Endothelial ZIP8 plays a minor role in BMP6 regulation by iron in mice.

ABSTRACT: Iron-mediated induction of bone morphogenetic protein (BMP)6 expression by liver endothelial cells is essential for iron homeostasis regulation. We used multiple dietary and genetic mouse cohorts to demonstrate a minor functional role for the metal-ion transporter ZIP8 in regulating BMP6 expression under high-iron conditions.

Quantitative proteomics and RNA-sequencing of mouse liver endothelial cells identify novel regulators of BMP6 by iron.

Hepcidin is the master hormone governing systemic iron homeostasis. Iron regulates hepcidin by activating bone morphogenetic protein (BMP)6 expression in liver endothelial cells (LECs), but the mechanisms are incompletely understood. To address this, we performed proteomics and RNA-sequencing on LECs from iron-adequate and iron-loaded mice. Gene set enrichment analysis identified transcription factors activated by high iron, including Nrf-2, which was previously reported to contribute to BMP6 regulation, and c-Jun. Jun (encoding c-Jun) knockdown blocked Bmp6 but not Nrf-2 pathway induction by iron in LEC cultures. Chromatin immunoprecipitation of mouse livers showed iron-dependent c-Jun binding to predicted sites in Bmp6 regulatory regions. Finally, c-Jun inhibitor blunted induction of Bmp6 and hepcidin, but not Nrf-2 activity, in iron-loaded mice. However, Bmp6 and iron parameters were unchanged in endothelial Jun knockout mice. Our data suggest that c-Jun participates in iron-mediated BMP6 regulation independent of Nrf-2, though the mechanisms may be redundant and/or multifactorial.

BMP5 contributes to hepcidin regulation and systemic iron homeostasis in mice.

Hepcidin is the master regulator of systemic iron homeostasis. The bone morphogenetic protein (BMP) signaling pathway is a critical regulator of hepcidin expression in response to iron and erythropoietic drive. Although endothelial-derived BMP6 and BMP2 ligands have key functional roles as endogenous hepcidin regulators, both iron and erythropoietic drives still regulate hepcidin in mice lacking either or both ligands. Here, we used mice with an inactivating Bmp5 mutation (Bmp5se), either alone or together with a global or endothelial Bmp6 knockout, to investigate the functional role of BMP5 in hepcidin and systemic iron homeostasis regulation. We showed that Bmp5se-mutant mice exhibit hepcidin deficiency at age 10 days, blunted hepcidin induction in response to oral iron gavage, and mild liver iron loading when fed on a low- or high-iron diet. Loss of 1 or 2 functional Bmp5 alleles also leads to increased iron loading in Bmp6-heterozygous mice and more profound hemochromatosis in global or endothelial Bmp6-knockout mice. Moreover, double Bmp5- and Bmp6-mutant mice fail to induce hepcidin in response to long-term dietary iron loading. Finally, erythroferrone binds directly to BMP5 and inhibits BMP5 induction of hepcidin in vitro. Although erythropoietin suppresses hepcidin in Bmp5se-mutant mice, it fails to suppress hepcidin in double Bmp5- and Bmp6-mutant males. Together, these data demonstrate that BMP5 plays a functional role in hepcidin and iron homeostasis regulation, particularly under conditions in which BMP6 is limited.

Exploring medical students' metacognitive and regulatory dimensions of diagnostic problem solving.

Solving clinical problems requires an individual to apply not only domain-specific medical knowledge and cognitive skills for reasoning, but also to be consciously aware of, monitor, and evaluate their thinking processes (i.e., metacognition). The purpose of this study was to map critical metacognitive dimensions of clinical problem solving and to explore the structural relationships among them, which may help frame a conceptual framework and better pedagogy for effective intervention. A context-specific inventory was adapted and modified from a domain-general instrument to capture essential metacognitive skills for learning and solving clinical problems. This inventory was administered to 72 undergraduate medical students to survey their capabilities in five dimensions: knowledge of cognition, objectives, problem representation, monitoring, and evaluation. The interplay among these dimensions was further examined using partial least squares structural equation modeling.Our findings revealed that the medical students fell short of some expert-like, metacognitive, and regulatory competence, even after receiving years of medical education and on-site training. In particular, they did not know when a holistic understanding of a problem had been reached. Many of them often do not have a set of clear diagnostic procedures in mind, nor do they concurrently monitor their thinking during diagnostic reasoning. Moreover, their lack of self-improving approaches seemed to worsen their learning. Finally, the structural equation model indicated that knowledge of cognition and objectives significantly predicted problem representation, suggesting that medical learners' knowledge of and goals for learning are influential in framing the clinical problems at hand. A significant linear prediction path was observed from problem representation, monitoring, to evaluation, signifying a possible sequenced process of clinical problem solving. Metacognitive-based instruction can help improve clinical problem-solving skills and awareness of potential biases or errors.

