SIZ1-mediated SUMOlation of CPSF100 promotes plant thermomorphogenesis by controlling alternative polyadenylation.

Under warm temperatures, plants adjust their morphologies for environmental adaption via precise gene expression regulation. However, the function and regulation of alternative polyadenylation (APA), an important fine-tuning of gene expression, remains unknown in plant thermomorphogenesis. Here we found that SUMOylation, a critical post-translational modification, was induced under a long-time treatment at warm temperatures mediated by a SUMO ligase SIZ1 in Arabidopsis. Depletion of SIZ1 altered the global usage of polyadenylation signals and affected the APA dynamic of thermomorphogenesis genes. CPSF100, a key subunit of the CPSF complex for polyadenylation regulation, was SUMOylated via SIZ1. Importantly, SUMOylation was essential for the function of CPSF100 in genome-wide polyadenylation site choice during thermomorphogenesis. The SUMO conjugation on CPSF100 attenuated its interaction with two isoforms of its partner CPSF30, increasing the nuclear accumulation of CPSF100 for polyadenylation regulation. In summary, we uncovered the mechanism for the regulation of APA via SUMOylation in plant thermomorphogenesis.

Multidimensional biomarker approach integrating tumor markers, inflammatory indicators, and disease activity indicators may improve prediction of rheumatoid arthritis-associated interstitial lung disease.

INTRODUCTION: Rheumatoid arthritis (RA) often leads to interstitial lung disease (ILD), significantly affecting patient outcomes. This study explored the diagnostic accuracy of a multi-biomarker approach to offer a more efficient and accessible diagnostic strategy for RA-associated ILD (RA-ILD). METHODS: Patients diagnosed with RA, with or without ILD, at Beijing Tiantan Hospital from October 2019 to October 2023 were analyzed. A total of 125 RA patients were included, with 76 diagnosed with RA-ILD. The study focused on three categories of indicators: tumor markers, inflammatory indicators, and disease activity measures. The heatmap correlation analysis was employed to analyze the correlation among these indicators. Logistic regression was used to determine odds ratios (OR) for indicators linked to RA-ILD risk. Receiver-operating characteristic (ROC) curve analysis was employed to evaluate the diagnostic potential of these indicators for RA-ILD. RESULTS: The results of logistic regression analysis showed that tumor markers (carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), and cytokeratin 19 fragment (CYFRA21-1)), as well as inflammatory indicators (neutrophil, neutrophil-to-lymphocyte ratio (NLR), platelet, C-reactive protein (CRP)) and disease activity measures (disease activity score-28-CRP (DAS28-CRP), rheumatoid factor (RF), and anti-cyclic peptide containing citrulline (anti-CCP)), were significantly associated with RA-ILD. The correlation coefficients among these indicators were relatively low. Notably, the combination indicator 4, which integrated the aforementioned three categories of biomarkers, demonstrated improved diagnostic accuracy with an AUC of 0.857. CONCLUSION: The study demonstrated that combining tumor markers, inflammatory indicators, and disease activity measures significantly enhanced the prediction of RA-ILD. Key Points • Multidimensional strategy: Integrated tumor markers, inflammatory indicators, and disease activity measures to enhance early detection of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). • Diagnostic accuracy: Employed heatmap correlation and logistic regression, identifying significant associations and improving diagnostic accuracy with a multidimensional biomarker combination. • Superior performance: The combined multidimensional biomarker strategy demonstrated higher diagnostic precision compared to individual or dual-category indicators. • Clinical relevance: Offers a promising, accessible approach for early detection of RA-ILD in clinical settings, potentially improving patient outcomes.

Effectiveness of tofacitinib monotherapy for patients with IgG4-RD or idiopathic retroperitoneal fibrosis.

