Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment.

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.

Dismissal of RNA Polymerase II Underlies a Large Ligand-Induced Enhancer Decommissioning Program.

Nuclear receptors induce both transcriptional activation and repression programs responsible for development, homeostasis, and disease. Here, we report a previously overlooked enhancer decommissioning strategy underlying a large estrogen receptor alpha (ERα)-dependent transcriptional repression program. The unexpected signature for this E2-induced program resides in indirect recruitment of ERα to a large cohort of pioneer factor basally active FOXA1-bound enhancers that lack cognate ERα DNA-binding elements. Surprisingly, these basally active estrogen-repressed (BAER) enhancers are decommissioned by ERα-dependent recruitment of the histone demethylase KDM2A, functioning independently of its demethylase activity. Rather, KDM2A tethers the E3 ubiquitin-protein ligase NEDD4 to ubiquitylate/dismiss Pol II to abrogate eRNA transcription, with consequent target gene downregulation. Thus, our data reveal that Pol II ubiquitylation/dismissal may serve as a potentially broad strategy utilized by indirectly bound nuclear receptors to abrogate large programs of pioneer factor-mediated, eRNA-producing enhancers.

Characteristics of Chinese breast cancer patients with double heterozygosity for BRCA1 and BRCA2 germline pathogenic variants.

PURPOSE: Despite of very rare, breast cancer patients with double heterozygosity (DH) variants in BRCA1 and BRCA2 genes have been identified in other ethnic groups and seem to be associated with distinctive phenotypes. However, little is known about the frequency and clinical characteristics of Chinese breast cancer patients with BRCA1/2 DH variants. METHODS: Four hundred and eleven unrelated patients with BRCA1 or BRCA2 pathogenic variants (PVs) were identified in a large series of unselected breast cancer patients. Another two siblings with metachronous bilateral breast cancer were referred for genetic counseling, after which BRCA1/2 DH variants were detected. RESULTS: Four unrelated breast cancer patients with BRCA1/2 DH were identified in the cohort of 411 patients with BRCA1 or BRCA2 PVs, the frequency of BRCA1/2 DH was 0.97%. In total, six BRCA1/2 DH patients from five families were found in this study. In two families, the hereditary pattern of DH was speculated to have originated from both sides of the family. BRCA1/2 DH patients were more likely to have a family history of breast cancer than patients with a BRCA1 (100% vs. 29.2%, P = 0.004) or BRCA2 (100% vs. 29.6%, P = 0.004) single PV. BRCA1/2 DH patients were more likely to be triple-negative breast tumors than patients with single BRCA2 PVs (66.7% vs. 14.1%, P = 0.020), which was comparable to the findings in patients with single BRCA1 PVs (66.7% vs. 56.9%, P = 1.00). CONCLUSION: Chinese patients with BRCA1/2 DH exhibit a high percentage of family history of breast cancer. The tumor pathological features of BRCA1/2 DH carriers are similar to those of BRCA1 PV carriers.

Risk factors for invasive pulmonary aspergillosis in patients with severe fever with thrombocytopenia syndrome: A multicenter retrospective study.

Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in patients with severe fever with thrombocytopenia syndrome (SFTS), yet SFTS-associated IPA (SAPA)'s risk factors remain undefined. A multicenter retrospective cohort study across Hubei and Anhui provinces (May 2013-September 2022) utilized least absolute shrinkage and selection operator (LASSO) regression for variable selection. Multivariable logistic regression identified independent predictors of SAPA, Cox regression highlighted mortality-related risk factors. Of the 1775 screened SFTS patients, 1650 were included, with 169 developing IPA, leading to a 42-day mortality rate of 26.6% among SAPA patients. Multivariable logistic regression revealed SAPA risk factors including advanced age, petechia, hemoptysis, tremor, low albumin levels, elongated activated partial thromboplastin time (APTT), intensive care unit (ICU) admission, glucocorticoid usage, intravenous immunoglobulin (IVIG) and prolonged hospital stays. Cox regression identified predictors of 42-day mortality, including ecchymosis at venipuncture sites, absence of ICU admission, elongated prothrombin time (PT), vasopressor and glucocorticoid use, non-antifungals. Nomograms constructed on these predictors registered concordance indexes of 0.855 (95% CI: 0.826-0.884) and 0.778 (95% CI: 0.702-0.854) for SAPA onset and 42-day mortality, respectively. Lower survival rates for SAPA patients treated with glucocorticoids (p < 0.001) and improved 14-day survival with antifungal therapy (p = 0.036). Improving IPA management in SFTS-endemic areas is crucial, with effective predictive tool.

