Explore the vast range of titles available.

Arabidopsis PIN2 protein directs transport of the phytohormone auxin from the root tip into the root elongation zone. Variation in hormone transport, which depends on a delicate interplay between PIN2 sorting to and from polar plasma membrane domains, determines root growth. By employing a constitutively degraded version of PIN2, we identify brassinolides as antagonists of PIN2 endocytosis. This response does not require de novo protein synthesis, but involves early events in canonical brassinolide signaling. Brassinolide-controlled adjustments in PIN2 sorting and intracellular distribution governs formation of a lateral PIN2 gradient in gravistimulated roots, coinciding with adjustments in auxin signaling and directional root growth. Strikingly, simulations indicate that PIN2 gradient formation is no prerequisite for root bending but rather dampens asymmetric auxin flow and signaling. Crosstalk between brassinolide signaling and endocytic PIN2 sorting, thus, appears essential for determining the rate of gravity-induced root curvature via attenuation of differential cell elongation. Brassinosteroid signaling can regulate auxin transport by influencing the sorting and accumulation of PIN auxin efflux carriers. Here, the authors show that in roots, brassinolide can modulate vacuolar degradation and endocytic sorting of PIN2, delimiting root curvature in response to gravity.

Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of proinflammatory cytokines, including IL-1β. IL-1β, type I IL-1 receptor (IL-1R1), and IL-1 receptor antagonist (IL-1Ra) are all important regulators of the IL-1 signaling complex, which plays a role in inflammation. Furthermore, IL-1β maturation is dependent on caspase-1 (Casp-1). Using IL-1Ra-treated mice as well as 3 mouse models deficient in regulators of IL-1β activation (Casp-1 and ASC) or signaling (IL-1R1), we found that IL-1β signaling is required for the development of alcohol-induced liver steatosis, inflammation, and injury. Increased IL-1β was due to upregulation of Casp-1 activity and inflammasome activation. The pathogenic role of IL-1 signaling in ALD was attributable to the activation of the inflammasome in BM-derived Kupffer cells. Importantly, in vivo intervention with a recombinant IL-1Ra blocked IL-1 signaling and markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. Furthermore, physiological doses of IL-1β induced steatosis, increased the inflammatory and prosteatotic chemokine MCP-1 in hepatocytes, and augmented TLR4-dependent upregulation of inflammatory signaling in macrophages. In conclusion, we demonstrated that Casp-1-dependent upregulation of IL-1β and signaling mediated by IL-1R1 are crucial in ALD pathogenesis. Our findings suggest a potential role of IL-1R1 inhibition in the treatment of ALD.

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of STING prevented IRF3 phosphorylation by ethanol or ER stress, and absence of IRF3 prevented hepatocyte apoptosis. The pathogenic role of IRF3 in ALD was independent of inflammation or Type-I interferons. Thus, STING and IRF3 are key determinants of ALD, linking ER stress signaling with the mitochondrial pathway of hepatocyte apoptosis.

One of the mechanisms by which signalling molecules regulate cellular behaviour is modulating subcellular protein translocation. This mode of regulation is often based on specialized vesicle trafficking, termed constitutive cycling, which consists of repeated internalization and recycling of proteins to and from the plasma membrane. No such mechanism of hormone action has been shown in plants although several proteins, including the PIN auxin efflux facilitators, exhibit constitutive cycling. Here we show that a major regulator of plant development, auxin, inhibits endocytosis. This effect is specific to biologically active auxins and requires activity of the Calossin-like protein BIG. By inhibiting the internalization step of PIN constitutive cycling, auxin increases levels of PINs at the plasma membrane. Concomitantly, auxin promotes its own efflux from cells by a vesicle-trafficking-dependent mechanism. Furthermore, asymmetric auxin translocation during gravitropism is correlated with decreased PIN internalization. Our data imply a previously undescribed mode of plant hormone action: by modulating PIN protein trafficking, auxin regulates PIN abundance and activity at the cell surface, providing a mechanism for the feedback regulation of auxin transport.

Key Points Inflammasomes are multiprotein complexes that assemble upon the sensing of danger signals and initiate the release of proinflammatory cytokines IL-1β and IL-18 via caspase-1 activation By responding to low-threshold signals, the inflammasome is able to fine-tune the inflammatory response The balance between a healthy inflammatory response and chronic damage is delicate and several inflammasomes, such as NLRP3, NLRP6 and AIM2, also have a role in liver diseases Among other diseases, inflammasome activation contributes to alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia–reperfusion injury, paracetamol-induced liver injury and liver fibrosis In liver diseases, inflammasome activation is a major contributor to hepatocyte damage, immune cell activation and amplification of inflammation. This Review provides a detailed account of the different types of inflammasomes that are involved, their activation and biological functions in the context of liver injury and disease progression. Inflammation contributes to the pathogenesis of most acute and chronic liver diseases. Inflammasomes are multiprotein complexes that can sense danger signals from damaged cells and pathogens and assemble to mediate caspase-1 activation, which proteolytically activates the cytokines IL-1β and IL-18. In contrast to other inflammatory responses, inflammasome activation uniquely requires two signals to induce inflammation, therefore setting an increased threshold. IL-1β, generated upon caspase-1 activation, provides positive feed-forward stimulation for inflammatory cytokines, thereby amplifying inflammation. Inflammasome activation has been studied in different human and experimental liver diseases and has been identified as a major contributor to hepatocyte damage, immune cell activation and amplification of liver inflammation. In this Review, we discuss the different types of inflammasomes, their activation and biological functions in the context of liver injury and disease progression. Specifically, we focus on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia–reperfusion injury and paracetamol-induced liver injury. The application and translation of these discoveries into therapies promises novel approaches in the treatment of inflammation in liver disease.

