Epigenetic and transcriptional consequences in the endosperm of chemically induced transposon mobilization in Arabidopsis.

Genomic imprinting, an epigenetic phenomenon leading to parent-of-origin-specific gene expression, has independently evolved in the endosperm of flowering plants and the placenta of mammals-tissues crucial for nurturing embryos. While transposable elements (TEs) frequently colocalize with imprinted genes and are implicated in imprinting establishment, direct investigations of the impact of de novo TE transposition on genomic imprinting remain scarce. In this study, we explored the effects of chemically induced transposition of the Copia element ONSEN on genomic imprinting in Arabidopsis thaliana. Through the combination of chemical TE mobilization and doubled haploid induction, we generated a line with 40 new ONSEN copies. Our findings reveal a preferential targeting of maternally expressed genes (MEGs) for transposition, aligning with the colocalization of H2A.Z and H3K27me3 in MEGs-both previously identified as promoters of ONSEN insertions. Additionally, we demonstrate that chemically-induced DNA hypomethylation induces global transcriptional deregulation in the endosperm, leading to the breakdown of MEG imprinting. This study provides insights into the consequences of chemically induced TE remobilization in the endosperm, revealing that chemically-induced epigenome changes can have long-term consequences on imprinted gene expression.

Transposition and duplication of MADS-domain transcription factor genes in annual and perennial Arabis species modulates flowering.

The timing of reproduction is an adaptive trait in many organisms. In plants, the timing, duration, and intensity of flowering differ between annual and perennial species. To identify interspecies variation in these traits, we studied introgression lines derived from hybridization of annual and perennial species, Arabis montbretiana and Arabis alpina, respectively. Recombination mapping identified two tandem A. montbretiana genes encoding MADS-domain transcription factors that confer extreme late flowering on A. alpina These genes are related to the MADS AFFECTING FLOWERING (MAF) cluster of floral repressors of other Brassicaceae species and were named A. montbretiana (Am) MAF-RELATED (MAR) genes. AmMAR1 but not AmMAR2 prevented floral induction at the shoot apex of A. alpina, strongly enhancing the effect of the MAF cluster, and MAR1 is absent from the genomes of all A. alpina accessions analyzed. Exposure of plants to cold (vernalization) represses AmMAR1 transcription and overcomes its inhibition of flowering. Assembly of the tandem arrays of MAR and MAF genes of six A. alpina accessions and three related species using PacBio long-sequence reads demonstrated that the MARs arose within the Arabis genus by interchromosomal transposition of a MAF1-like gene followed by tandem duplication. Time-resolved comparative RNA-sequencing (RNA-seq) suggested that AmMAR1 may be retained in A. montbretiana to enhance the effect of the AmMAF cluster and extend the duration of vernalization required for flowering. Our results demonstrate that MAF genes transposed independently in different Brassicaceae lineages and suggest that they were retained to modulate adaptive flowering responses that differ even among closely related species.

Effect of information encounter on concerns over healthy eating- mediated through body comparison and moderated by body mass index or body satisfaction.

BACKGROUND: Understanding factors that influence healthy or unhealthy eating can inform intervention strategies. This study ascertained whether and how unintentional exposure to food and nutrition information influenced healthy eating concerns. The study tested body comparison, body satisfaction, and body mass index as three mechanisms that potentially link food information encounter, commonly known as information scanning, to healthy eating concerns. METHODS: A sample of 440 online participants (mean age = 29.15 years) was used to investigate: (1) how unintentional exposure to food and nutrition information, i.e., information encounter (IE), affects healthy eating concerns (HEC); (2) how the effect of IE on HEC is mediated by body comparison (BC); (3) how the paths of the mediation model are moderated by body satisfaction (BS) or body mass index (BMI). RESULTS: The findings show a positive and sizable total effect of IE on HEC - a whole-scale increase in information encounter is associated with a substantial increase in healthy eating concerns by 15 percentage points (bp = 0.150). BC is found to mediate the effect of IE on HEC in an all-positive complementary mediation. Both the indirect and the direct-and-remainder paths show sizable effects. The mediated path contributes about 20% of the total effect between IE and HEC (cp = 20%), while the direct-and-remainder path contributes the rest (cp = 80%). BS was found to moderate the relationship between IE and BC, the first leg of the mediation. The moderation effect is large - the effect of IE on BC is much smaller on the highly and the moderately satisfied than on the lowly satisfied (slope differential bp = -.60). BMI was found to moderate the direct-and-remainder effect of IE on HEC, controlling BC. That is, the effect of IE on HEC, after filtering out the mediated effect through BC, is much larger for those with high or low BMI than those with healthy BMI (slope differential bp = .32). CONCLUSIONS: Exposure, even if unintentional, to food and nutrition information is an important predictor of HEC. BC, BS, and BMI are important factors that help to explain the process through which information affects behaviors.