Palmitic acid impairs human and mouse placental function by inhibiting trophoblast autophagy through induction of acyl-coenzyme A-binding protein (ACBP) upregulation.

STUDY QUESTION: Can exposure to palmitic acid (PA), a common saturated fatty acid, modulate autophagy in both human and mouse trophoblast cells through the regulation of acyl-coenzyme A-binding protein (ACBP)? SUMMARY ANSWER: PA exposure before and during pregnancy impairs placental development through mechanisms involving placental autophagy and ACBP expression. WHAT IS KNOWN ALREADY: High-fat diets, including PA, have been implicated in adverse effects on human placental and fetal development. Despite this recognition, the precise molecular mechanisms underlying these effects are not fully understood. STUDY DESIGN, SIZE, DURATION: Extravillous trophoblast (EVT) cell line HTR-8/SVneo and human trophoblast stem cell (hTSC)-derived EVT (hTSCs-EVT) were exposed to PA or vehicle control for 24 h. Female wild-type C57BL/6 mice were divided into PA and control groups (n = 10 per group) and subjected to a 12-week dietary intervention. Afterward, they were mated with male wild-type C57BL/6 mice and euthanized on Day 14 of gestation. Female ACBPflox/flox mice were also randomly assigned to control and PA-exposed groups (each with 10 mice), undergoing the same dietary intervention and mating with ACBPflox/floxELF5-Cre male mice, followed by euthanasia on Day 14 of gestation. The study assessed the effects of PA on mouse embryonic development and placental autophagy. Additionally, the role of ACBP in the pathogenesis of PA-induced placental toxicity was investigated. PARTICIPANTS/MATERIALS, SETTING, METHODS: The findings were validated using real-time PCR, Western blot, immunofluorescence, transmission electron microscopy, and shRNA knockdown approaches. MAIN RESULTS AND THE ROLE OF CHANCE: Exposure to PA-upregulated ACBP expression in both human HTR-8/SVneo cells and hTSCs-EVT, as well as in mouse placenta. PA exposure also induced autophagic dysfunction in HTR-8/SVneo cells, hTSCs-EVT, and mouse placenta. Through studies on ACBP placental conditional knockout mice and ACBP knockdown human trophoblast cells, it was revealed that reduced ACBP expression led to trophoblast malfunction and affected the expression of autophagy-related proteins LC3B-II and P62, thereby impacting embryonic development. Conversely, ACBP knockdown partially mitigated PA-induced impairment of placental trophoblast autophagy, observed both in vitro in human trophoblast cells and in vivo in mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Primary EVT cells from early pregnancy are fragile, limiting research use. Maintaining their viability is tough, affecting data reliability. The study lacks depth to explore PA diet cessation effects after 12 weeks. Without follow-up, understanding postdiet impacts on pregnancy stages is incomplete. Placental abnormalities linked to elevated PA diet in embryos lack confirmation due to absence of control groups. Clarifying if issues stem solely from PA exposure is difficult without proper controls. WIDER IMPLICATIONS OF THE FINDINGS: Consuming a high-fat diet before and during pregnancy may result in complications or challenges in successfully carrying the pregnancy to term. It suggests that such dietary habits can have detrimental effects on the health of both the mother and the developing fetus. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by the National Natural Science Foundation of China (82171664, 82301909) and the Natural Science Foundation of Chongqing Municipality of China (CSTB2022NS·CQ-LZX0062, cstc2019jcyj-msxmX0749, and cstc2021jcyj-msxmX0236). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Photonic convolution accelerator based on a hybrid integrated multi-wavelength laser array by photonic wire bonding for real-time image classification.

