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How unequal are the gains from trade? This paper develops a structural framework to quantify the consequences of international trade on welfare of consumers across the income distribution, allowing for nonhomothetic demand and endogenous quality choices by firms. Using random coefficients demand estimation techniques, I infer demand and supply parameters, as well as household-specific price indexes for more than 3,000 distinct industries and find the gains from trade to be moderately unequal except in wealthier and small economies. Further, not accounting for endogenous vertical differentiation would overstate the impact of trade on cost-of-living inequality by close to 50%.

Auxin is a crucial growth regulator that governs plant development and responses to environmental perturbations. It functions at the heart of many developmental processes, from embryogenesis to organ senescence, and is key to plant interactions with the environment, including responses to biotic and abiotic stimuli. As remarkable as auxin is, it does not act alone, but rather solicits the help of, or is solicited by, other endogenous signals, including the plant hormones abscisic acid, brassinosteroids, cytokinins, ethylene, gibberellic acid, jasmonates, salicylic acid, and strigolactones. The interactions between auxin and other hormones occur at multiple levels: hormones regulate one another's synthesis, transport, and/or response; hormone-specific transcriptional regulators for different pathways physically interact and/or converge on common target genes; etc. However, our understanding of this crosstalk is still fragmentary, with only a few pieces of the gigantic puzzle firmly established. In this review, we provide a glimpse into the complexity of hormone interactions that involve auxin, underscoring how patchy our current understanding is.

Xuanfeibaidu Formula (XFBD) is a Chinese medicine used in the clinical treatment of coronavirus disease 2019 (COVID-19) patients. Although XFBD has exhibited significant therapeutic efficacy in clinical practice, its underlying pharmacological mechanism remains unclear. Here, we combine a comprehensive research approach that includes network pharmacology, transcriptomics, and bioassays in multiple model systems to investigate the pharmacological mechanism of XFBD and its bioactive substances. High-resolution mass spectrometry was combined with molecular networking to profile the major active substances in XFBD. A total of 154 compounds were identified or tentatively characterized, including flavonoids, terpenes, carboxylic acids, and other types of constituents. Based on the chemical composition of XFBD, a network pharmacology-based analysis identified inflammation-related pathways as primary targets. Thus, we examined the anti-inflammation activity of XFBD in a lipopolysaccharide-induced acute inflammation mice model. XFBD significantly alleviated pulmonary inflammation and decreased the level of serum proinflammatory cytokines. Transcriptomic profiling suggested that genes related to macrophage function were differently expressed after XFBD treatment. Consequently, the effects of XFBD on macrophage activation and mobilization were investigated in a macrophage cell line and a zebrafish wounding model. XFBD exerts strong inhibitory effects on both macrophage activation and migration. Moreover, through multimodal screening, we further identified the major components and compounds from the different herbs of XFBD that mediate its anti-inflammation function. Active components from XFBD, including Polygoni cuspidati Rhizoma, Phragmitis Rhizoma, and Citri grandis Exocarpium rubrum, were then found to strongly downregulate macrophage activation, and polydatin, isoliquiritin, and acteoside were identified as active compounds. Components of Artemisiae annuae Herba and Ephedrae Herba were found to substantially inhibit endogenous macrophage migration, while the presence of ephedrine, atractylenolide, and kaempferol was attributed to these effects. In summary, our study explores the pharmacological mechanism and effective components of XFBD in inflammation regulation via multimodal approaches, and thereby provides a biological illustration of the clinical efficacy of XFBD.

DNAzyme has emerged as a promising gene silencer for therapeutic application. However, DNAzyme-based gene therapy against tumors is still restrained by controllable and specific activation in cance...

Heterogeneity within specific cell types is common and increasingly apparent with the advent of single cell transcriptomics. Transcriptional and functional cellular specialization has been described for insulin-secreting β cells of the endocrine pancreas, including so-called extreme β cells exhibiting >2-fold higher insulin gene activity. However, it is not yet clear whether β cell heterogeneity is stable or reflects dynamic cellular states. We investigated the temporal kinetics of endogenous insulin gene activity using live cell imaging, with complementary experiments employing FACS and single cell RNA sequencing, in β cells from Ins2GFP knock-in mice. In vivo staining and FACS analysis of islets from Ins2GFP mice confirmed that at a given moment, ~25% of β cells exhibited significantly higher activity at the conserved insulin gene Ins2. Live cell imaging captured Ins2 gene activity dynamics in single β cells over time. Autocorrelation analysis indicated that cells displaying fluctuations in Ins2 gene activity most commonly exhibited a frequency of 17 hours. Increased glucose concentrations stimulated more cells to oscillate and resulted in higher average Ins2 gene activity per cell. Single cell RNA sequencing determined that Ins2(GFP)HIGH β cells were enriched for markers of β cell maturity and had reduced expression of anti-oxidant genes. Ins2(GFP)HIGH β cells were also significantly less viable at all glucose concentrations and in the context of ER stress. Collectively, our results demonstrate that the heterogeneity of insulin production, observed in mouse and human β cells, can be accounted for by dynamic states of insulin gene activity. Our observations define a previously uncharacterized form of β cell plasticity. Understanding the dynamics of insulin production has relevance for understanding the pathobiology of diabetes and for regenerative therapy research.

Introduction: The consumption of large amounts of ethanol can directly lead to acute gastric mucosal bleeding, edema, and erosion, while long-term drinking has been associated with gastric ulcers. Previous research has demonstrated that Har Gabur, a traditional Mongolian medicine, alleviates gastric ulcers through the physical adsorption of its carbon components. It is well known that the immune response has an important role in gastric ulceration. Methods: In the present study, we used an ethanol-induced injury cell and mice model to investigate whether Har Gabur can inhibit the immune response stimulated by ethanol and identify the active constituents of Har Gabur involved in this process. Results: We found that Har Gabur significantly repressed the activated Fas/FasL signal pathway and endogenous Bax/Bcl-2 apoptosis pathway. The molecular mechanism of the protective effect most likely involved the transcription or mRNA stability, as Har Gabur remarkably reversed the change in mRNA level of apoptosis-related genes induced by ethanol. Conclusion: Har Gabur operated in a cell-state-specific manner in vivo without inducing adverse effects in normal mice. Importantly, GO was identified as the main active ingredient of Har Gabur for gastric ulcers.

