Electrostatic moiré potential from twisted hexagonal boron nitride layers.

Moiré superlattices host a rich variety of correlated electronic phases. However, the moiré potential is fixed by interlayer coupling, and it is dependent on the nature of carriers and valleys. In contrast, it has been predicted that twisted hexagonal boron nitride (hBN) layers can impose a periodic electrostatic potential capable of engineering the properties of adjacent functional layers. Here, we show that this potential is described by a theory of electric polarization originating from the interfacial charge redistribution, validated by its dependence on supercell sizes and distance from the twisted interfaces. This enables controllability of the potential depth and profile by controlling the twist angles between the two interfaces. Employing this approach, we further demonstrate how the electrostatic potential from a twisted hBN substrate impedes exciton diffusion in semiconductor monolayers, suggesting opportunities for engineering the properties of adjacent functional layers using the surface potential of a twisted hBN substrate.

Life goal selection pattern and purpose in adolescence: A latent class analysis.

PURPOSE: This study aims to investigate the goal selection patterns among adolescents and examines the extent to which goals focused on oneself, relationships, and the larger community were associated with variability of daily purpose and mean level sense of purpose in life. METHODS: Participants were 213 high school students with an average age of 15.18 years in an urban public school district in the Northeast United States. Students were asked to select their three most important goals one time and report on their sense of purpose once a day for 3 weeks in spring of 2022. Latent class analysis was used to classify students by the type of goals selected. Differences in the overall sense of purpose and its subscales by class were examined. RESULTS: A model with four classes (Self and Inner Circle, Inner Circle, Other-Oriented, and Self-Oriented) best fits the data. There were no statistical group differences in the variability of daily purpose and overall sense of purpose. Only one pairwise comparison was significant and indicated that students in the Other-Oriented group perceived their purpose as more meaningful than students in the Self and Inner Circle group. CONCLUSIONS: Findings from this study provide a lens into goal prioritization patterns among adolescents. Further, although students who were more likely to select other-oriented goals had somewhat higher perceptions of sense of purpose, findings support the concept of equifinality by suggesting that a sense of purpose may be actualized through a diverse set of specific goals.

Degradation of methyl orange by pyrite activated persulfate oxidation: mechanism, pathway and influences of water substrates.

Degradation mechanism of methyl orange (MO), a typical azo dye, with pyrite (FeS2) activated persulfate (PS) was explored. The results showed that when the initial concentration of MO was 0.1 mM, FeS2 was 1.6 g/L and PS was 1.0 mM, the removal rate of MO could reach 92.9% in 150 min, and the removal rate of total organic carbon could reach 14.1%. In addition, both pH ≤ 2 and pH ≥ 10 could have an inhibitory effect in the FeS2/PS system. Furthermore, Cl- and low concentrations of HCO-3 had little effect on the degradation of MO with FeS2/PS. However, H2PO-4 and high concentrations of HCO-3 could inhibit the degradation of MO in the system. Besides, MO in river water and tap water were not degraded in FeS2/PS system, but acidification (pH = 4) would greatly promote the degradation. In addition, the removal rate of MO with FeS2/PS could still reach about 90% after five cycles of FeS2. Furthermore, the intermediates and possible degradation pathways were speculated by LC-MS, and the degradation mechanism of MO by FeS2/PS was that the cycle of Fe(III)/Fe(II) could continuously activate persulfate to produce SO4•-. The results could provide technical support for azo dye degradation in the FeS2/PS system.

Association between diabetes mellitus and lung cancer: Meta-analysis.

BACKGROUND: This study aimed to summarize the association between diabetes mellitus (DM) and the incidence of lung cancer using a meta-analysis of cohort studies. MATERIALS AND METHODS: We systematically searched PubMed, Embase and the Cochrane Library to identify potential cohort studies. Relative risk (RR) was used to calculate the association between DM and the risk of lung cancer. Subgroup analysis, sensitivity analysis and test for publication bias were performed. Twenty cohort studies were selected. RESULTS: The participants with DM showed little or no significant effect on the risk of lung cancer (RR: 1.10; 95% CI: 0.99-1.23; P = .087). DM was not associated with the risk of lung cancer in men (RR: 1.11; 95%CI: 0.92-1.35; P = .270), but a significant association was observed in women (RR: 1.18; 95%CI: 1.10-1.28; P < .001). Subgroup analysis suggested that smoker status was confounding variables that could bias the relationship between DM and the incidence of lung cancer. CONCLUSIONS: This meta-analysis suggests that DM has no significant impact on the incidence of lung cancer in men but has a harmful effect on women.

