Hepcidin is a 25-amino acid peptide hormone produced by hepatocytes and plays a key role in body iron metabolism. Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemia, and its excess is associated with anemia of inflammation, chronic disease and iron deficiency anemia (IDA). The aims of this study was to evaluate HAMP gene mutation, namely IVS2 + 1(-G) (c.148-150 + 1del) and Gly71 Asp (c.212G>> A (rs104894696) association with iron status in IDA conditions. Our study participants were 500 IDA patients and 550 age and sex-matched healthy controls. Hepcidin, ferritin and CRP analysis was done by ELISA method while ESR analysis was done according to Wintrobe method. CBC analysis was done by auto-analyzer. Two mutations in the HAMP genes were analysed by PCR RFLP method. Among the IDA patients, 7 were heterozygous for Met50del IVS2 + 1(-G) mutation. Nine IDA patients were heterozygous for G71D G-A mutation and homozygous were not identified in both mutations.Controls were showing heterozygous frequency 1.8 and 2.1% of Met50del IVS2 + 1(-G) and G71D G-A mutations respectively. Mutation of HAMP (Met50del IVS2 + 1(-G) and G71D G-A) were clinically associated with IDA and act as modulator of disease.

Iron deficiency have been found to be linked to sleep disorders. Both genetic and environmental factors are risk factors for skewed iron metabolism, thus sleep disruptions in autism spectrum disorders (ASD). The aim of our study was to assess the prevalence of single nucleotide polymorphisms (SNPs) within transferrin gene (TF) rs1049296 C>T, rs3811647 G>A, transferrin receptor gene (TFR) rs7385804 A>C, and hepcidin antimicrobial peptide gene (HAMP) rs10421768 A>G in Polish individuals with ASD and their impact on sleep pattern. There were 61 Caucasian participants with ASD and 57 non-ASD controls enrolled. Genotypes were determined by real-time PCR using TaqMan SNP assays. The Athens Insomnia Scale (AIS) was used to identify sleep disruptions. There were 32 cases (57.14%) with insomnia identified. In the ASD group, the defined counts of genotypes were as follows: TF rs1049296, C/C n = 41 and C/T n = 20; TF rs3811647, G/G n = 22, G/A n = 34, and A/A n = 5; TFR rs7385804, A/A n = 22, A/C n = 29, and C/C n = 10; and HAMP rs10421768, A/A n = 34, A/G n = 23, and G/G n = 4. There were no homozygous carriers of the TF rs1049296 C>T minor allele in the ASD group. All analyzed SNPs were not found to be linked to insomnia. The investigated polymorphisms are not predictors of sleep disorders in the analyzed cohort of individuals with ASD.

Background: Thalassemia patients need repeated transfusion that lead to increased blood ferritin level and iron overload in the heart and liver. Because the roles of hepcidin antimicrobial peptide (HAMP) and hemocromatosis protein (HFE) in iron metabolism have been confirmed, this study investigated the effects of these gene's polymorphisms on blood ferritin levels and iron overload in the heart and liver in patients with beta thalassemia major Materials and Methods: This cross-sectional study was conducted on 91 patients referring to the Hajar Hospital in Shahrekord, Iran in 2015. After the blood samples were collected, the ferritin levels were measured, DNA was extracted from the blood cells, and the types of polymorphisms were determined using PCR-RFLP. Data of MRI T2^* in the heart and liver were drawn from the patients' medical files. Data analysis was conducted by t-test, chi-square test, Fisher's exact test, and Pearson correlation coefficient. Results: There was no significant correlation between blood ferritin level and c.-582 A>G polymorphisms of hepcidin gene (p=0.58), and H63D of HFE gene (p=0.818). In addition, there was no significant association between the polymorphisms and heart and liver MRI, but there was a significant association between blood ferritin level and qualitative heart and liver MRI (r=-0.34, p=0.035 and r=-0.001, p=0.609, respectively). Conclusion: In patients with β-thalassemia major, the presence of c.-582A>G HAMP and H63D HFE polymorphisms is not effective on blood ferritin level and iron overload in the heart and liver in the studied region.