We propose and experimentally demonstrate a compact and efficient photonic convolution accelerator based on a hybrid integrated multi-wavelength DFB laser array by photonic wire bonding. The photonic convolution accelerator operates at 60.12 GOPS for one 3 × 3 kernel with a convolution window vertical sliding stride of 1 and generates 500 images of real-time image classification. Furthermore, real-time image classification on the MNIST database of handwritten digits with a prediction accuracy of 93.86% is achieved. This work provides a novel, to the best of our knowledge, compact hybrid integration platform to realize the optical convolutional neural networks.

Peroral endoscopic myotomy is an effective treatment for achalasia combined with hiatal hernia.

PURPOSE: To explore the feasibility of peroral endoscopic myotomy (POEM) in patients with achalasia and hiatal hernia. MATERIALS AND METHODS: We performed a retrospective review of 2136 patients with achalasia between January 2016 and December 2022. Patients with achalasia and hiatal hernia were assigned into study group, and matched patients with achalasia but no hiatal hernia were assigned into control group. The preoperative baseline information, procedure-related adverse events (AEs) and follow-up data were compared between the two groups. RESULTS: Hiatal hernia was identified in 56/1564 (3.6%) patients with achalasia. All of these patients underwent POEM with success. The preoperative baseline characteristics were similar between the study and control group. The study group presented with a similar rate of mucosal injury (12.5% vs 16.1, P = 0.589), pneumothorax (3.6% vs 1.8%, P = 1.000), pleural effusion (8.9% vs 12.5%, P = 0.541) and major AEs (1.8% vs 1.8%, P = 1.000) compared with the control group. As for the follow-up data, no significant differences were observed in clinical success (96.4% vs 92.9%, P = 0.679; 93.6% vs 94.0%, P = 1.000; 86.5% vs 91.4%, P = 0.711) clinical reflux (25.0% vs 19.6%, P = 0.496; 31.9% vs 26.0%, P = 0.521; 35.1% vs 31.4%, P = 0.739) and proton pump inhibitor usage (17.9% vs 16.1%, P = 0.801; 29.8% vs 24.0%, P = 0.520; 32.4% vs 25.7%, P = 0.531) between the study group and control group at 1-year, 2-year and 3-year follow-ups. CONCLUSIONS: POEM is a safe and effective treatment for achalasia combined with hiatal hernia.

Feasibility and safety of percutaneous intramyocardial septal cryoablation: A canine model with 6-month follow-up.

Echocardiography-guided percutaneous intramyocardial septal radiofrequency ablation (PIMSRA, Liwen procedure) is a novel treatment option for hypertrophic obstructive cardiomyopathy (HOCM). The safety and feasibility of using this procedure for cryoablation are unknown. We aimed to investigate the feasibility and safety of echocardiography-guided percutaneous intramyocardial septal cryoablation (PIMSCA) for septal thickness reduction in a canine model. Eight canines underwent PIMSCA, and had electrocardiography, echocardiography(ECG), myocardial contrast echocardiography (MCE), serological and pathological examinations during the preoperative, immediate postoperative, and 6-month follow-up. All eight canines underwent successful cryoablation and continued to be in sinus rhythm during ablation and without malignant arrhythmias. MCE showed that the ablation area had decreased myocardial perfusion after the procedure. Troponin I levels were significantly elevated [0.010 (0.005, 0.297) ng/mL vs. 3.122 (1.152, 7.990) ng/mL, p < 0.05)]. At 6-month follow-up after the procedure, all animals were alive, with thinning of the interventricular septum (7.26 ± 0.52 mm vs. 3.86 ± 0.29 mm, p < 0.05). Echocardiography showed no significant decrease in the left ventricular ejection fractions (LVEF) (54.32 ± 2.93 % vs. 54.70 ± 2.47 %, p > 0.05) or changes by pulse-wave Doppler E/A (1.17 ± 0.43 vs. 1.07 ± 0.43, p > 0.05), E/e' (8.09 ± 1.49 vs. 10.05 ± 2.68, p > 0.05). Pathological findings proved the effectiveness of cryoablation in myocardial tissues. We observed pericardial effusions and premature ventricular complexes (PVCs) associated with the procedure. Our findings provided preliminary evidence of the safety and feasibility of PIMSCA in reducing interventricular septum, which provides a potentially new treatment option for HOCM.

