This study aimed to compare properties of retrograded starch acetates with an identical degree of substitution, but produced from raw materials of various botanical origin. Retrograded starch was produced from potato, wheat, corn, and tapioca starch, and afterwards acetylated with an acetic acid anhydride, adjusting reagent doses to achieve an identical degree of esterification of the modified preparation (2.1 g/100 g). Preparations of retrograded starch and acetylated retrograded starch differed significantly in their properties, which was due to the disparate botanical origin of starch. The highest susceptibility to acetylation was demonstrated for potato starch, and the lowest one for wheat starch. Acetylation of retrograded starch of various botanical origin increased its solubility in water, swelling power and viscosity of its pastes, as well as decreased its amylose content. Preparations of acetylated retrograded starches of disparate botanical origins may be deemed preparations of RS3/4 type resistant starch because they exhibit significant (23.5–34.0%) resistance to the activity of amylolytic enzymes. Intense investigations have been carried out within the last 30 years to identify production possibilities and properties of resistant starch, which is defined as products of its digestion not absorbed in the small intestine of a healthy man . ResistaThis study aimed to compare properties of retrograded starch acetates with an identical degree of substitution, but produced from raw materials of various botanical origins.Experimental materials included: Superior Standard potato starch manufactured by PEPEES Łomża S.A, wheat starch manufactured by Starch Production Plants of Grupa AWW Wawrzyniak , corn starch manufactured by Cargill Polska company , and tapioca starch produced in Bangkok, Thailand and distributed by EDMIR-POL company from Chorzów, Poland. Starch was acetylated with p.a. acetic acid anhydride purchased at POCH SA Gliwice company .Native potato, wheat, corn, and tapioca starches were used to prepare starch pastes with the concentration of 10 g starch/100 g solution. Starch was kept in a water bath  at a temperature of 94 °C for 6 h for complete gelatinization, then cooled and frozen at −20 °C for 72 h, and afterwards defrosted at 20 °C for 48 h. The produced starch having a spongy structure was disintegrated, rinsed with distilled water, dried in an air dryer  at a temperature of 35 °C for 24 h, ground, and sieved through a screen with mesh size of 400 μm [3/100 g starch). The resultant preparations of acetylated retrograded starch were rinsed with distilled water, dried in an air dryer  at a temperature of 30 °C for 24 h, ground, and sieved through a screen with a mesh size of 400 um.The manufactured preparations of retrograded starch were then subjected to the acetylation process according to the methodology provided in our previous work . Doses o3 of a 0.5 M NaOH solution were added to the mixture, which was shaken at a temperature of 25 °C for 35 min, and afterwards titrated with a 0.5 M solution of hydrochloric acid. The degree of esterification, expressed in grams of acid residues/100 g of the preparation, was computed from the following formula:P0—volume (mL) of titrated HCl solution used to titrate 25 mL of 0.5 mol/L NaOH, Pw—volume (mL) of titrated HCl solution used to titrate the sample with acetylated starch, Nk—acid titre, and M—content (g) of starch dry matter in the sample. The content of acetate groups was determined according to the methodology described by Wurzburg  and modiBased on the results achieved, the dependency between the degree of substitution and dose of acetic acid anhydride was determined for each type of starch. Afterwards, the analyzed starches were acetylated using doses of the reagent, ensuring the same degree of starch esterification in all modified preparations.The content of amylose was determined with the iodometric method after dissolution of starch samples in a solution of dimethyl sulfoxide and urea. The absorbance was measured against a reference sample (not containing starch), 15 min after iodine solution was added, using a CECIL CE 2010 spectrophotometer  at a wavelength of 635 nm . g. Then, supernatant was collected and determined for dry matter content with the gravimetric method, whereas precipitate left in the centrifuge tubes was weighed [A water suspension of acetylated retrograded starch was prepared (which contained 1 g starch/100 g solution) and shaken at a temperature of 80 °C for 30 min. Afterwards, it was cooled to a temperature of 20 °C and centrifuged for 30 min in a Biofuge 28RS centrifuge  at 22,500×  weighed . The pasting characteristics using the Brabender viscograph  was conducted in a measuring vessel (type 700 cmg). A sample of starch preparation was transferred into a cylinder of the apparatus using 450 mL of distilled water, which resulted in a suspension containing 4 g starch per 100 g solution. The suspension was heated to 40 °C with a stirring rate of 75 rpm, and kept at this temperature for 10 min. Next, the contents of the cylinder were heated to 94 °C by 1.5 °C increments per min. The mixture was kept for 10 min at this temperature, then cooled at a rate of 1.5 °C per min to 30 °C, and kept at this temperature for another 10 min .3 of an enzyme solution were added (at enzyme to buffer ratio of 1:4). The enzyme’s concentration was selected so as to enable complete saccharification of gelatinised native starch after 120 min of the process. Every hour, 1 cm3 of the hydrolysate was collected to centrifuge tubes that were centrifuged  with the speed of 1825× g for 5 min. Supernatant was collected from the centrifuged sample and mixed with a reagent from the Biosystem company (Glucose—containing glucose oxidase and peroxidase), and then incubated at 20 °C for 15 min. Afterwards, absorbance was measured using a CECIL CE 2010 colorimeter (Cecil Instruments) at the wavelength of λ = 500 nm. Measurements were conducted against a blank sample constituted by a reagent with an acetate buffer. The quantity of glucose was read out from the standard curve plotted as above using glucose (p.a.) solutions. The degree of saccharification was computed in respect of the theoretical quantity of glucose produced from the complete saccharification of a weighted portion of starch. The result of hydrolysis was final when three consecutive read outs of the absorbance did not differ between one another [Suspensions were prepared that contained 0.36 g of starch per 100 g of the solution. They were heated to the boiling point at continuous mixing and, then, cooled to a temperature of 37 °C, at which hydrolysis with amyloglucosidase (Amigase by Genecor) was conducted. To the prepared suspension of a starch preparation, acetate buffer (pH = 4.5) was added at the ratio of 1:1. The flask was placed in a water bath with a shaker, at a temperature of 37 °C , and 4 cm another .p < 0.01. Based on statistical computations , values of the least significant differences (LSD) and standard deviation were calculated. Values of the least significant differences (LSD) were determined with a Duncan’s test at α = 0.05. Computations were performed using Statistica ver. 13.1 software . To determine the effect of the botanical origin of starch on the values of the analyzed properties of the tested preparations, results achieved were subjected to a one-way analysis of variance at a significance level of The outcome of starch acetylation is determined by many factors including, i.a., type and dose of reagent, temperature, medium pH, and reaction duration ,21. In tThe key factor which differentiates properties of starch is its botanical origin . AmyloseNative starches of different botanical origins exhibit various solubility in water and swelling power. The highest swelling power has been reported for potato starch, whereas the swelling power of cereal starches is lower due to their different crystalline structure and the complexation of the part of their amylose chains with lipids’ substances, which reduces their water absorption capability . Figure Disparity in the structure resulting from the botanical origin and common modifications of starch, which alter the spatial structure of the starch chain, cause its partial resistance to the activity of digestive enzymes. Garcia-Alonso et al. investigated the effect of the botanical origin and of the method of the pastes’ production from wheat, corn, rice, and potato starches on the content of their resistant starch fraction . They deThe botanical disparity of native starch determined differences in properties of the manufactured preparations of retrograded starch and acetylated retrograded starch with an identical degree of substitution. Among the starches subjected to one-stage modification, the greatest susceptibility to acetylation, the highest content of amylose, the highest swelling power, solubility in water, viscosity of formed pastes, and resistance to amylolysis was demonstrated for retrograded potato starch, whereas the lowest values of the above parameters were shown for wheat starch. Acetylation of retrograded starches of various botanical origins enhanced all their studied properties except for the amylose content, which decreased irrespective of the raw material origin. Preparations of acetylated retrograded starches of various botanical origins may be deemed preparations of RS3/4 type resistant starch because they exhibit significant (23.5–34.0%) resistance to the activity of amylolytic enzymes.


International Journal of STEM Education. At the end of July 2018, the journal had completed four publication cycle years, that is, publication cycle 1 (PC-1): August 2014 – July 2015, publication cycle 2 (PC-2): August 2015 – July 2016, publication cycle 3 (PC-3): August 2016 – July 2017, and publication cycle 4 (PC-4): August 2017 – July 2018. Along with the rapid development of STEM education internationally, the journal has also established itself in the global field. Now is therefore a fitting time to briefly review and reflect on (1) the journal’s overall performance over the past four publication cycle years, (2) the journal’s publications during these four publication cycle years, and (3) the journal’s position in comparison with other journals in STEM education.The publication of five articles at the end of August 2014 marked the official launch of the One critical aspect of an academic journal’s performance is to look at the impact of the journal as a whole. Although there are different measures that can be used in a professional field to assess a journal’s impact , one commonly valued indicator is the number and type of indexing services that include the journal. After a journal has obtained an Impact Factor, scholars often want to know its value.International Journal of STEM Education has been selected and reviewed in the Web of Science’s Emerging Sources Citation Index (ESCI), in addition to other important professional services including SCOPUS, Google Scholar, and almost 20 other data searching and indexing services. Being accepted into ESCI is a first step in the evaluation process for obtaining an Impact Factor, which is exclusively published for journals included in Science Citation Index Expanded (SCIE) or Social Sciences Citation Index (SSCI)  on which the articles have focused. Specifically, our journal aims to serve as a multidisciplinary education journal that spans disciplinary boundaries. Thus, we are interested in learning about publication distributions in terms of their disciplinary focus: individual-discipline focused versus cross-discipline focused.Figure The results suggest that the journal has published more articles on cross-disciplinary than single-disciplinary issues and questions, and over the four publication cycle years there has been a generally increasing trend in this regard. These findings confirm that the journal is fulfilling its aim: to provide multidisciplinary perspectives needed to complement individual disciplinary-focused journals in STEM education Li, . Indeed,International Journal of STEM Education was established in 2014 as a multidisciplinary, open-access, peer-reviewed research journal. It complements individual disciplinary-focused journals in STEM education by “(1) providing an outlet to publish and share research from various disciplines and methods, (2) increasing access to research findings for researchers and educators through the journal’s open-access platform, and (3) galvanizing scientists and educational researchers to further our knowledge about STEM education.” , which is also published by Springer (see https://www.springer.com/41979). As noted by Li  complement each other in the following two main regards. First, the International Journal of STEM Education is an online open-access journal. Although authors who publish in this journal need to account for article processing charges (APCs), they also enjoy broad free accessibility of their published articles. In contrast, STEM-ER is a subscription-based journal that publishes in both print and electronic formats. Although authors who publish in STEM-ER do not need to concern about APCs, access to their published articles is restricted to those who pay to subscribe the journal.The journal’s nature distinguishes it from many other journals in education research, including the newly established ed by Li , these tSTEM-ER is established as an interdisciplinary education research journal. It is designed to promote research that helps identifying and addressing sets of basic questions that can not only reflect but also lead the rapid development of integrated STEM education around the globe (Li, International Journal of STEM Education is established as a platform to promote STEM education and research internationally by serving as a multidisciplinary education journal that spans disciplinary boundaries. Although interdisciplinary research contributions are preferred, the International Journal of STEM Education will remain a gathering place where disciplinary education scholars, who have traditionally been separated, can share both individual-disciplinary-based and cross-disciplinary educational research.The second difference relates to the aim and scope of these two journals. lobe Li, . In contInternational Journal of STEM Education has had a great journey over the past four publication cycle years. In many ways, its development mirrors the rapid development of STEM education research around the globe. I expect the journal to continue to grow to further support STEM education research and development. At the same time, I realize that every success of the journal originates from the great contributions and support from numerous authors, scholars, and readers around the world. Thank you all for making the journal an important place to share scholarly information about STEM education and research!As summarized and discussed above, the Last but not least, I want to take this opportunity to thank all members of the journal’s editorial board, and staff members at SpringerOpen, for their dedicated support. It is a great pleasure to work together with them.


