PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury.

Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.

Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction.

Membrane dynamics are important to the integrity and function of mitochondria. Defective mitochondrial fusion underlies the pathogenesis of multiple diseases. The ability to target fusion highlights the potential to fight life-threatening conditions. Here we report a small molecule agonist, S89, that specifically promotes mitochondrial fusion by targeting endogenous MFN1. S89 interacts directly with a loop region in the helix bundle 2 domain of MFN1 to stimulate GTP hydrolysis and vesicle fusion. GTP loading or competition by S89 dislodges the loop from the GTPase domain and unlocks the molecule. S89 restores mitochondrial and cellular defects caused by mitochondrial DNA mutations, oxidative stress inducer paraquat, ferroptosis inducer RSL3 or CMT2A-causing mutations by boosting endogenous MFN1. Strikingly, S89 effectively eliminates ischemia/reperfusion (I/R)-induced mitochondrial damage and protects mouse heart from I/R injury. These results reveal the priming mechanism for MFNs and provide a therapeutic strategy for mitochondrial diseases when additional mitochondrial fusion is beneficial.

Feasibility and safety of endoscopic full-thickness resection for submucosal tumors in the upper gastrointestinal tract, including predominantly extraluminal submucosal tumors (with video).

OBJECTIVES: Endoscopic full-thickness resection (EFTR) for submucosal tumors (SMTs) has been technically challenging. This retrospective study aimed to evaluate the feasibility, safety, and efficacy of EFTR for upper gastrointestinal (GI) SMTs, including extraluminal lesions. METHODS: We retrospectively investigated 232 patients with SMTs who underwent EFTR from January 2014 to August 2023. Clinicopathologic characteristics, procedure-related parameters, adverse events (AEs), and follow-up outcomes were assessed in all patients. RESULTS: The en-bloc resection and en-bloc with R0 resection rates were 98.7% and 96.1%, respectively. The average endoscopic tumor size measured 17.2 ± 8.7 mm, ranging from 6 to 50 mm. The resection time and suture time were 49.0 ± 19.4 min and 22.5 ± 11.6 min, respectively. In all, 39 lesions (16.8%) exhibited predominantly extraluminal growth. Gastrointestinal stromal tumors (GISTs) were the predominant pathology, accounting for 78.4% of the cases. Twenty-one patients (9.1%) encountered complications, including pneumothorax (1/232, 0.43%), hydrothorax (1/232, 0.43%), localized peritonitis (3/232, 1.29%), and fever (16/232, 6.9%). Although the incidence of postoperative fever was notably higher in the predominantly extraluminal group (7/39, 17.9%) compared to the predominantly intraluminal group (9/193, 4.7%, P = 0.008), there were no significant differences in outcomes of the EFTR procedure. No instances of recurrence were observed during the mean follow-up period of 3.7 ± 2.3 years. CONCLUSION: EFTR was found to be feasible, safe, and effective for resecting upper GI SMTs, including lesions with predominantly extraluminal growth. Further validation in a prospective study is warranted.

Decreased plasma exposure of clopidogrel active metabolite in rats after long-term treatment with clopidogrel.

Clopidogrel (Clop) is oxidized by cytochrome P450s (CYPs) to an active thiol metabolite, Clop-AM, to inhibit platelet activation and aggregation. As an irreversible inhibitor of CYP2B6 and CYP2C19, clopidogrel may inhibit its own metabolism after long-term administration. The study compared the pharmacokinetic profiles of clopidogrel and its metabolites in rats receiving a single or a 2 week administration of Clop. The mRNA and protein levels of hepatic clopidogrel-metabolizing enzymes and their enzymatic activities were analyzed to explore their contribution to any altered plasma exposure of Clop and its metabolites. The results showed that long-term treatment with clopidogrel significantly decreased the AUC(0-t) and Cmax values of Clop-AM in rats, accompanied with markedly impaired catalytic activities of Clop-metabolizing CYPs including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4. It suggests that consecutive administration of Clop to rats decreases hepatic CYPs activities, which may, in turn, inhibit clopidogrel metabolism and then reduce Clop-AM plasma exposure. Therefore, long-term treatment with clopidogrel has the potential to reduce its anti-platelet activity and to increase the risk of drug-drug interaction.

Antibiotics-induced disruption of gut microbiota increases systemic exposure of clopidogrel active metabolite in type 2 diabetic rats.