Background: Hepcidin and hemochromatosis (HFE) are iron regulatory proteins that are encoded by HAMP and HFE genes. Mutation in either HAMP gene or HFE gene causes Hepcidin protein deficiency that can lead to iron overload in beta thalassemia patients. The aim of this research work was to study the presence of G71D mutation of HAMP gene and H63D mutation of HFE gene in beta thalassemia major and minor group to check the association of these mutations with serum ferritin level of beta thalassemia patients.

Methods: The study was conducted on 42 beta thalassemia major and 20 beta thalassemia minor samples along with 20 control samples. The genotyping of both mutations has done by ARM-PCR technique with specific set of primers.

Results: Significant effect of G71D and H63D mutations was observed on serum ferritin level of thalassemia major group. The risk allele of HAMP G71D and HFE H63D was found with high frequency (48% and 49%, respectively) in beta thalassemia major than in control group. High genotypic frequency of HAMP and HFE gene mutation gene mutation was observed in beta thalassemia major than beta thalassemia minor and control group (7% and 9%, respectively).

Conclusion: It can be concluded that both HAMP and HFE gene mutations show high frequency in beta thalassemia major patients and mean significant association between mutations and high serum ferritin level of beta thalassemia major patients but the nonsignificant results of Odd ratios showed that both mutations do not act as major risk factor in beta thalassemia major.

Keywords: HAMP; HFE; G71D; H63D; Hemochromatosis; Hepcidin; beta thalassemia major.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. We have previously shown that hepatic reticuloendothelial system (RES) iron deposition is associated with an advanced degree of nonalcoholic steatohepatitis (NASH) in humans. In this study, we aimed to determine differentially expressed genes related to iron overload, inflammation and oxidative stress pathways, with the goal of identifying factors associated with NASH progression. Seventy five patients with NAFLD were evaluated for their biochemical parameters and their liver tissue analyzed for NASH histological characteristics. Gene expression analysis of pathways related to iron homeostasis, inflammation and oxidative stress was performed using real-time PCR. Gene expression was compared between subjects based on disease status and presence of hepatic iron staining. We observed increased gene expression of hepcidin (HAMP) (2.3 fold, p = 0.027), transmembrane serine proteinase 6 (TMPRSS6) (8.4 fold, p = 0.003), signal transducer and activator of transcription 3 (STAT3) (5.5 fold, p = 0.004), proinflammatory cytokines; IL-1β (2.7 fold, p = 0.046) and TNF-α (3.8 fold, p = 0.001) in patients with NASH. TMPRSS6, a negative regulator of HAMP, is overexpressed in patients with NASH and HIF1α (hypoxia inducible factor-1) is downregulated. NAFLD patients with hepatic iron deposition exhibited higher hepci-din expression (3.1 fold, p = 0.04) but lower expression of cytokines. In conclusion, we observed elevated hepatic HAMP expression in patients with NASH and in NAFLD patients who had hepatic iron deposition, while proinflammatory cytokines displayed elevated expression only in patients with NASH, suggesting a regulatory role for hepcidin in NAFL to NASH transition and in mitigating inflammatory responses.

