Extracellular vesicle-mediated communication between hepatocytes and natural killer cells promotes hepatocellular tumorigenesis.

Hepatocellular carcinoma (HCC) is frequently characterized by metabolic and immune remodeling in the tumor microenvironment. We previously discovered that liver-specific deletion of fructose-1, 6-bisphosphatase 1 (FBP1), a gluconeogenic enzyme ubiquitously suppressed in HCC tissues, promotes liver tumorigenesis and induces metabolic and immune perturbations closely resembling human HCC. However, the underlying mechanisms remain incompletely understood. Here, we reported that FBP1-deficient livers exhibit diminished amounts of natural killer (NK) cells and accelerated tumorigenesis. Using the diethylnitrosamine-induced HCC mouse model, we analyzed potential changes in the immune cell populations purified from control and FBP1-depleted livers and found that NK cells were strongly suppressed. Mechanistically, FBP1 attenuation in hepatocytes derepresses an zeste homolog 2 (EZH2)-dependent transcriptional program to inhibit PKLR expression. This leads to reduced levels of PKLR cargo proteins sorted into hepatocyte-derived extracellular vesicles (EVs), dampened activity of EV-targeted NK cells, and accelerated liver tumorigenesis. Our study demonstrated that hepatic FBP1 depletion promotes HCC-associated immune remodeling, partly through the transfer of hepatocyte-secreted, PKLR-attenuated EVs to NK cells.

Theoretical Study of Small Molecules Adsorption on Pristine and Transition Metal Doped GeSe Monolayer for Gas Sensing Application.

By using first-principles calculations, the sensing properties of pristine and transition metal (TM) atoms (Ti, V, and Co) embedded germanium selenide (GeSe) monolayer toward small gas molecules (H2, NH3, CO, O2, SO2, NO, and NO2) were investigated. The adsorption energies, electronic structure, optical properties, and recovery time of the adsorption systems were calculated and analyzed in detail. The results indicate that TM doped GeSe has stronger interaction with gas molecules compared with the pristine GeSe monolayer. Especially for Ti- and V-GeSe monolayer, the absolute value of adsorption energies are up to 2 eV for O2, NO, and NO2. The doping with TM atoms also changes the charge transfer and electronic structures of adsorption systems. Combined with the result of the calculated optical properties and recovery time, it can be concluded that Ti-GeSe monolayer has great potential for NH3 detection, while Co-GeSe monolayer can be very promising SO2 gas sensors.

Interfacial Engineering of Bi19Br3S27 Nanowires Promotes Metallic Photocatalytic CO2 Reduction Activity under Near-Infrared Light Irradiation.

Developing highly efficient photocatalysts to utilize solar radiation for converting CO2 into solar fuels is of great importance for energy sustainability and carbon neutralization. Herein, through an alkali-etching-introduced interface reconstruction strategy, a nanowire photocatalyst denoted as V-Bi19Br3S27, with rich Br and S dual-vacancies and surface Bi-O bonding introduced significant near-infrared (NIR) light response, has been developed. The as-obtained V-Bi19Br3S27 nanowires exhibit a highly efficient metallic photocatalytic reduction property for converting CO2 into CH3OH when excited solely under NIR light irradiation. Free of any cocatalyst and sacrificial agent, metallic defective V-Bi19Br3S27 shows 2.3-fold higher CH3OH generation than Bi19Br3S27 nanowires. The detailed interfacial structure evolution and reaction mechanism have been carefully illustrated down to the atomic scale. This work provides a unique interfacial engineering strategy for developing high-performance sulfur-based NIR photocatalysts for photon reducing CO2 into alcohol for achieving high-value solar fuel chemicals, which paves the way for efficiently using the solar radiation energy extending to the NIR range to achieve the carbon neutralization goal.

Gas sensing properties of buckled bismuthene predicted by first-principles calculations.

