Targetable leukaemia dependency on noncanonical PI3Kγ signalling.

Phosphoinositide-3-kinase-γ (PI3Kγ) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers1-4. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukaemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid and dendritic lineages. This dependency is characterized by innate inflammatory signalling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3Kγ5 and stabilizes the active enzymatic complex. We identify p21 (RAC1)-activated kinase 1 (PAK1) as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency and find that dephosphorylation of PAK1 by PI3Kγ inhibition impairs mitochondrial oxidative phosphorylation. Treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukaemias with activated PIK3R5. In addition, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukaemia xenografts with low baseline PIK3R5 expression, as residual leukaemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Together, our study reveals a targetable dependency on PI3Kγ-PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia.

A rhodamine-based fluorescent probe used to determine nitroxyl (HNO) in lysosomes.

The reactive nitrogen species (RNS) in lysosomes play a major role during the regulation of lysosomal microenvironment. Nitroxyl (HNO) belongs to active nitrogen species (RNS) and is becoming a potential diagnostic and therapeutic biomarker. However, the complex synthesis routes of HNO in biosystem always hinder the exact determination of HNO in living cells. Here, a rhodamine-based fluorescent probe used to determine nitroxyl (HNO) in lysosomes was constructed and synthesized. 2-(Diphenylphosphino)benzoate was utilized as the sensing unit for HNO and morpholine was chose as the targeting group for lysosome. Before the addition of HNO, the probe displayed a spirolactone structure and almost no fluorescence was found. After the addition of HNO, the probe existed as a conjugated xanthene form and an intense green fluorescence was observed. The fluorescent probe possessed fast response (3 min) and high selectivity for HNO. Furthermore, fluorescence intensity of the probe linearly related with the HNO concentration in the range of 6.0 × 10-8 to 6.0 × 10-5 mol L-1. The detection limit was found to be 1.87 × 10-8 mol L-1 for HNO. Moreover, the probe could selectively targeted lysosome with excellent biocompatibility and had been effectually utilized to recognize exogenous HNO in A549 cells.

OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition.

Ovarian cancer is an aggressive gynecological tumor characterized by a high relapse rate and chemoresistance. Ovarian cancer exhibits the cancer hallmark of elevated glycolysis, yet effective strategies targeting cancer cell metabolic reprogramming to overcome therapeutic resistance in ovarian cancer remain elusive. Here, we revealed that epigenetic silencing of Otubain 2 (OTUB2) is a driving force for mitochondrial metabolic reprogramming in ovarian cancer, which promotes tumorigenesis and chemoresistance. Mechanistically, OTUB2 silencing destabilizes sorting nexin 29 pseudogene 2 (SNX29P2), which subsequently prevents hypoxia-inducible factor-1 alpha (HIF-1α) from von Hippel-Lindau tumor suppressor-mediated degradation. Elevated HIF-1α activates the transcription of carbonic anhydrase 9 (CA9) and drives ovarian cancer progression and chemoresistance by promoting glycolysis. Importantly, pharmacological inhibition of CA9 substantially suppressed tumor growth and synergized with carboplatin in the treatment of OTUB2-silenced ovarian cancer. Thus, our study highlights the pivotal role of OTUB2/SNX29P2 in suppressing ovarian cancer development and proposes that targeting CA9-mediated glycolysis is an encouraging strategy for the treatment of ovarian cancer.

N6-methyladenosine-mediated feedback regulation of abscisic acid perception via phase-separated ECT8 condensates in Arabidopsis.