Predicting and Empowering Health for Generation Z by Comparing Health Information Seeking and Digital Health Literacy: Cross-Sectional Questionnaire Study.

BACKGROUND: Generation Z (born 1995-2010) members are digital residents who use technology and the internet more frequently than any previous generation to learn about their health. They are increasingly moving away from conventional methods of seeking health information as technology advances quickly and becomes more widely available, resulting in a more digitalized health care system. Similar to all groups, Generation Z has specific health care requirements and preferences, and their use of technology influences how they look for health information. However, they have often been overlooked in scholarly research. OBJECTIVE: First, we aimed to identify the information-seeking preferences of older individuals and Generation Z (those between the ages of 18 and 26 years); second, we aimed to predict the effects of digital health literacy and health empowerment in both groups. We also aimed to identify factors that impact how both groups engage in digital health and remain in control of their own health. METHODS: The Health Information National Trends Survey was adopted for further use in 2022. We analyzed 1862 valid data points by conducting a survey among Chinese respondents to address the research gap. A descriptive analysis, 2-tailed t test, and multiple linear regression were applied to the results. RESULTS: When compared with previous generations, Generation Z respondents (995/1862, 53.44%) were more likely to use the internet to find out about health-related topics, whereas earlier generations relied more on traditional media and interpersonal contact. Web-based information-seeking behavior is predicted by digital health literacy (Generation Z: ß=.192, P<.001; older population: ß=.337, P<.001). While this was happening, only seeking health information from physicians positively predicted health empowerment (Generation Z: ß=.070, P=.002; older population: ß=.089, P<.001). Despite more frequent use of the internet to learn about their health, Generation Z showed lower levels of health empowerment and less desire to look for health information, overall. CONCLUSIONS: This study examined and compared the health information-seeking behaviors of Generation Z and older individuals to improve their digital health literacy and health empowerment. The 2 groups demonstrated distinct preferences regarding their choice of information sources. Health empowerment and digital health literacy were both significantly related to information-seeking behaviors.

The Evolutionary Dynamics of Genetic Incompatibilities Introduced by Duplicated Genes in Arabidopsis thaliana.

Although gene duplications provide genetic backup and allow genomic changes under relaxed selection, they may potentially limit gene flow. When different copies of a duplicated gene are pseudofunctionalized in different genotypes, genetic incompatibilities can arise in their hybrid offspring. Although such cases have been reported after manual crosses, it remains unclear whether they occur in nature and how they affect natural populations. Here, we identified four duplicated-gene based incompatibilities including one previously not reported within an artificial Arabidopsis intercross population. Unexpectedly, however, for each of the genetic incompatibilities we also identified the incompatible alleles in natural populations based on the genomes of 1,135 Arabidopsis accessions published by the 1001 Genomes Project. Using the presence of incompatible allele combinations as phenotypes for GWAS, we mapped genomic regions that included additional gene copies which likely rescue the genetic incompatibility. Reconstructing the geographic origins and evolutionary trajectories of the individual alleles suggested that incompatible alleles frequently coexist, even in geographically closed regions, and that their effects can be overcome by additional gene copies collectively shaping the evolutionary dynamics of duplicated genes during population history.

Exploration of the role of Cuproptosis genes and their related long non-coding RNA in clear cell renal cell carcinoma: a comprehensive bioinformatics study.