The high mortality in larval-to-juvenile transition is a big problem in aquaculture which is related to the shifting from endogenous to exogenous feeding. However, the underlying causes remain poorly understood. Autophagy, an evolutionary regulated cellular mechanism, is highly conserved in eukaryotic organisms to maintain energy homeostasis against stress including starvation. To investigate whether autophagy plays a role during larval-to-juvenile transition, we generated atg7 and beclin1 zebrafish mutant lines using CRISPR/Cas9 gene editing technology. In this study, both atg7 and beclin1 null zebrafish died during larval-to-juvenile transition because atg7 and beclin1 mutants were unable to cope with the metabolic stress after yolk absorption and fail to activate autophagy in response to nutrient restriction. Meanwhile, dramatic defects in the intestine architecture and metabolic functions in the liver of these mutants were observed even though refeeding them. Treatment with rapamycin, an activator of autophagy, could effectively extend the survival time of both atg7 and beclin1 null zebrafish through decreasing the metabolic rate while it couldn't activate autophagy in mutants via the canonical pathway. Thus, our results revealed that autophagy played a crucial role in zebrafish ontogeny during larval-to-juvenile transition, and it could be considered as one of the most important endogenous factors judging the survival rate of the developing embryos during this period.

Acute liver failure (ALF) has an abrupt onset with a frequently fatal outcome. Previous studies have found that oral antibiotics prevent drug-induced liver injury in animal experiments, indicating that the gut microbiota plays a critical role in the pathophysiological process. However, the underlying mechanism has not been fully understood. This study explored the comprehensive role of the gut microbiota in ALF using multi-omics. A cocktail of broad-spectrum antibiotics (Abx) pretreatment by gavage for four weeks improved the survival of D-(+)-galactosamine hydrochloride (D-Gal)/lipopolysaccharide (LPS)-induced ALF in C57BL/6 mice. RNA sequencing showed that inflammatory responses were inhibited and metabolic pathways were upregulated in the liver of Abx-treated ALF mice. The 16S rRNA gene sequencing revealed that Abx reshaped the composition and function of the gut microbiota, with an increased proportion of tryptophan (Trp) metabolism. In addition, global metabolic profiling by ultra-performance liquid chromatography–mass spectrometry (UPLC–MS) indicated that the gut microbiota post-Abx intervention reduced Trp excretion, liberated more Trp to the host, and enhanced the kynurenine (Kyn) pathway with increased production of Kyn. As an endogenous aryl hydrocarbon receptor (AhR) ligand, Kyn has anti-inflammatory and immunosuppressive effects. Furthermore, AhR-targeted treatments affected the outcome of ALF mice with or without Abx pretreatment, indicating that AhR directly regulated susceptibility to ALF, at least in part. This study demonstrates that the gut microbiota-dependent control of the Trp metabolism could regulate host susceptibility to ALF by modulating the activity of AhR, and thus provides a promising target for better management of ALF.

The squash beetle Epilachna chrysomelina (F.) is an important insect pest which causes severe damage to cucurbit plants in Iraq. The aims of this study were to isolate and characterize an endogenous isolate of Myrothecium-like species from cucurbit plants and from soil in order to evaluate its pathogenicity to squash beetle. Paramyrothecium roridum (Tode) L. Lombard & Crous was isolated, its phenotypic characteristics were identified and ITS rDNA sequence analysis was done. The pathogenicity of P. roridum strain (MT019839) was evaluated at a concentration of 107 conidia · ml–1) water against larvae and adults of E. chrysomelina under laboratory conditions. The results revealed the pathogenicity of the isolate to larvae with variations between larvae instar responses. The highest mortality percentage was reported when the adults were placed in treated litter and it differed significantly from adults treated directly with the pathogen. Our results documented for the first time that P. roridum has potential as an insect pathogen.

Background: Mucosal-associated invariant T (MAIT) cells are unconventional T cells which recognize microbial metabolites presented by the major histocompatibility complex class I-related molecule MR1. Although MAIT cells have been shown to reside in human and murine skin, their contribution to atopic dermatitis (AD), an inflammatory skin disease associated with barrier dysfunction and microbial translocation, has not yet been determined. Methods: Genetic deletion of MR1 and topical treatment with inhibitory MR1 ligands, which result in the absence and functional inhibition of MAIT cells, respectively, were used to investigate the role of MR1-dependent immune surveillance in a MC903-driven murine model of AD. Results: The absence or inhibition of MR1 arrested AD disease progression through the blockade of both eosinophil activation and recruitment of IL-4- and IL-13-producing cells. In addition, the therapeutic efficacy of phototherapy against MC903-driven AD could be increased with prior application of folate, which photodegrades into the inhibitory MR1 ligand 6-formylpterin. Conclusion: We identified MAIT cells as sentinels and mediators of cutaneous type 2 immunity. Their pathogenic activity can be inhibited by topical application or endogenous generation, via phototherapy, of inhibitory MR1 ligands.

Knock-in mice are useful for evaluating endogenous gene expressions and functions in vivo. Instead of the conventional gene-targeting method using embryonic stem cells, an exogenous DNA sequence can be inserted into the target locus in the zygote using genome editing technology. In this chapter, I describe the generation of epitope-tagged mice using engineered endonuclease and single-stranded oligodeoxynucleotide through the mouse zygote as an example of how to generate a knock-in mouse by genome editing.