Chronic inflammatory diseases are often associated with anemia. In such conditions, anemia is generally treated with erythropoiesis stimulating agents (ESAs) which are associated with potentially hazardous side effects and poor outcomes. Suboptimal erythropoiesis in chronic inflammation is believed to be caused by elevated hepcidin levels, which causes blockade of iron in tissue stores. In the current work using rodent models of inflammation, an orally available small molecule prolyl hydroxylase inhibitor desidustat was assessed as an effective treatment of anemia of inflammation. In BALB/c mice, a single dose treatment of desidustat attenuated the effect of lipopolysaccharide (LPS) - or turpentine oil-induced inflammation and increased serum erythropoietin (EPO), iron, and reticulocyte count, and decreased serum hepcidin levels. In turpentine oil-induced anemia in BALB/c mice, repeated dose desidustat treatment increased hemoglobin, RBC and hematocrit in a dose related manner. In female Lewis rats, treatment with desidustat markedly reduced PGPS-induced anemia and increased hemoglobin, red blood cell (RBC) and white blood cell (WBC) count, hematocrit, serum iron and spleen iron. These effects of desidustat were associated with reduction in hepcidin (HAMP) expression as well as reduction in serum hepcidin, and increased EPO expression in liver and kidneys. Desidustat treatment caused a significant increase in expression of Duodenal cytochrome B (DcytB), ferroportin (FPN1) and divalent metal transporter 1 (DMT1) in duodenum, and FPN1 and monocyte chemoattractant protein-1 (MCP-1) in liver suggesting an overall influence on iron metabolism. Thus, pharmacological inhibition of prolyl hydroxylase enzymes can be useful in treatment of anemia of inflammation.

A 57-year-old man had been detected to have an elevated transaminase level. He had a history of alcohol consumption, and abdominal ultrasonography revealed an increase in the echogenicity of the liver;hence, he was diagnosed as having alcoholic liver disease. He restricted his alcohol intake, but the elevated transaminase level did not improve. Further medical examination was performed. He was found to have hyperferritinemia (serum ferritin, 6574ng/mL) and high transferrin saturation (TSAT, 90.5%). Computed tomography (CT) revealed high CT values of the liver and spleen (94 and 84HU, respectively). These findings differed from the characteristics of a typical alcoholic liver disease. Liver biopsy revealed iron deposition within the hepatocytes and Kupffer cells and liver fibrosis (F1-2). From the gene analysis of HFE, HJV, TFR2, HAMP, and SLC40A1 genes, he was heterozygous for the G>A (G490D) mutation in the ferroportin gene (SLC40A1). He was diagnosed as having ferroportin disease. It was reported that patients with a G490D mutation exhibited ferroportin disease A, which occurs owing to a loss-of-function mutation of SLC40A1. However, he was considered to have some characteristics of ferroportin disease B, which occurs owing to a gain-of-function mutation of SLC40A1. In this case, alcohol consumption might affect the progression of iron deposition in the liver. Therapeutic venesection was performed, and his hyperferritinemia with high TSAT gradually improved. In the course of the disease, other organ damages and progression of liver fibrosis did not occur.

Atonal homolog 8 (ATOH8) is defined as a positive regulator of hepcidin transcription, which links erythropoietic activity with iron-sensing molecules. In the present study, we investigated the association between hepcidin and ATOH8 expression in β-thalassemia. We found that inhibition of hepcidin expression in β-thalassemia is correlated with reduced ATOH8 expression. Hepatic hepcidin 1 (Hamp1) and Atoh8 mRNA expression were down-regulated in β-thalassemic mice. Hepcidin (HAMP) and ATOH8 mRNA expression were consistently suppressed in Huh7 cells cultured in medium supplemented with β-thalassemia patient serum. The Huh7 cells, which were transfected with ATOH8-FLAG expression plasmid and cultured in the supplemented medium, exhibited increased levels of ATOH8 mRNA, ATOH8-FLAG protein, pSMAD1,5,8, and HAMP mRNA. Interestingly, over-expression of ATOH8 reversed the effects of hepcidin suppression induced by the β-thalassemia patient sera. In conclusion, hepcidin suppression in β-thalassemia is associated with the down-regulation of ATOH8 in response to anemia. We, therefore, suggest that ATOH8 is an important transcriptional regulator of hepcidin in β-thalassemia.