Characterizing the emission trends and pollution evolution patterns during the transition period following COVID-19 at an industrial megacity of central China.

After the resumption of work and production following the COVID-19 pandemic, many cities entered a "transition phase", characterized by the gradual recovery of emission levels from various sources. Although the overall PM2.5 emission trends have recovered, the specific changes in different sources of PM2.5 remain unclear. Here, we investigated the changes in source contributions and the evolution pattern of pollution episodes (PE) in Wuhan during the "transition period" and compared them with the same period during the COVID-19 lockdown. We found that vehicle emissions, industrial processes, and road dust exhibited significant recoveries during the transition period, increasing by 5.4%, 4.8%, and 3.9%, respectively, during the PE. As primary emissions increased, secondary formation slightly declined, but it still played a predominant role (accounting for 39.1∼ 43.0% of secondary nitrate). The reduction in industrial activities was partially offset by residential burning. The evolution characteristics of PE exhibited significant differences between the two periods, with PM2.5 concentration persisting at a high level during the transition period. The differences in the evolution patterns of the two periods were also reflected in their change rates at each stage, which mostly depend on the pre-PE concentration level. The transition period shows a significantly higher value (8.4 µg m-3 h-1) compared with the lockdown period, almost double the amount. In addition to local emissions, regional transport should be a key consideration in pollution mitigation strategies, especially in areas adjacent to Wuhan. Our study quantifies the variations in sources between the two periods, providing valuable insights for optimizing environmental planning to achieve established goals.

Nanoscale Ultrafine Zinc Metal Anodes for High Stability Aqueous Zinc Ion Batteries.

Aqueous Zn batteries (AZBs) are a promising energy storage technology, due to their high theoretical capacity, low redox potential, and safety. However, dendrite growth and parasitic reactions occurring at the surface of metallic Zn result in severe instability. Here we report a new method to achieve ultrafine Zn nanograin anodes by using ethylene glycol monomethyl ether (EGME) molecules to manipulate zinc nucleation and growth processes. It is demonstrated that EGME complexes with Zn2+ to moderately increase the driving force for nucleation, as well as adsorbs on the Zn surface to prevent H-corrosion and dendritic protuberances by refining the grains. As a result, the nanoscale anode delivers high Coulombic efficiency (ca. 99.5%), long-term cycle life (over 366 days and 8800 cycles), and outstanding compatibility with state-of-the-art cathodes (ZnVO and AC) in full cells. This work offers a new route for interfacial engineering in aqueous metal-ion batteries, with significant implications for the commercial future of AZBs.

[Consistency evaluation of multidimensional quality attributes of Atractylodis Macrocephalae Rhizoma by fusion of multi-source information].

The quality control of Chinese medicinal decoction pieces is one of the key tasks in the traditional Chinese medicine industry. In this study, multi-source information fusion was employed to fuse the data from near-infrared spectroscopy, electronic tongues, and other tests and establish an overall quality consistency evaluation method for Atractylodis Macrocephalae Rhizoma, which provided methodological support for the overall quality evaluation of Atractylodis Macrocephalae Rhizoma. The near-infrared spectroscopy information was measured in both static and dynamic states for 23 batches of Atractylodis Macrocephalae Rhizoma samples from different sources, and the electronic tongue sensory information, moisture content, and leachate content were measured. The overall quality of Atractylodis Macrocephalae Rhizoma was evaluated by multi-source information fusion. The results showed that the near-infrared spectroscopy information of 16122103, 801000509, 801000352, 701003656, HX21L01, and 160956 was different from that of other batches of Atractylodis Macrocephalae Rhizoma powder in the static state, and 701003298, 16122103, 701003656, 701003107, 801000229, and 18090404 were the different batches in the dynamic state. The moisture content showed no significant difference between batches. The leachate content in the batch 801000509 was different from that in other batches. The electronic tongue sensory information of 150721004, 151237, 160703004, HX21M01, HX21K04, HX21K01, and 601003516 was different from that of other batches. Furthermore, data layer fusion was employed to analyze the overall quality of Atractylodis Macrocephalae Rhizoma. Four batches, 150721004, HX21M01, HX21K04, and HX21K01, showed the parameters exceeding the 95% control limits and differed from the other samples in terms of the overall quality. This study integrated the information of moisture, near-infrared spectroscopy, and other sources to evaluate the quality consistency among 23 batches of Atractylodis Macrocephalae Rhizoma samples, which provides a reference for the quality consistency evaluation of Chinese medicinal decoction pieces.