Correction to: The effect of corticosteroids on the mortality of patients with influenza pneumonia: a systematic review and meta-analysis.

An amendment to this paper has been published and can be accessed via the original article.

The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis.

BACKGROUND: The effect of corticosteroids on clinical outcomes in patients with influenza pneumonia remains controversial. We aimed to further evaluate the influence of corticosteroids on mortality in adult patients with influenza pneumonia by comparing corticosteroid-treated and placebo-treated patients. METHODS: The PubMed, Embase, Medline, Cochrane Central Register of Controlled Trials (CENTRAL), and Information Sciences Institute (ISI) Web of Science databases were searched for all controlled studies that compared the effects of corticosteroids and placebo in adult patients with influenza pneumonia. The primary outcome was mortality, and the secondary outcomes were mechanical ventilation (MV) days, length of stay in the intensive care unit (ICU LOS), and the rate of secondary infection. RESULTS: Ten trials involving 6548 patients were pooled in our final analysis. Significant heterogeneity was found in all outcome measures except for ICU LOS (I2 = 38%, P = 0.21). Compared with placebo, corticosteroids were associated with higher mortality (risk ratio [RR] 1.75, 95% confidence interval [CI] 1.30 ~ 2.36, Z = 3.71, P = 0.0002), longer ICU LOS (mean difference [MD] 2.14, 95% CI 1.17 ~ 3.10, Z = 4.35, P < 0.0001), and a higher rate of secondary infection (RR 1.98, 95% CI 1.04 ~ 3.78, Z = 2.08, P = 0.04) but not MV days (MD 0.81, 95% CI - 1.23 ~ 2.84, Z = 0.78, P = 0.44) in patients with influenza pneumonia. CONCLUSIONS: In patients with influenza pneumonia, corticosteroid use is associated with higher mortality. TRIAL REGISTRATION: PROSPERO (ID: CRD42018112384 ).

Can corticosteroids reduce the mortality of patients with severe sepsis? A systematic review and meta-analysis.

BACKGROUND: The effects of corticosteroids on clinical outcomes of patients with sepsis remains controversial. We aimed to further determine the effectiveness of corticosteroids in reducing mortality in adult patients with severe sepsis by comparison with placebo. METHODS: Pubmed, Embase, Medline, Cochrane Central Register of Controlled Trials (CENTRAL) as well as the Information Sciences Institute (ISI) Web of Science were searched for all controlled studies that compared corticosteroids and placebo in adult patients with severe sepsis. The primary outcome was the mortality 28-day mortality and the secondary outcomes were mortality at longest follow up, occurrence, and reoccurrence of septic shock. RESULTS: A total of 19 trials involving 7035 patients were pooled in our final analyses. No significant heterogeneity was found in any of the outcome measures. Compared with placebo, corticosteroids were associated with a lower 28-day mortality (RR 0.91, 95% CI 0.85-0.98, Z = 2.57, P = 0.01) both in patients having sepsis and in those who developed septic shock (RR 0.92, 95% CI 0.85-0.99, Z = 2.19, P = 0.03), while no significant difference was found in mortality with the longest follow up in patients either having sepsis (RR 0.94, 95% CI 0.89-1.00, Z = 1.93, P = 0.05), or occurrence (RR 0.83, 95% CI 0.56-1.24, Z = 0.90, P = 0.37) or reoccurrence of septic shock (RR 1.08, 95% CI 1.00-1.16, Z = 1.89, P = 0.06). CONCLUSIONS: Corticosteroids were effective in reducing the 28-day mortality in patients with severe sepsis and in those with septic shock.

The effect of hyperoxia on mortality in critically ill patients: a systematic review and meta analysis.