Yersinia pestis), PgtE , SopA (Shigella flexneri), OmpT, and OmpP (Escherichia coli), confirmed their high cross-homology with respect to the identified epitope clusters and possible involvement of individual epitopes in host–pathogen interaction.Omptins represent a family of proteases commonly found in various Gram-negative pathogens. These proteins play an important role in host–pathogen interaction and have been recognized as key virulence factors, highlighting the possibility of developing an omptin-based broad-spectrum vaccine. The prototypical omptin, His-tagged recombinant Pla, was used as a model target antigen. In total, 46 linear and 24 conformational epitopes for the omptin family were predicted by the use of ElliPro service. Among these we selected highly conserved, antigenic, non-allergenic, and immunogenic B-cell epitopes. Five epitopes  could be the first choice for the development of the new generation of target-peptide-based vaccine against plague. The partial residues of omptin epitopes 6, 8, and 10  could be promising targets for the multi-pathogen vaccine against a group of enterobacterial infections. The comparative analysis and 3D modeling of amino acid sequences of several omptin family proteases, such as Pla ( Currently, infectious diseases (IDs) are responsible for about 30% of global human mortality per year ,2. They It is considered that vaccines have achieved extraordinary success in the history of public health, yielding substantial reductions in worldwide morbidity and mortality from IDs over the past half century ,9. This Among a number of different types of vaccines, the WHO recognizes four main types, categorized by the antigen used in their preparation: (i) live attenuated (LAV); (ii) inactivated (killed antigen); (iii) subunit (purified antigen); and (iv) toxoid (inactivated toxins). Further, vaccines may be classified as: (i) monovalent, containing a single antigen to protect against a particular ID); (ii) polyvalent, containing two or more variants of the same antigen aiming to protect against a distinct ID; and (iii) combination vaccine, consisting of several individual specific antigens combined in a single injection to prevent the relevant target diseases or to protect against multiple strains of infectious agents causing the same disease . UnfortuA number of pathogens enter the body via mucosal surfaces using airways, intestines, etc., overcoming innate immunity to establish the infection. This highlights the necessity to induce an efficient mucosal immune response, which is critically important for protection against IDs caused by both foodborne (enteric) and airborne pathogens. Th1 and Th17 cell-mediated immune responses play a critical role in the induction of accelerated and efficient mucosal immune responses. Moreover, the induction of Th17 polarization elicits a protective effect directed to outer membrane proteins (OMPs), providing clade-specific serovar-independent immunity including encapsulated bacteria . Thus, tSalmonella, Shigella, Escherichia coli, and Yersinia pestis. These microbes infect both humans and animals and are associated with high levels of morbidity and mortality, an increased emergence of multidrug-resistant strains, as well as with the need to cover protection against different serovars [Understanding the epitope–antibody interaction is the key for the construction of potent vaccines. B-cell epitope mapping is a promising approach for identifying the main antigenic determinants of microorganisms. Epitope-based vaccines have a remarkable advantage over the conventional ones, since they are safe, strictly specific, able to avoid undesirable immune responses, generate long-lasting immunity, and are reasonably cheaper . In factserovars .For this purpose, we investigated the omptins family of outer membrane proteases commonly found in these pathogens that are also known as omptin-expressing bacterial species . These pn = 18) who received multiple annual immunizations with LPV and unvaccinated healthy individuals (n = 6) who had never been in contact with either Y. pestis or its antigens participated in the study. Unvaccinated donors including those who had an anamnestic immune response proved their possible previous history of enteric bacterial infections.A detailed protocol of this study has been published, describing the study design, study population, and methods including consenting procedures, assessment of immune-serological B-cells, and T-cells immune responses of human donors vaccinated with LPV as well as non-vaccinated donors ,29,30. OThe study was conducted in compliance with the Declaration of Helsinki and the regulatory requirements of the Russian Federation. Study protocols were approved by the Institutional Review Board of The Saratov State Medical University named after V. I. Razumovsky  #: FWA00009567). Signed written informed consent was obtained from all participants.Y. pestis CO92), OmpT and OmpP (E. coli), PgtE , and SopA (Shigella flexneri) were downloaded from GenBank (https://www.ncbi.nlm.nih.gov/genbank/). The sequence retrieval accession numbers for each individual omptin along with other information are listed in The sequences of the omptin proteins, including Pla (http://tools.immuneepitope.org/toolsElliPro/) using both protein sequences and structural information for each omptin.B-cell epitopes were predicted using ElliPro  and rendered in POV-Ray v. 3.7. (http://www.povray.org/), based on alignments of the amino acid sequences of Pla, OmpP, OmpT, PgtE, and SopA.Ribbon diagram models of the three-dimensional (3D) structures of the omptin protein family were generated with Swiss-PdbViewer/DeepView v. 4.1  was made by GenScript, Piscataway, NJ, USA as described recently .http://crdd.osdd.net), AllerTOP v. 2.0 (http://www.ddg-pharmfac.net/AllerTOP), and ANTIGENpro [http://scratch.proteomics.ics.uci.edu/) services were used for prediction of allergenicity (AlgPred and AllerTop) and antigenicity (ANTIGEN).AlgPred  , SopA (Shigella flexneri), and OmpT and OmpP (E. coli) revealed the location of predicted linear B-cell epitopes in either identical positions or in a very close proximity to all nine Pla epitopes predicted by ElliPro and identified serologically using human anti-Pla antisera [Overall, ElliPro predicted 46 linear and 24 conformational epitopes for the omptin family . The subantisera . Linear The predicted immuno-reactivity potency of the B-cell linear epitopes were tested and validated by their mapping with the use of a panel of human sera positive in ELISA and immunoblotting for the presence of antibodies to Pla at a detectable level ,29,30. FThese immuno-reactive peptides were grouped into four separate clusters of peptides, suggesting the presence of four major reactive regions within the pro-omptin molecule . These iThe subsequent comparative analysis of the sequences of these four clusters of the pro-omptin Pla with other omptin family proteases revealed their cross-homology in the range of 26.6%–84.0% . The higThe epitopes specific for either Pla alone or the remaining four omptins were selected based on the positive reaction with human sera derived from either vaccinated or unvaccinated donors. Thus, in total there were five epitopes and certain regions of the epitopes specific for Pla only  and eight epitopes and their particular regions specific for other omptins . In fact, at least three complete epitopes  were found to be specific for all five omptins.We visualized the location of immunoreactive clusters identified during the screening of the omptin peptide sequences ias an the 3D models of different omptins. The comparison of the ribbon diagrams of the 3D models showed high similarity between the omptin structures . All fouAll five omptins tested were predicted to be non-allergenic while possessing antigenic activity . HoweverFinally, all five Pla-specific epitopes were predicted to be non-allergic while the other omptin-specific epitopes 1, 9, and 11 could potentially produce allergic reaction against a single omptin epitope . Thus, tShigella  [Salmonella (the genus includes more than 2400 serovars) [E. coli (pathogenic bacteria are categorized into six pathotypes) [Y. pestis Pla, was chosen for the following reasons: (i) the antigen is a surface-located outer-membrane integral protease with high similarity in 3D structure to other omptin family members [Y. pestis during the course of evolution [Y. pestis into circulation and is known as one of the major virulence determinants of this pathogen [Y. pestis at 26 °C [Y. pestis lacking capsular antigen F1 [Klebsiella pneumonia that could be approximated to other omptin-expressing pathogens. Indeed, based on a computer structural 3D model  , Salmoneerovars) , and E. hotypes)  significhotypes) . Here, wvolution ,38,39; pathogen ; (v) Plaat 26 °C . Importaat 26 °C , in miceat 26 °C , and in at 26 °C ,28,29,30at 26 °C ,47. Impotigen F1 ,49. Thistigen F1 ,51, becatigen F1 . Also, ctigen F1 ,21. Thistigen F1  on the m3D model  all immundidates .In conclusion, our data suggest excellent progress in the prompt development of a peptide-based vaccine against plague and other enteropathogenic IDs. We also suggest that it could be a single vaccine for multiple pathogens with improved characteristics due to the presence of predicted non-allergenic epitopes. These epitopes could be further evaluated in immunologic and protective studies to assess their potency as promising components of an effective broad-spectrum synthetic mucosal omptin-based peptide vaccine against omptin-expressing pathogens.