Impact of multifocal or multicentric disease on local recurrence and survival in breast cancer patients with or without BRCA1/2 variants.

PURPOSE: Multifocal or multicentric (MFMC) breast cancer is mainly focused on breast cancer patients with unknown BRCA status, the incidence and clinical relevance of MFMC disease in BRCA1/2 carriers is less explored to date. Our study was to investigate the incidence of MFMC disease in BRCA1/2 carriers and whether MFMC disease influences local recurrence and clinical outcomes. METHODS: In this retrospective study, 479 breast cancer patients with BRCA1/2 variants and 1437 age-matched noncarriers were enrolled and patients received either breast-conserving therapy (BCT) or mastectomy with or without radiotherapy. RESULTS: The rates of MFMC disease in BRCA1 and BRCA2 carriers, and noncarriers were 33.0% (61 of 185), 37.4% (110 of 294), and 31.2% (449 of 1437), respectively. MFMC disease in BRCA2 carriers was significantly higher than that in noncarriers (P = 0.039). After a median follow-up of 8.1 years, among patients treated with BCT, BRCA2 carriers with MFMC disease experienced a significantly higher rate of ipsilateral breast tumor recurrence (IBTR) than those with unifocal disease (16.7% vs 4.1%, P = 0.044). Moreover, BRCA2 carriers with MFMC disease had a significantly worse RFS (unadjusted hazard ratio [HR], 3.65 [95% CI 1.40-9.52]; P = 0.008), DRFS (unadjusted HR, 3.07 [95% CI 1.07-8.80]; P = 0.037), and OS (unadjusted HR, 4.96 [95% CI 1.18-20.02]; P = 0.029) than those with unifocal disease when treated with BCT. CONCLUSION: MFMC breast cancer is more common in BRCA2 carriers, and BRCA2 carriers with MFMC disease treated with BCT exhibit a higher rate of IBTR and may have a poor survival.

Inherent Capability of Self-Assembling Nanostructures in Specific Proteasome Activation for Cancer Cell Pyroptosis.

Understanding the direct interaction of nanostructures per se with biological systems is important for biomedical applications. However, whether nanostructures regulate biological systems by targeting specific cellular proteins remains largely unknown. In the present work, self-assembling nanomicelles are constructed using small-molecule oleanolic acid (OA) as a molecular template. Unexpectedly, without modifications by functional ligands, OA nanomicelles significantly activate cellular proteasome function by directly binding to 20S proteasome subunit alpha 6 (PSMA6). Mechanism study reveals that OA nanomicelles interact with PSMA6 to dynamically modulate its N-terminal domain conformation change, thereby controlling the entry of proteins into 20S proteasome. Subsequently, OA nanomicelles accelerate the degradation of several crucial proteins, thus potently driving cancer cell pyroptosis. For translational medicine, OA nanomicelles exhibit a significant anticancer potential in tumor-bearing mouse models and stimulate immune cell infiltration. Collectively, this proof-of-concept study advances the mechanical understanding of nanostructure-guided biological effects via their inherent capacity to activate proteasome.

The spatiotemporal matching pattern of Ezrin/Periaxin involved in myoblast differentiation and fusion and Charcot-Marie-Tooth disease-associated muscle atrophy.