BACKGROUND: Studies investigating the role of hyperoxia in critically ill patients have reported conflicting results. We did this analysis to reveal the effect of hyperoxia in the patients admitted to the intensive care unit (ICU). METHODS: Electronic databases were searched for all the studies exploring the role of hyperoxia in adult patients admitted to ICU. The primary outcome was mortality. Random-effect model was used for quantitative synthesis of the adjusted odds ratio (aOR). RESULTS: We identified 24 trials in our final analysis. Statistical heterogeneity was found between hyperoxia and normoxia groups in patients with mechanical ventilation (I2 = 92%, P < 0.01), cardiac arrest(I2 = 63%, P = 0.01), traumatic brain injury (I2 = 85%, P < 0.01) and post cardiac surgery (I2 = 80%, P = 0.03). Compared with normoxia, hyperoxia was associated with higher mortality in overall patients (OR 1.22, 95% CI 1.12~1.33), as well as in the subgroups of cardiac arrest (OR 1.30, 95% CI 1.08~1.57) and extracorporeal life support (ELS) (OR 1.44, 95% CI 1.03~2.02). CONCLUSIONS: Hyperoxia would lead to higher mortality in critically ill patients especially in the patients with cardiac arrest and ELS.

Chromogenic, Fluorescent, and Redox Sensors for Multichannel Imaging and Detection of Hydrogen Peroxide in Living Cell Systems.

Hydrogen peroxide (H2O2) is an important reactive oxygen species (ROS). Maintaining the H2O2 concentration at a normal level is critical to achieve the normal physiological activities of cells, which otherwise might trigger various diseases. Therefore, it is necessary to develop new and practical multisignaling sensors for both visualization of intracellular H2O2 and accurate detection of extracellular H2O2. In this paper, a novel multichannel signaling fluorescence-electrochemistry combined probe 1 (FE-H2O2) is presented for imaging and detection of H2O2 in living cell systems. In our design, the probe FE-H2O2 consists of a H2O2 reaction site and 4-ferrocenyl(vinyl)pyridine unit which affords chromogenic, fluorescent, and electrochemical signals. These structural motifs yield a combined chromogenic, fluorescent, and redox sensor in a single molecule. Probe FE-H2O2 showed a "Turn-On" fluorescence response to H2O2, which can be used for monitoring intracellular H2O2 in vivo. Furthermore, the electrochemical response of probe FE-H2O2 was decreased after the addition of H2O2, which can be applied for accurate detection of H2O2 released from living cells. When the fluorescence imaging method is combined with electrochemical analysis technology, it is hopeful that the well-designed multimodule probe can serve as a practical tool for understanding the metabolism and homeostasis of H2O2 in a complex biological system.

The effect of aspirin in preventing the acute respiratory distress syndrome/acute lung injury: A meta-analysis.

BACKGROUND: The effects of aspirin in preventing the occurrence of acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) among adult patients are controversial. We aimed to further determine the effectiveness of aspirin in reducing the rate of ARDS/ALI. METHODS: The Pubmed, Embase, Medline, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) as well as the Information Sciences Institute (ISI) Web of Science were searched for all controlled studies that research the role of aspirin in adult patients who have the risk of ARDS/ALI. The outcomes were the ARDS/ALI rate and the mortality. Cochrane systematic review software, Review Manager (RevMan), the R software for statistical computing version 3.2.0, and the metafor package were used to test the hypothesis by Mann-Whitney U test. The heterogeneity test and sensitivity analyses were conducted, and random-effects or fixed-effects model was applied to calculate odds ratio (OR) and mean difference (MD) for dichotomous and continuous data, respectively. RESULTS: Six trials involving 6562 patients were pooled in our final study. No significant heterogeneity was found in outcome measures. Aspirin could reduce the rate of ARDS/ALI (OR 0.71, 95% confidence interval (CI) 0.58-0.86) but not the mortality (OR 0.87, 95% CI 0.71-1.07). CONCLUSIONS: In patients with risk of ARDS/ALI, aspirin could provide protective effect on the rate of ARDS/ALI, but it could not reduce the mortality.

