receptor antagonist. These results suggest that RGS4 in the PVN regulates blood corticosteroid-related GABAB receptor signaling during the acute stress response.

Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice.

Sirtuin 1 (SIRT1) is a mammalian NAD(+)-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-κB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

Tonicity-responsive enhancer binding protein regulates the expression of aldose reductase and protein kinase C δ in a mouse model of diabetic retinopathy.

Recent studies revealed that Tonicity-responsive enhancer binding protein (TonEBP) directly regulates the transcription of aldose reductase (AR), which catalyzes the first step of the polyol pathway of glucose metabolism. Activation of protein kinase C δ (PKCδ) is dependent on AR and it has been linked to diabetic complications. However, whether TonEBP affects expressions of AR and PKCδ in diabetic retinopathy was not clearly shown. In this study, we used TonEBP heterozygote mice to study the role of TonEBP in streptozotocin (STZ)-induced diabetic retinopathy. We performed immunofluorescence staining and found that retinal expressions of AR and PKCδ were significantly reduced in the heterozygotes compared to wild type littermates, particularly in ganglion cell layer. To examine further the effect of TonEBP reduction in retinal tissues, we performed intravitreal injection of TonEBP siRNA and confirmed the decrease in AR and PKCδ levels. In addition, we found that a proapoptotic factor, Bax level was reduced and a survival factor, Bcl2 level was increased after injection of TonEBP siRNA, indicating that TonEBP mediates apoptotic cell death. In parallel, TonEBP siRNA was applied to the in vitro human retinal pigment epithelial (ARPE-19) cells cultured in high glucose media. We have consistently found the decrease in AR and PKCδ levels and changes in apoptotic factors for survival. Together, these results clearly demonstrated that hyperglycemia-induced TonEBP plays a crucial role in increasing AR and PKCδ levels and leading to apoptotic death. Our findings suggest that TonEBP reduction is an effective therapeutic strategy for diabetic retinopathy.

Cancer cells forgo translating mRNA transcribed from genes of nonspecialized tasks.

The coupling of transcription and translation enables prokaryotes to regulate mRNA stability and reduce nonfunctional transcripts. Eukaryotes evolved other means to perform these functions. Here, we quantify the disparity between gene expression and protein levels and attempt to explain its origins. We collected publicly available simultaneous measurements of gene expression, protein level, division rate, and growth inhibition of breast cancer cells under drug perturbation. We used the cell lines as entities with shared origin, different evolutionary trajectories, and cancer hallmarks to define tasks subject to specializing and trading-off. We observed varying average mRNA and protein correlation across cell lines, and it was consistently higher for the gene products in the cancer hallmarks. The enrichment of hallmark gene products signifies the resources invested in it as a task. Enrichment based on mRNA or protein abundance corresponds to the relative resources dedicated to transcription and translation. The differences in gene- and protein-based enrichment correlated with nominal division rates but not growth inhibition under drug perturbations. Comparing the range of enrichment scores of the hallmarks within each cell signifies the resources dedicated to each. Cells appear to have a wider range of enrichment in protein synthesis relative to gene transcription. The difference and range of enrichment of the hallmark genes and proteins correlated with cell division and inhibition in response to drug treatments. We posit that cancer cells may express the genes coding for seemingly nonspecialized tasks but do not translate them to the corresponding proteins. This trade-off may cost the cells under normal conditions but confer benefits during stress.