To assess if the administration of gadoxetate disodium (Gd-EOB-DTPA) significantly affects hepatic magnetic resonance elastography (MRE) measurements in the delayed hepatobiliary phase (DHBP).A total of 47 patients  were assigned to standard hepatic magnetic resonance imaging (MRI) with application of Gd-EOB-DTPA and hepatic MRE. MRE was performed before injection of Gd-EOB-DTPA and after 40–50 min in the DHBP. Liver stiffness values were obtained before and after contrast media application and differences between pre- and post-Gd-EOB-DTPA values were evaluated using a Bland-Altman plot and the Mann-Whitney-Wilcoxon test. In addition, the data were compared with regard to the resulting fibrosis classification.p < 0.001) with no significant difference between the two measurements (p =0.49)). Bland-Altman plot did not show a systematic effect for the difference between pre- and post-stiffness measurements . Regarding the classification of fibrosis stages, the overall agreement was 87.23% and the intraclass correlation coefficient was 96.4%, indicating excellent agreement.Mean hepatic stiffness for pre-Gd-EOB-DTPA measurements was 4.01 kPa and post-Gd-EOB-DTPA measurements yielded 3.95 kPa. We found a highly significant individual correlation between pre- and post-Gd-EOB-DTPA stiffness values (Pearson correlation coefficient of r = 0.95 (Administration of Gd-EOB-DTPA does not significantly influence MRE stiffness measurements of the liver in the DHBP. Therefore, MRE can be performed in the DHBP.• MRE of the liver can reliably be performed in the delayed hepatobiliary phase.• Gd-EOB-DTPA does not significantly influence MRE stiffness measurements of the liver.• MRE performed in the delayed hepatobiliary-phase is reasonable in patients with reduced liver function. Magnetic resonance elastography (MRE) is increasingly used to obtain information regarding tissue stiffness, particularly of the liver, and is comparable to the performance of ‘virtual palpation’ . MRE hasThe liver-specific contrast medium gadoxetate disodium (Gd-EOB-DTPA), also known as Primovist in Europe or Eovist in North America (Bayer Schering Pharma AG), is widely used and has outstanding benefits for liver evaluation . It alloThe purpose of our study was to assess if Gd-EOB-DTPA administration affects hepatic MRE measurements in DHBP. Therefore, we compared hepatic MRE results for each patient before and after Gd-EOB-DTPA administration.We retrospectively enrolled 47 patients referred to our department  between August 2016 and January 2017 from the gastroenterological department to perform a standardised hepatic MRI, including Gd-EOB-DTPA administration with DHBP imaging and hepatic MRE. Inclusion criteria were a minimum age of 18 years as well as an entirely performed hepatic MRI protocol  with an 18-channel body phased-array surface coil. The succession of sequences used for our hepatic MRI protocol is shown in Tables Patients received 10 ml of Gd-EOB-DTPA via manual injection through a peripheral intravenous line inserted at the cubital fossa or forearm, with an approximate injection rate of 1.5–2.0 ml/s, followed by a 20-ml saline flush. Hepatic MRE was performed before and 40–50 min after Gd-EOB-DTPA administration (i.e. in DHBP). Mechanical 60-Hz vibrations were applied using a circular passive acoustic driver  placed against the right abdominal wall and fixed using an elastic band. A two-dimensional commercial phase-contrast gradient-echo (GRE) sequence as provided by the manufacturer was applied, which performs inline calculation of wave and stiffness images together with a 95% confidence map showing areas with less reliable stiffness crossed out . For eveTo assess the hepatic iron state a commercially available 3D multi-echo gradient (GRE) sequence (t1 vibe q-dixon) was used .For each patient, all three transverse hepatic MRE slices before and after Gd-EOB-DTPA administration were evaluated. Stiffness values were reported in kPa units. An as large as possible polygonal region of interest (ROI) was selected in the liver parenchyma of every transverse section within the 95% confidence region of the acquired stiffness maps. Manual ROI placement was carefully performed by one radiologist with over 6 years’ experience in liver imaging (PM) examining wave images for proper wave propagation and using the magnitude image to avoid major vessels, liver surface and artefacts . For further analysis, the mean values of the three polygonal ROIs were used. Patients were classified by the authors into four fibrosis stages according to their mean stiffness value, based on values from the actual literature , 11: F0 p-values of <0.05. To determine the correlation between pre- and post-Gd-EOB-DTPA MRE data, Pearson’s correlation coefficient was calculated, and the data were compared using a Bland–Altman plot. To determine the agreement between fibrosis staging data before and after Gd-EOB-DTPA administration, contingency tables were created; Pearson’s chi-squared test was performed, and overall agreement, as well as the Cohen’s Kappa coefficient with equal weights and the two-way intraclass correlation coefficient was calculated using the irr-package for R [Statistical calculations were performed using the R Project for Statistical Computing . The Shage for R .A total of 47 patients  were enrolled in this study. All patients had the clinical suspicion of impaired liver function: 14/47 patients were transferred post-liver transplantation, 14/47 had unclear, suspicious liver lesions and 19/47 patients suffered from diffuse liver injury including cirrhosis, fibrosis, iron overload or primary sclerosing cholangitis. Of all patients only one was found to have minimal iron overload (R2* of 102 1/s).2 . The mean hepatic stiffness values of all pre- and post-Gd-EOB-DTPA ROI measurements were 4.01 kPa  and 3.95 kPa , respectively . The Bland–Altman plot .The individual correlation between pre- and post-Gd-EOB-DTPA stiffness values is shown in Fig. lot Fig.  did not p < 0.001) and the two-way intraclass correlation coefficient was 0.96 , indicating excellent agreement. Overall, the obtained fibrosis stage deviated between pre- and post-Gd-EOB-DTPA measurements in only six patients. The individual mean stiffness values for these patients are listed in Table The classification of patients according to their mean stiffness values into different fibrosis stages led to the following results for pre-Gd-EOB-DTPA measurements: 15 patients were classified as stage F0 ; seven as stage F1; 13, stage F2; seven, stage F3; and five, stage F4. Regarding the post-Gd-EOB-DTPA data, 12 patients were classified as stage F0; 11, stage F1; 12, stage F2; seven, stage F3; and five, stage F4. The resulting contingency table is presented as Table Typical exemplary stiffness maps are shown in Figs. Hepatic MRI with Gd-EOB-DTPA administration is a standard imaging procedure for the assessment of various hepatic conditions . The addp < 0.001), with no significant differences between the two values (p = 0.49). Furthermore, no systematic effect was observed for the difference between pre- and post-stiffness measurements  using the Bland–Altman plot.Our results indicate a high, significant correlation between pre- and post-Gd-EOB-DTPA stiffness values  the administration in the DHBP. By this time, Gd-EOB-DTPA has entirely been taken up by the hepatocytes, increasing the T1 relaxation and raising the normal liver signal intensity, which may theoretically influence the stiffness measurements . HalinanOwing to its structure, Gd-EOB-DTPA is rapidly absorbed at a high dose by hepatocytes, leading to better visualisation of normal hepatic tissue through parenchymal enhancement . Some stFor MRE, motion encoding gradients are used, leading to prolonged echo times and consequently to decreased image quality in case of T2 or T2* reduction, as for example is the case for iron overload . TherefoOur study has some limitations that must be addressed. First, our study population was rather small compared with those of other studies. Furthermore, some conditions, e.g. inflammation, congestion, portal hypertension and cholestasis, can also cause increased liver stiffness . Kim et In conclusion, Gd-EOB-DTPA administration does not significantly influence hepatic MRE stiffness measurements in the DHBP, 40–50 min after contrast medium administration. Therefore, for daily clinical routine, hepatic MRE measurements can reliably be performed at any time in the DHBP.