Sleep is regulated by the homeostatic system and the circadian clock. The circadian clock governs the timing of sleep-wake cycles and the homeostatic mechanisms modulate the amount and depth of sleep. Caffeine intake promotes wakefulness inDrosophila. In humans, caffeine is consumed on a daily basis and hence it is important to understand the effect of prolonged caffeine intake on both circadian and homeostatic regulation of sleep. Furthermore, sleep changes with age and the impact of caffeine on age dependent sleep fragmentation is yet to be understood. Hence in the present study, we examined the effect of short exposure to caffeine on homeostatic sleep and age dependent sleep fragmentation inDrosophila. We further assessed the effect of prolonged exposure to caffeine on homeostatic sleep and circadian clock inDrosophila. The results of our study showed that short exposure to caffeine reduces sleep in flies and enhances sleep fragmentation with increasing age. On the other hand, prolonged caffeine exposure did not exert any significant effect on duration of sleep in mature flies. Nevertheless, prolonged caffeine ingestion decreased the morning and evening anticipatory activity in these flies indicating that it affects the circadian rhythm. These flies also exhibited phase delay in the clock genetimelesstranscript oscillation and altered behavioral rhythm with either a longer free running period or arrhythmicity under constant darkness. In summary, the results of our studies showed that short exposure to caffeine increases the sleep fragmentation with age whereas prolonged caffeine exposure disrupts the circadian clock.Statement of SignificanceIn the present study, we assessed the effect of duration of caffeine intake on age dependent sleep fragmentation and circadian clock by usingDrosophilaas a model organism. We found that short exposure to caffeine reduced sleep and food intake in flies. It also increased the sleep fragmentation with age. On the other hand prolonged caffeine exposure did not affect the sleep and feeding indicating that these flies developed tolerance to caffeine. As in mammals, caffeine slows down the circadian clock in flies. Most importantly, prolonged caffeine treatment disrupted the circadian rhythm inDrosophila. Our studies provide new insights into the differential effect of duration of caffeine intake on circadian clock and sleep.

Following our early discovery of arginylation in 1963, we have performed several studies to correlate its activity with essential biological processes. We employed cell- and tissue-based assays to detect both the level of acceptor proteins and the level of ATE1 activity under different conditions. Remarkably, in these assays, we found a close correlation between arginylation and aging, a discovery that we believe has longer-term implications in uncovering the importance of ATE1 in normal biology and disease therapies. Here we describe the original methods we used to measure ATE1 activity in tissues and correlate it with key biological events.

Graphene oxide (GO) exhibits good mechanical and physicochemical characteristics and has extensive application prospects in bone tissue engineering. However, its effect on angiogenesis is unclear, and its potential toxic effects are heavily disputed. Herein, we found that nanographene oxide (NGO) synthesized by one-step water electrolytic oxidation is smaller and shows superior biocompatibility. Moreover, NGO significantly enhanced angiogenesis in calvarial bone defect areas in vivo, providing a good microenvironment for bone regeneration. Endothelial tip cell differentiation is an important step in the initiation of angiogenesis. We verified that NGO activates endothelial tip cells by coupling with lysophosphatidic acid (LPA) in serum via strong hydrogen bonding interactions, which has not been reported. In addition, the mechanism by which NGO promotes angiogenesis was systematically studied. NGO-coupled LPA activates LPAR6 and facilitates the formation of migratory tip cells via Hippo/Yes-associated protein (YAP) independent of reactive oxygen species (ROS) stimulation or additional complex modifications. These results provide an effective strategy for the application of electrochemically derived NGO and more insight into NGO-mediated angiogenesis., Graphical abstract Schematic representation of the mechanisms by which NGO promotes early angiogenesis at the bone defect site. NGO-bound endogenous LPA activates LPAR6 and induces the nuclear translocation of YAP, thereby inducing tip cell specialization and promoting angiogenesis.Image 1, Highlights • Electrochemically derived nanographene oxide (NGO) has good cytocompatibility without upregulating reactive oxygen species. • NGO exhibits better dispersibility and couples with endogenous lysophosphatidic acid (LPA) in body fluid. • NGO enhances the angiogenesis by recruiting endogenous LPA and promoting endothelial tip cell formation.

Short-chain fatty acids (SCFAs) are major products of intestinal microbial fermentation with beneficial effects for human health. The dynamic balance and real-time monitoring of endogenous SCFA biosynthesis are important for understanding their physiological functions. We discuss the promising future of applying CRISPRi genetic systems and biosensors for targeted SCFA improvement.

Glioma is a common intracranial malignant tumor with high mortality and high recurrence rate. In recent years, increasing evidence has demonstrated that circular RNAs (circRNAs) are potential biomarkers and therapeutic targets for many tumors. However, the role of circRNAs in glioma remains unclear. In this study, we found that circRNA-0002109 was highly expressed in glioma tissues and cell lines. Downregulation of circRNA-0002109 expression inhibited the proliferation, migration, and invasion of glioma cells and inhibited the malignant progression of tumors in vivo. Investigations into the relevant mechanisms showed that circRNA-0002109 upregulated the expression of EMP2 through endogenous competitive binding of microRNA-129-5P (miR-129-5P), which partially alleviated the inhibitory effect of miR-129-5P on epithelial membrane protein-2 (EMP2) and ultimately promoted the malignant development of glioma. Our results indicate that circRNA-0002109 plays an important role in the proliferation, invasion, and migration of glioma cells by regulating the miR-129-5P/EMP2 axis, which provides a new potential therapeutic target for glioma., Graphical abstract, In this paper, we identified a novel circRNA named circRNA-0002109 and identified it as an oncogene. Moreover, we found that circRNA-0002109 promotes glioma proliferation, migration, and invasion by regulating the miR-129-5P/EMP2 axis.

Significance: Previously, sulfur dioxide (SO2) was recognized as an air pollutant. However, it is found to be endogenously produced in mammalian tissues. As a new gasotransmitter, SO

Significance: Hydrogen sulfide (H2S) is an endogenous signaling molecule, regulating numerous physiological functions from vasorelaxation to neuromodulation. Iron is a well-known bioacti...