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNAs, yet how plants recognize this chemical modification to swiftly adjust developmental plasticity under environmental stresses remains unclear. Here we show that m6A mRNA modification and its reader protein EVOLUTIONARILY CONSERVED C-TERMINAL REGION 8 (ECT8) act together as a key checkpoint for negative feedback regulation of abscisic acid (ABA) signalling by sequestering the m6A-modified ABA receptor gene PYRABACTIN RESISTANCE 1-LIKE 7 (PYL7) via phase-separated ECT8 condensates in stress granules in response to ABA. This partially depletes PYL7 mRNA from its translation in the cytoplasm, thus reducing PYL7 protein levels and compromising ABA perception. The loss of ECT8 results in defective sequestration of m6A-modified PYL7 in stress granules and permits more PYL7 transcripts for translation. This causes overactivation of ABA-responsive genes and the consequent ABA-hypersensitive phenotypes, including drought tolerance. Overall, our findings reveal that m6A-mediated sequestration of PYL7 by ECT8 in stress granules negatively regulates ABA perception, thereby enabling prompt feedback regulation of ABA signalling to prevent plant cell overreaction to environmental stresses.

Association Between Different Types of Physical Activity and Hepatic Steatosis and Liver Fibrosis: A Cross-Sectional Study Based on NHANES.

BACKGROUND AND AIMS: Many studies have shown a link between physical activity (PA) and nonalcoholic fatty liver disease (NAFLD). However, more research is needed to investigate the relationship between different types of PA and NAFLD. This study aimed to explore the potential link between different types of PA, hepatic steatosis, and liver fibrosis. STUDY: A cross-sectional study was conducted using the data set from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. A multiple linear regression model was used to examine the linear relationship between different types of PA, the controlled attenuation parameter (CAP), and liver stiffness measurement (LSM). In addition, smoothing curve fitting and threshold effect analysis were used to depict their nonlinear relationship. RESULTS: This study involved 5933 adults. Multiple linear regression analysis revealed a significantly negative correlation between leisure-time PA and CAP, while the relationship between occupation-related PA, transportation-related PA, and CAP was not significant. Subgroup analysis further revealed that leisure-time PA was significantly negatively correlated with CAP in women and younger age groups (under 60 y old), while the relationship was not significant in men and older age groups. In addition, there was a significant negative correlation between leisure-time PA and liver fibrosis in men. CONCLUSIONS: Leisure-time PA can prevent hepatic steatosis, and women and young people benefit more. Occupation-related PA is not associated with hepatic steatosis and cannot replace leisure-time PA. In men, increasing leisure-time PA is more effective in preventing liver fibrosis.

The application of encapsulation technology in the food Industry: Classifications, recent Advances, and perspectives.

Encapsulation technology has been extensively used to enhance the stability, specificity, and bioavailability of essential food ingredients. Additionally, it plays a vital role in improving product quality and reducing production costs. This study presents a comprehensive classification of encapsulation techniques based on the state of different cores (solid, liquid, and gaseous) and offers a detailed description and analysis of these encapsulation methods. Specifically, it introduces the diverse applications of encapsulation technology in food, encompassing areas such as antioxidant, protein activity, physical stability, controlled release, delivery, antibacterial, and probiotics. The potential impact of encapsulation technology is expected to make encapsulation technology a major process and research hotspot in the food industry. Future research directions include applications of encapsulation for enzymes, microencapsulation of biosensors, and novel technologies such as self-assembly. This study provides a valuable theoretical reference for the in-depth research and wide application of encapsulation technology in the food industry.

Diurnal variation of cerebral blood flow in healthy humans under normal entrained conditions.