An appropriate initial pH facilitated the formation of diester bonds between HPAS and citric acid during extrusion, but too low initial pH levels resulted in hydrolysis of starch molecules and reduced the mechanical properties.Hydroxypropyl amylomaize starch (HPAS) films were prepared by hot press. The effects of initial pH of HPAS on the mechanical properties, molecular interaction, structure, and cross-linking degree of the resultant films were investigated. A weak acidic condition was suitable for cross-linking of citric acid and HPAS by reactive extrusion. The film of HPAS with an initial pH of 5.66 had the maximum tensile strength of 7.20 MPa and elongation-at-break of 94.53%, and the weight average molecular weight of HPAS increased to 4.17 × 10 Starches are promising materials for the preparation of biodegradable plastic and their industrial application can reduce the environmental costs of petroleum-derived materials . ThermopHowever, the poor processability of starch is one of the main reasons that limited the application of starch film. Natural starch granule has a hierarchical periodic structure formed by alternating amorphous and semicrystalline growth rings . This unSome studies have shown that the films prepared from amylomaize starch had higher tensile strength than those from normal maize starch ,7. NeverBy disrupting the hydrogen bonds in the starch granules, hydroxypropyl groups render amylomaize starch more likely to gelatinize at lower temperature  with betCitric acid (CA) is a trifunctional carboxylic acid and has been used in the production of cross-linked starch . The addIn this study, hydroxypropyl high amylomaize starch with non-neutralized sodium hydroxide has been used as film-forming initial material. Different amounts of citric acid were added as acid to adjust the pH of hydroxypropyl high amylomaize starch and cross-linking agent to prepare cross-linking starch by reactive extrusion. The effects of different citric acid amounts on the properties of hydroxypropyl high amylomaize starch film have been investigated. The mechanism of performance improvement of hydroxypropyl high amylomaize starch films with citric acid had been discussed. Amylomaize starch with 70% amylose was purchased from Ingredion China Limited . Dimethyl sulfoxide (DMSO), citric acid, and glycerol (AR) were purchased from Tianjin Kaitong Chemical Reagent Co., Ltd. . Deionized water was prepared using an AK Exceed-D lab pure water system . High amylomaize starch was mixed with 2% NaOH powder (based on dry starch mass) for 5 min at room temperature. Then, 25% anhydrous ethanol and 10% epoxypropane (based on dry starch mass) were slowly added into the mixture in a reactor. The reactor was heated up to 80 °C by steam and mechanically stirred for 4 h. The hydroxypropyl high amylomaize starch with degree of substitution of 0.3 was obtained after cooling to room temperature. The hydroxypropyl high amylomaize starch was not neutralized after hydroxypropylation and the pH was 10.92 for 1% suspension. A certain amount of citric acid was dissolved in glycerol. Non-neutralized hydroxypropyl amylomaize starch was thoroughly mixed with citric acid–glycerol solution in a SHR-50A high-speed mixer . The 1 g mixture of hydroxypropyl amylomaize starch, glycerol and citric acid was dispersed in 100 mL deionized water and stirred for 30 min at room temperature. The pH of the suspension was determined by FE-20 pH Meter . The sample codes and relevant sample information were presented in Thermoplastic HPAS-CA composite was obtained by extrusion using a SHJ-20B co-rotating twin-screw extruder . The extruder barrel temperature profile was 85-90-100-105-100-95 °C from the feeder to the die end. The screw rotation speed was 150 rpm. The thermoplastic HPAS-CA composite was cut into pellets after cooling to room temperature.A hot press technique was used to prepare the HPAS-CA films. About 16 g of the thermoplastic HPAS-CA pellets was placed between two 20 cm × 20 cm stainless steel plates completely covered with a tetrafluoroethylene sheet at 120 °C for 2 min. The pressure was then raised and held at 10 MPa for an additional 7 min. To reduce the thickness of the films, a pressure of 30 MPa was applied for 5 min, after which the mold was cooled to 35 °C using cold water circulation. The HPAS-CA films were stored in an HWS-60 constant temperature and humidity chamber  at 23 °C and 53% relative humidity for 72 h.The degree of diesterification (DDE) between citric acid and HPAS was determined based on the complexometric titration of citric acid with copper (II)-sulfate . Two indThe HPAS-CA film of 300 mg was cut into pieces, and totally dissolved either in 50 mL of deionized water or in 50 mL of 0.1 M KOH for 20 min in a boiling water bath. The pH of the solutions was then adjusted to 8.5 with acetic acid and borax/boric acid buffers at room temperature. The solution was made up to 250 mL and titration was carried out with 0.02 M copper sulfate where in 1 mL of copper (II) solution consumed 3.842 mg of citric acid. Murexide  was used as the indicator. The difference between the titration of the two film solutions enabled the calculation of DDE and diester proportion of total citric acid . All meaThe thicknesses of the HPAS-CA nanocomposite films were determined using 211-101F micrometers . All the films were tested randomly, and the thicknesses of the HPAS-CA films were calculated by averaging the results of six replicate measurements.The tensile strength  and elongation-at-break  of the HPAS-CA films were determined with an XLW (PC) Auto Tensile Tester  in accordance with ASTM D882-12 . Each tr−1. The number of accumulated scans and the scanning rate were 32 and 4 cm−1, respectively. To better identify the vibrations of hydroxypropyl high amylomaize starch and citric acid that significantly overlap with one another, differential spectra and deconvolution were performed at the bands that are relative to the hydroxypropyl high amylomaize starch short-range order structure and esterification between hydroxypropyl high amylomaize starch and citric acid using Peakfit software version 4.0 .Fourier-transform infrared (FT-IR) analysis was performed on the HPAS-CA films using a Nicolet iS 5 spectrometers with an attenuated total reflectance (ATR) accessory  over a wavenumber range of 4000 to 400 cm13C solid-state nuclear magnetic resonance (13C SSNMR) was performed using a Bruker Avance III 400 MHz wide bore spectrometer  equipped with a 4-mm broadband double-resonance cross-polarized magic angle spinning probe. Each film (500 mg) was placed onto the rotor and introduced to the center of a magnetic field. The spectra were decomposed using the Peakfit software.The One milligram of HPAS-CA film was dissolved into 1 mL dimethyl sulfoxide (DMSO) with 50 mM LiCl and stirred for 2 h at 90 °C. The solution was then magnetic-stirred for 8 h at room temperature and filtered through a 1.0-μm nylon-66 Millipore filter .w) of HPAS-CA film using a BI-200SM research goniometer and laser light scattering system . The light source was a laser (λ = 633 nm). The dn/dc value was 0.147. The tests of SLS were performed in the angle range of 30 to 140° in steps of 5°. The Mw of the various HPAS-CA films were calculated using the Berry method.Static light scattering (SLS) was employed to measure the weight average molecular weight  FEI QUANTA FEG25 . The surfaces were vacuum coated with gold for SEM and the magnification was 2000 times.The crystallinity and crystal structure of the HAS film were tested by X-ray diffraction (XRD) using a D8 Advance X-ray diffractometer . The Cu target line was used, λ = 0.15406 nm, 2θ = 5–40°, and the step frequency was 0.02°/s.The data in tables and figures are represented in terms of mean values ± standard deviation (SD). Any significant differences in the group mean values, at the 95% significance level, were tested using analysis of variance (ANOVA), followed by post-hoc Duncan’s multiple range tests using SPSS software 21 .With the decrease of initial pH of hydroxypropyl high amylomaize starch, the appearance of starch film changed from brown to colorless . The preThe elongation at break (EAB) values of the HPAS-CA films slightly changed with different initial pH of starch . HoweverThe thickness of HPAS-CA films significantly decreased with the decrease of the initial pH of starch. As the mass of the pellets and the processing parameters of hot press were identical across all samples, the addition of citric acid appeared to soften the thermoplastic hydroxypropyl high amylomaize starch, rendering it easier to be pressed into films . The HPAThe morphology of HPAS-CA films is shown in The XRD patterns of HPAS-CA films with different pH values are shown in −1, correlating with sodium citrate, ester group, including monoester and diester, formed by hydroxypropyl high amylomaize starch and citric acid, and carboxyl group [ATR-FTIR spectroscopy was employed to investigate the interactions between hydroxypropyl high amylomaize starch and citric acid in HPAS-CA films. Although all the films had similar spectra, differences appeared mainly in two zones . Zone I yl group ,28.−1. The peak at 1732 cm−1 could be attributed to the esterification between citric acid and hydroxypropyl high amylomaize starch during reactive extrusion [−1 correlated with a carboxylate–metal ion interaction, including CA−, CA2−, and CA3− [−1 had a significantly decreased that could be suspected as the citric acid molecular changed from fully deprotonated to doubly protonated. The strong peak at 1577 cm−1 in the spectrum of the HPAS-8.68 film  were correlated with the stretching peaks of C–C and C–O in the starch molecule, which was sensitive to changes in the short-range structure during extrusion and hot pressing [−1. After extrusion and esterification between citric acid and hydroxypropyl high amylomaize starch, the weakening of the interaction between the starch molecules resulted in the C–OH peak shifting to 1018 cm−1 [−1, which should be located at 1047 cm−1 in an intact starch molecule, represented the organized part of the starch in the HPAS-CA film. The ordered and amorphous starch structure at short range was measured by the ratio of the intensity of the peak at 1039 cm−1 to that at 1018 cm−1 (R1039/1018)  . As the id films . HoweverIn all the HPAS-CA films, the proportion of diester ranged from 2.57% to 21.45% of the total citric acid . The HPAw of HPAS-CA films . The ordered spectrum at the C1 peak could be resolved into the single helix V-type component (102–103 ppm) and the double helices component (99–102 ppm). The spectrum at the C4 peak was related to the amorphous structure of the HPAS-CA films. The relative proportions of single helix, double helices, and amorphous structures in the six kinds of the HPAS-CA films are shown in The ch other . The regd starch . Althougow field . The proCompared to HPAS-10.92 film, the HPAS-8.68 film had greater amorphous area and double helices but lower single helix area. This indicates that the addition of citric acid neutralized the alkali which might play a role in transforming the double helices structures into single helix ones . The citThe cross-linking reaction between citric acid and hydroxypropyl high amylomaize starch was achieved by reactive extrusion while preparing thermoplastic starch. The HPAS-CA film with initial pH at 5.66 had tensile strength at 7.20 MPa and elongation at break at 94.53%. The tensile strength of the film had an obvious decrease as the pH decreased. Citric acid would prefer neutralize NaOH at alkaline condition and promoted the gelatinization of hydroxypropyl high amylomaize starch during reactive extrusion. The weak acid condition would be more suitable for esterification and produce diester cross-linked structure between hydroxypropyl high amylomaize starch and citric acid and reinforced the film. The acidolysis was enhanced as pH further decreased which degraded starch molecule and reduced the properties of starch film.


Dear Sir,Split-thickness skin grafts are commonly used to resurface wounds in plastic surgery. Surgical staples are a quick way to secure the graft to the wound bed and facilitate take. Despite these advantages, the process of removing staples can cause inadvertent trauma to the newly inset, fragile graft. We describe a novel method where a 4-mm biopsy punch is used to cut 3 holes in series at the bottom of a polypropylene gallipot placed upon a hard surface . This pe


Concerns have been raised that the transplants performed in the local context at the time of procedures reported in this article  may haveDetails as to the donor sources and methods of obtaining informed consent from donors were not reported in , and theIn addition, the authors did not provide documentation when requested by the journal to confirm that the study had institutional ethics approval, and they did not respond to inquiries about the availability of underlying data supporting this study.PLOS ONE Editors retract this article.Owing to the lack of documentation to demonstrate this study had prospective ethical approval, insufficient reporting, unresolved concerns around the source of transplanted organs and whether they included organs from prisoners, and in compliance with international ethical standards for organ/tissue donation and transplantation, the The authors did not respond to the retraction notification.


Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14750. Nuclear hormone receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands ( They regulate (either promoting or repressing) transcription of these target genes in response to a variety of endogenous ligands. Endogenous agonists are hydrophobic entities which, when bound to the receptor promote conformational changes in the receptor to allow recruitment (or dissociation) of protein partners, generating a large multiprotein complex.Two major subclasses of nuclear receptors with identified endogenous agonists can be identified: steroid and non‐steroid hormone receptors. Steroid hormone receptors function typically as dimeric entities and are thought to be resident outside the nucleus in the unliganded state in a complex with chaperone proteins, which are liberated upon agonist binding. Migration to the nucleus and interaction with other regulators of gene transcription, including RNA polymerase, acetyltransferases and deacetylases, allows gene transcription to be regulated. Non‐steroid hormone receptors typically exhibit a greater distribution in the nucleus in the unliganded state and interact with other nuclear receptors to form heterodimers, as well as with other regulators of gene transcription, leading to changes in gene transcription upon agonist binding.Selectivity of gene regulation is brought about through interaction of nuclear receptors with particular consensus sequences of DNA, which are arranged typically as repeats or inverted palindromes to allow accumulation of multiple transcription factors in the promoter regions of genes.NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors ) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2635) and thyroid hormone (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2634). Once activated by a ligand, the receptor acts as a transcription factor either as a monomer, homodimer or heterodimer with members of the retinoid X receptor family. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2633 has been described as an antagonist at TRs with modest selectivity for TRβ [http://www.ncbi.nlm.nih.gov/pubmed/12109914?dopt=AbstractPlus].Thyroid hormone receptors  Thyroid Hormone Mimetics: the Past, Current Status and Future Challenges. Curr Atheroscler Rep18: 14 https://www.ncbi.nlm.nih.gov/pubmed/26886134?dopt=AbstractPlusElbers LP et al. (2006) International Union of Pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol. Rev. 58: 705‐11 https://www.ncbi.nlm.nih.gov/pubmed/17132849?dopt=AbstractPlusFlamant F et al. (2017) New insights into thyroid hormone action. Pharmacol. Ther. 173: 135‐145 https://www.ncbi.nlm.nih.gov/pubmed/28174093?dopt=AbstractPlusMendoza A NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [nomenclature as agreed by the http://www.ncbi.nlm.nih.gov/pubmed/17132850?dopt=AbstractPlus]) are nuclear hormone receptors of the NR1B family activated by the vitamin A‐derived agonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2644 (ATRA) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2645, and the RAR‐selective synthetic agonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2646 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5429. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2641 is a family‐selective antagonist [http://www.ncbi.nlm.nih.gov/pubmed/19477412?dopt=AbstractPlus].Retinoic acid receptors  The molecular physiology of nuclear retinoic acid receptors. From health to disease. Biochim. Biophys. Acta1812: 1023‐31 [https://www.ncbi.nlm.nih.gov/pubmed/20970498?dopt=AbstractPlus]Duong V et al. (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol. Rev. 58: 712‐25 https://www.ncbi.nlm.nih.gov/pubmed/17132850?dopt=AbstractPlusGermain P et al. (2016) Retinoic Acid and Retinoic Acid Receptors as Pleiotropic Modulators of the Immune System. Annu. Rev. Immunol. 34: 369‐94 https://www.ncbi.nlm.nih.gov/pubmed/27168242?dopt=AbstractPlusLarange A et al. (2017) The interrelationship between bile acid and vitamin A homeostasis. Biochim. Biophys. Acta1862: 496‐512 https://www.ncbi.nlm.nih.gov/pubmed/28111285?dopt=AbstractPlusSaeed A PPARs, nomenclature as agreed by theNC‐IUPHARSubcommittee on Nuclear Hormone Receptors [http://www.ncbi.nlm.nih.gov/pubmed/17132851?dopt=AbstractPlus]) are nuclear hormone receptors of the NR1C family, with diverse roles regulating lipid homeostasis, cellular differentiation, proliferation and the immune response. PPARs have many potential endogenous agonists , including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1877, prostacyclin (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1915), many fatty acids and their oxidation products, lysophosphatidic acid (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2906) [http://www.ncbi.nlm.nih.gov/pubmed/12502787?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5426, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3401, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5427, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5428 and leukotriene B4 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2487). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2668 acts as a non‐selective agonist for the PPAR family [http://www.ncbi.nlm.nih.gov/pubmed/10691680?dopt=AbstractPlus]. These receptors also bind hypolipidaemic drugs (PPARα) and anti‐diabetic thiazolidinediones (PPARγ), as well as many non‐steroidal anti‐inflammatory drugs, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5425 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1909. Once activated by a ligand, the receptor forms a heterodimer with members of the retinoid X receptor family and can act as a transcription factor. Although radioligand binding assays have been described for all three receptors, the radioligands are not commercially available. Commonly, receptor occupancy studies are conducted using fluorescent ligands and truncated forms of the receptor limited to the ligand binding domain.Peroxisome proliferator‐activated receptors . Agonists with mixed activity at PPARα and PPARγ have also been described .As with the estrogen receptor antagonists, many agents show tissue‐selective efficacy  The peroxisome proliferator‐activated receptors in cardiovascular diseases: experimental benefits and clinical challenges. Br. J. Pharmacol. 172: 5512‐22 [https://www.ncbi.nlm.nih.gov/pubmed/25438608?dopt=AbstractPlus]Cheang WS et al. (2017) PPARs in obesity‐induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol13: 36‐49 [https://www.ncbi.nlm.nih.gov/pubmed/27636730?dopt=AbstractPlus]Gross B et al. (2016) The elusive endogenous adipogenic PPARγ agonists: Lining up the suspects. Prog. Lipid Res. 61: 149‐62 [https://www.ncbi.nlm.nih.gov/pubmed/26703188?dopt=AbstractPlus]Hallenborg P et al. (2006) International Union of Pharmacology. LXI. Peroxisome proliferator‐activated receptors. Pharmacol. Rev. 58: 726‐41 [https://www.ncbi.nlm.nih.gov/pubmed/17132851?dopt=AbstractPlus]Michalik L Trends Pharmacol. Sci. 36: 688‐704 [https://www.ncbi.nlm.nih.gov/pubmed/26435213?dopt=AbstractPlus]Sauer S. (2015) Ligands for the Nuclear Peroxisome Proliferator‐Activated Receptor Gamma. nomenclature as agreed by theNC‐IUPHARSubcommittee on Nuclear Hormone Receptors [http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]) have yet to be officially paired with an endogenous ligand, but are thought to be activated by heme.Rev‐erb receptors  International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 [https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]Benoit G et al. (2015) Nuclear receptors in acute and chronic cholestasis. Dig Dis33: 357‐66 [https://www.ncbi.nlm.nih.gov/pubmed/26045270?dopt=AbstractPlus]Gonzalez‐Sanchez E et al. (2015) Emerging models for the molecular basis of mammalian circadian timing. Biochemistry54: 134‐49 [https://www.ncbi.nlm.nih.gov/pubmed/25303119?dopt=AbstractPlus]Gustafson CL et al. (2017) Drug discovery targeting heme‐based sensors and their coupled activities. J. Inorg. Biochem. 167: 12‐20 [https://www.ncbi.nlm.nih.gov/pubmed/27893989?dopt=AbstractPlus]Sousa EH nomenclature as agreed by theNC‐IUPHARSubcommittee on Nuclear Hormone Receptors [http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]) have yet to be assigned a definitive endogenous ligand, although RORα may be synthesized with a ‘captured’ agonist such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2718 .Retinoic acid receptor‐related orphan receptors  International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 [https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]Benoit G et al. (2016) Recent progress on nuclear receptor RORγ modulators. Bioorg. Med. Chem. Lett. 26: 4387‐4393 [https://www.ncbi.nlm.nih.gov/pubmed/27542308?dopt=AbstractPlus]Cyr P et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685‐704 [https://www.ncbi.nlm.nih.gov/pubmed/17132848?dopt=AbstractPlus]Germain P et al. (2016) Oxysterols in Metabolic Syndrome: From Bystander Molecules to Bioactive Lipids. Trends Mol Med22: 594‐614 [https://www.ncbi.nlm.nih.gov/pubmed/27286741?dopt=AbstractPlus]Guillemot‐Legris O et al. (2016) Oxysterols: From cholesterol metabolites to key mediators. Prog. Lipid Res. 64: 152‐169 [https://www.ncbi.nlm.nih.gov/pubmed/27687912?dopt=AbstractPlus]Mutemberezi V nomenclature as agreed by theNC‐IUPHARSubcommittee on Nuclear Hormone Receptors [http://www.ncbi.nlm.nih.gov/pubmed/17132852?dopt=AbstractPlus]) are members of a steroid analogue‐activated nuclear receptor subfamily, which form heterodimers with members of the retinoid X receptor family. Endogenous ligands for LXRs include hydroxycholesterols (OHC), while FXRs appear to be activated by bile acids. In humans and primates, NR1H5P is a pseudogene. However, in other mammals, it encodes a functional nuclear hormone receptor that appears to be involved in cholesterol biosynthesis [http://www.ncbi.nlm.nih.gov/pubmed/12529392?dopt=AbstractPlus].Liver X and farnesoid X receptors  LXR Regulation of Brain Cholesterol: From Development to Disease. Trends Endocrinol. Metab. 