Effects of cognitive stimulus therapy on middle-aged and elderly institutionalized patients with chronic schizophrenia with declined cognition.

PURPOSE: This study investigates whether using group Cognitive Stimulation Therapy (CST) effectively improves functioning among middle-aged and elderly patients with chronic schizophrenia and a below-normal cognitive range. METHODS: The study included an experimental group (N = 24), which was divided into two sub-groups to receive group CST, and a control group (N = 24), who received treatment as usual (TAU). We assessed cognitive functions using the Mini-Mental Status Examination (MMSE). We evaluated the emotional status, psychotic symptoms, and quality of life using the Geriatric Depression Scale short-form 15 (GDS-15), the Brief Psychiatric Rating Scale (BPRS), and the Dementia-Quality of Life (D-QoL) instrument. We performed all measures at three-time points: pre-CST, post-CST, and 3-month follow-up. RESULTS: We found group CST can significantly improve cognitive performance, especially the ability to use new information, after group CST intervention. However, the experimental group did not maintain this effect at the 3-month follow-up. RESULTS: We found group CST can significantly improve cognitive performance, especially the ability to use new information, after group CST intervention. However, the experimental group did not maintain this effect at the 3-month follow-up. CONCLUSION: This study supports group CST can delay the degradation of some cognitive functions in long-term hospitalized patients with chronic schizophrenia for the duration of the intervention. This finding has important clinical implications for long-term institutionalized middle-aged and elderly chronic schizophrenic patients with a below-normal cognitive range in an aging society.

Design of Low-Complexity Convolutional Neural Network Accelerator for Finger Vein Identification System.

In the biometric field, vein identification is a vital process that is constrained by the invisibility of veins as well as other unique features. Moreover, users generally do not wish to have their personal information uploaded to the cloud, so edge computing has become popular for the sake of protecting user privacy. In this paper, we propose a low-complexity and lightweight convolutional neural network (CNN) and we design intellectual property (IP) for shortening the inference time in finger vein recognition. This neural network system can operate independently in client mode. After fetching the user's finger vein image via a near-infrared (NIR) camera mounted on an embedded system, vein features can be efficiently extracted by vein curving algorithms and user identification can be completed quickly. Better image quality and higher recognition accuracy can be obtained by combining several preprocessing techniques and the modified CNN. Experimental data were collected by the finger vein image capture equipment developed in our laboratory based on the specifications of similar products currently on the market. Extensive experiments demonstrated the practicality and robustness of the proposed finger vein identification system.

Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in ß-thalassemia.

Transferrin receptor 1 (TfR1) performs a critical role in cellular iron uptake. Hepatocyte TfR1 is also proposed to influence systemic iron homeostasis by interacting with the hemochromatosis protein HFE to regulate hepcidin production. Here, we generated hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), either alone or together with Hfe knockout or ß-thalassemia, to investigate the extent to which hepatocyte TfR1 function depends on HFE, whether hepatocyte TfR1 impacts hepcidin regulation by serum iron and erythropoietic signals, and its contribution to hepcidin suppression and iron overload in ß-thalassemia. Compared with Tfrcfl/fl;Alb-Cre- controls, Tfrcfl/fl;Alb-Cre+ mice displayed reduced serum and liver iron; mildly reduced hematocrit, mean cell hemoglobin, and mean cell volume; increased erythropoietin and erythroferrone; and unchanged hepcidin levels that were inappropriately high relative to serum iron, liver iron, and erythroferrone levels. However, ablation of hepatocyte Tfrc had no impact on iron phenotype in Hfe knockout mice. Tfrcfl/fl;Alb-Cre+ mice also displayed a greater induction of hepcidin by serum iron compared with Tfrcfl/fl;Alb-Cre- controls. Finally, although acute erythropoietin injection similarly reduced hepcidin in Tfrcfl/fl;Alb-Cre+ and Tfrcfl/fl;Alb-Cre- mice, ablation of hepatocyte Tfrc in a mouse model of ß-thalassemia intermedia ameliorated hepcidin deficiency and liver iron loading. Together, our data suggest that the major nonredundant function of hepatocyte TfR1 in iron homeostasis is to interact with HFE to regulate hepcidin. This regulatory pathway is modulated by serum iron and contributes to hepcidin suppression and iron overload in murine ß-thalassemia.