Group 2 innate lymphoid cells (ILC2s) play an important role in allergic airway inflammation. Despite recent advances in defining molecular mechanisms that control ILC2 development and function, the role of endogenous metabolites in the regulation of ILC2s remains poorly understood. Herein, we demonstrated that bilirubin, an end product of heme catabolism, was a potent negative regulator of ILC2s. Bilirubin metabolism was found to be significantly induced during airway inflammation in mouse models. The administration of unconjugated bilirubin (UCB) dramatically suppressed ILC2 responses to interleukin (IL)-33 in mice, including cell proliferation and the production of effector cytokines. Furthermore, UCB significantly alleviated ILC2-driven airway inflammation, which was aggravated upon clearance of endogenous UCB. Mechanistic studies showed that the effects of bilirubin on ILC2s were associated with downregulation of ERK phosphorylation and GATA3 expression. Clinically, newborns with hyperbilirubinemia displayed significantly lower levels of ILC2 with impaired function and suppressed ERK signaling. Together, these findings indicate that bilirubin serves as an endogenous suppressor of ILC2s and might have potential therapeutic value in the treatment of allergic airway inflammation.

Melastoma malabathricum (M. malabathricum) extracts have been reported to exert various pharmacological activities including antioxidants, anti-inflammatory and antiproliferative activities. The objective of the present study was to determine the anticarcinogenic activity of its methanol extract (MEMM) against the azoxymethane (AOM)-induced early colon carcinogenesis in rats. Rats were randomly assigned to five groups (n=6) namely normal control, negative control, and treatment (50, 250 or 500 mg/kg of MEMM) groups. Colon tissues were harvested for histopathological analysis and endogenous antioxidant system determination. MEMM was also subjected to HPLC analysis. Findings showed that MEMM significantly (p

The circadian clock and gut microbiome play integral roles in preserving metabolic homeostasis. Circadian rhythms represent an endogenous time-keeping system that regulates cell and organ functions and synchronizes physiology with external cues to establish metabolic homeostasis. A variety of functions throughout the gastrointestinal tract and liver are under circadian control, including nutrient transport, processing, and detoxification. The gut microbiota also plays an essential role in host metabolism, regulating processes such as digestion, inflammatory modulation, and bile acid metabolism. Both the circadian clock and the gut microbiota influence each other in a reciprocal fashion, as gut dysbiosis can precipitate circadian asynchrony, and vice-versa. Disruption of either system impacts homeostasis in a bidirectional manner and can contribute to metabolic dysfunction. Evidence suggests such disruptions can lead to the development of metabolic diseases, including obesity, diabetes, NAFLD, cirrhosis, and hepatocellular carcinoma. This review will provide a basic overview of the circadian and gut microbial systems, how they are intertwined, and their impact on the liver and gastrointestinal tract and in the development of metabolic disease. Particular areas of discussion will include epigenetic regulation of circadian pathways as well as a mechanistic overview of microbial dysbiosis In addition, therapeutic targets of these systems, including dietary modifications, behavioral modifications, and microbial-directed therapies, will be explored.

Therapeutic mRNA has the potential to revolutionize the treatment of myriad diseases and, in 2020, facilitated the most rapid vaccine development in history. Among the substantial advances in mRNA technology made in recent years, the incorporation of base modifications into therapeutic mRNA sequences can reduce immunogenicity and increase translation. However, experiments from our lab and others have shown that the incorporation of base modifications does not always yield superior protein expression. We hypothesized that the variable benefit of base modifications may relate to lipid nanoparticle chemistry, formulation, and accumulation within specific organs. To test this theory, we compared IV-injected lipid nanoparticles formulated with reporter mRNA incorporating five base modifications (ψ, m1ψ, m5U, m5C/ψ, and m5C/s2U) and four ionizable lipids (C12-200, cKK-E12, ZA3-Ep10, and 200O(i10)) with tropism for different organs. In general, the m1ψ base modification best enhanced translation, producing up to 15-fold improvements in total protein expression compared to unmodified mRNA. Expression improved most dramatically in the spleen (up to 50-fold) and was attributed to enhanced protein expression in monocytic lineage splenocytes. The extent to which these effects were observed varied with delivery vehicle and correlated with differences in innate immunogenicity. Through comparison of firefly luciferase and erythropoietin mRNA constructs, we also found that mRNA modification-induced enhancements in protein expression are limited outside of the spleen, irrespective of delivery vehicle. These results highlight the complexity of mRNA-loaded lipid nanoparticle drug design and show that the effectiveness of mRNA base modifications depend on the delivery vehicle, the target cells, and the site of endogenous protein expression.

The present study investigates ameliorative effect of silicon nanoparticles (SiNPs) and indole acetic acid (IAA) alone and in combination against hexavalent chromium (CrVI) toxicity in rice seedlings. The results of the study revealed protective effects of SiNPs and IAA against CrVI toxicity. The 100μM of CrVI imposed toxic effects in rice seedlings at morphological, physiological and biochemical levels which coincided with increased level of intracellular CrVI and declined level of endogenous nitric oxide (NO). The CrVI enhanced levels of superoxide radicals (SOR) (59.51% and 50.1% in shoot and root, respectively) and H2O2 (19.5% and 23.69% in shoot and root, respectively). However, when SiNPs and IAA were applied to plants under CrVI stress, they enhanced tolerance and defence mechanisms as manifested in terms of increased biomass, endogenous NO, photosynthetic pigments, and antioxidants level (ascorbate-glutathione cycle). It was also noticed that CrVI arrested cell cycle at G2/M phase whereas growth was restored as compared to control when SiNPs and IAA were supplemented. Thus, the hypothesis that combined application of SiNPs and IAA will be effective in alleviating CrVI toxicity is validated from the results of this study. Moreover, in SiNPs and IAA-mediated mitigation of CrVI toxicity, endogenous NO has a positive role. The importance of the study will be that the combination of SiNPs and IAA can be utilized against heavy metal stress and even when supplied alone, they will enhance the crop productivity parameters with and without stress conditions.