Housed pigs are often exposed to elevated concentrations of atmospheric ammonia. This aerial pollutant is widely considered to be an environmental stressor that also predisposes to reduced growth rates and poor health, although evidence to support this view is limited. Hepatic gene expression is very responsive to stress and metabolic effects. Two batches of growing pigs were therefore exposed to a nominal concentration of atmospheric ammonia of either 5 ppm (low) or 20 ppm (high) from 4 weeks of age for 15 weeks. Growth rates were monitored. Samples of liver were taken after slaughter (at ∼19 weeks of age). Samples from the second batch were analysed for global gene expression using 23 K Affymetrix GeneChip porcine genome arrays. Samples from both batches were subsequently tested for five candidate genes using quantitative real-time PCR (qPCR). The array analysis failed to detect any significant changes in hepatic gene expression following chronic exposure to atmospheric ammonia. Animals clustered into two main groups but this was not related to the experimental treatment. There was also no difference in growth rates between groups. The qPCR analyses validated the array results by showing similar fold changes in gene expression to the arrays. They revealed a significant batch effect in expression of lipin 1 (LPIN1), Chemokine (C-X-C motif) ligand 14 (CXCL14), serine dehydratase (SDS) and hepcidin antimicrobial peptide (HAMP). Only CXCL14, a chemotactic cytokine for monocytes, was significantly down-regulated in response to ammonia. As chronic exposure to atmospheric ammonia did not have a clear influence on hepatic gene expression, this finding implies that 20 ppm of atmospheric ammonia did not pose a significant material risk to the health or metabolism of housed pigs.

It has been suggested that childhood exposure to neurotoxicants may increase the risk of Parkinson's disease (PD) or other neurodegenerative disease in adults. Some recessive forms of PD have been linked to loss-of-function mutations in the Park2 gene that encodes for parkin. The purpose of this pilot study was to evaluate whether responses to neonatal manganese (Mn) exposure differ in mice with a Park2 gene defect (parkin mice) when compared with a wildtype strain (C57BL/6J). Neonatal parkin and C57BL/6J littermates were randomly assigned to 0, 11, or 25mg Mn/kg-day dose groups with oral exposures occurring from postnatal day (PND) 1 through PND 28. Motor activity was measured on PND 19-22 and 29-32. Tissue Mn concentrations were measured in liver, femur, olfactory bulb, frontal cortex, and striatum on PND 29. Hepatic and frontal cortex gene expression of Slc11a2, Slc40a1, Slc30a10, Hamp (liver only), and Park2 were also measured on PND 29. Some strain differences were seen. As expected, decreased hepatic and frontal cortex Park2 expression was seen in the parkin mice when compared with C57BL/6J mice. Untreated parkin mice also had higher liver and femur Mn concentrations when compared with the C57BL/6J mice. Exposure to≥11mg Mn/kg-day was associated with increased brain Mn concentrations in all mice, no strain difference was observed. Manganese exposure in C57Bl6, but not parkin mice, was associated with a negative correlation between striatal Mn concentration and motor activity. Manganese exposure was not associated with changes in frontal cortex gene expression. Decreased hepatic Slc30a10, Slc40a1, and Hamp expression were seen in PND 29 C57BL/6J mice given 25mg Mn/kg-day. In contrast, Mn exposure was only associated with decreased Hamp expression in the parkin mice. Our results suggest that the Parkin gene defect did not increase the susceptibility of neonatal mice to adverse health effects associated with high-dose Mn exposure.