Gut microbiota play an important role in the pathophysiology of type 2 diabetic mellitus (T2DM) and biodisposition of drugs. Our previous study demonstrated that T2DM rats had the decreased plasma exposure of clopidogrel active metabolite (Clop-AM) due to upregulation of P-glycoprotein (P-gp). However, whether the change to clopidogrel (Clop) disposition under T2DM condition is associated with gut microbiota needs to be elucidated. In the study, we used an antibiotic cocktail consisting of ampicillin, vancomycin, metronidazole, and neomycin to disrupt gut microbiota and observed their influence on pharmacokinetic profiles of Clop-AM. Antibiotic administration markedly alleviated T2DM rats' phenotype including hyperglycemia, insulin resistance, oxidative stress, inflammation, hyperlipidemia, and liver dysfunction. Meanwhile, treatment with antibiotics significantly reversed the reduced systemic exposure of Clop-AM in T2DM rats relative to control rats, which was associated with the decreased intestinal P-gp level that might promote Clop absorption, resulting in more Clop transformation to Clop-AM. Fecal microbiome analysis exhibited a serious disruption of gut microbiota after antibiotic treatment with the sharply reduced microbial load and the altered microbial composition. Interestingly, an in vitro study showed that antibiotics had no influence on P-gp mRNA leve in SW480 cells, suggesting the microbiome disruption, not the direct role of antibiotics on P-gp expression, contributes to the altered P-gp level and Clop disposition in T2DM rats. The findings add new insights into the potential impact of gut microbiota on Clop biodisposition. Significance Statement 1.Antibiotics increase systemic exposure of Clop-AM in T2DM rats, which is associated with the downregulation of P-gp level.2.Antibiotics-induced disruption of gut microbiota, not direct effect of antibiotics on P-gp and CYPs expression, contributes to the altered Clop disposition.3.Antibiotics also alleviate T2DM phenotype including hyperglycemia, hyperlipidemia, insulin resistance, liver dysfunction and inflammation.

Palladium-Catalyzed Enantioselective Intramolecular Heck Carbonylation Reactions: Asymmetric Synthesis of 2-Oxindole Ynones and Carboxylic Acids.

Herein, we report a Pd-catalyzed enantioselective domino Heck carbonylation reaction of o-iodoacrylanilides with terminal alkynes and water as the nucleophiles, affording a diversity of ß-carbonylated 2-oxindole derivatives bearing a 3,3-disubstituted all-carbon quaternary stereocenter, in high yields (55-99 %) with good to excellent enantioselectivities (up to 99 % ee). The synthetic utilities of the protocol were demonstrated in the gram-scale synthesis of 2-oxindole-derived ynone 3 ea and carboxylic acid 4 a, as well as the facile synthesis of chiral 2-oxindoles with a pyrazole or isoxazole moiety.

Poorly differentiated cluster grade-a vital predictor for lymph node metastasis and oncological outcomes in patients with T1 colorectal cancer: a retrospective study.

BACKGROUND: T1 colorectal cancers have a low lymph node metastasis rate and good prognosis. Thus, endoscopic resection is an attractive choice. This study aimed to describe the value of poorly differentiated cluster grade in identifying endoscopically curable T1 colorectal cancers. METHODS: We included 183 T1 colorectal cancer patients who underwent curative resection. Univariate and multivariate logistic regressions were used to identify lymph node metastasis predictors. The Akaike information criterion was used to determine whether poorly differentiated cluster grade was the best predictor. Backward regression was used to screen the variables. Survival analyses were conducted to determine the prognostic predictive power of poorly differentiated cluster grade. Correlations among predictors and concordance between our pathologists were also investigated. RESULTS: Poorly differentiated cluster grade was an independent predictor for lymph node metastasis (adjusted odds ratio [OR]G 3 = 0.001; 95% confidence interval [95% CI]G 3 = < 0.001, 0.139) in T1 colorectal cancer patients; moreover, it had the best predictive value (AIC = 61.626) among all indicators. It was also screened for inclusion in the predictive model. Accordingly, a high poorly differentiated cluster grade independently indicated shorter overall survival (hazard ratio [HR]G 2 = 4.315; 95% CIG 2 = 1.506, 12.568; HRG 3 = 5.049; 95% CIG 3 = 1.326, 19.222) and disease-free survival (HRG 3 = 6.621; 95% CIG 3 = 1.472, 29.786). CONCLUSIONS: Poorly differentiated cluster grade is a vital reference to manage T1 colorectal cancer. It could serve as an indicator to screen endoscopically curable T1 colorectal cancers.