Functional role of endothelial transferrin receptor 1 in iron sensing and homeostasis.

Systemic iron homeostasis is regulated by the hepatic hormone hepcidin to balance meeting iron requirements while limiting toxicity from iron excess. Iron-mediated induction of bone morphogenetic protein (BMP) 6 is a central mechanism for regulating hepcidin production. Liver endothelial cells (LECs) are the main source of endogenous BMP6, but how they sense iron to modulate BMP6 transcription and thereby hepcidin is uncertain. Here, we investigate the role of endothelial cell transferrin receptor 1 (TFR1) in iron uptake, BMP6 regulation, and systemic iron homeostasis using primary LEC cultures and endothelial Tfrc (encoding TFR1) knockout mice. We show that intracellular iron regulates Bmp6 expression in a cell-autonomous manner, and TFR1 mediates iron uptake and Bmp6 expression by holo-transferrin in primary LEC cultures. In addition, endothelial Tfrc knockout mice exhibit altered iron homeostasis compared with littermate controls when fed a limited iron diet, as evidenced by increased liver iron and inappropriately low Bmp6 and hepcidin expression relative to liver iron. However, endothelial Tfrc knockout mice have a similar iron phenotype compared to littermate controls when fed an iron-rich standard diet. Finally, ferritin and non-transferrin bound iron (NTBI) are additional sources of iron that mediate Bmp6 induction in primary LEC cultures via TFR1-independent mechanisms. Together, our data demonstrate a minor functional role for endothelial cell TFR1 in iron uptake, BMP6 regulation, and hepatocyte hepcidin regulation under iron limiting conditions, and suggest that ferritin and/or NTBI uptake by other transporters have a dominant role when iron availability is high.

Drowsiness Detection System Based on PERCLOS and Facial Physiological Signal.

Accidents caused by fatigue occur frequently, and numerous scholars have devoted tremendous efforts to investigate methods to reduce accidents caused by fatigued driving. Accordingly, the assessment of the spirit status of the driver through the eyes blinking frequency and the measurement of physiological signals have emerged as effective methods. In this study, a drowsiness detection system is proposed to combine the detection of LF/HF ratio from heart rate variability (HRV) of photoplethysmographic imaging (PPGI) and percentage of eyelid closure over the pupil over time (PERCLOS), and to utilize the advantages of both methods to improve the accuracy and robustness of drowsiness detection. The proposed algorithm performs three functions, including LF/HF ratio from HRV status judgment, eye state detection, and drowsiness judgment. In addition, this study utilized a near-infrared webcam to obtain a facial image to achieve non-contact measurement, alleviate the inconvenience of using a contact wearable device, and for use in a dark environment. Furthermore, we selected the appropriate RGB channel under different light sources to obtain LF/HF ratio from HRV of PPGI. The main drowsiness judgment basis of the proposed drowsiness detection system is the use of algorithm to obtain sympathetic/parasympathetic nervous balance index and percentage of eyelid closure. In the experiment, there are 10 awake samples and 30 sleepy samples. The sensitivity is 88.9%, the specificity is 93.5%, the positive predictive value is 80%, and the system accuracy is 92.5%. In addition, an electroencephalography signal was used as a contrast to validate the reliability of the proposed method.

Reduced symmetric dimethylation stabilizes vimentin and promotes metastasis in MTAP-deficient lung cancer.

The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell-based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl-protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP-deficient cells, lower sDMA modification prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post-translational regulation.

Equivalent legibility font size for traditional Chinese character compared to early treatment diabetic retinopathy study near visual acuity.