First-principles calculations are used to study the structural, electronic, transport and optical properties of buckled bismuthene with the adsorption of various gas molecules such as CO, O2, H2O, NH3, SO2, NO and NO2. By considering the van der Waals interactions between the gas molecules and buckled bismuthene, we find that the buckled bismuthene shows superior gas sensing performance to other 2D materials such as graphene and MoS2. The adsorption of CO, O2, H2O and NH3 molecules is physisorption, whereas SO2, NO and NO2 are chemisorbed on the buckled bismuthene with large charge transfer and strong adsorption energy. After adsorption, charges are transferred from buckled bismuthene to the molecules and the quantum conductance is changed by the adsorbed molecules. Furthermore, the work function of buckled bismuthene is changed with the adsorption of different molecules. Our results show that the electronic, transport and optical properties of buckled bismuthene are sensitive to the adsorption of gas molecules, which suggests that buckled bismuthene holds great potential for application in gas sensors.

Vacancy-Rich Monolayer BiO2-x as a Highly Efficient UV, Visible, and Near-Infrared Responsive Photocatalyst.

Vacancy-rich layered materials with good electron-transfer property are of great interest. Herein, a full-spectrum responsive vacancy-rich monolayer BiO2-x has been synthesized. The increased density of states at the conduction band (CB) minimum in the monolayer BiO2-x is responsible for the enhanced photon response and photo-absorption, which were confirmed by UV/Vis-NIR diffuse reflectance spectra (DRS) and photocurrent measurements. Compared to bulk BiO2-x , monolayer BiO2-x has exhibited enhanced photocatalytic performance for rhodamine B and phenol removal under UV, visible, and near-infrared light (NIR) irradiation, which can be attributed to the vacancy VBi-O ''' as confirmed by the positron annihilation spectra. The presence of VBi-O ''' defects in monolayer BiO2-x promoted the separation of electrons and holes. This finding provides an atomic level understanding for developing highly efficient UV, visible, and NIR light responsive photocatalysts.

The association and underlying mechanism of the digit ratio (2D:4D) in hypospadias.

The second-to-fourth digit (2D:4D) ratio is thought to be associated with prenatal androgen exposure. However, the relationship between the 2D:4D ratio and hypospadias is poorly understood, and its molecular mechanism is not clear. In this study, by analyzing the hand digit length of 142 boys with hypospadias (23 distal, 68 middle, and 51 proximal) and 196 controls enrolled in Shanghai Children's Hospital (Shanghai, China) from December 2020 to December 2021, we found that the 2D:4D ratio was significantly increased in boys with hypospadias ( P < 0.001) and it was positively correlated with the severity of the hypospadias. This was further verified by the comparison of control mice and prenatal low testosterone mice model obtained by knocking out the risk gene (dynein axonemal heavy chain 8 [ DNAH8 ]) associated with hypospadias. Furthermore, the discrepancy was mainly caused by a shift in 4D. Proteomic characterization of a mouse model validated that low testosterone levels during pregnancy can impair the growth and development of 4D. Comprehensive mechanistic explorations revealed that during the androgen-sensitive window, the downregulation of the androgen receptor (AR) caused by low testosterone levels, as well as the suppressed expression of chondrocyte proliferation-related genes such as Wnt family member 5a ( Wnt5a ), Wnt5b , Smad family member 2 ( Smad2 ), and Smad3 ; mitochondrial function-related genes in cartilage such as AMP-activated protein kinase ( AMPK ) and nuclear respiratory factor 1 ( Nrf-1 ); and vascular development-related genes such as myosin light chain ( MLC ), notch receptor 3 ( Notch3 ), and sphingosine kinase 1 ( Sphk1 ), are responsible for the limitation of 4D growth, which results in a higher 2D:4D ratio in boys with hypospadias via decreased endochondral ossification. This study indicates that the ratio of 2D:4D is a risk marker of hypospadias and provides a potential molecular mechanism.

Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer.

Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.

ROS-regulated phosphorylation of ITPKB by CAMK2G drives cisplatin resistance in ovarian cancer.

Platinum resistance accounts for much of the high mortality and morbidity associated with ovarian cancer. Identification of targets with significant clinical translational potential remains an unmet challenge. Through a high-throughput synthetical lethal screening for clinically relevant targets using 290 kinase inhibitors, we identify calcium/calmodulin-dependent protein kinase II gamma (CAMK2G) as a critical vulnerability in cisplatin-resistant ovarian cancer cells. Pharmacologic inhibition of CAMK2G significantly sensitizes ovarian cancer cells to cisplatin treatment in vitro and in vivo. Mechanistically, CAMK2G directly senses ROS, both basal and cisplatin-induced, to control the phosphorylation of ITPKB at serine 174, which directly regulates ITPKB activity to modulate cisplatin-induced ROS stress. Thereby, CAMK2G facilitates the adaptive redox homeostasis upon cisplatin treatment and drives cisplatin resistance. Clinically, upregulation of CAMK2G activity and ITPKB pS174 correlates with cisplatin resistance in human ovarian cancers. This study reveals a key kinase network consisting of CAMK2G and ITPKB for ROS sense and scavenging in ovarian cancer cells to maintain redox homeostasis, offering a potential strategy for cisplatin resistance treatment.