27: 404‐414 [https://www.ncbi.nlm.nih.gov/pubmed/27113081?dopt=AbstractPlus]Courtney R et al. (2018) Recent Advances in the Medicinal Chemistry of Liver X Receptors. J. Med. Chem. 61: 10935‐10956 [https://www.ncbi.nlm.nih.gov/pubmed/30004226?dopt=AbstractPlus]El‐Gendy BEM et al. (2010) Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease. Biochim. Biophys. Acta1801: 683‐92 [https://www.ncbi.nlm.nih.gov/pubmed/20399894?dopt=AbstractPlus]Gadaleta RM et al. (2017) Bile acids and their receptors during liver regeneration: “Dangerous protectors”. Mol. Aspects Med. 56: 25‐33 [https://www.ncbi.nlm.nih.gov/pubmed/28302491?dopt=AbstractPlus]Merlen G et al. (2006) International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor. Pharmacol. Rev. 58: 742‐59 [https://www.ncbi.nlm.nih.gov/pubmed/17132852?dopt=AbstractPlus]Moore DD et al. (2016) Liver X receptors: from cholesterol regulation to neuroprotection‐a new barrier against neurodegeneration in amyotrophic lateral sclerosis? Cell. Mol. Life Sci. 73: 3801‐8 [https://www.ncbi.nlm.nih.gov/pubmed/27510420?dopt=AbstractPlus]Mouzat K FEBS Lett. 591: 2978‐2991 [https://www.ncbi.nlm.nih.gov/pubmed/28555747?dopt=AbstractPlus]Schulman IG. (2017) Liver X receptors link lipid metabolism and inflammation. NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [nomenclature as agreed by the http://www.ncbi.nlm.nih.gov/pubmed/17132852?dopt=AbstractPlus]) are members of the NR1I family of nuclear receptors, which form heterodimers with members of the retinoid X receptor family. PXR and CAR are activated by a range of exogenous compounds, with no established endogenous physiological agonists, although high concentrations of bile acids and bile pigments activate PXR and CAR [http://www.ncbi.nlm.nih.gov/pubmed/17132852?dopt=AbstractPlus].Vitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors  International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlusBenoit G et al. (2015) Vitamin D receptor and RXR in the post‐genomic era. J. Cell. Physiol. 230: 758‐66 https://www.ncbi.nlm.nih.gov/pubmed/25335912?dopt=AbstractPlusLong MD et al. (2006) International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor. Pharmacol. Rev. 58: 742‐59 https://www.ncbi.nlm.nih.gov/pubmed/17132852?dopt=AbstractPlusMoore DD NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]. While linoleic acid has been identified as the endogenous ligand for HNF4α its function remains ambiguous [http://www.ncbi.nlm.nih.gov/pubmed/19440305?dopt=AbstractPlus]. HNF4γ has yet to be paired with an endogenous ligand.The nomenclature of hepatocyte nuclear factor‐4 receptors is agreed by the et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlusBenoit G et al. (2016) Lipid‐sensors, enigmatic‐orphan and orphan nuclear receptors as therapeutic targets in breast‐cancer. Oncotarget7: 42661‐42682 https://www.ncbi.nlm.nih.gov/pubmed/26894976?dopt=AbstractPlusGarattini E et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685‐704 https://www.ncbi.nlm.nih.gov/pubmed/17132848?dopt=AbstractPlusGermain P Acta Pharm Sin B6: 393‐408 https://www.ncbi.nlm.nih.gov/pubmed/27709008?dopt=AbstractPlusLu H. (2016) Crosstalk of HNF4α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids. et al. (2015) Role of hepatocyte nuclear factor 4α (HNF4α) in cell proliferation and cancer. Gene Expr. 16: 101‐8 https://www.ncbi.nlm.nih.gov/pubmed/25700366?dopt=AbstractPlusWalesky C NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [nomenclature as agreed by the http://www.ncbi.nlm.nih.gov/pubmed/17132853?dopt=AbstractPlus]) are NR2B family members activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2645 and the RXR‐selective agonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2807 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2808, sometimes referred to as rexinoids. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2816 [http://www.ncbi.nlm.nih.gov/pubmed/17947383?dopt=AbstractPlus] and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8079 [http://www.ncbi.nlm.nih.gov/pubmed/10748721?dopt=AbstractPlus] have been described as a pan‐RXR antagonists. These receptors form RXR‐RAR heterodimers and RXR‐RXR homodimers .Retinoid X receptors  International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol. Rev. 58: 760‐72 https://www.ncbi.nlm.nih.gov/pubmed/17132853?dopt=AbstractPlusGermain P et al. (2015) Vitamin D receptor and RXR in the post‐genomic era. J. Cell. Physiol. 230: 758‐66 https://www.ncbi.nlm.nih.gov/pubmed/25335912?dopt=AbstractPlusLong MD et al. (2017) The multi‐faceted role of retinoid X receptor in bone remodeling. Cell. Mol. Life Sci. 74: 2135‐2149 https://www.ncbi.nlm.nih.gov/pubmed/28105491?dopt=AbstractPlusMenéndez‐Gutiérrez MP NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [nomenclature as agreed by the http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]) have yet to be officially paired with an endogenous ligand, although testicular receptor 4 has been reported to respond to retinoids.Testicular receptors  International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlusBenoit G et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685‐704 https://www.ncbi.nlm.nih.gov/pubmed/17132848?dopt=AbstractPlusGermain P et al. (2014) Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol. Endocrinol. 28: 157‐72 https://www.ncbi.nlm.nih.gov/pubmed/24295738?dopt=AbstractPlusSafe S et al. (2016) The emerging roles of orphan nuclear receptors in prostate cancer. Biochim. Biophys. Acta1866: 23‐36 https://www.ncbi.nlm.nih.gov/pubmed/27264242?dopt=AbstractPlusWu D NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [nomenclature as agreed by the http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]) have yet to be officially paired with an endogenous ligand.Tailless‐like receptors  TLX: An elusive receptor. J. Steroid Biochem. Mol. Biol. 157: 41‐7 https://www.ncbi.nlm.nih.gov/pubmed/26554934?dopt=AbstractPlusBenod C et al. (2006) International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlusBenoit G et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685‐704 https://www.ncbi.nlm.nih.gov/pubmed/17132848?dopt=AbstractPlusGermain P et al. (2018) Regulation of behaviour by the nuclear receptor TLX. Genes Brain Behav. 17: e12357 https://www.ncbi.nlm.nih.gov/pubmed/27790850?dopt=AbstractPlusO’Leary JD NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [nomenclature as agreed by the http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]) have yet to be officially paired with an endogenous ligand.COUP‐TF‐like receptors  International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlusBenoit G et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685‐704 https://www.ncbi.nlm.nih.gov/pubmed/17132848?dopt=AbstractPlusGermain P et al. (2016) The emerging roles of orphan nuclear receptors in prostate cancer. Biochim. Biophys. Acta1866: 23‐36 https://www.ncbi.nlm.nih.gov/pubmed/27264242?dopt=AbstractPlusWu D etal. (2016) Choose your destiny: Make a cell fate decision with COUP‐TFII. J. Steroid Biochem. Mol. Biol. 157: 7‐12 https://www.ncbi.nlm.nih.gov/pubmed/26658017?dopt=AbstractPlusWu SP NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [nomenclature as agreed by the http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]) have yet to be officially paired with an endogenous ligand.Estrogen‐related receptors  International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlusBenoit G et al. (2016) Estrogen‐related receptor β (ERRβ) ‐ renaissance receptor or receptor renaissance? Nucl Recept Signal14: e002 https://www.ncbi.nlm.nih.gov/pubmed/27507929?dopt=AbstractPlusDivekar SD et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685‐704 https://www.ncbi.nlm.nih.gov/pubmed/17132848?dopt=AbstractPlusGermain P et al. (2016) There and back again: The journey of the estrogen‐related receptors in the cancer realm. J. Steroid Biochem. Mol. Biol. 157: 13‐9 https://www.ncbi.nlm.nih.gov/pubmed/26151739?dopt=AbstractPlusTam IS et al. (2016) The emerging roles of orphan nuclear receptors in prostate cancer. Biochim. Biophys. Acta1866: 23‐36 https://www.ncbi.nlm.nih.gov/pubmed/27264242?dopt=AbstractPlusWu D NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [nomenclature as agreed by the http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]) have yet to be officially paired with an endogenous ligand.Nerve growth factor IB‐like receptors  International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlusBenoit G etal. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685‐704 https://www.ncbi.nlm.nih.gov/pubmed/17132848?dopt=AbstractPlusGermain PJ. Recept. Signal Transduct. Res. 35: 184‐8 https://www.ncbi.nlm.nih.gov/pubmed/25089663?dopt=AbstractPlusRanhotra HS. (2015) The NR4A orphan nuclear receptors: mediators in metabolism and diseases. et al. (2017) The NR4A subfamily of nuclear receptors: potential new therapeutic targets for the treatment of inflammatory diseases. Expert Opin. Ther. Targets21: 291‐304 https://www.ncbi.nlm.nih.gov/pubmed/28055275?dopt=AbstractPlusRodríguez‐Calvo R et al. (2016) Nuclear receptor 4A (NR4A) family ‐ orphans no more. J. Steroid Biochem. Mol. Biol. 157: 48‐60 https://www.ncbi.nlm.nih.gov/pubmed/25917081?dopt=AbstractPlusSafe S NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [nomenclature as agreed by the http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]) have yet to be officially paired with an endogenous ligand.Fushi tarazu F1‐like receptors  International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlusBenoit G et al. (2016) Lipid‐sensors, enigmatic‐orphan and orphan nuclear receptors as therapeutic targets in breast‐cancer. Oncotarget7: 42661‐42682 https://www.ncbi.nlm.nih.gov/pubmed/26894976?dopt=AbstractPlusGarattini E et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685‐704 https://www.ncbi.nlm.nih.gov/pubmed/17132848?dopt=AbstractPlusGermain P et al. (2016) Structures and regulation of non‐X orphan nuclear receptors: A retinoid hypothesis. J. Steroid Biochem. Mol. Biol. 157: 27‐40 https://www.ncbi.nlm.nih.gov/pubmed/26159912?dopt=AbstractPlusZhi X et al. (2015) Nuclear receptor variants in liver disease. Dig Dis33: 415‐9 https://www.ncbi.nlm.nih.gov/pubmed/26045277?dopt=AbstractPlusZimmer V NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors [nomenclature as agreed by the http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]) have yet to be officially paired with an endogenous ligand.Germ cell nuclear factor receptors  International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlusBenoit G et al. (2016) Lipid‐sensors, enigmatic‐orphan and orphan nuclear receptors as therapeutic in breast‐cancer. Oncotarget7: 42661‐42682 https://www.ncbi.nlm.nih.gov/pubmed/26894976?dopt=AbstractPlusGarattini E et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685‐704 https://www.ncbi.nlm.nih.gov/pubmed/17132848?dopt=AbstractPlusGermain P et al. (2014) Minireview: role of orphan nuclear receptors in cancer and potential as drug Mol. Endocrinol. 28: 157‐72 https://www.ncbi.nlm.nih.gov/pubmed/24295738?dopt=AbstractPlusSafe S et al. (2016) Structures and regulation of non‐X orphan nuclear receptors: A retinoid hypothesis. J. Steroid Biochem. Mol. Biol. 157: 27‐40 https://www.ncbi.nlm.nih.gov/pubmed/26159912?dopt=AbstractPlusZhi X nomenclature as agreed by theNC‐IUPHARSubcommittee on Nuclear Hormone Receptors [http://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlus]) have yet to be officially paired with an endogenous ligand.Dax‐like receptors  International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58: 798‐836 https://www.ncbi.nlm.nih.gov/pubmed/17132856?dopt=AbstractPlusBenoit G et al. (2016) Lipid‐sensors, enigmatic‐orphan and orphan nuclear receptors as therapeutic targets in breast‐cancer. Oncotarget7: 42661‐42682 https://www.ncbi.nlm.nih.gov/pubmed/26894976?dopt=AbstractPlusGarattini E et al. (2006) Overview of nomenclature of nuclear receptors. Pharmacol. Rev. 58: 685‐704 https://www.ncbi.nlm.nih.gov/pubmed/17132848?dopt=AbstractPlusGermain P et al. (2014) Minireview: role of orphan nuclear receptors in cancer and potential as drug targets. Mol. Endocrinol. 