Clear cell renal cell carcinoma is a common malignant tumor of the urinary system. The mechanism of its occurrence and development is unknown, and there is currently few effective comprehensive predictive markers for prognosis and treatment response. With the discovery of a new cell death process - cuproptosis drew the attention of researchers. We constructed a model for the prediction of clinical prognosis and immunotherapy response through integrative analysis of gene expression datasets from KIRC samples in The Cancer Genome Atlas (TCGA) database. During the course of the study, we found that cuproptosis genes are significantly differentially expressed between clear cell renal cell carcinoma samples and normal samples. Based on this, we put forward the prognostic model for cuproptosis gene related-long non-coding RNA. And through various statistic and external independent cohorts, we proved that the model is accurate and stable, worthy of clinical application and further exploration and validation.

Pentacoordinate Al3+ Sites Anchoring Synthesis of Palladium Intermetallic Catalysts on Al2O3 Supports.

Size control of supported Pd-based intermetallic nanoparticles (i-NPs) remains a major challenge because the required high-temperature annealing for atomic diffusion and ordering easily causes metal sintering. Here, we described a pentacoordinate Al3+ site (Al3+penta) anchoring approach for the preparation of Pd-based i-NPs with controlled size, which takes advantage of the strong chemical interaction between Al3+penta sites and Pd-based i-NPs to realize size control. We synthesized six types of Pd-based i-NPs, and four of them can remain an average particle size of <6 nm. Furthermore, one of our prepared Pd-based i-NPs (that is, Pd3Pb) demonstrated outstanding performance in catalyzing the semihydrogenation of phenylacetylene.

Modification of activated carbon using urea to enhance the adsorption of dioxins.

Activated carbon is commonly used to remove dioxins from flue gas via adsorption. Improving the targeted adsorption capacity of activated carbon for dioxins can reduce the consumption of adsorbents and help achieve emission standards for target pollutants. Here, commercial coal-based activated carbon was used as a raw material and modified by urea impregnation along with treatment at high temperature under a nitrogen atmosphere. It was found that modification with urea effectively improved the pore structure of activated carbon while incorporating a certain amount of nitrogen. The best modification effect was achieved at a modification temperature of 600 °C, an impregnation ratio of urea to activated carbon of 1:1, and with high-temperature treatment for 2 h. The mesopore volume of the modified activated carbon (AC600) reached 0.38 cm3/g, accounting for 57.58% of the total pore volume. With an impregnation ratio of urea to activated carbon of 1:1, high-temperature treatment for 2 h, and a modification temperature of 800 °C, a certain amount of nitrogen was introduced into the carbon rings to form a modified activated carbon (AC800) rich in pyridine and pyrrole groups (atomic percentage = 4.84%). The activated carbon modified by urea and the unmodified activated carbon were subsequently selected for dioxin adsorption experiments using a dioxin generation and adsorption system. AC600 showed the highest adsorption efficiency for dioxins, reaching 97.65%, based on toxicity equivalents. Although AC800 has poor pore properties, it has more pyridine and pyrrole groups than AC600. Consequently, the efficiency of AC800 at adsorbing low-concentration dioxins reached 85.24% based on toxicity equivalents. Overall, this study describes two mechanisms for effectively modifying activated carbon with urea based on (1) optimizing the pore structure of activated carbon and (2) incorporating nitrogen.

Monoterpenoid indole alkaloids from the fruits of Gelsemium elegans and their anti-inflammatory activities.

Two novel monoterpenoid indole alkaloids (MIAs), gelsechizines A-B (1-2), along with four known ones (3-6) were isolated from the fruits of Gelsemium elegans. Compound 1 features a new carbon skeleton with two additional carbon atoms forming a 4-methylpyridine unit. Their structures with absolute configurations were elucidated by NMR, MS, X-ray diffraction and electronic circular dichroism (ECD) calculations. Compounds 1-3 showed significant anti-inflammatory effects in vivo and in vitro, which may be related to the inhibition of the trecruitment of neutrophils and macrophages as well as the secretion of TNF-α and IL-6. Preliminary structure-activity relationship analysis revealed that the ß-N-acrylate moiety plays an important role in the anti-inflammatory effect.

Improving and correcting the contiguity of long-read genome assemblies of three plant species using optical mapping and chromosome conformation capture data.