BACKGROUND: Clinically, Charcot-Marie-Tooth disease (CMT)-associated muscle atrophy still lacks effective treatment. Deletion and mutation of L-periaxin can be involved in CMT type 4F (CMT4F) by destroying the myelin sheath form, which may be related to the inhibitory role of Ezrin in the self-association of L-periaxin. However, it is still unknown whether L-periaxin and Ezrin are independently or interactively involved in the process of muscle atrophy by affecting the function of muscle satellite cells. METHOD: A gastrocnemius muscle atrophy model was prepared to mimic CMT4F and its associated muscle atrophy by mechanical clamping of the peroneal nerve. Differentiating C2C12 myoblast cells were treated with adenovirus-mediated overexpression or knockdown of Ezrin. Then, overexpression of L-periaxin and NFATc1/c2 or knockdown of L-periaxin and NFATc3/c4 mediated by adenovirus vectors were used to confirm their role in Ezrin-mediated myoblast differentiation, myotube formation and gastrocnemius muscle repair in a peroneal nerve injury model. RNA-seq, real-time PCR, immunofluorescence staining and Western blot were used in the above observation. RESULTS: For the first time, instantaneous L-periaxin expression was highest on the 6th day, while Ezrin expression peaked on the 4th day during myoblast differentiation/fusion in vitro. In vivo transduction of adenovirus vectors carrying Ezrin, but not Periaxin, into the gastrocnemius muscle in a peroneal nerve injury model increased the numbers of muscle myosin heavy chain (MyHC) I and II type myofibers, reducing muscle atrophy and fibrosis. Local muscle injection of overexpressed Ezrin combined with incubation of knockdown L-periaxin within the injured peroneal nerve or injection of knockdown L-periaxin into peroneal nerve-injured gastrocnemius muscle not only increased the number of muscle fibers but also recovered their size to a relatively normal level in vivo. Overexpression of Ezrin promoted myoblast differentiation/fusion, inducing increased MyHC-I+ and MyHC-II + muscle fiber specialization, and the specific effects could be enhanced by the addition of adenovirus vectors for knockdown of L-periaxin by shRNA. Overexpression of L-periaxin did not alter the inhibitory effects on myoblast differentiation and fusion mediated by knockdown of Ezrin by shRNA in vitro but decreased myotube length and size. Mechanistically, overexpressing Ezrin did not alter protein kinase A gamma catalytic subunit (PKA-γ cat), protein kinase A I alpha regulatory subunit (PKA reg Iα) or PKA reg Iß levels but increased PKA-α cat and PKA reg II α levels, leading to a decreased ratio of PKA reg I/II. The PKA inhibitor H-89 remarkably abolished the effects of overexpressing-Ezrin on increased myoblast differentiation/fusion. In contrast, knockdown of Ezrin by shRNA significantly delayed myoblast differentiation/fusion accompanied by an increased PKA reg I/II ratio, and the inhibitory effects could be eliminated by the PKA reg activator N6-Bz-cAMP. Meanwhile, overexpressing Ezrin enhanced type I muscle fiber specialization, accompanied by an increase in NFATc2/c3 levels and a decrease in NFATc1 levels. Furthermore, overexpressing NFATc2 or knocking down NFATc3 reversed the inhibitory effects of Ezrin knockdown on myoblast differentiation/fusion. CONCLUSIONS: The spatiotemporal pattern of Ezrin/Periaxin expression was involved in the control of myoblast differentiation/fusion, myotube length and size, and myofiber specialization, which was related to the activated PKA-NFAT-MEF2C signaling pathway, providing a novel L-Periaxin/Ezrin joint strategy for the treatment of muscle atrophy induced by nerve injury, especially in CMT4F.

Cold stress regulates accumulation of flavonoids and terpenoids in plants by phytohormone, transcription process, functional enzyme, and epigenetics.

