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Cadmium (Cd) is a high‐risk pathogenic toxin for hepatic diseases. Excessive mitophagy is a hallmark in Cd‐induced hepatotoxicity. However, the underlying mechanism remains obscure. Mitochondrial calcium uniporter (MCU) is a key regulator for mitochondrial and cellular homeostasis. Here, Cd exposure upregulated MCU expression and increased mitochondrial Ca2+ uptake are found. MCU inhibition through siRNA or by Ru360 significantly attenuates Cd‐induced excessive mitophagy, thereby rescues mitochondrial dysfunction and increases hepatocyte viability. Heterozygous MCU knockout mice exhibit improved liver function, ameliorated pathological damage, less mitochondrial fragmentation, and mitophagy after Cd exposure. Mechanistically, Cd upregulates MCU expression through phosphorylation activation of cAMP‐response element binding protein at Ser133(CREBS133) and subsequent binding of MCU promoter at the TGAGGTCT, ACGTCA, and CTCCGTGATGTA regions, leading to increased MCU gene transcription. The upregulated MCU intensively interacts with voltage‐dependent anion‐selective channel protein 1 (VDAC1), enhances its dimerization and ubiquitination, resulting in excessive mitophagy. This study reveals a novel mechanism, through which Cd upregulates MCU to enhance mitophagy and hepatotoxicity. After cadmium (Cd) exposure, the cytosolic Ca2+‐dependent increases and activation of cAMP‐response element binding protein (CREB) orchestrally upregulates mitochondrial calcium uniporter (MCU) gene transcription, and promotes its translocation into mitochondria. The upregulated MCU in mitochondria directly interacts with voltage‐dependent anion‐selective channel protein 1 (VDAC1) and further enhances the dimerization and ubiquitination of VDAC1, which then overactivates mitophagy and leads to hepatocyte death.

Bending sensing was realized by constructing a tapered four-core optical fiber (TFCF) sensor. The four-core fiber (FCF) between the fan-in and fan-out couplers was tapered and the diameter became smaller, so that the distance between the four cores arranged in a square became gradually smaller to produce supermodes. The two ends of the TFCF were respectively connected to the fan-in and fan-out couplers so that the individual cores in the FCF could link to the separate single-mode fibers. A broadband light source (superluminescent diodes (SLD)) spanning 1250–1650 nm was injected into any one of the four cores, and the orientation was thus determined. In the tapering process, the remaining three cores gradually approached the excitation core in space to excite several supermodes based on the tri-core structure first, and then transited to the quadruple-core structure. The field distributions of the excited supermodes were asymmetric due to the corner-core excitation scheme, and the interference thus resulted in a higher measurement sensitivity. When the diameter of the TFCF was 7.5 μm and the tapered length was 2.21 mm, the sensitivity of the bending sensor could reach 16.12 nm/m−1.

Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate. In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736. Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6–6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group. Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes. Gilead Sciences.

Recent advance on highly realistic AI‐synthesised video approaches makes it hard to distinguish whether a speaker in video is real. Many existing DeepFakes detection approaches can be invalidated by using them as supervision in adversarial training, which in turn improves the performance of DeepFakes. This makes the problem a dilemma. However, human can recognise the identity of familiar persons by observing their motion styles. Inspired by this, the paper proposes a novel method to recognise original speaker's identity clues in DeepFakes videos by learning individual motion styles. As a biological signature, motion styles can neither be used in the training process of DeepFakes nor be modified to deceive detection methods without reducing realistic performance. Also, this paper proposes a novel pipeline to continuously restore the original frames from DeepFakes videos without knowing the DeepFakes approach in advance. Based on above ideas, our scheme makes it possible to restore DeepFakes videos. Through training the cross‐modal transfer module, the appearance embedding can be inferred from the identity code. Extensive experiments are conducted to reveal the effectiveness of the method, it shows for the first time that the original persons can be identified automatically and the original video from DeepFakes videos can be generated.

Introduction and hypothesisThis study aimed to compare the expression levels of extracellular matrix (ECM) and apoptosis proteins in the uterosacral ligament (USL) of patients with and without pelvic organ prolapse (POP).MethodsThe USL were obtained from patients with POP-Q ≥ III (n = 35) and without POP (n = 20). Immunohistochemistry (IHC) staining and RT-qPCR were conducted to assess the protein and mRNA levels, respectively. The levels of type I collagen (COLI), type III collagen (COLIII), matrix metalloproteinase (MMP)1, MMP2, MMP9, tissue inhibitor of metalloproteinase (TIMP)1, TIMP2, estrogen receptor (ER)α, ERβ and apoptosis-related gene B cell lymphoma 2 (Bcl-2)-associated agonist of cell death (Bad) and Bcl-2-associated X (Bax) in the USL were analyzed.ResultsThe protein expression and mRNA levels of MMP2 and MMP9, mRNA levels of BAD and BAX, and protein expression of active cleaved-Caspase3 were significantly higher in the POP group. There were no evident differences in COLIII, MMP1 or ERβ expression at either the mRNA or protein level or in TIMP1, TIMP2 or Caspase3 by IHC between the two groups. However, obvious decreases in COLI and ERα were evident at both the mRNA and protein levels in the POP group, and the mRNA levels of TIMP1 and TIMP2 were also decreased compared to those of the control group.ConclusionECM in the USL tissues of POP patients is remodeled compared with non-POP patients and is characterized by decreased synthesis and increased degradation of collagen; moreover, the levels of the main proteins involved in apoptosis are increased in POP tissue.