The presence of a circadian cycle of cerebral blood flow may have implications for the occurrence of daily variations in cerebrovascular events in humans, but how cerebral blood flow varies throughout the day and its mechanism are still unclear. The study aimed to explore the diurnal variation of cerebral blood flow in healthy humans and its possible mechanisms. Arterial spin labelling images were collected at six time-points (09:00 hours, 13:00 hours, 17:00 hours, 21:00 hours, 01:00 hours, 05:00 hours) from 18 healthy participants (22-39 years old; eight females) to analyse diurnal variations in cerebral blood flow. Resting heart rate and blood pressure at six time-points and blood indicators (20-hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acids, prostaglandin E2, noradrenaline and nitric oxide) related to cerebral vascular tone at two time-points (09:00 hours and 21:00 hours) were collected to analyse possible influences on diurnal variations in cerebral blood flow. From 21:00 hours to 05:00 hours, parietal cortical relative cerebral blood flow tended to increase, while frontal cortical and cerebellar relative cerebral blood flow tended to decrease. There was a time-dependent negative correlation between parietal cortical relative cerebral blood flow and resting heart rate, whereas there was a time-dependent positive correlation between cerebellar relative cerebral blood flow and resting heart rate. The change of parietal cortical relative cerebral blood flow was positively correlated with the change of nitric oxide. There was also a time-dependent positive correlation between mean arterial pressure and mean whole-brain cerebral blood flow. The findings indicated that parietal cortical relative cerebral blood flow and frontal cortical/cerebellar relative cerebral blood flow showed roughly opposite trends throughout the day. The diurnal variations in relative cerebral blood flow were regional-specific. Diurnal variation of nitric oxide and neurogenic regulation may be potential mechanisms for diurnal variation in regional relative cerebral blood flow.

Improving Wear Resistance and Corrosive Resistance of Cemented Carbide for Mud Pulser Rotor by Deep Cryogenic Treatment.

Cemented carbide used in the rotor of a mud pulser is subjected to the scouring action of solid particles and corrosive mud media for a long time, which causes abrasive wear and electrochemical corrosion. To improve the wear and corrosive resistance of cemented carbide, samples with different cobalt content (WC-5Co, WC-8Co, and WC-10Co) receive deep cryogenic treatment (DCT) at -196 °C for 2.5 h. An optical metalloscope (OM) and X-ray diffractometer (XRD) are used to observe the phase changes of cemented carbides, and the XRD is also used to observe the change in residual stress on the cemented carbide's surface. A scanning electron microscope (SEM) is used to characterize the wear and electrochemical corrosion surface microstructure of cemented carbides (untreated and DCT). The results show that the DCT promotes the precipitation of the η phase, and the diffraction peak of ε-Co tends to intensify. Compared with the untreated, the wear rates of WC-5Co, WC-8Co, and WC-10Co can be reduced by 14.71%, 37.25%, and 41.01% by DCT, respectively. The wear form of the cemented carbides is mainly the extrusion deformation of Co and WC shedding. The precipitation of the η phase and the increase in WC residual compressive stress by DCT are the main reasons for the improvement of wear resistance. The electrochemical corrosion characteristic is the dissolution of the Co phase. DCT causes the corrosion potential of cemented carbide to shift forward and the corrosion current density to decrease. The enhancement of the corrosion resistance of cemented carbide caused by DCT is due to the Co phase transition, η phase precipitation, and the increase in the compressive stress of cemented carbide.

Rhodium-Catalyzed Diastereoselective C-H Activation/[4 + 2] Annulation of α,ß-Unsaturated Amides with Bicyclic Alkenes.

Herein, we report a rare example of rhodium-catalyzed C-H activation/[4 + 2] annulation of alkenyl amides with bicyclic alkenes under mild and green conditions. The reactivity of the rhodium catalyst in this study differed from that observed in cobalt-catalyzed C-H activation/[3 + 2] annulation between vinylic amides and bicyclic alkenes. In addition, the reaction was performed in EtOH at room temperature, which also displayed excellent diastereoselectivity, good functional group tolerance, and air compatibility. A series of novel bridged-ring skeletons were obtained in good to excellent yields. Scale-up experiments were carried out with 1 or 0.75 mol % rhodium catalyst, affording the desired bridged-ring skeleton in excellent yields.

Research progress on occurrence characteristics and source analysis of microfibers in the marine environment.

Synthetic microfiber pollution is a growing concern in the marine environment. However, critical issues associated with microfiber origins in marine environments have not been resolved. Herein, the potential sources of marine microfibers are systematically reviewed. The obtained results indicate that surface runoffs are primary contributors that transport land-based microfibers to oceans, and the breakdown of larger fiber plastic waste due to weathering processes is also a notable secondary source of marine microfibers. Additionally, there are three main approaches for marine microplastic source apportionment, namely, anthropogenic source classification, statistical analysis, and numerical simulations based on the Lagrangian particle tracking method. These methods establish the connections between characteristics, transport pathways and sources of microplastics, which provides new insights to further conduct microfiber source apportionment. This study helps to better understand sources analysis and transport pathways of microfibers into oceans and presents a scientific basis to further control microfiber pollution in marine environments.