Plants make different defense mechanisms in response to different environmental stresses. One common way is to produce secondary metabolites. Temperature is the main environmental factor that regulates plant secondary metabolites, especially flavonoids and terpenoids. Stress caused by temperature decreasing to 4-10 °C is conducive to the accumulation of flavonoids and terpenoids. However, the accumulation mechanism under cold stress still lacks a systematic explanation. In this review, we summarize three aspects of cold stress promoting the accumulation of flavonoids and terpenoids in plants, that is, by affecting (1) the content of endogenous plant hormones, especially jasmonic acid and abscisic acid; (2) the expression level and activity of important transcription factors, such as bHLH and MYB families. This aspect also includes post-translational modification of transcription factors caused by cold stress; (3) key enzyme genes expression and activity in the biosynthesis pathway, in addition, the rate-limiting enzyme and glycosyltransferases genes are responsive to cold stress. The systematic understanding of cold stress regulates flavonoids, and terpenoids will contribute to the future research of genetic engineering breeding, metabolism regulation, glycosyltransferases mining, and plant synthetic biology.

Amino acid metabolism regulated by lncRNAs: the propellant behind cancer metabolic reprogramming.

Metabolic reprogramming is one of the main characteristics of cancer cells and plays pivotal role in the proliferation and survival of cancer cells. Amino acid is one of the key nutrients for cancer cells and many studies have focused on the regulation of amino acid metabolism, including the genetic alteration, epigenetic modification, transcription, translation and post-translational modification of key enzymes in amino acid metabolism. Long non-coding RNAs (lncRNAs) are composed of a heterogeneous group of RNAs with transcripts of more than 200 nucleotides in length. LncRNAs can bind to biological molecules such as DNA, RNA and protein, regulating the transcription, translation and post-translational modification of target genes. Now, the functions of lncRNAs in cancer metabolism have aroused great research interest and significant progress has been made. This review focuses on how lncRNAs participate in the reprogramming of amino acid metabolism in cancer cells, especially glutamine, serine, arginine, aspartate, cysteine metabolism. This will help us to better understand the regulatory mechanism of cancer metabolic reprogramming and provide new ideas for the development of anti-cancer drugs. Video Abstract.

One-Electron Oxidant-Induced Transformations of Aromatic Alcohol to Ketone Moieties in Dissolved Organic Matter Increase Trichloromethane Formation.

Radicals in advanced oxidation processes (AOPs) degrade micropollutants during water and wastewater treatment, but the transformation of dissolved organic matter (DOM) may be equally important. Ketone moieties in DOM are known disinfection byproduct precursors, but ketones themselves are intermediates produced during AOPs. We found that aromatic alcohols in DOM underwent transformation to ketones by one-electron oxidants (using SO4•- as a representative), and the formed ketones significantly increased trichloromethane (CHCl3) formation potential (FP) upon subsequent chlorination. CHCl3-FPs from aromatic ketones (Ar-CO-CH3, average of 22 mol/mol) were 6-24 times of CHCl3-FPs from aromatic alcohols (Ar-CH(OH)-CH3, average of 0.85 mol/mol). At a typical SO4•- exposure of 7.0 × 10-12 M·s, CHCl3-FPs from aromatic alcohol transformation increased by 24.8%-112% with an average increase of 53.4%. Notably, SO4•- oxidation of aliphatic alcohols resulted in minute changes in CHCl3-FPs due to their low reactivities with SO4•- (∼107 M-1 s-1). Other one-electron oxidants (Cl2•-, Br2•-,and CO3•-) are present in AOPs and also lead to aromatic alcohol-ketone transformations similar to SO4•-. This study highlights that subtle changes in DOM physicochemical properties due to one-electron oxidants can greatly affect the reactivity with free chlorine and the formation of chlorinated byproducts.

Endoscopic submucosal dissection for anastomotic lesions after colorectal surgery.