Available structures of HAMP domains suggest rotation as one potential mechanism in intraprotein signal transduction. It has been proposed that in poly-HAMP modules the signal sign is inverted with each additional HAMP. We examined signal transduction through the HAMP tandem domain from the phototaxis transducer of the halophilic archaeon Natronomonas pharaonis in membrane-bound chimeras consisting of the Escherichia coli chemotaxis receptor for serine, Tsr, as an input and the mycobacterial adenylyl cyclase Rv3645 as an output domain, i.e. the basic chimera was 'Tsr-NpHAMP tandem-Rv3645 cyclase'. Neither of the NpHAMP units alone nor the NpHAMP tandem transduced a serine signal. After five targeted point mutations in the first α-helix of NpHAMPHAMP modules combined into a functional HAMP tandem. 1 mm serine significantly inhibited cyclase activity (-35%; IC50 = 30 μm) in disagreement with the structure-based predictions. Surprisingly, replacement of NpAS11 in the tandem by the respective AS1 from HAMPT sr resulted in signal inversion, i.e. serine activated cyclase (+129%; EC50 = 10 μm). Examination of 48 mutants of AS11 in the HAMP tandem including two residues of a putative N-terminal control cable identified five residues in NpAS11 which probably define different ground states of the output domain and thus affect the sign of signal output. The data question the predicted HAMP rotation as the predominant mechanism of intraprotein signal transduction and point to as yet unrecognized conformational motions of HAMP domains in intraprotein signaling.

BACKGROUND

Hepcidin, encoding by HAMP gene, is the pivotal regulator of iron metabolism, controlling the systemic absorption and transportation of irons from intracellular stores. Abnormal levels of HAMP expression alter plasma iron parameters and lead to iron metabolism disorders. Therefore, it is an important goal to understand the mechanisms controlling HAMP gene expression.

RESULTS

Overexpression of Sox2 decrease basal expression of HAMP or induced by IL-6 or BMP-2, whereas, knockdown of Sox2 can increase HAMP expression, furthermore, two potential Sox2-binding sites were identified within the human HAMP promoter. Indeed, luciferase experiments demonstrated that deletion of any Sox2-binding site impaired the negative regulation of Sox2 on HAMP promoter transcriptional activity in basal conditions. ChIP experiments showed that Sox2 could directly bind to these sites. Finally, we verified the role of Sox2 to negatively regulate HAMP expression in human primary hepatocytes.

CONCLUSIONS

We found that Sox2 as a novel factor to bind with HAMP promoter to negatively regulate HAMP expression, which may be further implicated as a therapeutic option for the amelioration of HAMP-overexpression-related diseases, including iron deficiency anemia.

The reactions of [Ru₂(O₂CCH₃)₄Cl] with 2-aminopyridine (Hamp) and 2-amino-4-methylpyridine (Hammp) afforded two novel Ru₂ complexes, [Ru₂(amp)₄Cl₂] (1) and [Ru₂(ammp)₄Cl₂] (2), respectively. Single crystal X-ray diffraction analyses revealed that 1 and 2 adopted typical paddlewheel-type structures, where the Ru₂ units are coordinated with four aminopyridinate ligands with a cis-2:2 arrangement at the equatorial positions and two chloride ligands at the axial positions. The stabilities of 1 and 2 were supported by unrestricted density functional theory (uDFT) calculations. The zero-point energies of the three structural isomers (trans-2:2, 3:1, and 4:0 arrangements) of 1 and 2 were less stable than those of the respective cis-2:2 arrangements. Temperature-dependences of the magnetic susceptibility measurements and uDFT calculations showed that the oxidation and spin states of the Ru₂ units in 1 and 2 were commonly Ru₂⁶⁺ and triplet states, respectively. Cyclic voltammetry showed that 1 and 2 underwent one-electron reduction processes, i.e., 1/1^- and 2/2^-, at redox potentials (E_1/2) of -0.08 and -0.18 V vs. SCE, respectively. These results agreed well with the DFT-calculated E_1/2 values of 1 (-0.08 V vs. SCE) and 2 (-0.18 V vs. SCE) and were theoretically attributed to Ru₂-centred (δ*(Ru₂)) redoxes. Moreover, 1 and 2 showed unique near-infrared absorption bands at approximately 1200-1500 nm, which were theoretically attributed to the ligand-to-metal charge transfer (LMCT) with π(amp or ammp) →δ*(Ru₂) transition characteristics.