Made available in DSpace on 2022-05-01T09:47:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 This study aimed to evaluate the immunomodulatory effect of vitamin D (VD) on the NLRP1 and NLRP3 inflammasomes in placental explants from preeclamptic (PE) and normotensive (NT) pregnant women. Placental explants from eight PE and eight NT pregnant women were cultured with or without hydrogen peroxide (H2O2), VD or H2O2 + VD. Gene and protein expression of NLRP1, NLRP3, HMGB1, caspase-1, IL-1β, TNF-α and IL-18 were determined by qPCR and Western blotting/ELISA. Compared to NT pregnant women, the endogenous gene expression of NLRP1, NLRP3, HMGB1, IL-1β, TNF-α and IL-18 was significantly higher in explants from PE and became decreased after VD treatment. Similarly, VD decreased the protein expression of NLRP1, NLRP3, caspase-1, HMGB1, IL-1β, TNF-α and IL-18 in PE. Placental explants from NT cultured with H2O2 showed increased gene and protein expression of NLRP1, NLRP3, caspase-1, IL-1β, TNF-α and HMGB1, while H2O2 was also able to increase TNF-α and caspase-1 gene expression in PE. Treatment with H2O2 + VD decreased gene/protein expression of NLRP1, NLRP3, caspase-1, HMGB1, IL-1β, TNF-α and IL-18 in PE and NT explants with H2O2. NLRP1 and NLRP3 are upregulated in the PE. VD may play an immunomodulatory role in the placental inflammation and downregulates oxidative stress induced in vitro by H2O2. Botucatu Medical School Sao Paulo State University (Unesp) Institute of Biosciences Sao Paulo State University (Unesp) Botucatu Medical School Sao Paulo State University (Unesp) Institute of Biosciences Sao Paulo State University (Unesp)

Abnormal changes in intracellular viscosity and cysteine are both associated with several important biological processes such as reversible redox reaction, which plays a pivotal role in the process of inflammation. However, it remains unclear how cysteine and viscosity alter in inflammation. Herein, we firstly report a high sensitivity and selectivity near-infrared imaging probe (FCV) for tracking intracellular viscosity and endogenous cysteine. This dual-functional probe displays excellent photostability and large Stokes shifts. FCV exhibites a 54-fold enhancement in fluorescence emission at 560 nm with the increasing of Cys (λex =420 nm), and increases about 63-fold at 660 nm (λex = 460 nm) with the viscosity from 1.0 cP to 952.5 cP. Moreover, FCV reveals the synergistic relationship between viscosity and cysteine in the inflammation model of living cells and zebrafish for the first time. Thus, FCV is a promising vehicle to identify the alternation of Cys and viscosity in associated diseases.

The Frank–Starling response of the heart is known to be mediated by nitric oxide (NO) signaling, which is regulated by reduced glutathione (GSH) and hydrogen sulfide (H2S). We hypothesized that stimulation of endogenous H2S or GSH synthesis would improve the Frank–Starling response. Wistar male rats were injected with propargylglycine (PAG; 11.3 mg/kg, 40 min, n = 12), an inhibitor of H2S-producing enzyme (cystationine-γ-lyase), and l-cysteine (121 mg/kg, 30 min, n = 20), a precursor of H2S and GSH. Pretreatment with PAG or l-cysteine separately slightly improved the pressure-volume (P-V) dependence of the isolated rat heart, but the combination of PAG and l-cysteine (n = 12) improved heart contractile activity. H2S content, Ca2+-dependent NOS activity (cNOS) activity, nitrate reductase activity, and nitrite content increased by 2, 3.83, 2.5, and 1.3 times in cardiac mitochondria, and GSH and oxidized glutathione (GSSG) levels increased by 2.24 and 1.86 times in the heart homogenates of the PAG + l-cysteine group compared with the control (all P < 0.05). Inhibition of glutathione with DL-buthionine-sulfoximine (BSO; 22.2 mg/kg, 40 min, n = 6) drastically decreased Frank–Starling response of the heart and prevented PAG + l-cysteine–induced increase of GSH and GSSG levels (BSO + PAG + l-cysteine, n = 9). Inhibition of NOS, N-nitro-l-arginine-methylester hydrochloride (l-NAME; 40 min, 27 mg/kg) abolished positive inotropy induced by PAG+l-cysteine pretreatment (l-NAME + PAG + l-cysteine, n = 7). Thus, PAG + l-cysteine administration improves the Frank–Starling response by upregulating mitochondrial H2S, glutathione, and NO synthesis, which may be a promising approach in the treatment of myocardial dysfunction.

Formaldehyde (FA) is a crucial reactive signaling molecule participating in epigenetic and metabolic pathway. Whereas abnormally elevated levels of FA are implicated in various diseases spanning from tumors to neurodegenerative disorders. Although highly selective for FA, current 2-aza-Cope-based fluorescent probes leave room for improvement because their relatively slow reaction kinetics (1-9 hours for responsive time) hinder the capability to track biological transient FA. Herein, we presented a ratiometric fluorescent probe, FormAFP, based on excited state intramolecular photon transfer (ESIPT) for rapid (within 10 min), selective (above 70-fold over other RCS) and sensitive (240-times fluorescence enhancement with 66 nM of detection limit) detection of FA via 2-aza-cope rearrangement. The probe also displayed fast response (

A novel method-of-moments approach is proposed for the estimation of factor-augmented panel data models with endogenous regressors when T is fixed. The underlying methodology involves approximating the unobserved common factors using observed factor proxies. The resulting moment conditions are linear in the parameters. The proposed approach addresses several issues which arise with existing nonlinear estimators that are available in fixed T panels, such as local minima-related problems, a sensitivity to particular normalization schemes, and a potential lack of global identification. We apply our approach to a large panel of households and estimate the price elasticity of urban water demand. A simulation study confirms that our approach performs well in finite samples.