Intracerebral hemorrhage (ICH) is a devastating disease, in which neuroinflammation substantially contributes to brain injury. Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier family, which uncouples oxidative phosphorylation from ATP synthesis by facilitating proton leak across the mitochondrial inner membrane. UCP2 has been reported to modulate inflammation. In this study we investigated whether and how UCP2 modulated neuroinflammation through microglia/macrophages following ICH in vitro and in vivo. We used an in vitro neuroinflammation model in murine BV2 microglia to mimic microglial activation following ICH. ICH in vivo model was established in mice through collagenase infusion into the left striatum. ICH mice were treated with anetholetrithione (ADT, 50 mg· kg −1  ·d −1 , ip) or the classical protonophoric uncoupler FCCP (injected into hemorrhagic striatum). We showed that the expression and mitochondrial location of microglial UCP2 were not changed in both in vitro and in vivo ICH models. Knockdown of UCP2 exacerbated neuroinflammation in BV2 microglia and mouse ICH models, suggesting that endogenous UCP2 inhibited neuroinflammation and therefore played a protective role following ICH. ADT enhanced mitochondrial ROS production thus inducing mitochondrial uncoupling and activating UCP2 in microglia. ADT robustly suppressed neuroinflammation, attenuated brain edema and improved neurological deficits following ICH, and these effects were countered by striatal knockdown of UCP2. ADT enhanced AMP-activated protein kinase (AMPK) activation in the hemorrhagic brain, which was abrogated by striatal knockdown of UCP2. Moreover, striatal knockdown of AMPK abolished the suppression of neuroinflammation by ADT following ICH. On the other hand, FCCP-induced mitochondrial uncoupling was independent of UCP2 in microglia; and striatal knockdown of UCP2 did not abrogate the suppression of neuroinflammation by FCCP in ICH mice. In conclusion, the uncoupling activity is essential for suppression of neuroinflammation by UCP2. We prove for the first time the concept that activators of endogenous UCP2 such as anetholetrithione are a new class of uncouplers with translational significance.

Acute liver failure (ALF) is a fatal clinical syndrome with no special drug. Recent evidence shows that modulation of macrophage to inhibit inflammation may be a promising strategy for ALF treatment. In this study we investigated the potential therapeutic effects of melittin, a major peptide component of bee venom both in mice model of ALF and in LPS-stimulated macrophages in vitro, and elucidated the underlying mechanisms. ALF was induced in mice by intraperitoneal injection of d -galactosamine/LPS. Then the mice were treated with melittin (2, 4, and 8 mg/kg, ip). We showed that melittin treatment markedly improved mortality, attenuated severe symptoms and signs, and alleviated hepatic inflammation in d -galactosamine/LPS-induced ALF mice with the optimal dose being 4 mg/kg. In addition, melittin within the effective doses did not cause significant in vivo toxicity. In LPS-stimulated RAW264.7 macrophages, melittin (0.7 μM) exerted anti-oxidation and anti-inflammation effects. We showed that LPS stimulation promoted aerobic glycolysis of macrophages through increasing glycolytic rate, upregulated the levels of Warburg effect-related enzymes and metabolites including lactate, LDHA, LDH, and GLUT-1, and activated Akt/mTOR/PKM2/HIF-1α signaling. Melittin treatment suppressed M2 isoform of pyruvate kinase (PKM2), thus disrupted the Warburg effect to alleviate inflammation. Molecular docking analysis confirmed that melittin targeted PKM2. In LPS-stimulated RAW264.7 macrophages, knockdown of PKM2 caused similar anti-inflammation effects as melittin did. In d -galactosamine/LPS-induced ALF mice, melittin treatment markedly decreased the expression levels of PKM2 and HIF-1α in liver. This work demonstrates that melittin inhibits macrophage activation-mediated inflammation via inhibition of aerobic glycolysis by targeting PKM2, which highlights a novel strategy of using melittin for ALF treatment.