BACKGROUND: Endoscopic submucosal dissection (ESD) for anastomotic lesions is technically challenging. We aimed to characterize the clinicopathologic characteristics, feasibility, and effectiveness of ESD for anastomotic lesions of the lower gastrointestinal tract. METHOD: We retrospectively investigated 55 patients with anastomotic lesions of the lower gastrointestinal tract who underwent ESD from February 2008 to January 2021. The lesions involving one or both sides of anastomoses were classified into the unilaterally involving anastomosis (UIA) or straddling anastomosis (SA) group, respectively. We collected clinicopathological characteristics, procedure-related parameters and outcomes, and follow-up data and analyzed the impact of anastomotic involvement. RESULTS: The mean age was 62.5 years, and the median procedure duration was 30 min. The rates of en bloc resection and R0 resection were 90.9% and 85.5%, respectively. Four patients (7.3%) experienced major adverse events (AEs). During a median follow-up of 66 months (range 14-169), seven patients had local recurrence, and six patients had metastases. The 5-year disease-free survival and overall survival rates were 82.4% and 90.7%, respectively. The 5-year disease -specific survival (DSS) rate was 93.3%. Compared with the UIA group, the SA group had significantly longer procedure duration, larger specimen, lower rates of en bloc resection and R0 resection, and shorter disease-free survival (all P < 0.05). However, rates of AEs did not differ significantly between the two groups. CONCLUSIONS: The short-term and long-term outcomes of ESD for colorectal anastomotic lesions were favorable. Although with technically challenging, ESD could be performed safely and effectively for lesions at the anastomoses.

A cross-sectional study reveals a chronic low-grade inflammation in achalasia.

BACKGROUND AND AIM: Immune-mediated neuroinflammation has been proposed to underlie the loss of lower esophageal sphincter (LES) myenteric neurons in achalasia. However, the immune status and key pathogenic immune subpopulations remain unclear. This study aims to evaluate the inflammatory status of patients with achalasia and their correlation with clinical characteristics, and further explore the key pathogenic subpopulations. METHODS: We investigated the complete blood cell count and inflammatory markers in a large population of patients with achalasia (n = 341) and healthy controls (n = 80). The subpopulations of lymphocytes were analyzed by flow cytometry. Immunofluorescence was used to determine immune cell infiltration in the LES. Transcriptome changes of the key subpopulation were determined by RNA sequencing analysis. RESULTS: NLR, MLR, CRP, globulin, IL-6 and IL-10 were significantly elevated in patients with achalasia. MLR and globulin were positively correlated with disease duration. The absolute count and percentage of CD8+ T cells in peripheral blood and its infiltration around ganglion in the LES were significantly increased in achalasia. Transcriptome analysis indicated that CD8+ T cells were activated and proliferative. In addition to multiple inflammatory pathways, regulation of neuroinflammatory response pathway was also significantly up-regulated in achalasia. GSEA analysis revealed a close association with autoimmune diseases. CONCLUSIONS: Patients with achalasia suffered from chronic low-grade inflammation with dysregulated immune cells and mediators associated with disease duration. CD8+ T cells might be the key pathogenic subpopulation of achalasia. Our results provide an important immune cell signature of the pathogenesis of achalasia.

Endoscopic submucosal dissection for lesions involving the anastomosis after upper gastrointestinal surgery.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) for anastomotic lesions is technically challenging due to severe fibrosis, deformity, staples, and limited space for procedure. We aimed to characterize the clinicopathological characteristics, feasibility, and effectiveness of ESD for anastomotic lesions of the upper gastrointestinal tract. METHODS: We retrospectively investigated 43 patients with lesions involving the anastomoses of the upper GI tract who underwent ESD from April 2007 to February 2021. We collected clinicopathological characteristics, procedure­related parameters and outcomes, and follow­up data and analyzed the impact of anastomotic involvement. RESULTS: The median duration from previous upper GI surgery was 60 months and the median procedure duration was 30 min. The rate of en bloc resection and en bloc with R0 resection was 90.7% and 81.4%, respectively. Two patients (4.7%) experienced major adverse events, including delayed bleeding and febrile episode. During a median follow-up of 80 months, 3 patients had local recurrence and 4 patients had metastases. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 89.6% and 95.1%, respectively. Compared with the unilaterally involving group, the straddling anastomosis group had significantly longer procedure duration, larger specimen, lower rates of en bloc resection and en bloc with R0 resection, and shorter DFS and OS (all P < 0.05). However, rates of adverse events did not differ significantly between the two groups. CONCLUSIONS: The short­ and long-term outcomes of ESD for upper GI anastomotic lesions were favorable. Although with technically challenging, ESD could be performed safely and effectively for anastomotic lesions.