Propionic acidemia (PA) is a severe autosomal recessive metabolic disease caused by deficiency of propionyl-CoA carboxylase (PCC). We studied PA transgenic (Pat) mice that lack endogenous PCC but express a hypoactive human PCCA cDNA, permitting their survival. Pat cohorts followed from 3 to 20 weeks of age showed growth failure and lethal crises of lethargy and hyperammonemia, commoner in males (27/50, 54%) than in females (11/52, 21%) and occurring mainly in Pat mice with the most severe growth deficiency. Groups of Pat mice were studied under basal conditions (P-Ba mice) and during acute crises (P-Ac). Plasma acylcarnitines in P-Ba mice, compared to controls, showed markedly elevated C3- and low C2-carnitine, with a further decrease in C2-carnitine in P-Ac mice. These clinical and biochemical findings resemble those of human PA patients. Liver acyl-CoA measurements showed that propionyl-CoA was a minor species in controls (propionyl-CoA/acetyl-CoA ratio, 0.09). In contrast, in P-Ba liver the ratio was 1.4 and in P-Ac liver, 13, with concurrent reductions of the levels of acetyl-CoA and other acyl-CoAs. Plasma ammonia levels in control, P-Ba and P-Ac mice were 109 ± 10, 311 ± 48 and 551 ± 61 μmol/L respectively. Four-week administration to Pat mice, of carglumate (N-carbamyl-L-glutamic acid), an analogue of N-carbamylglutamate, the product of the only acyl-CoA-requiring reaction directly related to the urea cycle, was associated with increased food consumption, improved growth and absence of fatal crises. Pat mice showed many similarities to human PA patients and provide a useful model for studying tissue pathophysiology and treatment outcomes.

KiSS-1, first identified as an anti-metastasis gene in melanoma, encodes C-terminally amidated peptide products, including kisspeptin-145, kisspeptin-54, kisspeptin-14, kisspeptin-13 and kisspeptin-10. These products are endogenous ligands coupled to G protein-coupled receptor 54 (GPR54)/hOT7T175/AXOR12. To date, the regulatory activities of the KiSS-1/GPR54 system, such as puberty initiation, antitumor metastasis, fertility in adulthood, hypothalamic-pituitary-gonadal axis (HPG axis) feedback, and trophoblast invasion, have been investigated intensively. Accumulating evidence has demonstrated that KiSS-1 played a key role in reproduction and served as a promising biomarker relative to the diagnosis, identification of therapeutic targets and prognosis in various carcinomas, while few studies have systematically summarized its subjective factors and concluded the functions of KiSS-1/GPR54 signaling in physiology homeostasis and cancer biology. In this review, we retrospectively summarized the regulators of the KiSS-1/GPR54 system in different animal models and reviewed its functions according to physiological homeostasis regulations and above all, cancer biology, which provided us with a profound understanding of applying the KiSS-1/GPR54 system into medical applications.

Objective The beneficial effect of angiotensin(1–7) (Ang(1–7)), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how Ang(1–7) or MAS-1 affects insulin secretion remains elusive and whether the endogenous level of Ang(1–7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl− channel, in the regulation of insulin secretion. Here, we tested the possible involvement of CFTR in mediating Ang(1–7)’s effect on insulin secretion and measured the level of Ang(1–7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes. Methods Ang(1–7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, Western blotting as well as insulin ELISA in a pancreatic β-cell line, RINm5F. Human blood samples were collected from 333 individuals with (n = 197) and without (n = 136) type 2 diabetes. Ang(1–7), MAS-1 and CFTR levels in the human blood were determined by ELISA. Results In RINm5F cells, Ang(1–7) induced intracellular cAMP increase, cAMP-response element binding protein (CREB) activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not Ang(1–7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2 diabetic but not non-diabetic subjects. Conclusion These results suggested that MAS-1 and CFTR as key players in mediating Ang(1–7)-promoted insulin secretion in pancreatic β-cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.

The matrix metalloproteinases (MMPs) and their endogenous inhibitory factors, tissue inhibitors of metalloproteinases (TIMPs), are implicated in many diseases. However, the mammalian MMPs ( 20) and TIMPs ( 3) are larger in number, and so little is known about their individual roles in organisms. Hence, we have systematically studied the roles of all three MMPs and one TIMP in silkworm innate immunity and metamorphosis. We observed that MMPs and TIMP are highly expressed during the pupation stage of the silkworms, and TIMP could interact with each MMPs. High-activity MMPs and low-activity TIMP may enhance the infection of B. mori nucleopolyhedrovirus in both in vitro and in vivo. MMPs' knockout and TIMP overexpression delayed silkworm development and even caused death. Interestingly, different MMPs' knockout led to different tubular tissue dysplasia. These findings provide insights into the conserved functions of MMPs and TIMP in human organogenesis and immunoregulation.

In this article, we consider a panel stochastic frontier model in which the composite error term εit has four components, that is, εit=τi−ηi+vit−uit, where ηi and uit are persistent and transient inefficiency components, τi consists of the random firm effects and vit is the random noise. Two distinguishing features of the proposed model are (i) the inputs are allowed to be correlated with one or more of the error components in the production function; (ii) time-invariant and time-varying components, that is, (τi−ηi) and (vit−uit), are allowed to be correlated. To keep the formulation general, we do not specify whether this correlation comes from the correlations between (i) ηi and uit, (ii) τi and uit, (iii) τi and vit, (iv) ηi and vit, or some other combination of them. Further, we also consider the case when the correlation in the composite error arises from the time dependence of εit. To estimate the model parameters and predict (in)efficiency, we propose a two-step procedure. In the first step, either the within or the first difference transformation that eliminates the time-invariant components is proposed. We then use either the 2SLS or the GMM approach to obtain unbiased and consistent estimators of the parameters in the frontier function, except for the intercept. In the second step, the maximum simulated likelihood method is used to estimate the parameters associated with the distributions of τi and vit, ηi and uit as well as the intercept. The copula approach is used in this step to model the dependence between the time-varying and time-invariant components. Formulas to predict transient and persistent (in)efficiency are also derived. Finally, results from both simulated and real data are provided.

The proliferative burst of B lymphocytes is essential for antigen receptor repertoire diversification during the development and selective expansion of antigen-specific clones during immune responses. High proliferative activity inevitably promotes oncogenesis, the risk of which is further elevated in B lymphocytes by endogenous gene rearrangement and somatic mutations. However, B-cell–derived cancers are rare, perhaps owing to putative intrinsic tumor-suppressive mechanisms. We show that c-MYC facilitates B-cell proliferation as a protumorigenic driver and unexpectedly coengages counteracting tumor suppression through its downstream factor TFAP4. TFAP4 is mutated in human lymphoid malignancies, particularly in >10% of Burkitt lymphomas, and reduced TFAP4 expression was associated with poor survival of patients with MYC-high B-cell acute lymphoblastic leukemia. In mice, insufficient TFAP4 expression accelerated c-MYC–driven transformation of B cells. Mechanistically, c-MYC suppresses the stemness of developing B cells by inducing TFAP4 and restricting self-renewal of proliferating B cells. Thus, the pursuant transcription factor cascade functions as a tumor suppressor module that safeguards against the transformation of developing B cells.