The effect of high-flow nasal cannula in reducing the mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy and noninvasive positive pressure ventilation. A systematic review and meta-analysis.

BACKGROUND: The effects of high flow nasal cannula (HFNC) on adult patients when used before mechanical ventilation (MV) are unclear. We aimed to determine the effectiveness of HFNC when used before MV by comparison to conventional oxygen therapy (COT) and noninvasive positive pressure ventilation (NIPPV). METHODS: The Pubmed, Embase, Medline, Cochrane Central Register of Controlled Trials (CENTRAL) as well as the Information Sciences Institute (ISI) Web of Science were searched for all the controlled studies that compared HFNC with NIPPV and COT when used before MV in adult patients. The primary outcome was the rate of endotracheal intubation and the secondary outcomes were intensive care unit (ICU) mortality and length of ICU stay (ICU LOS). RESULTS: Eight trials with a total of 1084 patients were pooled in our final studies. No significant heterogeneity was found in outcome measures. Compared both with COT and NIPPV, HFNC could reduce both of the rate of endotracheal intubation (OR 0.62, 95% CI 0.38-0.99, P=0.05; OR 0.48, 95% CI 0.31-0.73, P=0.0006) and ICU mortality (OR 0.47, 95% CI 0.24-0.93, P=0.03; OR 0.36, 95% CI 0.20-0.63, P=0.0004). As for the ICU LOS, we did not find any advantage of HFNC over COT or NIPPV. CONCLUSIONS: When used before MV, HFNC can improve the prognosis of patients compared both with the COT and NIPPV.

Can body mass index predict clinical outcomes for patients with acute lung injury/acute respiratory distress syndrome? A meta-analysis.

BACKGROUND: The effects of body mass index (BMI) on the prognosis of acute respiratory distress syndrome (ARDS) are controversial. We aimed to further determine the relationship between BMI and the acute outcomes of patients with ARDS. METHODS: We searched the Pubmed, Embase, Medline, Cochrane Central Register of Controlled Trials (CENTRAL), and ISI Web of Science for trials published between 1946 and July 2016, using "BMI" or "body mass index" or "overweight" or "obese" and "ARDS" or "ALI" or "acute respiratory distress syndrome" or "acute lung injury", without limitations on publication type or language. Heterogeneity and sensitivity analyses were conducted, and a random-effects model was applied to calculate the odds ratio (OR) or mean difference (MD). Review Manager (RevMan) was used to test the hypothesis using the Mann-Whitney U test. The primary outcome was unadjusted mortality, and secondary outcomes included mechanical ventilation (MV)-free days and length of stay (LOS) in the intensive care unit (ICU) and in hospital. RESULTS: Five trials with a total of 6268 patients were pooled in our final analysis. There was statistical heterogeneity between normal-weight and overweight patients in LOS in the ICU (I 2 = 71%, χ 2 = 10.27, P = 0.02) and in MV-free days (I 2 = 89%, χ 2 = 18.45, P < 0.0001). Compared with normal weight, being underweight was associated with higher mortality (OR 1.59, 95% confidence interval (CI) 1.22, 2.08, P = 0.0006), while obesity and morbid obesity were more likely to result in lower mortality (OR 0.68, 95% CI 0.57, 0.80, P < 0.00001; OR 0.72, 95% CI 0.56, 0.93, P = 0.01). MV-free days were much longer in patients with morbid obesity (MD 2.64, 95% CI 0.60, 4.67, P = 0.01), but ICU and hospital LOS were not influenced by BMI. An important limitation of our analysis is the lack of adjustment for age, sex, illness severity, comorbid illness, and interaction of outcome parameters. CONCLUSIONS: Obesity and morbid obesity are associated with lower mortality in patients with ARDS.

The effect of sedation and/or analgesia as rescue treatment during noninvasive positive pressure ventilation in the patients with Interface intolerance after Extubation.