RUNX1-IT1 acts as a scaffold of STAT1 and NuRD complex to promote ROS-mediated NF-κB activation and ovarian cancer progression.

Dysregulated expression of long-stranded non-coding RNAs is strongly associated with carcinogenesis. However, the precise mechanisms underlying their involvement in ovarian cancer pathogenesis remain poorly defined. Here, we found that lncRNA RUNX1-IT1 plays a crucial role in the progression of ovarian cancer. Patients with high RUNX1-IT1 expression had shorter survival and poorer outcomes. Notably, knockdown of RUNX1-IT1 suppressed the proliferation, migration and invasion of ovarian cancer cells in vitro, and reduced the formation of peritoneum metastasis in vivo. Mechanistically, RUNX1-IT1 bound to HDAC1, the core component of the NuRD complex, and STAT1, acting as a molecular scaffold of the STAT1 and NuRD complex to regulate intracellular reactive oxygen homeostasis by altering the histone modification status of downstream targets including GPX1. Consequently, RUNX1-IT1 activated NF-κB signaling and altered the biology of ovarian cancer cells. In conclusion, our findings demonstrate that RUNX1-IT1 promotes ovarian malignancy and suggest that targeting RUNX1-IT1 represents a promising therapeutic strategy for ovarian cancer treatment.

Hole-Transporting Materials based on Oligo(hetero)aryls with a Naphthodithiophene Core - Succinct Synthesis by Twofold Direct C-H Olefination.

This work demonstrated the first synthetic application of direct C-H olefinations in the step-saving preparation of various hole-transporting materials (HTM) for efficient perovskite solar cells (PSC). Cross-dehydrogenative couplings of naphthodithiophene (NDT) with vinyl arenes under palladium-catalysis facilely generated various new oligo(hetero)aryls with internal alkenes. Reaction conditions were optimized, which gave the product isolated yields of up to 71 % with high (E)-stereoselectivity. These readily accessible NDT core-based small molecules involving olefin as π-spacers displayed immediate power conversion efficiencies of up to 17.2 % without a device oxidation process that is required for the commercially available spiro-OMeTAD and most other existing HTMs while fabricated in corresponding PSC devices.

Unveiling high-power and high-safety lithium-ion battery separator based on interlayer of ZIF-67/cellulose nanofiber with electrospun poly(vinyl alcohol)/melamine nonwoven membranes.

Due to the poor thermal stability of conventional separators, lithium-ion batteries require a suitable separator to maintain system safety for long-term cycling performance. It must have high porosity, superior electrolyte uptake ability, and good ion-conducting properties even at high temperatures. In this work, we demonstrate a novel composite membrane based on sandwiching of zeolitic imidazole frameworks-67 decorated cellulose acetate nanofibers (ZIF-67@CA) with electrospun poly(vinyl alcohol)/melamine (denoted as PVAM) nonwoven membranes. The as-prepared sandwich-type membranes are called PVAM/x%ZIF-67@CA/PVAM. The middle layer of composite membranes is primarily filled with different weight percentages of ZIF-67 nanoparticles (x = 5, 15, and 25 wt%), which both reduces the non-uniform porous structure of CA and increases its thermal stability. Therefore, our sandwich-type PVAM/x%ZIF-67@CA/PVAM membrane exhibits a higher thermal shrinkage effect at 200 °C than the commercial polyethylene (PE) separator. Due to its high electrolyte uptake (646.8%) and porosity (85.2%), PVAM/15%ZIF-67@CA/PVAM membrane achieved high ionic conductivity of 1.46 × 10-3 S cm-1 at 70 °C, as compared to the commercial PE separator (ca. 6.01 × 10-4 S cm-1 at 70 °C). Besides, the cell with PVAM/15%ZIF-67@CA/PVAM membrane shows an excellent discharge capacity of about 167.5 mAh g-1after 100 cycles at a 1C rate with a capacity retention of 90.3%. The ZIF-67 fillers in our sandwich-type composite membrane strongly attract anions (PF6-) through Lewis' acid-base interaction, allowing uniform Li+ ion transport and suppressing Li dendrites. As a result, we found that the PVAM/15%ZIF-67@CA/PVAM composite nonwoven membrane is applicable to high-power, high-safety lithium-ion battery systems that can be used in electric vehicles (EVs).