28: 157‐72 https://www.ncbi.nlm.nih.gov/pubmed/24295738?dopt=AbstractPlusSafe S et al. (2016) The emerging roles of orphan nuclear receptors in prostate cancer. Biochim. Biophys. Acta1866: 23‐36 https://www.ncbi.nlm.nih.gov/pubmed/27264242?dopt=AbstractPlusWu D NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors ) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3‐hydroxysteroids (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2818 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1013) and 3‐ketosteroids . These receptors exist as dimers coupled with chaperone molecules  and immunophilin FKBP52:https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3720, http://www.uniprot.org/uniprot/Q02790), which are shed on binding the steroid hormone. Although rapid signalling phenomena are observed , the principal signalling cascade appears to involve binding of the activated receptors to nuclear hormone response elements of the genome, with a 15‐nucleotide consensus sequence AGAACAnnnTGTTCT  as homo‐ or heterodimers. They also affect transcription by protein‐protein interactions with other transcription factors, such as activator protein 1 (AP‐1) and nuclear factor κB (NF‐κB). Splice variants of each of these receptors can form functional or non‐functional monomers that can dimerize to form functional or non‐functional receptors. For example, alternative splicing of PR mRNA produces A and B monomers that combine to produce functional AA, AB and BB receptors with distinct characteristics [http://www.ncbi.nlm.nih.gov/pubmed/8264658?dopt=AbstractPlus].Steroid hormone receptors  has been described. Human orthologues of 7TM ’membrane progestin receptors’ , initially discovered in fish , appear to localize to intracellular membranes and respond to ’non‐genomic’ progesterone analogues independently of G proteins [http://www.ncbi.nlm.nih.gov/pubmed/18603275?dopt=AbstractPlus].A 7TM receptor responsive to estrogen  activity regulates diverse physiological processes http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2822 exhibits partial agonist activity at ERα . Estrogen receptors may be blocked non‐selectively by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1016 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2820 and labelled by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1012 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5384. Many agents thought initially to be antagonists at estrogen receptors appear to have tissue‐specific efficacy , hence the descriptor SERM (selective estrogen receptor modulator) or SnuRM (selective nuclear receptor modulator). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5430 has been suggested to be an ERα‐selective estrogen receptor modulator [http://www.ncbi.nlm.nih.gov/pubmed/17115070?dopt=AbstractPlus].et al. (2017) DNA Sequence Constraints Define Functionally Active Steroid Nuclear Receptor Binding Sites in Chromatin. Endocrinology158: 3212‐3234 https://www.ncbi.nlm.nih.gov/pubmed/28977594?dopt=AbstractPlusCoons LA et al. (2006) International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol. Rev. 58: 773‐81 https://www.ncbi.nlm.nih.gov/pubmed/17132854?dopt=AbstractPlusDahlman‐Wright K et al. (2015) Nuclear receptors in acute and chronic cholestasis. Dig Dis33: 357‐66 https://www.ncbi.nlm.nih.gov/pubmed/26045270?dopt=AbstractPlusGonzalez‐Sanchez E et al. (2016) What’s new in estrogen receptor action in the female reproductive tract. J. Mol. Endocrinol. 56: R55‐71 https://www.ncbi.nlm.nih.gov/pubmed/26826253?dopt=AbstractPlusHewitt SC et al. (2017) Estrogen receptor agonists/antagonists in breast cancer therapy: A critical review. Bioorg. Chem. 71: 257‐274 https://www.ncbi.nlm.nih.gov/pubmed/28274582?dopt=AbstractPlusJameera Begam A et al. (2017) Estrogen Receptor β as a Pharmaceutical Target. Trends Pharmacol. Sci. 38: 92‐99 https://www.ncbi.nlm.nih.gov/pubmed/27979317?dopt=AbstractPlusWarner M NC‐IUPHAR Subcommittee on Nuclear Hormone Receptors ) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3‐hydroxysteroids (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2818 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1013) and 3‐ketosteroids .Steroid hormone receptors  and Type II (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3448) groups. These groups appear to promote binding of PR to DNA with different efficacies and evoke distinct conformational changes in the receptor, leading to a transcription‐neutral complex . Mutations in AR underlie testicular feminization and androgen insensitivity syndromes, spinal and bulbar muscular atrophy (Kennedy’s disease).et al. (2017) 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function. J. Endocrinol. 234: T1‐T16 https://www.ncbi.nlm.nih.gov/pubmed/28468932?dopt=AbstractPlusBaker ME et al. (2017) Deciphering the divergent roles of progestogens in breast cancer. Nat. Rev. Cancer17: 54‐64 https://www.ncbi.nlm.nih.gov/pubmed/27885264?dopt=AbstractPlusCarroll JS et al. (2017) Nuclear Receptor Function through Genomics: Lessons from the Glucocorticoid Receptor. Trends Endocrinol. Metab. 28: 531‐540 https://www.ncbi.nlm.nih.gov/pubmed/28495406?dopt=AbstractPlusCohen DM et al. (2017) Brain mineralocorticoid receptor function in control of salt balance and stress‐adaptation. Physiol. Behav. 178: 13‐20 https://www.ncbi.nlm.nih.gov/pubmed/28089704?dopt=AbstractPlusde Kloet ER et al. (2017) Progesterone‐Mediated Non‐Classical Signaling. Trends Endocrinol. Metab. 28: 656‐668 https://www.ncbi.nlm.nih.gov/pubmed/28651856?dopt=AbstractPlusGarg D et al. (2006) International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol. Rev. 58: 782‐97 https://www.ncbi.nlm.nih.gov/pubmed/17132855?dopt=AbstractPlusLu NZ et al. (2017) Genomic and non‐genomic effects of androgens in the cardiovascular system: clinical implications. Clin. Sci. 131: 1405‐1418 https://www.ncbi.nlm.nih.gov/pubmed/28645930?dopt=AbstractPlusLucas‐Herald AK et al. (2017) Androgen receptor splice variants and prostate cancer: From bench to bedside. Oncotarget8: 18550‐18576 https://www.ncbi.nlm.nih.gov/pubmed/28077788?dopt=AbstractPlusWadosky KM et al. (2017) Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat. Rev. Mol. Cell Biol. 18: 159‐174 https://www.ncbi.nlm.nih.gov/pubmed/28053348?dopt=AbstractPlusWeikum ER


The aim of this study was to investigate the relationship between spleen stiffness value, splenic volume and the liver fibrosis stages.This retrospective study was approved by the institutional review board of our institute. We enrolled 109 patients that had undergone abdominal MR imaging and histopathological examination. The preoperative MR imaging, MR elastography and laboratory data were reviewed. Liver stiffness and spleen stiffness were determined with MR elastography, and splenic volume was calculated. Liver fibrosis stage was determined using surgical pathology.The correlation coefficient between the liver stiffness and the fibrosis stage was r = 0.72 and r = 0.62 when the passive driver was on right chest wall and the left chest wall, respectively. The correlation coefficient between the spleen stiffness and the fibrosis stage was r = 0.63 and r = 0.18 when the passive driver was on the left chest wall and the right chest wall, respectively. The correlation coefficient between the splenic volume and the fibrosis stage was r = 0.31. The diagnostic performance of spleen stiffness was similar to liver stiffness in prediction of advanced liver fibrosis. The combination of spleen stiffness and liver stiffness provided greater sensitivity in prediction of advanced fibrosis than spleen or liver stiffness alone, but no significant difference was found.According to our study, the spleen stiffness value was useful in staging liver fibrosis. The combination of spleen stiffness and liver stiffness could provide higher diagnostic sensitivity than liver stiffness alone in prediction of advanced fibrosis. Chronic liver disease is a major health concern and can lead to liver fibrosis. Liver fibrosis can be reversible with specific treatment; however, treatment is associated with an increased risk of morbidity and mortality ,2. Thus,Splenomegaly is very common in patients with advanced liver fibrosis, and splenic volume increases with the degree of fibrosis stage ,17. TalwThe institutional review board of our institute approved this retrospective study, and the informed consent was waived. Between January 2015 and December 2015, patients having undergone abdominal MR imaging and histopathological examination within a 3-month interval were retrospectively identified from medical records . FinallyAll MR imaging was performed via a 1.5T MR scanner  with a 16-channel body coil. The MR elastography used an active driver system  to generate acoustic vibrations. A 19 cm diameter cylindrical passive driver was placed against the right chest wall and the left chest wall with the center of the passive driver at the level of the xiphoid process. The passive driver was connected by a flexible plastic tube to the acoustic active driver outside the MRI room. Acoustic vibrations at 60 Hz were generated by the active driver to detect shear waves propagating in the liver and spleen. An MRE pulse sequence with an axial 2D gradient echo was used to detect the propagating shear waves. The parameters of the MRE pulse sequence were the following: imaging frequency, 63.5 MHz; section thickness, 5 mm; acquisition matrix, 256 × 64; FOV, 40 cm × 40 cm; TR/TE, 50/22.7; bandwidth, 260 Hz/pixel; and flip angle, 25°. The scanning time was 21 seconds for one imaging slice. An MRE image was obtained with breath-hold at the end-expiratory period for each image slice. Five axial slices for the liver  and three axial slices for the spleen  in different levels were obtained for each patient. The imaging slices for each patient were arranged so that the center slice was located at the largest organ diameter on coronal scout view and each slice gap was 1cm. The elastograms were generated automatically using intrinsic postprocessing software. In measurement of the liver/spleen stiffness, the values were depicted in kilopascals. Confidence maps of the elastogram were generated automatically to indicate the regions with adequate wave amplitudes for measurement. The confidence mapping of the elastogram was then checked by the intrinsic software for imaging quality assessment. In case a suboptimal elastogram was found, changing the position of the passive driver on the chest wall to improve the elastogram was done in our daily practice.Imaging review and analysis were performed using a dual screen diagnostic workstation . A radiologist evaluated the MR elastography images, including anatomic images, the MRE elastogram, and the propagating wave images. The radiologist had more than 20 years of clinical experience in abdominal MRI and was blinded to the