BACKGROUND: Sedation and/or analgesia can relieve the patient-ventilator asynchrony. However, whether sedation and/or analgesia can benefit the clinical outcome of the patients with interface intolerance is still unclear. METHODS: A retrospective study was performed on patients with interface intolerance who received noninvasive positive pressure ventilation (NIPPV) after extubation in seven intensive care units (ICU) of West China Hospital, Sichuan University. The primary outcome was rate of NIPPV failure (defined as need for reintubation and mechanical ventilation); Secondary outcomes were hospital mortality rate and length of ICU stay after extubation. RESULTS: A total of 80 patients with oral-nasal mask (90%) and facial mask (10%) were included in the analysis. 41 out of 80 patients received sedation and/or analgesia treatment (17 used analgesia, 11 used sedation and 13 used both) at some time during NIPPV. They showed a decrease of NIPPV failure rate, (15% vs. 38%, P = 0.015; adjusted odd ratio [OR] 0.29, 95% confidence interval [CI] 0.10-0.86, P = 0.025), mortality rate (7% vs. 33%, P = 0.004; adjusted OR 0.14, 95% CI 0.03-0.60, P = 0.008), and the length of ICU stay after extubation. CONCLUSION: This clinical study suggests that sedation and/or analgesia treatment can decrease the rate of NIPPV failure, hospital mortality rate and ICU LOS in patients with interface intolerance after extubution during NIPPV.

Can high-flow nasal cannula reduce the rate of reintubation in adult patients after extubation? A meta-analysis.

BACKGROUND: The effects of high flow nasal cannula (HFNC) on adult patients after extubation remain controversial. We aimed to further determine the effectiveness of HFNC in comparison to noninvasive positive pressure ventilation (NIPPV) and conventional oxygen therapy (COT). METHODS: The Pubmed, Embase, Medline, Cochrane Central Register of Controlled Trails (CENTRAL) as well as the Information Sciences Institute (ISI) Web of Science were searched for all the controlled study comparing HFNC with NIPPV and COT in adult patients after extubation. The primary outcome was rate of reintubation and the secondary outcomes were intensive care unit (ICU) mortality and length of ICU stay (ICU LOS). RESULTS: Eight trials with a total of 2936 patients were pooled in our final studies. No significant heterogeneity was found in outcome measures. Compared with COT, HFNC was associated with lower rate of reintubation (Z = 2.97, P = 0.003), and the same result was found in the comparison between HFNC and NIPPV (Z = 0.87, P = 0.38). As for the ICU mortality and ICU LOS, we did not find any advantage of HFNC over COT or NIPPV. CONCLUSIONS: In patients after extubation, HFNC is a reliable alternative of NIPPV to reduce rate of reintubation compared with COT.

Nuclear export of PML promotes p53-mediated apoptosis and ferroptosis.

Promyelocytic leukemia protein (PML), a tumor suppressor protein, plays a key role in cell cycle regulation, apoptosis, senescence and cellular metabolism. Here, we report that PML promotes apoptosis and ferroptosis. Our data showed that PML over-expression inhibited cell proliferation and migration. PML over-expression increased apoptotic cells, nuclear condensation and the loss of mitochondrial membrane potential, accompanied by regulation of Bcl-2 family proteins and reactive oxygen species (ROS) level, suggesting that PML enhanced apoptosis. Meanwhile, PML over-expression not only increased lipid ROS accumulation and Malondialdehyde (MDA) content but also downregulated solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, indicating that PML enhanced ferroptosis. Additionally, knockdown of p53 attenuated the effect of PML on SLC7A11 and GPX4, and inhibited the increase of lipid ROS and ROS by PML over-expression. Moreover, translocation of PML from nucleus to cytoplasm not only promoted apoptosis and ferroptosis, but also inhibited cell proliferation. Taken together, PML promotes apoptosis and ferroptosis, in which the mediation of p53 and the nuclear export of PML play important roles.

Sleep apnea-related hypoxic burden as a predictor of pregnancy and neonatal outcome.