Discovery, Structure-Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein-Protein Interactions between AF9/ENL and AF4 or DOT1L.

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5-10% acute leukemias with poor clinical outcomes. Protein-protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several benzothiophene-carboxamide compounds were identified as novel inhibitors of these PPIs with IC50 values as low as 1.6 µM. Structure-activity relationship studies of 77 benzothiophene and related indole and benzofuran compounds show that a 4-piperidin-1-ylphenyl or 4-pyrrolidin-1-ylphenyl substituent is essential for the activity. The inhibitors suppressed expression of MLL target genes HoxA9, Meis1 and Myc, and selectively inhibited proliferation of MLL-r and other acute myeloid leukemia cells with EC50 values as low as 4.7 µM. These inhibitors are useful chemical probes for biological studies of AF9/ENL, as well as pharmacological leads for further drug development against MLL-r and other leukemias.

Ginsenoside Rb1 enhanced immunity and altered the gut microflora in mice immunized by H1N1 influenza vaccine.

Background: Influenza is an acute infectious respiratory disease caused by the influenza virus that seriously damages human health, and the essential way to prevent influenza is the influenza vaccine. Vaccines without adjuvants produce insufficient specific antibodies and therefore require adjuvants to boost antibody titers. Microbes and hosts are a community that needs to "promote bacteria," which could provide new value for the immune effect. Methods: (1) The H1N1 influenza vaccine, in combination with Ginsenoside Rb1, was co-injected into mice intraperitoneally (I.P.). Then, immunoglobulin G and antibody subtype levels were tested by enzyme-linked immunosorbent assay (ELISA). Moreover, mice were infected with a lethal dose of the H1N1 influenza virus (A/Michigan/45/2015), and survival status was recorded for 14 days. Lung tissues were stained by hematoxylin and eosin (H&E), and ELISA detected inflammatory factor expression levels. (2) Mice were immunized with Ginsenoside Rb1 combined with quadrivalent influenza inactivated vaccine(IIV4), and then IgG levels were measured by ELISA. (3) Fresh stool was collected for fecal 16S rDNA analysis. Results: Ginsenoside Rb1 boosted IgG and antibody subtypes in the H1N1 influenza vaccine, improved survival of mice after virus challenge, attenuated lung histopathological damage, and reduced inflammatory cytokines expression in IL-6 and TNF-α. The results of 16S rDNA showed that Rb1 decreased species diversity but increased species richness compared to the PBS group and increased the abundance of Akkermansiaceae and Murbaculaceae at the Family and Genus levels compared with the HA+Alum group. Conclusion: Ginsenoside Rb1 has a boosting effect on the immune efficacy of the H1N1 influenza vaccine and is promising as a novel adjuvant to regulate the microecological balance and achieve an anti-infective effect.

m6A demethylase FTO stabilizes LINK-A to exert oncogenic roles via MCM3-mediated cell-cycle progression and HIF-1α activation.