Chara has been used as a model for decades in the field of plant physiology, enabling the investigation of fundamental physiological processes. In electrophysiological studies, Chara has been utilized thanks to its large internodal cells that can be easily manipulated. Additionally, Chara played a pioneering role in elucidating the presence and function of the cytoskeleton in cytoplasmic streaming, predating similar findings in terrestrial plants. Its representation considerably declined following the establishment and routine application of genetic transformation techniques in Arabidopsis. Nevertheless, the recent surge in evo-devo studies can be attributed to the whole genome sequencing of the Chara braunii, which has shed light on ancestral traits prevalent in land plants. Surprisingly, the Chara braunii genome encompasses numerous genes that were previously regarded as exclusive to land plants, suggesting their acquisition prior to the colonization of terrestrial habitats. This review summarizes the established methods used to study Chara, while incorporating recent molecular data, to showcase its renewed importance as a model organism in advancing plant evolutionary developmental biology.

Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein‐coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT‐777, and INT‐767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in two mouse models (3‐day binge model and prolonged Lieber DeCarli diet for 12 days) of early ALD. Serum alanine aminotransferase and liver histology were used to assess liver injury, Oil Red O staining of liver sections to assess steatosis, and real‐time polymerase chain reaction to assess changes in gene expression. In the ethanol binge model, treatment with OCA and INT‐777 decreased hepatic macrovesicular steatosis and protected from ethanol‐induced liver injury. After prolonged ethanol administration, mice treated with OCA, INT‐767, or INT‐777 showed decreased hepatic steatosis, associated with reduced liver fatty acid synthase protein expression, and protection from liver injury. Treatment with BA receptor agonists in both models of ethanol administration modulated lipogenic gene expression, and decreased liver interleukin‐1β mRNA expression associated with increased ubiquitination of NLRP3 inflammasome through cyclic adenosine monophosphate–induced activation of protein kinase A. Conclusion: OCA, INT‐767, or INT‐777 administration is effective in reducing acute and chronic ethanol‐induced steatosis and inflammation in mice, with varying degrees of efficacy depending on the duration of ethanol administration, indicating that both FXR and TGR5 activation can protect from liver injury in ALD models. Bile acids (BAs) activate various dedicated receptors, including Farnesoid X Receptor (FXR), and Takeda G protein‐coupled Receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licenced for the treatment of primary biliary cholangitis and has shown promising results in nonalcoholic steatohepatitis (NASH) patients, while TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, where hepatic inflammation plays a major role. OCA, INT‐777, and INT‐767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively.

Introduction A leading cause of death among non-Hispanic American Indians or Alaskan Natives (AI/ANs), apart from cardiovascular disease and unintentional injuries, is chronic liver disease (CLD). This study analyzed recent trends in AI/AN ALD mortality, given their increased incidence of alcoholic liver disease (ALD) and high burden of CLD. Methods This cross-sectional study used data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER). Geographic, age and sex-based temporal mortality trends of ALD deaths were analyzed among the AI/AN population in the US from 1999 to 2020. Joinpoint regression analyses determined trends in ALD crude and age-adjusted mortality rates, identifying the annual percent change (APC) in each subgroup. Results In 1999–2020, the overall age-adjusted mortality rate (AAMR) among AI/ANs increased significantly from 27.2/100,000 to 88.4/100,000. Although men had a higher mortality rate overall, women had a higher increase in APC (2003–2008 APC was 17.7 [95% Cl: 9.9–26.0] and 2018–2020 APC was 25.3 [95% Cl: 11.4–40.9]) compared to men (1999–2020 APC was 5.8 [95% Cl 4.8–6.8]). All age groups studied witnessed an increase in AAMR. However, the age group 45–64 had the highest mortality overall in the preceding 2 decades. Non-metropolitan geographic regions had the highest mortality rate (2018–2020 APC of 25.5 [95% Cl: 5.0–50.0]) compared to medium/small or large metro areas. Western and Midwestern US Census regions had the highest mortality rates. Conclusions Male sex, age 44–65, and rural dwelling was associated with a greater ALD AAMR in AI/AN populations. Social changes due to the Covid-19 pandemic may have led to increased ALD mortality. Discerning the underlying causality of these associations and examining the impact of the social determinants of health, may represent important opportunities to enhance care for AI/ANs as a vulnerable minority population.

Fluorescence light microscopy provided convincing evidence for the domain organization of plant plasma membrane (PM) proteins. Both peripheral and integral PM proteins show an inhomogeneous distribution within the PM. However, the size of PM nanodomains and protein clusters is too small to accurately determine their dimensions and nano-organization using routine confocal fluorescence microscopy and super-resolution methods. To overcome this limitation, we have developed a novel correlative light electron microscopy method (CLEM) using total internal reflection fluorescence microscopy (TIRFM) and advanced environmental scanning electron microscopy (A-ESEM). Using this technique, we determined the number of auxin efflux carriers from the PINFORMED (PIN) family (NtPIN3b-GFP) within PM nanodomains of tobacco cell PM ghosts. Protoplasts were attached to coverslips and immunostained with anti-GFP primary antibody and secondary antibody conjugated to fluorochrome and gold nanoparticles. After imaging the nanodomains within the PM with TIRFM, the samples were imaged with A-ESEM without further processing, and quantification of the average number of molecules within the nanodomain was performed. Without requiring any post-fixation and coating procedures, this method allows to study details of the organization of auxin carriers and other plant PM proteins.