STUDY OBJECTIVES: To determine the clinical impact of sleep apnea-related hypoxic burden in pregnant women and neonates. METHODS: This is a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) study. Hypoxia burden was calculated from the home sleep apnea test (HSAT) and defined as the total area under respiratory events. Logistic regression analysis assessed the relationship between hypoxia burden and pregnancy/neonatal outcomes. RESULTS: A total of 3006 subjects in the early term, and 2326 subjects in the middle term of pregnancy, had HSAT. A hypoxic burden greater than 6.8%min was present in 1740 at early term and associated with a higher risk of preeclampsia (odds ratio 1.297, 95 % confidence interval 1.032-1.630, p: 0.026) after adjusted by obstructive sleep apnea (OSA) severity. In the middle term, 1058 subjects had a hypoxia burden more than 11.8%min, which was a predictor for higher incidence of gestational diabetes (OR 1.795, 95 % CI 1.097-2.938, p: 0.020) and an Apgar <7 at 1 min (OR 1.446, 95 % CI 1.079-1.939, p: 0.012) after adjusted by obstructive sleep apnea (OSA) severity. After adjusted by oxygenation disturbance index, HB was not related with Apgar <7 at 1 min (p:0.565). CONCLUSIONS: The hypoxic burden is an independent predictor for preeclampsia and gestational diabetes and an Apgar <7 at 1 min.

The association between the effective apnea-hypopnea index and blood pressure reduction efficacy following CPAP/oxygen treatment.

BACKGROUND: The effect of sleep apnea treatment on reducing cardiovascular disease risk remains inconclusive. This study aims to assess if the effective apnea hypopnea index (eAHI), a measure of residual sleep apnea burden post-treatment, is a factor in determining blood pressure (BP) response to continuous positive airway pressure therapy. The eAHI integrates time on therapy, residual apnea, and % of sleep time untreated. METHODS: A secondary analysis of the Heart Biomarker Evaluation in Apnea Treatment (HeartBEAT) study, a randomized, controlled, parallel group assessment of continuous positive airway pressure (CPAP), oxygen and sleep hygiene. The Delta-AHI (▲AHI) was defined as the difference between baseline AHI and effective AHI at 12 weeks. Logistic and linear regression models estimated the predictors for nocturnal systolic BP change following sleep apnea therapy. RESULTS: One hundred and sixty-nine subjects with a mean age of 62.82 ± 6.99 years were included in the final analysis. Fifty subjects had ▲AHI ≤8/hour of sleep and 119 subjects were higher. After adjustment, baseline mean nighttime systolic blood pressure (OR 1.036, 95% CI 1.015-1.058, p: 0.001) and ▲AHI ≥8/hour (OR 2.406, 95% CI 1.116-5.185, p:0.025) were independent predictors for mean nighttime systolic blood pressure change >3 mm Hg. The higher effective AHI was negatively related with BNP (ß: -2.564, SE: 1.167, p: 0.029) and positively related with troponin change (ß: 0.703, SE: 0.256, p: 0.007). CONCLUSION: The ▲AHI was an independent predictor of the blood pressure response to sleep apnea treatment. REGISTER NUMBER: NCT01086800.

Psychrobacter species enrichment as potential microplastic degrader and the putative biodegradation mechanism in Shenzhen Bay sediment, China.

Microplastic (MP) pollution has emerged as a pressing environmental concern due to its ubiquity and longevity. Biodegradation of MPs has garnered significant attention in combatting global MP contamination. This study focused on MPs within sediments near the sewage outlet of Shenzhen Bay. The objective was to elucidate the microbial communities in sediments with varying MPs, particularly those with high MP loads, and to identify microorganisms associated with MP degradation. The results revealed varying MP abundance, ranging from 211 to 4140 items kg-1 dry weight (d. w.), with the highest concentration observed near the outfall. Metagenomic analysis confirmed the enrichment of Psychrobacter species in sediments with high MP content. Psychrobacter accounted for ∼16.71% of the total bacterial community and 41.71% of hydrocarbon degrading bacteria at the S3 site, exhibiting a higher abundance than at other sampling sites. Psychrobacter contributed significantly to bacterial function at S3, as evidenced by the Kyoto Encyclopedia of Genes and Genomes pathway and enzyme analysis. Notably, 28 enzymes involved in MP biodegradation were identified, predominantly comprising oxidoreductases, hydrolases, transferases, ligases, lyases, and isomerases. We propose a putative mechanism for MP biodegradation, involving the breakdown of long-chain plastic polymers and subsequent oxidation of short-chain oligomers, ultimately leading to thorough mineralization.