The asymmetric unit of the title compound, (C(6)H(9)N(2))(4)[BiCl(6)]Cl·H(2)O, contains four protonated 2-amino-6-methyl-pyridine (HAMP) cations and two-halves of two [BiCl(6)](3-) anions, together with one water mol-ecule and one chloride anion. The Bi(III) atoms are hexa-coordinated by Cl atoms, forming distorted octa-hedral geometries. In the crystal structure, intra-molecular O-H⋯Cl and N-H⋯Cl, and inter-molecular O-H⋯Cl and N-H⋯O inter-actions link the mol-ecules into a three-dimensional network.

BACKGROUND

Our original studies reported an association between the iron-metabolism gene HFE and risk of childhood acute lymphoblastic leukemia (ALL), and a birth weight association in ALL. Through its effect on cell proliferation, iron is involved in both fetal development and cancer. We hypothesize that HFE links higher infant birth weight with leukemia risk and that maternal HFE genotype modifies this association.

METHODS

Nine hundred ninety-five infants and their mothers from the North Cumbria Community Genetics Project, and 163 incident childhood ALL cases from the Newcastle Haematology Biobank were genotyped for HFE, HAMP, TFRC variants and 21 genomic control loci. Cord blood iron levels were measured in 217 control infants.

RESULTS

Three HFE variants showed correlations with birth weight with a gene-dosage relationship in males (gender effect). The association was stronger in homozygotes for TFRC S142G and when the mother was positive for any HFE variant (maternal effect). The genotypes expected to increase fetal iron levels correlated with birth weight in males and their association with ALL was stronger in females who, we postulate, could not offset iron excess by increasing their weight.

CONCLUSIONS

Certain materno-fetal genotype combinations that increase fetal iron exposure showed associations with higher birth weight in males and somewhat higher ALL risk in females. Gender-specific use of iron during fetal growth may lead to this dichotomy in birth weight change. Only the materno-fetal genotype combinations that increase iron levels most extremely correlated with birth weight and ALL risk in males.

Background: Atypical clinical symptoms of juvenile hereditary hemochromatosis (JHH) often leads to misdiagnosis and underdiagnosis bringing ominous outcomes, even death.

Methods: The whole exome was sequenced and interpreted. A literature review assisted to analyze and verify the phenotype-genotype relationships. We revealed the entire process of diagnosis, treatments, and outcome of two diabetic onset of JHH families to provide new insights for genotype-phenotype relation with novel compound heterozygous mutations in the hepcidin antimicrobial peptide (HAMP, OMIM: 606464).

Results: Two probands were diagnosed and treated as type 1 diabetes initially because of specific symptoms and positive islet autoantibodies. Poor control of hyperglycemia and progressive symptoms occurred. Sequencing informed that the compound heterozygous and homozygous mutations c.166C>G and c.223C>T in HAMP caused type 1 diabetic-onset JHH. The two patients accessed irregular phlebotomy treatments, and then, experienced poor prognosis. We summarized the process of overall clinical management of reported 26 cases comparing to our novel atypical diabetic onsets Juvenile Hereditary Hemochromatosis cases.

Conclusion: It was first reported that positive pancreatic islet autoantibodies diabetes onset of JHH resulted from loss-of-function mutations of HAMP, of which the atypical JHH should be differentially diagnosed with type 1 diabetes at the onset. Early administration of phlebotomy and vital organs protection and surveillance might be important for the treatment of atypical JHH.

Keywords: HAMP; juvenile hereditary hemochromatosis; pancreatic autoimmune antibody; type 1 diabetes.