Long-read sequencing can overcome the weaknesses of short reads in the assembly of eukaryotic genomes; however, at present additional scaffolding is needed to achieve chromosome-level assemblies. We generated Pacific Biosciences (PacBio) long-read data of the genomes of three relatives of the model plant Arabidopsis thaliana and assembled all three genomes into only a few hundred contigs. To improve the contiguities of these assemblies, we generated BioNano Genomics optical mapping and Dovetail Genomics chromosome conformation capture data for genome scaffolding. Despite their technical differences, optical mapping and chromosome conformation capture performed similarly and doubled N50 values. After improving both integration methods, assembly contiguity reached chromosome-arm-levels. We rigorously assessed the quality of contigs and scaffolds using Illumina mate-pair libraries and genetic map information. This showed that PacBio assemblies have high sequence accuracy but can contain several misassemblies, which join unlinked regions of the genome. Most, but not all, of these misjoints were removed during the integration of the optical mapping and chromosome conformation capture data. Even though none of the centromeres were fully assembled, the scaffolds revealed large parts of some centromeric regions, even including some of the heterochromatic regions, which are not present in gold standard reference sequences.

Chiral Isolation and Absolute Configuration of (+)- and (-)-Xanchryones F and G from Xanthostemon chrysanthus.

(+)- and (-)-Xanchryones F and G ((+)- and (-)-1 and 2) were isolated from the plant Xanthostemon chrysanthus by chiral separation. Compounds 1 and 2 featured a new carbon skeleton with cinnamoyltriketone-flavone adducts. Their structures with absolute configurations were elucidated by detailed spectroscopic analyses and chemical calculations. The antibacterial and anti-inflammatory activities of (+)- and (-)-1 and 2 were evaluated.

Antibacterial Triketone-Phloroglucinol-Triketone Adducts from Myrtus communis.

Myrtucyclitones A-C ((+)- and (-)-1-3), three pairs of new triketone-phloroglucinol-triketone hybrids were isolated from the plant Myrtus communis. Their structures with absolute configurations were established by NMR analysis and chemical calculations. Myrtucyclitones B and C exhibited remarkable antibacterial effect.

Strengths and potential pitfalls of hay transfer for ecological restoration revealed by RAD-seq analysis in floodplain Arabis species.

Achieving high intraspecific genetic diversity is a critical goal in ecological restoration as it increases the adaptive potential and long-term resilience of populations. Thus, we investigated genetic diversity within and between pristine sites in a fossil floodplain and compared it to sites restored by hay transfer between 1997 and 2014. RAD-seq genotyping revealed that the stenoecious floodplain species Arabis nemorensis is co-occurring with individuals that, based on ploidy, ITS-sequencing and morphology, probably belong to the close relative Arabis sagittata, which has a documented preference for dry calcareous grasslands but has not been reported in floodplain meadows. We show that hay transfer maintains genetic diversity for both species. Additionally, in A. sagittata, transfer from multiple genetically isolated pristine sites resulted in restored sites with increased diversity and admixed local genotypes. In A. nemorensis, transfer did not create novel admixture dynamics because genetic diversity between pristine sites was less differentiated. Thus, the effects of hay transfer on genetic diversity also depend on the genetic make-up of the donor communities of each species, especially when local material is mixed. Our results demonstrate the efficiency of hay transfer for habitat restoration and emphasize the importance of prerestoration characterization of microgeographic patterns of intraspecific diversity of the community to guarantee that restoration practices reach their goal, that is maximize the adaptive potential of the entire restored plant community. Overlooking these patterns may alter the balance between species in the community. Additionally, our comparison of summary statistics obtained from de novo- and reference-based RAD-seq pipelines shows that the genomic impact of restoration can be reliably monitored in species lacking prior genomic knowledge.

Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator of α7 nAChR that can reverse acoustic gating deficits in a mouse prepulse inhibition model.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca2+-permeable homopentameric ion channel implicated in cognition and neuropsychiatric disorders. Pharmacological enhancement of α7 nAChR function has been suggested for improvement of cognitive deficits. In the present study, we characterized a thiazolyl heterocyclic derivative, 6-(2-chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (JWX-A0108), as a novel type I α7 nAChR positive allosteric modulator (PAM), and evaluated its ability to reverse auditory gating and spatial working memory deficits in mice. In Xenopus oocytes expressing human nAChR channels, application of JWX-A0108 selectively enhanced α7 nAChR-mediated inward current in the presence of the agonist ACh (EC50 value = 4.35 ± 0.12 µM). In hippocampal slices, co-application of ACh and JWX-A0108 (10 µM for each) markedly increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in pyramidal neurons, but JWX-A0108 did not affect GABA-induced current in oocytes expressing human GABAA receptor α1ß3γ2 and α5ß3γ2 subtypes. In mice with MK-801-induced deficits in auditory gating, administration of JWX-A0108 (1, 3, and 10 mg/kg, i.p.) dose-dependently attenuates MK-801-induced auditory gating deficits in five prepulse intensities (72, 76, 80, 84, and 88 dB). Furthermore, administration of JWX-A0108 (0.03, 0.1, or 0.3 mg/kg, i.p.) significantly reversed MK-801-induced impaired spatial working memory in mice. Our results demonstrate that JWX-A0108 is a novel type I PAM of α7 nAChR, which may be beneficial for improvement of cognitive deficits commonly found in neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.

Chromosome-level assembly of Arabidopsis thaliana Ler reveals the extent of translocation and inversion polymorphisms.

Resequencing or reference-based assemblies reveal large parts of the small-scale sequence variation. However, they typically fail to separate such local variation into colinear and rearranged variation, because they usually do not recover the complement of large-scale rearrangements, including transpositions and inversions. Besides the availability of hundreds of genomes of diverse Arabidopsis thaliana accessions, there is so far only one full-length assembled genome: the reference sequence. We have assembled 117 Mb of the A. thaliana Landsberg erecta (Ler) genome into five chromosome-equivalent sequences using a combination of short Illumina reads, long PacBio reads, and linkage information. Whole-genome comparison against the reference sequence revealed 564 transpositions and 47 inversions comprising ∼3.6 Mb, in addition to 4.1 Mb of nonreference sequence, mostly originating from duplications. Although rearranged regions are not different in local divergence from colinear regions, they are drastically depleted for meiotic recombination in heterozygotes. Using a 1.2-Mb inversion as an example, we show that such rearrangement-mediated reduction of meiotic recombination can lead to genetically isolated haplotypes in the worldwide population of A. thaliana Moreover, we found 105 single-copy genes, which were only present in the reference sequence or the Ler assembly, and 334 single-copy orthologs, which showed an additional copy in only one of the genomes. To our knowledge, this work gives first insights into the degree and type of variation, which will be revealed once complete assemblies will replace resequencing or other reference-dependent methods.

Extensive sequence divergence between the reference genomes of two elite indica rice varieties Zhenshan 97 and Minghui 63.

Asian cultivated rice consists of two subspecies: Oryza sativa subsp. indica and O. sativa subsp. japonica Despite the fact that indica rice accounts for over 70% of total rice production worldwide and is genetically much more diverse, a high-quality reference genome for indica rice has yet to be published. We conducted map-based sequencing of two indica rice lines, Zhenshan 97 (ZS97) and Minghui 63 (MH63), which represent the two major varietal groups of the indica subspecies and are the parents of an elite Chinese hybrid. The genome sequences were assembled into 237 (ZS97) and 181 (MH63) contigs, with an accuracy >99.99%, and covered 90.6% and 93.2% of their estimated genome sizes. Comparative analyses of these two indica genomes uncovered surprising structural differences, especially with respect to inversions, translocations, presence/absence variations, and segmental duplications. Approximately 42% of nontransposable element related genes were identical between the two genomes. Transcriptome analysis of three tissues showed that 1,059-2,217 more genes were expressed in the hybrid than in the parents and that the expressed genes in the hybrid were much more diverse due to their divergence between the parental genomes. The public availability of two high-quality reference genomes for the indica subspecies of rice will have large-ranging implications for plant biology and crop genetic improvement.

Low expression level of HMBOX1 in high-grade serous ovarian cancer accelerates cell proliferation by inhibiting cell apoptosis.