YAP upregulates AMPKα1 to induce cancer cell senescence.

Yes-associated protein (YAP)-a major effector protein of the Hippo pathway- regulates cell proliferation, differentiation, apoptosis, and senescence. Amp-activated protein kinase (AMPK) is a key sensor that monitors cellular nutrient supply and energy status. Although YAP and AMPK are considered to regulate cellular senescence, it is still unclear whether AMPK is involved in YAP-regulated cellular senescence. Here, we found that YAP promoted AMPKα1 aggregation and localization around mitochondria by co-transfecting CFP-YAP and YFP-AMPKα1 plasmids. Subsequent live cell fluorescence resonance energy transfer (FRET) assay did not exhibit direct interaction between YAP and AMPKα1. FRET, Co-immunoprecipitation, and western blot experiments revealed that YAP directly bound to TEAD, enhancing the expression of AMPKα1 and p-AMPKα. Treatment with verteporfin inhibited YAP's binding to TEAD and reversed the elevated expression of AMPKα1 in the cells overexpressing CFP-YAP. Verteporfin also reduced the proportion of AMPKα1 puncta in the cells co-expressing CFP-YAP and YFP-AMPKα1. In addition, the AMPKα1 puncta were demonstrated to inhibit cell viability, autophagy, and proliferation, and ultimately promote cell senescence. In conclusion, YAP binds to TEAD to upregulate AMPKα1 and promotes the formation of AMPKα1 puncta around mitochondria under the condition of co-expression of CFP-YAP and YFP-AMPKα1, in which AMPKα1 puncta lead to cellular senescence.

Unraveling the mechanism of thermotolerance by Set302 in Cryptococcus neoformans.

The underlying mechanism of thermotolerance, which is a key virulence factor essential for pathogenic fungi such as Cryptococcus neoformans, is largely unexplored. In this study, our findings suggest that Set302, a homolog of Set3 and a subunit of histone deacetylase complex Set3C, contributes to thermotolerance in C. neoformans. Specifically, the deletion of the predicted Set3C core subunit, Set302, resulted in further reduction in the growth of C. neoformans at 39°C, and survival of transient incubation at 50°C. Transcriptomics analysis revealed that the expression levels of numerous heat stress-responsive genes altered at both 30°C and 39°C due to the lack of Set302. Notably, at 39°C, the absence of Set302 led to the downregulation of gene expression related to the ubiquitin-proteasome system (UPS). Based on the GFP-α-synuclein overexpression model to characterize misfolded proteins, we observed a pronounced accumulation of misfolded GFP-α-synuclein at 39°C, consequently inhibiting C. neoformans thermotolerance. Furthermore, the loss of Set302 exacerbated the accumulation of misfolded GFP-α-synuclein during heat stress. Interestingly, the set302∆ strain exhibited a similar phenotype under proteasome stress as it did at 39°C. Moreover, the absence of Set302 led to reduced production of capsule and melanin. set302∆ strain also displayed significantly reduced pathogenicity and colonization ability compared to the wild-type strain in the murine infection model. Collectively, our findings suggest that Set302 modulates thermotolerance by affecting the degradation of misfolded proteins and multiple virulence factors to mediate the pathogenicity of C. neoformans.IMPORTANCECryptococcus neoformans is a pathogenic fungus that poses a potential and significant threat to public health. Thermotolerance plays a crucial role in the wide distribution in natural environments and host colonization of this fungus. Herein, Set302, a critical core subunit for the integrity of histone deacetylase complex Set3C and widely distributed in various fungi and mammals, governs thermotolerance and affects survival at extreme temperatures as well as the formation of capsule and melanin in C. neoformans. Additionally, Set302 participates in regulating the expression of multiple genes associated with the ubiquitin-proteasome system (UPS). By eliminating misfolded proteins under heat stress, Set302 significantly contributes to the thermotolerance of C. neoformans. Moreover, Set302 regulates the pathogenicity and colonization ability of C. neoformans in a murine model. Overall, this study provides new insight into the mechanism of thermotolerance in C. neoformans.