Juvenile hemochromatosis (JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage, hypogonadotropic hypogonadism, cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation (g.47G>A), treated with phlebotomies and deferasirox. She presented symptoms such as weakness, skin hyperpigmentation, joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin (SF): 5696 ng/mL, transferrin saturation (TS): 85%]. After sessions of phlebotomies (450 mL every 15 d), the patient presented partial symptomatic improvements and biochemical parameters (SF: 1000 ng/mL, Hb: 11 g/dL). One year later, deferasirox (15 mg/kg per day) was introduced to the treatment, and the patient showed total symptomatic improvement, with significant clearing of the skin, SF: 169 ng/mL, and TS: 50%. Furthermore, after the combined deferasirox-phlebotomy therapy, magnetic resonance imaging measurements revealed normalized level for liver iron (30 μmol/g; reference value < 36 μmol/g). In conclusion, combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.

Flagellated bacteria modulate their swimming behavior in response to environmental cues through the CheA/CheY signaling pathway. In addition to responding to external chemicals, bacteria also monitor internal conditions that reflect the availability of oxygen, light, and reducing equivalents, in a process termed "energy taxis." In Escherichia coli, the transmembrane receptor Aer is the primary energy sensor for motility. Genetic and physiological data suggest that Aer monitors the electron transport chain through the redox state of its FAD cofactor. However, direct biochemical data correlating FAD redox chemistry with CheA kinase activity have been lacking. Here, we test this hypothesis via functional reconstitution of Aer into nanodiscs. As purified, Aer contains fully oxidized FAD, which can be chemically reduced to the anionic semiquinone (ASQ). Oxidized Aer activates CheA, whereas ASQ Aer reversibly inhibits CheA. Under these conditions, Aer cannot be further reduced to the hydroquinone, in contrast to the proposed Aer signaling model. Pulse ESR spectroscopy of the ASQ corroborates a potential mechanism for signaling in that the resulting distance between the two flavin-binding PAS (Per-Arnt-Sim) domains implies that they tightly sandwich the signal-transducing HAMP domain in the kinase-off state. Aer appears to follow oligomerization patterns observed for related chemoreceptors, as higher loading of Aer dimers into nanodiscs increases kinase activity. These results provide a new methodological platform to study Aer function along with new mechanistic details into its signal transduction process.

Proteins have highly conserved domains that determine their functionality. Out of the thousands of domains discovered so far across all living forms, some of the predominant clinically-relevant domains include IENR1, HNHc, HELICc, Pro-kuma_activ, Tryp_SPc, Lactamase_B, PbH1, ChtBD3, CBM49, acidPPc, G3P_acyltransf, RPOL8c, KbaA, HAMP, HisKA, Hr1, Dak2, APC2, Citrate_ly_lig, DALR, VKc, YARHG, WR1, PWI, ZnF_BED, TUDOR, MHC_II_beta, Integrin_B_tail, Excalibur, DISIN, Cadherin, ACTIN, PROF, Robl_LC7, MIT, Kelch, GAS2, B41, Cyclin_C, Connexin_CCC, OmpH, Bac_rhodopsin, AAA, Knot1, NH, Galanin, IB, Elicitin, ACTH, Cache_2, CHASE, AgrB, PRP, IGR, and Antimicrobial21. These domains are distributed in nucleases/helicases, proteases, esterases, lipases, glycosylase, GTPases, phosphatases, methyltransferases, acyltransferase, acetyltransferase, polymerase, kinase, ligase, synthetase, oxidoreductase, protease inhibitors, nucleic acid binding proteins, adhesion and immunity-related proteins, cytoskeletal component-manipulating proteins, lipid biosynthesis and metabolism proteins, membrane-associated proteins, hormone-like and signaling proteins, etc. These domains are ubiquitous stretches or folds of the proteins in pathogens and allergens. Pathogenesis alleviation efforts can benefit enormously if the characteristics of these domains are known. Hence, this review catalogs and discusses the role of such pivotal domains, suggesting hypotheses for better understanding of pathogenesis at molecular level.