Joint Communications and Sensing Employing Multi- or Single-Carrier OFDM Communication Signals: A Tutorial on Sensing Methods, Recent Progress and a Novel Design.

Joint communications and sensing (JCAS) has recently attracted extensive attention due to its potential in substantially improving the cost, energy and spectral efficiency of Internet of Things (IoT) systems that need both radio frequency functions. Given the wide applicability of orthogonal frequency division multiplexing (OFDM) in modern communications, OFDM sensing has become one of the major research topics of JCAS. To raise the awareness of some critical yet long-overlooked issues that restrict the OFDM sensing capability, a comprehensive overview of OFDM sensing is provided first in this paper, and then a tutorial on the issues is presented. Moreover, some recent research efforts for addressing the issues are reviewed, with interesting designs and results highlighted. In addition, the redundancy in OFDM sensing signals is unveiled, on which, a novel method is based and developed in order to remove the redundancy by introducing efficient signal decimation. Corroborated by analysis and simulation results, the new method further reduces the sensing complexity over one of the most efficient methods to date, with a minimal impact on the sensing performance.

Testicular miRNAs and tsRNAs provide insight into gene regulation during overwintering and reproduction of Onychostoma macrolepis.

The late overwintering period and breeding period are two important developmental stages of testis in Onychostoma macrolepis. Small non-coding RNAs (sncRNAs) are well-known regulators of biological processes associated with numerous biological processes. This study aimed to elucidate the roles of four sncRNA classes (microRNAs [miRNAs], Piwi-interacting RNAs [piRNAs], tRNA-derived small RNAs [tsRNAs], and rRNA-derived small RNAs [rsRNAs]) across testes in the late overwintering period (in March) and breeding period (in June) by high-throughput sequencing. The testis of O. macrolepis displayed the highest levels of piRNAs and lowest levels of rsRNAs. Compared with miRNAs and tsRNAs in June, tsRNAs in March had a higher abundance, while miRNAs in March had a much lower abundance. Bioinformatics analysis identified 1,362 and 1,340 differentially expressed miRNAs and tsRNAs, respectively. Further analysis showed that miR-200-1, miR-143-1, tRFi-Lys-CTT-1, and tRFi-Glu-CTC-1 could play critical roles during the overwintering and breeding periods. Our findings provided an unprecedented insight to reveal the epigenetic mechanism underlying the overwintering and reproduction process of male O. macrolepis.

Water-Induced Formation of Ni2 P-Ni12 P5 Interfaces with Superior Electrocatalytic Activity toward Hydrogen Evolution Reaction.

The interface between two material phases typically exhibits unique electronic states distinct from their pure phases, thus, providing a very promising channel to construct catalysts with excellent activity and stability. Here, water-induced formation of Ni2 P-Ni12 P5 through a one-step phosphorization of nickel foam (NF) is demonstrated for the first time. The abundant interfaces endow Ni2 P-Ni12 P5 /NF with excellent electrocatalytic hydrogen evolution reaction (HER) activity in alkaline condition, with an overpotential of 76 mV at a current density of 10 mA cm-2 and of 147 mV at a current density of 100 mA cm-2 , and a Tafel slope of 68.0 mV dec-1 . The Ni2 P-Ni12 P5 /NF also exhibits better durability than Pt/C/NF during HER at relatively large overpotential. Density functional theory calculations show that the electronic states at the Ni2 P-Ni12 P5 interface are greatly altered, which enables optimal hydrogen adsorption, accelerates the charge transfer kinetics, and thus enhances the HER electrocatalytic activity. Superior overall water-splitting performance is also obtained by combining Ni2 P-Ni12 P5 /NF with NiFe-layered double hydroxide (LDH) oxygen evolution reaction (OER) catalyst. Overpotentials of the cell for achieving 10 mA cm-2 are only 324 mV. This work provides a facile method for the preparation of interfaces between different nickel phosphide polymorphs toward HER.

Ni-Catalyzed Regioselective Hydroarylation of 1-Aryl-1,3-Butadienes with Aryl Halides.

An efficient nickel-catalyzed regioselective hydroarylation of 1,3-dienes with aryl halides and a silane has been developed, affording a range of allylic arenes in good to excellent yields under mild conditions. This method exhibits broad substrate scope, and excellent functional group tolerance. Late-stage modification of complex architectures was demonstrated.

Synthesis of gem-Dimethylcyclopentane-Fused Arenes with Various Topologies via TBD-Mediated Dehydro-Diels-Alder Reaction.