RNA N6-methyladenosine (m6A) modification is implicated in cancer progression, yet its role in regulating long noncoding RNAs during cancer progression remains unclear. Here, we report that the m6A demethylase fat mass and obesity-associated protein (FTO) stabilizes long intergenic noncoding RNA for kinase activation (LINK-A) to promote cell proliferation and chemoresistance in esophageal squamous cell carcinoma (ESCC). Mechanistically, LINK-A promotes the interaction between minichromosome maintenance complex component 3 (MCM3) and cyclin-dependent kinase 1 (CDK1), increasing MCM3 phosphorylation. This phosphorylation facilitates the loading of the MCM complex onto chromatin, which promotes cell-cycle progression and subsequent cell proliferation. Moreover, LINK-A disrupts the interaction between MCM3 and hypoxia-inducible factor 1α (HIF-1α), abrogating MCM3-mediated HIF-1α transcriptional repression and promoting glycolysis and chemoresistance. These results elucidate the mechanism by which FTO-stabilized LINK-A plays oncogenic roles and identify the FTO/LINK-A/MCM3/HIF-1α axis as a promising therapeutic target for ESCC.

High anisotropy in electrical and thermal conductivity through the design of aerogel-like superlattice (NaOH)0.5NbSe2.

Interlayer decoupling plays an essential role in realizing unprecedented properties in atomically thin materials, but it remains relatively unexplored in the bulk. It is unclear how to realize a large crystal that behaves as its monolayer counterpart by artificial manipulation. Here, we construct a superlattice consisting of alternating layers of NbSe2 and highly porous hydroxide, as a proof of principle for realizing interlayer decoupling in bulk materials. In (NaOH)0.5NbSe2, the electric decoupling is manifested by an ideal 1D insulating state along the interlayer direction. Vibration decoupling is demonstrated through the absence of interlayer models in the Raman spectrum, dominant local modes in heat capacity, low interlayer coupling energy and out-of-plane thermal conductivity (0.28 W/mK at RT) that are reduced to a few percent of NbSe2's. Consequently, a drastic enhancement of CDW transition temperature (>110 K) and Pauling-breaking 2D superconductivity is observed, suggesting that the bulk crystal behaves similarly to an exfoliated NbSe2 monolayer. Our findings provide a route to achieve intrinsic 2D properties on a large-scale without exfoliation.

Bioaccessibility of polypropylene microfiber-associated tetracycline and ciprofloxacin in simulated human gastrointestinal fluids.

Microplastics residues in natural waters can adsorb organic contaminants owing to their rough surface morphology and high specific surface area, potentially harming human health when ingested. Although humans inevitably ingest microplastics, the bioaccessibility of microplastic-associated chemicals in the human gastric and intestinal fluids remains unresolved. This study investigated the mechanism and primary factor controlling the bioaccessibility of polypropylene (PP) microplastic fiber-associated tetracycline (TC) and ciprofloxacin (CIP) in simulated human gastrointestinal fluids. After mixing 0.1 g of PP microfiber with 10 mg/L of TC (or CIP) for 96 h and exposure to simulated human gastrointestinal fluids, the TC concentrations were 0.440, 0.678, and 1.840 mg/L and the CIP concentrations were 0.700, 1.367, and 3.281 mg/L CIP in the simulated human saliva, gastric, and intestinal fluids after incubation for 60 s, 4 h, and 8 h, respectively. This indicated that the antibiotics TC and CIP adsorbed onto microfiber surface are readily released into human gastrointestinal fluids upon ingestion. Gastric and intestinal fluids showed enhanced bioaccessibility to TC/CIP adhered to PP microfiber. The primary factors affecting the bioaccessibility to TC/CIP adhered to PP microfiber surfaces were found to be pepsin in human gastric fluid and trypsin in human intestinal fluid. Molecular docking and simulated molecular dynamic analyses results showed that pepsin and trypsin stablish connections with TC via hydrogen bonds (reaction sites: pepsin TC: T139, T136, S97, D94, D277 and Y251; trypsin TC: S257, H120, K235, G274, and G276) and CIP via hydrophobic interactions (reaction sites: pepsin CIP: Y137, T136, T139, F173, I362, V353, and I275; trypsin CIP: W273, I161, C253, and C277). Our findings highlight that microplastic ingestion increases the risk of microplastics and the co-contaminants adsorbed to human health; thus, these findings are helpful to assess the risk of microplastics and co-contaminants to human health.