pathological finding. The propagating wave images should be checked first for imaging quality in measuring liver/spleen stiffness. The region of interest (ROI) was manually drawn to include only the parenchyma of the liver or spleen as large as possible in each image with confidence mapping . The ROI2). The calculation of splenic volume (cm3) was obtained by adding up all the measurements of the spleen areas, multiplying by 5mm and then dividing by 1000.Based on 3D FFE T1W images , the splenic volume was calculated by manually drawing the spleen contour on every slice and recording the measurements of the area  or percutaneous liver biopsy (n = 13) and from 16 liver donors. The specimens of all patients were stained with H&E and Masson trichrome. All pathological specimens were interpreted by a pathologist who was blinded to the clinical data and MRE data. The METAVIR system was used to classify the hepatic fibrosis stage. There were five grades (F0-F4) in the METAVIR system. According to the METAVIR system, stage F0 was defined as no fibrosis, stage F1 was defined as portal fibrosis without septa, stage F2 was defined as portal fibrosis with a few septa, stage F3 was defined as numerous septa without cirrhosis, and F4 was defined as cirrhosis. A fibrotic stage of F3 or above was considered to be advanced liver fibrosis.Spearman rank correlation was used to test the association between MRE liver stiffness value, spleen stiffness value, splenic volume and hepatic pathological fibrosis stage. Chi-square test was used to compare the differences of fibrosis stages between HBV and non-HBV groups. The differences between the means of the liver stiffness and spleen stiffness values at each fibrosis stage were compared using a one-way analysis of variance (ANOVA). A receiver operating characteristic (ROC) curve analysis was applied to detect the optimal cut-off points and area under the ROC curve (AUROC) for liver stiffness, spleen stiffness, and splenic volume. The AUROC values were compared by DeLong’s test. The highest Youden index (the sum of sensitivity and specificity) was used in determining the optimal cutoff values for liver stiffness, spleen stiffness and splenic volume. Statistical significance was set at a p-value less than 0.05, and all tests were two-tailed. All statistical analyses were performed using SPSS software  and MedCalc software .According to Spearman’s rank correlation, the correlation coefficient between the liver stiffness and the fibrosis stage was r = 0.72 when the passive driver was on the right chest wall and r = 0.62 when the passive driver was on the left chest wall . ScatterA comparison of the spleen stiffness values acquired when the passive driver was placed at the right location and the left location is shown in 3 ; F1, 198.36±87.19 cm3 (79.13~398.6 cm3); F2, 186.14±66.08 cm3 (89.39~332.23 cm3); F3, 245.06±81.81 cm3 (170.31~520.12 cm3); F4, 286.15±139.94 cm3 (111.26~706.74 cm3). The correlation coefficient between the splenic volume and the fibrosis stage was r = 0.31 according to Spearman’s rank correlation. The patients were further divided into two subgroups: a group of 55 patients whose conditions ranged from no fibrosis to substantial fibrosis (F0~F2) and a group of 54 patients with advanced liver fibrosis (F3~F4). The mean splenic volume data (mean±standard deviation) at each fibrosis stage are as follows: F0, 197.29±73.61 cm2 = 0.75), and a splenic stiffness value ≥ 10.5 kPa was associated with a 100% rate of esophageal varices [In our study, the combination of spleen stiffness and liver stiffness could provide higher AUC than spleen or liver stiffness alone, although no significant difference was found. There were two major components for the elevation of hepatic stiffness in patients with chronic liver disease: structural change or fibrosis and portal/venous pressure . Talwalk varices . The mea varices . Yin et  varices . The comIn our study, MRE showed good performance in determining the liver fibrosis stage, and liver stiffness depicted good correlation (r = 0.72) with the histopathologic liver fibrosis stage. Our result was similar to several previous studies of patients with chronic hepatitis B/C or nonalcoholic fatty liver disease –24. MeanAs shown in 3 for splenic volume, we could differentiate advanced liver fibrosis (F3-F4) from relatively early fibrosis stages (F0-F2) with a sensitivity of 72.22% and a specificity of 61.82%. Liu et al. reported splenic volume with a cutoff value of 358.67 cm3 was useful in differentiating advanced liver fibrosis, but not in early fibrosis stage [Our study revealed that splenic volume has a positive correlation with liver fibrosis stage and can be used to estimate the degree of fibrosis. Splenic volume had been reported to be useful in monitoring and diagnosing liver fibrosis stage and liver cirrhosis ,31. HoweThere are some potential limitations in the study. First, this study was a retrospective study with a relatively small patient number. In the study population, the underlying disease and the distribution of fibrosis stages were uneven. Second, the influences of liver steatosis, iron deposition and other confounder factors for MRE measurement were not evaluated in this study. Third, 2D gradient echo MRE was used in our study. 3D MRE enables the acquisition of the full wave field, additional parameters, artifact reduction and fewer assumptions about the material model during inversion . HoweverOur study verified the feasibility of staging liver fibrosis via splenic volume calculation and MR elastography of the spleen. Spleen stiffness could provide useful information in characterization of different liver fibrosis stages. A combination of spleen stiffness and liver stiffness could provide higher sensitivity in detection of advanced fibrosis stages than liver stiffness alone.


Int J Epidemiol, 2018, 47(3), 942–952, doi: https://doi.org/10.1093/ije/dyx263.First published online: 14 December 2017, International Journal of Epidemiology ‘Rapidly increasing body mass index among children, adolescents and young adults in a transitioning population, South Africa, 2008–15’ by B Sartorius, K Sartorius, M Taylor, J Aagaard-Hansen, N Dukhi, C Day, N Ndlovu, R Slotow and K Hofman published online on 14 December 2017 and in the International Journal of Epidemiology, Volume 47, Issue 3, June 2018, Pages 942–952 by Oxford University Press has been retracted by agreement between the journal Editor, Professor Stephen Leeder, the lead author Professor Benn Sartorius and all co-authors, the International Epidemiological Association and Oxford University Press.The above article from The retraction follows the discovery of a mistake relating to the analysis and interpretation of the South African National Income Dynamics Study (SA-NIDS) data, especially that from Wave 4 presented in Figure 1. This error resulted from not incrementing age between Waves 1 and 4 and so not accounting for the normal increase with age in BMI among young people. Recalculation of the estimates shows that there is little change in mean BMI by age over the period between Waves 1 and 4 and thus no evidence of the large increase in the prevalence of overweight and obesity in young people shown in Figure 3 that is the main finding of the study. All authors accept responsibility and apologise for this error.


P = 0.00023). Additionally, IRF8 demonstrated significant differences among STA, IFTA and IFTA-I groups, suggesting that IRF8 had the capacity to discriminate the different classifications of graft biopsies well. Also, with Kaplan-Meier and log-rank methods, we found that IRF8 could serve as the prognostic marker for renal graft failure in those biopsies without rejection (AUC = 0.75) and the recipients expressing high had a higher risk for renal graft loss (P < 0.0001). This research may provide new targets for therapeutic prevention and intervention for post-transplantation IFTA with or with inflammation.Interstitial fibrosis and tubular atrophy (IFTA) with inflammation (IFTA-I) is strongly correlated with kidney allograft failure. Diagnosis of IFTA-I accurately and early is critical to prevent graft failure and improve graft survival. In the current study, through analyzing the renal allograft biopsy in patients with stable function after kidney transplantation (STA), IFTA and IFTA-I group with semi-supervised principal components methods, we found that CD2, IL7R, CCL5 based signature could not only distinguish STA and IFTA-I well, but predict IFTA-I with a high degree of accuracy with an area under the curve (AUC) of 0.91 ( Based on GPL570, the samples which were diagnosed as Stable function after kidney transplantation (STA), chronic Interstitial fibrosis and tubular atrophy (IFTA) or IFTA with inflammation (IFTA-I) and more than 6 months post-transplant, based on pathology, were included. Those samples without STA, chronic IFTA or IFTA-I diagnosis and those with IFTA or IFTA based on pathology but less than 6 months post-transplant, were excluded. Finally, GSE22459, GSE7392, GSE9489, and GSE9492 were included, which contained 56 samples, including 40 allograft renal biopsies classified with STA and 16 biopsies with IFTA-I. The clinical information was listed in the Microarray data Gene expression profiles of allograft protocol biopsies were obtained from the GEO database (P < 0.001) were considered as DEGs and analyzed with principal component analysis (PCA) with R version 3.4.3.All gene expression data were integrated and normalized by the gcRMA algorithm . Then suP < 0.05 was used as the cutoff) [To identify key DEGs related to prognosis, the 56 samples were randomly divided into a training and testing set at 6:4. A semi-supervised principal components (SPC) method and the random forest were used to select significant genes (Hazard Ratios > 1 or < 1 with  cutoff) , 33. Thehttp://string-db.org) database and those validated interactions with a combined score < 0.4 were selected and PPI networks were constructed and screened using the plug-in Molecular Complex Detection . The key genes whose MCODE score > 3 and the number of nodes > 4 were included.PPI was analyzed according to the previous report . BrieflyThe prognostic score was calculated in the training group as follows: Prognostic score = (3.833 × CCL5) + (6.133 × IL7R) + (4.14 × CD2). Therefore, the 3-gene signature was developed using the linear signature prognostic model. The optimal cutoff point of the prognostic score was obtained in ROC curve analysis for predicting the accuracy of the signature in the test group and in GSE76882 database [To distinguish IFTA-I from IFTA, DEGs among STA, IFTA, and IFTA-I groups were selected for further analysis. The optimal cutoff point of the prognostic score was obtained in ROC curve analysis and used for dividing the biopsies into high-expressed and low-expressed groups. Then Kaplan-Meier and log-rank methods were used for predicting renal graft failure in GSE21374 database . To furtSupplementary FiguresSupplementary TablesSupplementary Table 6