Background The impact of psychological factors on oral health-related quality of life (OHRQoL) in prosthodontic patients should not be ignored. It is unclear about the extent to which stigma affects OHRQoL. The purpose of this study was to examine the relationship between stigma and OHRQoL in prosthodontic patients. Methods A total of 139 patients were included. Stigma Scale for Chronic Illness (SSCI) and its subscales (enacted stigma (ES) and internalized stigma (IS)) were used to measure stigma. OHRQoL was evaluated utilizing 5-item Oral Health Impact Profile (OHIP-5), Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) and its subscales (Social Impact (SI), Psychological Impact (PI), Aesthetic Concern (AC) and Dental Self-Confidence (DSC)). The association between SSCI and OHIP/PIDAQ was detected employing Spearman correlation coefficients and multiple linear regression analysis. Results Univariate analysis revealed that SSCI-total, ES, and IS scores were positively correlated with OHIP-5 (r s =0.350, 0.362, 0.279, P  < 0.001); the first three were also positively correlated with PIDAQ-total (r s =0.625, 0.589, 0.566, P  < 0.001), SI (r s =0.605, 0.548, 0.572, P  < 0.001), PI (r s =0.649, 0.634, 0.551, P  < 0.001), and AC (r s =0.580, 0.536, 0.534, P  < 0.001), except for PIDAQ-DSC ( P  > 0.05). Upon controlling for confounders in multivariate analysis, SSCI-total, ES and IS maintained a strong positive correlation with OHIP-5 (B = 0.354, 0.427, 0.866, P  < 0.001), PIDAQ-total (B = 2.329, 3.044, 5.138, P  < 0.001), SI (B = 1.057, 1.458, 2.155, P  < 0.001), PI (B = 0.813, 1.020, 1.893, P  < 0.001), and AC (B = 0.423, 0.561, 0.916, P  < 0.001), with the exception of PIDAQ-DSC ( P  > 0.05). Conclusions Stigma was negatively correlated with OHRQoL in prosthodontic patients. Higher stigma may impair OHRQoL. Interventions to alleviate the stigma in such patients is recommended to improve OHRQoL.

This study evaluated the utility of the 2HELPS2B score in predicting seizures from routine electroencephalographs (rEEGs). In total, 670 rEEGs obtained in a medical intensive care unit (MICU) between October 2018 and March 2023 were analyzed. More than 75% of these rEEGs were requested due to seizures and unexplained altered consciousness. Seizures occurred most frequently in patients with rEEGs characterized by brief, potentially ictal rhythmic discharges and electrographic seizures. A history of seizures was the most prevalent risk factor identified by the 2HELPS2B score. Seizures occurred in 28% of the cohort who experienced a seizure within 24 h of the rEEG and in 38% of the cohort who experienced a seizure before MICU discharge. Among the patients with suspected altered consciousness, the seizure incidence before MICU discharge (9.2%) was twice that within 24 h of the initial rEEG (4.7%). The seizure rate also increased from 12% for a 2HELPS2B score of 1 to 100% for scores ≥ 4. A score ≥ 2 was the optimal cutoff for predicting post-rEEG seizures and guiding antiseizure medication (ASM) treatment. Seizures occurred most frequently in patients whose ASMs were supplemented with new medications, and most new prescriptions for antiseizure medication were issued to patients with altered consciousness. These results demonstrate that the 2HELPS2B score can effectively predict seizures on the basis of rEEG results.

Purpose Differential diagnosis between central neurocytoma and ependymoma is very important for making preoperative scheme. We explored the application of diffusion-weighted imaging (DWI) combined with apparent diffusion coefficient (ADC) in differential diagnosis between both. Methods The data of preoperative MR plain and contrast-enhanced scan, DWI and ADC values of neoplastic solid parts from 18 cases with central neurocytoma and 19 cases with lateral ventricular ependymoma, were retrospectively analyzed. Mann-Whitney test was used for the comparison of ADC values between central neurocytoma and ependymoma. The application of ADC values in the differential diagnosis between central neurocytoma and ependymoma was evaluated by ROC curve. Results The lesions showed hyperintensity-dominant mixed signal intensity on DWI and mean ADC was (0.65 ± 0.13) × 10 −3  mm 2 /s in the 18 cases with central neurocytoma. In the 19 cases with ependymoma, 13 had hyperintensity-dominant mixed signal intensity on DWI and 6 had hypointensity-dominant mixed signal intensity on DWI, and mean ADC was (1.20 ± 0.23) × 10 −3  mm 2 /s. The mean ADC value was significantly higher in the 19 cases with ependymoma than in the 18 cases with central neurocytoma ( P  < 0.001). The ADC of 0.87 × 10 −3  mm 2 /s might be used as a threshold for differential diagnosis between central neurocytoma and ependymoma with an area under ROC curve of 0.98 ± 0.02 and a 95% confidence interval of 0.95–1.00. Its sensitivity, specificity, and accuracy were 90%, 100%, and 90%, respectively. Conclusion There is a certain overlap in MRI imaging features between central neurocytoma and ependymoma. DWI combined with ADC value can improve peoperative diagnostic accuracy.