Herein, the mechanisms of colistin heteroresistance (CHR) were assessed in 12 Escherichia coli isolates from swine in China. CHR was investigated by population analysis profile tests. CHR stability was studied by culturing for five overnight incubation periods in colistin-free medium. Subsequently, the mcr-phoPQ and its target gene pagP, its negative regulator gene mgrB, as well as pmrAB and its target genes pmrHFIJKLM and pmrC were determined by real-time relative quantitative PCR. Eleven of the twelve isolates were confirmed to show CHR, with seventeen resistant subpopulations. Also, eleven of the seventeen subpopulations (64.71%) harbored point mutations in PmrB and/or PhoQ, differing from their parental isolates. However, only one stable resistant subpopulation (EPF42-4) was identified; it harbored an arginine to proline substitution at position 93 (R⁹³P) within the PmrB HAMP domain. Compared to the pmrB expression levels in the parental isolate EPF42 and E. coli K-12 MG1655, remarkable pmrB overexpression was observed in EPF42-4, which showed upregulated pmrA, pmrK, and pmrC expression. Structural analysis demonstrated that the R⁹³P substitution promotes conformational changes in the HAMP domain, leading to an acceleration in its signal-transduction ability and activation of PmrB expression. In conclusion, point mutations in PmrB and/or PhoQ were primarily associated with CHR. The R⁹³P substitution resulted in the establishment of stable resistant subpopulations in E. coli showing CHR.

Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacteria. MicroRNA-122 (miR-122) is specifically expressed in the liver. This study focuses on the role of miR-122 in MC-LR-induced dysregulation of hepatic iron homeostasis in C57BL/6 mice. The thirty mice were randomly divided into five groups (Control, 12.5 μg/kg·BW MC-LR, 25 μg/kg·BW MC-LR, Negative control agomir and 25 μg/kg·BW MC-LR + miR-122 agomir). The results show that MC-LR decreases the expressions of miR-122, Hamp, and its related regulators, while increasing the content of hepatic iron and the expressions of FPN1 and Tmprss6. Furthermore, miR-122 agomir pretreatment improves MC-LR induced dysregulation of hepatic iron homeostasis by arousing the related regulators and reducing the expression of Tmprss6. These results suggest that miR-122 agomir can prevent the accumulation of hepatic iron induced by MC-LR, which may be related to the regulation of hepcidin by BMP/SMAD and IL-6/STAT signaling pathways.

Plants perceive insect herbivores via a sophisticated surveillance system that detects a range of alarm signals, including herbivore-associated molecular patterns (HAMPs). Fatty acid-amino acid conjugates (FACs) are HAMPs present in oral secretions (OS) of lepidopteran larvae that induce defense responses in many plant species. In contrast to eggplant (Solanum melongena), tomato (S. lycopersicum) does not respond to FACs present in OS from Manduca sexta (Lepidoptera). Since both plants are found in the same genus, we tested whether loss of sensitivity to FACs in tomato may be a domestication effect. Using highly sensitive MAP kinase (MAPK) phosphorylation assays, we demonstrate that four wild tomato species and the closely related potato (S. tuberosum) do not respond to the FACs N-linolenoyl-L-glutamine and N-linolenoyl-L-glutamic acid, excluding a domestication effect. Among other genera within the Solanaceae, we found that bell pepper (Capsicum annuum) is responsive to FACs, while there is a differential responsiveness to FACs among tobacco (Nicotiana) species, ranging from strong responsiveness in N. benthamiana to no responsiveness in N. knightiana. The Petunia lineage is one of the oldest lineages within the Solanaceae and P. hybrida was responsive to FACs. Collectively, we demonstrate that plant responsiveness to FACs does not follow simple phylogenetic relationships in the family Solanaceae. Instead, sensitivity to FACs is a dynamic ancestral trait present in monocots and eudicots that was repeatedly lost during the evolution of Solanaceae species. Although tomato is insensitive to FACs, we found that other unidentified factors in M. sexta OS induce defenses in tomato.