Removing the Oxygen-Induced Donor-like Effect for High Thermoelectric Performance in n-Type Bi2Te3-Based Compounds.

Bismuth telluride-based alloys are the best performing thermoelectric materials near room temperature. Grain size refinement and nanostructuring are the core stratagems for improving thermoelectric and mechanical properties. However, the donor-like effect induced by grain size refinement strongly restricts the thermoelectric properties especially in the vicinity of room temperature. In this study, the formation mechanism for the donor-like effect in Bi2Te3-based compounds was revealed by synthesizing five batches of polycrystalline samples. We demonstrate that the donor-like effect in Bi2Te3-based compounds is strongly related to the vacancy defects (VBi‴ and VTe···) induced by the fracturing process and oxygen in air for the first time. The oxygen-induced donor-like effect dramatically increases the carrier concentration from 2.5 × 1019 cm-3 for the zone melting ingot and bulks sintered with powders ground under an inert atmosphere to 7.5 × 1019 cm-3, which is largely beyond the optimum carrier concentration and seriously deteriorates the thermoelectric performance. Moreover, it is found that both avoiding exposure to air and eliminating the thermal vacancy defects (VBi‴ and VTe···) via heat treatment before exposure to air can effectively remove the donor-like effect, producing almost the same carrier concentration and Seebeck coefficient as those of the zone melting ingot for these samples. Therefore, a defect equation of oxygen-induced donor-like effect was proposed and was further explicitly corroborated by positron annihilation measurement. With the removal of donor-like effect and improved texturing via multiple hot deformation (HD) processes, a maximum power factor of 3.5 mW m-1 K-2 and a reproducible maximum ZT value of 1.01 near room temperature are achieved. This newly proposed defect equation of the oxygen-induced donor-like effect will provide a guideline for developing higher-performance V2VI3 polycrystalline materials for near-room-temperature applications.

Plasma Metabolic Profiling of Pediatric Sepsis in a Chinese Cohort.

Sepsis represents one of the most pressing problems in pediatrics, characterized by pathogenic bacteria invading the blood, growing and multiplying in the blood circulation, and ultimately causing severe infections. Most children with sepsis have a rapid disease onset and frequently exhibit sudden high fever or first chills. Here we performed comprehensive metabolomic profiling of plasma samples collected from pediatric sepsis patients to identify specific metabolic alterations associated with these patients (n = 84, designated as case subjects) as compared to healthy cohorts (n = 59, designated as control subjects). Diagnostic models were constructed using MetaboAnalyst, R packages, and multiple statistical methods, such as orthogonal partial least squares-discriminant analysis, principal component analysis, volcano plotting, and one-way ANOVA. Our study revealed a panel of metabolites responsible for the discrimination between case and control subjects with a high predictive value of prognosis. Moreover, significantly altered metabolites in sepsis survivors versus deceased patients (non-survivors) were identified as those involved in amino acids, fatty acids, and carbohydrates metabolism. Nine metabolites including organic acids and fatty acids were also identified with significantly higher abundance in sepsis patients with related microbes, implicating greater potentials to distinguish bacterial species using metabolomic analysis than blood culture. Pathway enrichment analysis further revealed that fatty acid metabolism might play an important role in the pathogenesis of sepsis.

Fucoidan-Supplemented Diet Potentiates Immune Checkpoint Blockage by Enhancing Antitumor Immunity.