The development of efficient methods for the synthesis of substituted polycyclic arenes with various topologies is in high demand due to their excellent electrical and optical properties. In this work, a series of gem-dimethylcyclopentane-fused arenes with more than ten topologies were synthesized via a 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD)-mediated dehydro-Diels-Alder reaction with moderate to good yields. The introduction of the near-planar gem-dimethylcyclopentane moiety not only impacts the molecular conjugative system but also regulates the intermolecular π-π interactions and crystal packing, which are critical for the photoelectric performance of arenes. The photophysical properties, molecular geometry, molecular packing of these compounds, and electrochemical properties were investigated by UV-vis absorption, fluorescence emission spectra, DFT calculations, single-crystal X-ray structure analysis, and cyclic voltammetry study.

Inulin supplementation ameliorates hyperuricemia and modulates gut microbiota in Uox-knockout mice.

PURPOSE: Inulin is a type of fermentable dietary fiber, which is non-digestible, and can improve metabolic function by modulating intestinal microbiota. This study aimed to evaluate the role of inulin in hyperuricemia and microbial composition of the gut microbiota in a mouse model of hyperuricemia established through knockout of Uox (urate oxidase) gene. METHODS: KO (Uox-knockout) and WT (wild-type) mice were given inulin or saline by gavage for 7 weeks. The effect of inulin to combat hyperuricemia was determined by assessing the changes in serum UA (uric acid) levels, inflammatory parameters, epithelial barrier integrity, fecal microbiota alterations, and SCFA (short-chain fatty acid) concentrations in KO mice. RESULTS: Inulin supplementation can effectively alleviate hyperuricemia, increase the expressions of ABCG2 in intestine, and downregulate expression and activity of hepatic XOD (xanthine oxidase) in KO mice. It was revealed that the levels of inflammatory cytokines and the LPS (lipopolysaccharide) were remarkably higher in the KO group than those in the WT group, indicating systemic inflammation of hyperuricemic mice, but inulin treatment ameliorated inflammation in KO mice. Besides, inulin treatment repaired the intestinal epithelial barrier as evidenced by increased levels of intestinal TJ (tight junction) proteins [ZO-1 (zonula occludens-1) and occluding] in KO mice. Moreover, serum levels of uremic toxins, including IS (indoxyl sulfate) and PCS (p-cresol sulfate), were reduced in inulin-treated KO mice. Further investigation unveiled that inulin supplementation enhanced microbial diversity and raised the relative abundance of beneficial bacteria, involving SCFAs-producing bacteria (e.g., Akkermansia and Ruminococcus). Additionally, inulin treatment increased the production of gut microbiota-derived SCFAs (acetate, propionate and butyrate concentrations) in KO mice, which was positively correlated with the effectiveness of hyperuricemia relief. CONCLUSIONS: Our findings showed that inulin may be a promising therapeutic candidate for the treatment of hyperuricemia. Moreover, alleviation of hyperuricemia by inulin supplementation was, at least, partially conciliated by modulation of gut microbiota and its metabolites.

Silence Is Golden.

Speech-induced atrial tachycardia (AT) is extremely rare. We presented a case of focal AT that could be triggered by speech and terminated with the cessation of conversation. An electrophysiological study showed that the outbreak was associated with left atrial pressure rose. Radiofrequency ablation at the left atrial posterior-superior wall (earliest activation site) resulted in the immediate termination of AT. These electrophysiological characteristics indicated that the cardiac autonomic nervous system and/or left atrial pressure might play essential roles in the occurrences of speech-induced AT.

Exploring essential travel during COVID-19 quarantine: Evidence from China.

The COVID-19 has created significant impacts on the economy and individual life around the world. Various countries and cities have adopted corresponding control measures to reduce transport activities and maintain social distance to combat the spread of COVID-19. In the circumstances, residents only maintained essential travel to ensure a normal and fundamental life. In order to explore the impacts of the epidemic and control measures on individually essential travel, we have collected 513 questionnaires between February and March 2020 in China to investigate the various characteristics of essential travel. Using a multivariate logistic regression model, we examine the major factors that potentially impact the mode choices of essential travel. Results show that various socioeconomic, transport supply, health concern and travel purpose have significantly influenced travel mode choices of essential travel. The concept of essential travel will, in the era of port-pandemic, have profound implications on transportation policy making, especially on how to improve the fundamental welfare of the disadvantaged population.

Intracellular distribution of pseudorabies virus UL2 and detection of its nuclear import mechanism.