Endothelial cells (ECs) are key players in the development and maintenance of the vascular tree, the establishment of the blood brain barrier and control of blood flow. Disruption in ECs is an early and active component of vascular pathogenesis. However, our ability to selectively target ECs in the CNS for identification and manipulation is limited. Here, in the mouse retina, a tractable model of the CNS, we utilized a recently developed AAV-BR1 system to identify distinct classes of ECs along the vascular tree using a GFP reporter. We then developed an inducible EC-specific ectopic Connexin 43 (Cx43) expression system using AAV-BR1-CAG-DIO-Cx43-P2A-DsRed2 in combination with a mouse line carrying inducible CreERT2 in ECs. We targeted Cx43 because its loss has been implicated in microvascular impairment in numerous diseases such as diabetic retinopathy and vascular edema. GFP-labeled ECs were numerous, evenly distributed along the vascular tree and their morphology was polarized with respect to the direction of blood flow. After tamoxifen induction, ectopic Cx43 was specifically expressed in ECs. Similarly to endogenous Cx43, ectopic Cx43 was localized at the membrane contacts of ECs and it did not affect tight junction proteins. The ability to enhance gap junctions in ECs provides a precise and potentially powerful tool to treat microcirculation deficits, an early pathology in numerous diseases. This article is protected by copyright. All rights reserved.

BACKGROUND High oxygen treatment has been proven to be effective in fresh-cut white mushrooms preservation, however, the preservation effect and possible mechanisms in high oxygen controlled atmosphere pretreatment (HOCAP) under on wounding stress are incompletely understood. RESULTS In this study, based on the time chosen of HOCAP research, whole white mushroom treated with 3 h HOCAP (80 % O2 + 20 % CO2 ) and the wounding resistant responses of their slices were mainly investigated through phenylpropane pathway, ROS scavenging system, and ascorbate-glutathione (AsA-GSH) cycle. Results showed that 3 h HOCAP can induce the production of H2 O2 and O2-. in the early stage, as well as the NADPH oxidase activity. Enzymes and endogenous antioxidants involved in reactive oxygen species (ROS) scavenging were enhanced by HOCAP during the whole storage. Besides, HOCAP maintained high level of phenylalanine ammonia-yase (PAL) activity, enhanced the content of total phenolic and lignin, accelerated the AsA-GSH cycle. CONCLUSION The results demonstrated that HOCAP induced defense responses by increasing the ROS in the early stage which stimulated the activities of ROS scavenging enzymes, along with the capability of increasing for wounding stress defense and resistance. This study provides a theoretical pretreatment technology for fresh-cut white mushroom preservation. This article is protected by copyright. All rights reserved.

It is well-known that the pregnane X receptor (PXR)/Nr1i2 is a critical xenobiotic-sensing nuclear receptor enriched in liver and intestine and is responsible for drug-drug interactions, due to its versatile ligand binding domain (LBD) and target genes involved in xenobiotic biotransformation. PXR can be modulated by various xenobiotics including pharmaceuticals, nutraceuticals, dietary factors, and environmental chemicals. Microbial metabolites such as certain secondary bile acids (BAs) and the tryptophan metabolite indole-3-propionic acid (IPA) are endogenous PXR activators. Gut microbiome is increasingly recognized as an important regulator for host xenobiotic biotransformation and intermediary metabolism. PXR regulates and is regulated by the gut-liver axis. This review summarizes recent research advancements leveraging pharmaco- and toxico-metagenomic approaches that have redefined the previous understanding of PXR. Key topics covered in this review include: (1) genome-wide investigations on novel PXR-target genes, novel PXR-DNA interaction patterns, and novel PXR-targeted intestinal bacteria; (2) key PXR-modulating activators and suppressors of exogenous and endogenous sources; (3) novel bidirectional interactions between PXR and gut microbiome under physiologic, pathophysiological, pharmacological, and toxicological conditions; and (4) modifying factors of PXR-signaling including species and sex differences and time (age, critical windows of exposure, and circadian rhythm). The review also discusses critical knowledge gaps and important future research topics centering around PXR. SIGNIFICANCE STATEMENT: This review summarizes recent research advancements leveraging O'mics approaches that have redefined the previous understanding of the xenobiotic-sensing nuclear receptor pregnane X receptor (PXR). Key topics include: (1) genome-wide investigations on novel PXR-targeted host genes and intestinal bacteria as well as novel PXR-DNA interaction patterns; (2) key PXR modulators including microbial metabolites under physiological, pathophysiological, pharmacological, and toxicological conditions; and (3) modifying factors including species, sex, and time.

Prohibitin-2 (PHB2) is a scaffold protein that has pleiotropic functions, which include interacting with γ-glutamylcyclotransferase (GGCT) in the cytoplasm and repressing the transcriptional activities of the p21Waf1/Cip (p21) gene in the nucleus. The cytotoxic drug fluorizoline binds to PHB1/2 and exerts antiproliferative actions on cancer cells. However, the precise mechanism underlying the antiproliferative effects of fluorizoline is not fully elucidated. In the present study, we first show that fluorizoline induces p21 expression in several human cancer cell lines,including MCF7 breast cancer cells. Treatment of MCF7 cells with fluorizoline suppressed proliferation and prevented cells from entering into theDNA synthesis phase.Knockdown of p21 rescued the suppressed proliferation, indicating that fluorizoline inhibited MCF7 cell growth via the induction of p21. Overexpression of PHB2 in MCF7 cells prevented the induction of p21 expression by fluorizoline, and restored the antiproliferative effects and blockade of cell cycle progression. Moreover, treatment of MCF7 cells with fluorizoline inhibited the interaction between endogenous PHB2 and GGCT proteins, and reduced the level of nuclear localization of PHB2 proteins. These results indicate that targeting PHB2 with fluorizoline induces the expression of p21 and consequently blocks proliferation of cancer cells. Significance Statement This study shows that fluorizoline may be a promising novel anticancer drug candidate that induces p21 expression and blocks cell-cycle progression in human cancer cell lines. In addition, we show that fluorizoline inhibits the interaction between PHB2 and GGCT and reduces the nuclear localization of PHB2 proteins that regulates p21 expression.