PURPOSES: To investigate the legibility of a standardized logarithmic print size of traditional Chinese (TC) characters and compare it with Early Treatment Diabetic Retinopathy Study (ETDRS) near chart. MATERIALS AND METHODS: A total of 1243 commonly used TC characters were chosen and divided into three groups according to its stroke complexity: Group A with 2-9 strokes, Group B with 10-17 strokes, and Group C with 18-25 strokes. For each group of characters, near charts were created using randomly chosen characters arranged in decreasing logarithmic size. In a well-illuminated room, healthy controls were fully corrected to test both ETDRS near chart and our set of TC near charts. The smallest legible font sizes (SLFS) in TC near charts were recorded and analyzed. RESULTS: Forty-two healthy eyes (21 participants) (age 29 ± 8.9 years old) were included. The mean near best-corrected visual acuity (nBCVA) in ETDRS chart was 0.06 ± 0.05 logMAR. We found that the mean SLFS in TC charts (0.33 ± 0.09 logMAR) was significantly larger than the nBCVA in ETDRS chart (P < 0.001). The SLFS of Group B and the SLFS of Group C was significantly larger than that of Group A (P < 0.001). CONCLUSION: According to our results, to recognize TC characters, normal-sight readers need a 0.22-0.30 logMAR (1.7-2.0 fold) enlargement of the acuity size measured by ETDRS near chart. The low-stroke TC charts may provide a new method to assess the postsurgical outcomes for comparable functional visual acuity in reading TC characters.

Rapid polymerase chain reaction test for the early diagnosis of gonococcal keratoconjunctivitis.

PURPOSES: A case of gonococcal keratoconjunctivitis rapidly diagnosed by a vaginal swab PCR Xpert® CT/NG assay. METHODS: Case report. RESULTS: A 26-year-old woman presented to our emergency department with severe perilimbal stromal melting in both eyes and profuse purulent discharge for one day. Upon emergent ocular consultation, gonococcal keratoconjunctivitis was suspected. A vaginal swab was sent for rapid PCR Xpert® CT/NG assay which reported positive Neisseria gonorrhoeae (NG) and Chlamydia Trachoma (CT) DNA detection within 90 min. Due to the rapid diagnosis, adequate medical intervention with ceftriaxone injection was administered. Gonococcal keratitis with stromal melting was stabilized within 5 days of presentation. The patient was discharged with complete epithelial healing by the 8th day. However, 10 weeks after discharge, inadvertent rubbing of the left eye resulted in corneal perforation with iris prolapse. Lamellar keratoplasty with corneal patch graft was performed with amniotic membrane grafting. Xpert® CT/NG assay was performed again with conjunctival swab for recurring mild eye discharge. Both NG and CT were negative. The patient thus stabilized with no further complications. CONCLUSIONS: Rapid stromal melting can occur with un-diagnosed or delayed diagnosis of gonorrhea with ocular involvement. Speedy and accurate diagnosis by the highly sensitive and specific Xpert® CT/NG assay can provide early definite diagnosis for prompt treatment in prevention of gonococcal infection induced corneal perforations.

Effect of body lipid content is linked to nutritional adaptation in the acclimation responses of mesic-adapted Paederus to seasonal variations in desiccation stress.

Desiccation stress causes mesic-adapted arthropods to lose their body water content. However, mesic-adapted Paederus beetles can survive over prolonged periods under dry field conditions, suggesting that these beetles adopt an array of water conservation mechanisms. We investigated the water balance mechanisms of field-collected Paederus adults over a 14-month sampling period. We also assessed their nutritional adaptations by performing a stable isotope analysis to examine their diet. The water loss rate (WLR) of the beetles was significantly associated with the rice crop cycle and saturation deficit. The cuticular permeability (CP) of adult beetles was maintained at < 30 µg cm-2h-1 mmHg-1; however, CP increased significantly with the WLR. This result indicates that CP might play a minor role in reducing excessive water loss in beetles. The beetles' body water content and percentage total body water content increased when the WLR was high. Trehalose, glucose, and glycogen did not appear to play a central role in enhancing the water reserves in the insects. The body lipid content ranged from 0.22 ± 0.06 to 0.87 ± 0.07 mg and was negatively associated with the WLR. This association indicates that the increase in internal metabolic water was mediated by lipid catabolism. Stable isotope analysis results revealed that the Paederus beetles shifted their diet to carbohydrate-rich plants when the saturation deficit increased and the associated WLR reached its peak; otherwise, they consumed a high amount of staple carbohydrate-poor herbivore prey. The accumulation of energy reserves in the form of lipids through seasonal dietary shifts may exert major effects on the survival and population success of mesic-adapted Paederus beetles.

MITF functions as a tumor suppressor in non-small cell lung cancer beyond the canonically oncogenic role.