Pseudorabies virus (PRV) UL2 (pUL2) is a multifunctional protein, which is homologous with herpes simplex virus 1 early protein UL2 (hUL2) and crucial for the viral propagation. Yet, how pUL2 executes its roles in the viral life cycle remain inadequately understood. In order to uncover its effect on the procedure of PRV infection, investigation was performed to examine the subcellular distribution of pUL2 and establish its trafficking mechanism. In the present study, enhanced yellow fluorescent protein or Myc tag fused pUL2 was transiently overexpressed in transfected cells and exhibited an absolutely nuclear accumulation without the existence of other PRV proteins. Additionally, the nuclear trafficking of pUL2 was proved to rely on Ran-, transportin-1, importin ß1, importin α1, α3 and α5. Accordingly, these data will benefit the knowledge of pUL2-mediated biological effects in PRV infection cycle.

The combination therapy of transarterial chemoembolisation and sorafenib is the preferred palliative treatment for advanced hepatocellular carcinoma patients: a meta-analysis.

BACKGROUND: To compare the efficacy of three types of palliative therapy for advanced hepatocellular carcinoma (HCC), including transarterial chemoembolisation (TACE) monotherapy, sorafenib alone and their combination. METHODS: The databases of PubMed, Embase and Cochrane Library were retrieved. The odds ratio (OR) with its 95% confidence interval (CI) was used to investigate the binary variables, and the standardised mean difference (SMD) with its 95% CI was employed to evaluate the continuous variables. All statistical tests were performed by using Stata/SE, version 12.0. RESULTS: Thirty-one clinical studies, containing 5125 unique cases of patients with advanced HCC, were included. There were significant improvements in overall survival (OS) (pooled SMD = 2.54; 95% CI 1.74-3.34) and time to progression (TTP) (pooled SMD = 2.49; 95% CI 0.87-4.12) of the patients after receiving the combination therapy of TACE and sorafenib, compared to TACE monotherapy, and the OS in the combined treatment cohort was also longer than that in the sorafenib-alone cohort (pooled SMD = 2.92; 95% CI 1.72-4.13). The combination therapy group in comparison to the TACE group benefited a significantly increased overall response rate (ORR) (pooled OR = 2.61; 95% CI 1.43-4.77), 1-year (pooled OR = 2.96; 95% CI 1.71-5.14) and 2-year (pooled OR = 1.64; 95% CI 1.18-2.28) survival rates and reduced disease progression rate (DPR) (pooled OR = 0.47; 95% CI 0.33-0.68); in parallel, the ORR in the group was also significantly higher than that in the sorafenib-alone group (pooled OR = 3.62; 95% CI 1.28-10.22), although without a difference in the DPR (pooled OR = 0.28; 95% CI 0.05-1.48). In addition, we discovered that the 1-year (pooled OR = 1.39; 95% CI 0.84-2.29) and 2-year (pooled OR = 1.70; 95% CI 0.69-4.18) survival rates in the TACE monotherapy cohort were not significantly different to those in the sorafenib-alone cohort. CONCLUSION: The combination therapy is more effective than monotherapy in improving the prognostic outcomes of patients with advanced HCC. Therefore, we recommend it as the preferred treatment intervention for those patients.

Analog Least Mean Square Loop for Self-Interference Cancellation: A Practical Perspective.

Self-interference (SI) is the key issue that prevents in-band full-duplex (IBFD) communications from being practical. Analog multi-tap adaptive filter is an efficient structure to cancel SI since it can capture the nonlinear components and noise in the transmitted signal. Analog least mean square (ALMS) loop is a simple adaptive filter that can be implemented by purely analog means to sufficiently mitigate SI. Comprehensive analyses on the behaviors of the ALMS loop have been published in the literature. This paper proposes a practical structure and presents an implementation of the ALMS loop. By employing off-the-shelf components, a prototype of the ALMS loop including two taps is implemented for an IBFD system operating at the carrier frequency of 2.4 GHz. The prototype is firstly evaluated in a single carrier signaling IBFD system with 20 MHz and 50 MHz bandwidths, respectively. Measured results show that the ALMS loop can provide 39 dB and 33 dB of SI cancellation in the radio frequency domain for the two bandwidths, respectively. Furthermore, the impact of the roll-off factor of the pulse shaping filter on the SI cancellation level provided by the prototype is presented. Finally, the experiment with multicarrier signaling shows that the performance of the ALMS loop is the same as that in the single carrier system. These experimental results validate the theoretical analyses presented in our previous publications on the ALMS loop behaviors.