Обстежені 63 пацієнти з гіпертонічною хворобою та цукровим діабетом 2-го типу. Контрольну групу становили 16 практично здорових осіб. Комплекс обстеження включав загальноприйняті клініко-лабораторні та інструментальні методи, ультразвукове дослідження серця з допплерографією, визначення концентрації апеліну в крові імуноферментним методом. У пацієнтів із гіпертонічною хворобою та цукровим діабетом 2-го типу порівняно з групою контролю відзначається вірогідне зниження рівня апеліну, що асоціюється з розвитком патологічного ремоделювання серця, збільшенням розмірів лівого передсердя та діастолічною дисфункцією серця.

Background: Endometrial carcinoma (EC) is one of the most common malignancies in women worldwide. For EC patients discovered at an early stage, the prognosis is good. However, the advanced EC patients (stage III-IV) have very poor prognoses. The competitive endogenous RNAs (ceRNA) regulatory network in EC remains unclear, and the relationship between hub RNAs and important clinical characters (clinical stage) has not been strictly studied yet. Objective: In order to study the development of endometrial carcinoma and the identification of early diagnostic markers, the relationship between hub RNAs and important clinical traits (clinical stage) was strictly studied. Methods: The co-expression networks of mRNA, lncRNA, and miRNA were constructed by weighted gene co-expression network analysis. Gene ontology (GO) biological process terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out for DEmRNA. AceRNA regulated network was constructed based on miRcode, miRDB, TargetScan, and miRTarBase. Furthermore, survival analysis, regression analysis of mRNA-lncRNA pairs, and gene set enrichment analysis were carried out. Results: A ceRNA network containing 11 mRNAs, 4 miRNAs, and 18 lncRNAs was constructed based on aberrantly expressed RNAs in the co-expression modules. In this network, 7 mRNAs, 4 lncRNAs, and 1 miRNA were found closely related to the overall survival of EC. The positive correlations of 35 pairs of mRNA and lncRNA in the ceRNA network were obtained. Notably, 5 mRNAs, 3 lncRNAs, and 1 miRNA were identified as potential prognostic biomarkers for EC. Single gene GSEA analysis revealed that the signal pathways related to cell cycle and cancer were highly enriched. Conclusion: Identification of five mRNAs (CBX6, PIM1, RIMS3, SOX11, and XKR7), three lncRNA (WT1-AS, LINC00494, and LINC00501), and one miRNA (miR-195) as potential prognostic biomarkers for EC was helpful for the early diagnosis, prognosis, and development of new treatment strategies of EC patients.

KEY MESSAGE Endogenous U6 promoters increase CRISPR/Cas9 editing efficiency in sorghum and may be useful for gene editing applications in other cereals.

Ribosomal protein L3-like (RPL3L) is a poorly characterized ribosomal protein that is exclusively expressed in skeletal and cardiac muscle. RPL3L is also downregulated in Duchenne muscular dystrophy (DMD), suggesting that it may play an important role in muscle biology. In this study, we investigated the role of RPL3L in skeletal muscle of healthy C57 and dystrophic mdx mice. We show that RPL3L is developmentally regulated and that intramuscular adeno-associated virus (AAV)-mediated RPL3L knockdown in the tibialis anterior of C57 and mdx mice results in increased specific force with improved resistance to eccentric contraction induced muscle damage in dystrophic muscles. The mechanism by which RPL3L knockdown improves muscle function remains unclear. Histological observations showed a significant increase in muscle length and decrease in muscle cross-sectional area after RPL3L inhibition suggesting that this ribosomal protein may play a role in myofiber morphology. The endogenous downregulation of RPL3L in DMD may be a protective mechanism that attempts to improve skeletal muscle function and counteract the dystrophic phenotype.

Endothelial cell senescence is one of the most important causes of vascular dysfunction and atherosclerosis. Circular RNAs (circRNAs) are endogenous RNA molecules with covalently closed-loop structures, which have been reported to be abnormally expressed in many human diseases. However, the potential role of circRNAs in endothelial cell senescence and atherosclerosis remains largely unknown. Here, we compared the expression patterns of circRNAs in young and senescent human endothelial cells with RNA sequencing. Among the differentially expressed circRNAs, circGNAQ, a circRNA enriched in vascular endothelium, was significantly downregulated in senescent endothelial cells. circGNAQ silencing triggered endothelial cell senescence, as determined by a rise in senescence-associated β-galactosidase activity, reduced cell proliferation, and suppressed angiogenesis; circGNAQ overexpression showed the opposite effects. Mechanistic studies revealed that circGNAQ acted as an endogenous miR-146a-5p sponge to increase the expression of its target gene PLK2 by decoying the miR-146a-5p, thereby delaying endothelial cell senescence. In vivo studies showed that circGNAQ overexpression in the endothelium inhibited endothelial cell senescence and atherosclerosis progression. These results suggest that circGNAQ plays critical roles in endothelial cell senescence and consequently the pathogenesis of atherosclerosis, implying that the management of circGNAQ provides a potential therapeutic approach for limiting the progression of atherosclerosis., Graphical abstract, Endothelial cell senescence is one of the most important causes of vascular dysfunction and atherosclerosis. We found that circGNAQ, a circular RNA enriched in vascular endothelium, inhibited endothelial cell senescence and atherosclerosis progression, implying that circGNAQ-based gene therapy could serve as a novel therapeutic strategy to protect against atherosclerosis development.