Microphthalamia-associated transcription factor (MITF) is a critical mediator in melanocyte differentiation and exerts oncogenic functions in melanoma progression. However, the role of MITF in non-small cell lung cancer (NSCLC) is still unknown. We found that MITF is dominantly expressed in the low-invasive CL1-0 lung adenocarcinoma cells and paired adjacent normal lung tissues. MITF expression is significantly associated with better overall survival and disease-free survival in NSCLC and serves as an independent prognostic marker. Silencing MITF promotes tumor cell migration, invasion and colony formation in lung adenocarcinoma cells. In xenograft mouse model, MITF knockdown enhances metastasis and tumorigenesis, but decreases angiogenesis in the Matrigel plug assay. Whole transcriptome profiling of the landscape of MITF regulation in lung adenocarcinoma indicates that MITF is involved in cell development, cell cycle, inflammation and WNT signaling pathways. Chromatin immunoprecipitation assays revealed that MITF targets the promoters of FZD7, PTGR1 and ANXA1. Moreover, silencing FZD7 reduces the invasiveness that is promoted by silencing MITF. Strikingly, MITF has significantly inverse correlations with the expression of its downstream genes in lung adenocarcinoma. In summary, we demonstrate the suppressive role of MITF in lung cancer progression, which is opposite to the canonical oncogenic function of MITF in melanoma.

Polymeric Gelatin Scaffolds Affect Mesenchymal Stem Cell Differentiation and Its Diverse Applications in Tissue Engineering.

Studies using polymeric scaffolds for various biomedical applications, such as tissue engineering, implants and medical substitutes, and drug delivery systems, have attempted to identify suitable material for tissue regeneration. This study aimed to investigate the biocompatibility and effectiveness of a gelatin scaffold seeded with human adipose stem cells (hASCs), including physical characteristics, multilineage differentiation in vitro, and osteogenic potential, in a rat model of a calvarial bone defect and to optimize its design. This functionalized scaffold comprised gelatin-hASCs layers to improve their efficacy in various biomedical applications. The gelatin scaffold exhibited excellent biocompatibility in vitro after two weeks of implantation. Furthermore, the gelatin scaffold supported and specifically regulated the proliferation and osteogenic and chondrogenic differentiation of hASCs, respectively. After 12 weeks of implantation, upon treatment with the gelatin-hASCs scaffold, the calvarial bone harboring the critical defect regenerated better and displayed greater osteogenic potential without any damage to the surrounding tissues compared to the untreated bone defect. These findings suggest that the present gelatin scaffold is a good potential carrier for stem cells in various tissue engineering applications.

The impact of DRP1 on myocardial fibrosis in the obese minipig.

BACKGROUND: The heart is a highly oxidative tissue, thus mitochondria play a major role in maintaining optimal cardiac function. Our previous study established a dietary-induced obese minipig with cardiac fibrosis. The aim of this study was to elucidate the role of mitochondrial dynamics in cardiac fibrosis of obese minipigs. DESIGN: Four-month-old Lee-Sung minipigs were randomly divided into two groups: a control group (C) and an obese group (O) by feeding a control diet or a high-fat diet (HFD) for 6 months. Exposure of H9c2 cardiomyoblasts to palmitate was used to explore the effects of high-fat on induction of myocardial injury in vitro. RESULTS: The O pigs displayed greater heart weight and cardiac collagen accumulation. Obese pigs exhibited a lower antioxidant capacity, ATP concentration, and higher oxidative stress in the left ventricle (LV). The HFD caused downregulation in protein expression of PGC-1α and OPA1, and upregulation of DRP1, FIS1, and PINK1 in the LV of O compared to C pigs. Furthermore, palmitate induced apoptosis and decreased ATP content in H9c2 cells. Palmitate elevated the protein expression of DRP1 and PINK1 in these cells. Inhibition of DRP1 protein expression by siDRP1 in H9c2 cells resulted in enhanced ATP and decreased palmitate-induced apoptosis. CONCLUSIONS: These results suggest that mitochondrial dynamics were linked to the progression of obesity-related cardiac injury. Inhibition of DRP1 after palmitate exposure in H9c2 cells resulted in improved ATP level and decreased apoptosis in vitro suggesting that mitochondrial fission serves a key role in progression of obesity-induced cardiac fibrosis.