Immune checkpoint blockade (ICB) therapies such as PD-1 antibodies have produced significant clinical responses in treating a variety of human malignancies, yet only a subset of cancer patients benefit from such therapy. To improve the ICB efficacy, combinations with additional therapeutics were under intensive investigation. Recently, special dietary compositions that can lower the cancer risk or inhibit cancer progression have drawn significant attention, although few were reported to show synergistic effects with ICB therapies. Interestingly, Fucoidan is naturally derived from edible brown algae and exhibits antitumor and immunomodulatory activities. Here we discover that fucoidan-supplemented diet significantly improves the antitumor activities of PD-1 antibodies in vivo. Specifically, fucoidan as a dietary ingredient strongly inhibits tumor growth when co-administrated with PD-1 antibodies, which effects can be further strengthened when fucoidan is applied before PD-1 treatments. Immune analysis revealed that fucoidan consistently promotes the activation of tumor-infiltrating CD8+ T cells, which support the evident synergies with ICB therapies. RNAseq analysis suggested that the JAK-STAT pathway is critical for fucoidan to enhance the effector function of CD8+ T cells, which could be otherwise attenuated by disruption of the T-cell receptor (TCR)/CD3 complex on the cell surface. Mechanistically, fucoidan interacts with this complex and augments TCR-mediated signaling that cooperate with the JAK-STAT pathway to stimulate T cell activation. Taken together, we demonstrated that fucoidan is a promising dietary supplement combined with ICB therapies to treat malignancies, and dissected an underappreciated mechanism for fucoidan-elicited immunomodulatory effects in cancer.

Vacancy-Based Defect Regulation for High Thermoelectric Performance in Ge9Sb2Te12-x Compounds.

Defect engineering is the core strategy for improving thermoelectric properties. Herein, cation doping along with modulation of cation vacancy has been developed in GeTe-based materials as an effective method to induce vacancy-based defects to boost their thermoelectric performance. A series of ternary compounds of Ge9Sb2Te12-x (x = 0, 0.03, 0.06, 0.09, 0.12, 0.15) was prepared by vacuum-melting and annealing combined with the spark plasma sintering (SPS) process. The role of Sb doping and cation vacancy on thermoelectric properties was systematically investigated. It is found that alloying Sb2Te3 into GeTe increases the concentration of cation vacancies, which is corroborated by both positron annihilation measurements and theoretical calculations. The vacancies, stacking faults, and planar defect interactions determine the thermoelectric transport properties. Adjusting the deficiency of Te effectively tunes the concentration of cation vacancies and dopant defects in the structure. In turn, this tunes the carrier concentration close to its optimum. A high power factor of 32.6 µW cm-1 K-2 is realized for Ge9Sb2Te11.91 at 725 K. Moreover, large strains induced by the defect structures, including Sb dopant, vacancy, staking faults, as well as planar defects intensify phonon scattering, leading to a significant decrease in the thermal conductivity from 7.6 W m-1 K-1 for pristine GeTe to 1.18 W m-1 K-1 for Ge9Sb2Te11.85 at room temperature. All of the above contribute to a high ZT value of 2.1 achieved for the Ge9Sb2Te11.91 sample at 775 K.

A Feedback Circuitry between Polycomb Signaling and Fructose-1, 6-Bisphosphatase Enables Hepatic and Renal Tumorigenesis.

Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intriguingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics. SIGNIFICANCE: A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth.See related commentary by Leithner, p. 657.

Current perspectives on the correlation of nocturnal enuresis with obstructive sleep apnea in children.

BACKGROUND: Obstructive sleep apnea (OSA) and nocturnal enuresis (NE) are common clinical problems in children. OSA and NE are thought to be interrelated, but the exact pathophysiological mechanisms are not yet clear. This review aims to explain the possible pathogenesis of NE in children with OSA. DATE SOURCES: We have retrieved all relevant original articles from Database that have been published so far, including the prevalence studies of NE and OSA in children, sleep characteristic studies that use polysomnography (PSG) to focus on children with NE, and studies on the relationship between OSA and NE. RESULTS: Clinical studies have revealed that the risk of NE in children with OSA was increased compared with that of their healthy peers. This increased risk may be associated with sleep disorders, bladder instability, detrusor overactivity, nocturnal polyuria, endocrine and metabolic disorders, and inflammation. CONCLUSIONS: Cardiopulmonary and renal reflex-induced neuroendocrine disorder may play an important role in the mechanism of NE in children with OSA, but this remains to be confirmed by animal studies. Other causes such as oxidative stress and inflammatory responses need to be further researched.