Homeobox-containing 1 (HMBOX1) has been described as a transcription factor involved in the occurrence of some tumors, but its roles in ovarian cancer have never been reported. Here we aimed to investigate the roles of HMBOX1 on high-grade serous ovarian carcinoma (HGSOC). In this present study, HMBOX1 expression was decreased in HGSOC tissues and ovarian cancer cell lines (HO8910 and A2780) compared with ovarian surface epithelial tissues or normal human ovarian surface epithelial cell line (HOSEpiC). The cell proliferation of HOSEpiC was weaker than ovarian cancer cell lines. By altering the expression of HMBOX1 in A2780 and HOSEpiC, we demonstrated that HMBOX1 inhibited the cell proliferation and promoted the cell apoptosis. Furthermore, our study revealed that HMBOX1 downregulated the expression of anti-apoptotic proteins (Bcl-2, Bcl-xL), raised the expression of pro-apoptotic-regulated proteins (Bad, Bax), apoptotic executionior (Caspase3), and P53. In conclusion, HMBOX1 played important roles in occurrence of HGSOC through regulation of proliferation and apoptosis, which implied that HMBOX1 might serve as a new therapeutic target for HGSOC.

Rice Stripe Virus Infection Alters mRNA Levels of Sphingolipid-Metabolizing Enzymes and Sphingolipids Content in Laodelphax striatellus.

Sphingolipids and their metabolites have been implicated in viral infection and replication in mammal cells but how their metabolizing enzymes in the host are regulated by viruses remains largely unknown. Here we report the identification of 12 sphingolipid genes and their regulation by Rice stripe virus in the small brown planthopper (Laodelphax striatellus Fallén), a serious pest of rice throughout eastern Asia. According to protein sequence similarity, we identified 12 sphingolipid enzyme genes in L. striatellus. By comparing their mRNA levels in viruliferous versus nonviruliferous L. striatellus at different life stages by qPCR, we found that RSV infection upregulated six genes (LsCGT1, LsNAGA1, LsSGPP, LsSMPD4, LsSMS, and LsSPT) in most stages of L. striatellus Especially, four genes (LsCGT1, LsSMPD2, LsNAGA1, and LsSMS) and another three genes (LsNAGA1, LsSGPP, and LsSMS) were significantly upregulated in viruliferous third-instar and fourth-instar nymphs, respectively. HPLC-MS/MS results showed that RSV infection increased the levels of various ceramides, such as Cer18:0, Cer20:0, and Cer22:0 species, in third and fourth instar L. striatellus nymphs. Together, these results demonstrate that RSV infection alters the transcript levels of various sphingolipid enzymes and the contents of sphingolipids in L. striatellus, indicating that sphingolipids may be important for RSV infection or replication in L. striatellus.

Oral Anticoagulant Use in Atrial Fibrillation-Associated Ischemic Stroke: A Retrospective, Multicenter Survey in Northwestern China.

BACKGROUND: Anticoagulation therapy has been recommended by major guidelines to reduce the risk of recurrent stroke in patients with atrial fibrillation-associated ischemic stroke (AFAIS). However, in real-world clinical practice, oral anticoagulants with either vitamin K antagonists or nonvitamin K antagonists are often underused for these patients. Here, we sought to investigate the current status of oral anticoagulant use in patients with AFAIS in northwestern China. METHODS: We reviewed medical records of consecutive patients with AFAIS discharged from 14 hospitals in northwestern China between January 2012 and May 2015. RESULTS: A total of 1014 cases were included in this study. The mean age of the patients was 70.3 ± 10.8 years. Fifty-four percent were female. Among all participants, only 20.0% received anticoagulants (19.4% warfarin and .6% nonvitamin K antagonist oral anticoagulants), whereas 57.5% took antiplatelet drugs and 22.5% received neither anticoagulant nor antiplatelet treatment. Anticoagulant use decreased with increasing age and CHA2DS2-VASc scores. The proportions of anticoagulant use at discharge in patients younger than 65 years, 65-74 years, and 75 years or older were 28.5%, 20.7%, and 13.9%, respectively. Nonvalvular atrial fibrillation patients with CHA2DS2-VASc scores of 2, 3, 4, 5, 6, and 7 had anticoagulant use rates at discharge of 19.2%, 24.8%, 20.3%, 13.7%, 8.1%, and 8.0%, respectively. CONCLUSIONS: In northwestern China, oral anticoagulants are substantially underutilized in patients with AFAIS, especially in patients at higher risk of stroke, suggesting a large treatment gap in the secondary prevention management in patients with AFAIS.