Endothelial Bone Morphogenetic Protein 2 (Bmp2) Knockout Exacerbates Hemochromatosis in Homeostatic Iron Regulator (Hfe) Knockout Mice but not Bmp6 Knockout Mice.

BACKGROUND AND AIMS: Bone morphogenetic proteins BMP2 and BMP6 play key roles in systemic iron homeostasis by regulating production of the iron hormone hepcidin. The homeostatic iron regulator (HFE) also regulates hepcidin through a mechanism that intersects with the BMP-mothers against decapentaplegic homolog 1/5/8 (SMAD1/5/8) pathway. However, the relative roles of BMP2 compared with BMP6 and whether HFE regulates hepcidin through a BMP2-dependent mechanism remain uncertain. APPROACH AND RESULTS: We therefore examined the iron phenotype of mice deficient for both Bmp2 and Bmp6 or both Bmp2 and Hfe compared with single knockout (KO) mice and littermate controls. Eight-week-old double endothelial Bmp6/Bmp2 KO mice exhibited a similar degree of hepcidin deficiency, serum iron overload, and tissue iron overload compared with single KO mice. Notably, dietary iron loading still induced liver SMAD5 phosphorylation and hepcidin in double Bmp6/endothelial Bmp2 KO mice, although no other BMP ligand mRNAs were increased in the livers of double KO mice, and only Bmp6 and Bmp2 mRNA were induced by dietary iron loading in wild-type mice. In contrast, double Hfe/endothelial Bmp2 KO mice exhibited reduced hepcidin and increased extrahepatic iron loading compared to single Hfe or endothelial Bmp2 KO mice. Liver phosphorylated SMAD5 and the SMAD1/5/8 target inhibitor of DNA binding 1 (Id1) mRNA were also reduced in double Hfe/endothelial Bmp2 KO compared with single endothelial Bmp2 KO female mice. Finally, hepcidin and Id1 mRNA induction by homodimeric BMP2, homodimeric BMP6, and heterodimeric BMP2/6 were blunted in Hfe KO primary hepatocytes. CONCLUSIONS: These data suggest that BMP2 and BMP6 work collaboratively to regulate hepcidin expression, that BMP2-independent and BMP6-independent SMAD1/5/8 signaling contributes a nonredundant role to hepcidin regulation by iron, and that HFE regulates hepcidin at least in part through a BMP2-independent but SMAD1/5/8-dependent mechanism.

Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin.

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The Nrf2 transcription factor orchestrates cell-intrinsic protective antioxidant responses, and the peptide hormone hepcidin maintains systemic iron homeostasis, but is pathophysiologically decreased in haemochromatosis and beta-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives Bmp6 expression in liver sinusoid endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6-hepcidin response to oral and parenteral iron is impaired and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6-hepcidin axis, improving iron homeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in beta-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to control of systemic iron homeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders.

Adult Paederus fuscipes (Coleoptera: Staphylinidae) Beetles Overcome Water Loss With Increased Total Body Water Content, Energy Metabolite Storage, and Reduced Cuticular Permeability: Age, Sex-Specific, and Mating Status Effects on Desiccation.

The ability of Paederus beetles to resist desiccation stress is vital to their adaptability in various ecological niches. How water relations and their response to desiccation vary among adult beetles of different age, sex, and mating status is unclear. We examined the water relations of adult Paederus fuscipes Curtis and the mechanisms used to reduce desiccation stress. One-day-old beetles had an exceptionally high percent total body water (%TBW) content and tolerated a high level of %TBW loss. Newly emerged beetles contained a high level of trehalose and 40 to 60% lipid content of their total dry mass, which allowed them to endure desiccation. Beetles that were 10 wk old and older exhibited reduced cuticular permeability. Glucose, glycogen, and lipid contents were crucial throughout most of the adult life span, as they helped compensate for water loss via increased water vapor absorption and metabolic water. In particular, the accumulation of lipid after mating was significant and may further confer tolerance to water loss. The effect of melanization on the desiccation tolerance of beetles was not significant. Females had better tolerance in response to desiccation stress compared with males. We suggest that the observed differences between sexes likely were a function of water relations and an effect of energy metabolite reserves. However, the mortality of females at 24-h postdesiccating stage was marginally significant compared with males. These results demonstrate that P. fuscipes adults prevent dehydration using multiple mechanisms that collectively reduce desiccation stress and increase dehydration tolerance.