OBJECTIVES: To explore the effectiveness of tofacitinib for immunoglobulin G4-related disease (IgG4-RD) and idiopathic retroperitoneal fibrosis (IRF), and investigate the expression of JAKs in the lesion of these diseases. METHODS: Clinical data of patients with IgG4-RD or IRF who were administered with tofacitinib monotherapy were collected. IgG4-RD responder index (IgG4-RD RI) was assessed. The expression of JAK1, JAK2, JAK3, and TYK2 were analysed with immunohistochemistry staining in three salivary glands specimens of IgG4-RD and one retroperitoneal tissue of IRF. RESULTS: Two patients with IRF and two patients with IgG4-RD used tofacitinib monotherapy. Two patients with IRF achieved complete remission with diminished retroperitoneal mass and decreased CRP, as IgG4-RD RI decreased from 6 to 1 in both of them. One with IgG4-RD achieved complete remission with alleviated enlargement of pancreas and IgG4 level decreased from 13.7 g/L to 2.4 g/L, as IgG4-RD RI decreased from 12 to 1. One with IgG4-RD achieved partial response with IgG4 level decreased from 77.1g/L to 25.8g/L as IgG4-RD RI from 18 to 6. JAK1, JAK2, JAK3, and TYK2 expression were detected in biopsy tissues. The staining intensity of the JAK family on the lesion from one IRF patient was similar to those from IgG4-RD patients. CONCLUSIONS: Tofacitinib is a potentially effective treatment for IgG4-RD and IRF and it is reasonable to conduct clinical trial to validate its efficacy. The JAKs were expressed in the inflammatory lesions of IgG4-RD and IRF and they may share a common pathogenesis pathway that is independent of IgG4 production.

Clinical characteristics of Guillain-Barré syndrome in patients with primary Sjögren's syndrome.

To investigate the clinical characteristics of Guillain-Barré syndrome (GBS) in patients with primary Sjögren's syndrome (SS). Records of patients with positive anti-SSA antibodies hospitalized in the Beijing Tiantan Hospital between December 2011 and May 2020 were retrieved. Patients who fulfilled the criteria for diagnosis of GBS and primary SS were included, and their clinical data were analyzed. Among the 785 patients with positive anti-SSA, 52 patients were identified in this study. They were 27 males and 25 females with median age of 59 years old. Besides anti-SSA antibodies, multiple autoantibodies were detected in these patients including antinuclear antibody, anti-Ro52, anti-mitochondrial M2, anti-thyroid peroxidase and anti-thyroglobulin autoantibodies. Preceding infection was reported in 42 patients. Hyporeflexia/areflexia and limbs weakness were the most common manifestation and 35 patients presented cranial nerve injuries. GBS disability score of 3, 4 and 5 was scaled in 28 (53.8%), 15 (28.8%) and 3 (5.8%) patients respectively. Forty-six patients received intravenous immunoglobulin (IVIG) monotherapy, 5 patients were treated by IVIG plus glucocorticoids, and 51 patients improved during hospitalization. The frequency of male gender among the patients with both GBS and primary SS suggests an independent onset of GBS and the co-existence of these autoimmune diseases in patients with multiple autoantibodies. Majority of patients with GBS and primary SS experience benign disease course.

Amphiphilic Phosphorus Dendrons Associated with Anti-inflammatory siRNA Reduce Symptoms in Murine Collagen-Induced Arthritis.

Small interfering RNA (siRNA) holds promise for treating rheumatoid arthritis by inhibiting major cytokines such as tumor necrosis factor-α (TNF-α). We developed original cationic amphiphilic phosphorus dendrons to produce dendriplexes associated with TNF-α siRNA. The dendrons were made of 10 pyrrolidinium end groups and a C17 aliphatic chain. The dendriplexes demonstrated the ability to protect siRNA from nuclease degradation and to promote macrophage uptake. Moreover, they led to potent inhibition of TNF-α expression in the lipopolysaccharide-activated mouse macrophage cell line RAW264.7 in vitro model. A significant anti-inflammatory effect in the murine collagen-induced arthritis model was observed through arthritis scoring and histological observations. These results open up essential perspectives in using this original amphiphilic dendron to reduce the disease burden and improve outcomes in chronic inflammatory diseases.

SUMO E3 ligase AtMMS21-dependent SUMOylation of AUXIN/INDOLE-3-ACETIC ACID 17 regulates auxin signaling.

Changes in plant auxin levels can be perceived and converted into cellular responses by auxin signal transduction. AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) proteins are auxin transcriptional inhibitors that play important roles in regulating auxin signal transduction. The stability of Aux/IAA proteins is important for transcription initiation and downstream auxin-related gene expression. Here, we report that the Aux/IAA protein IAA17 interacts with the small ubiquitin-related modifier (SUMO) E3 ligase METHYL METHANESULFONATE-SENSITIVE 21 (AtMMS21) in Arabidopsis (Arabidopsis thaliana). AtMMS21 regulated the SUMOylation of IAA17 at the K41 site. Notably, root length was suppressed in plants overexpressing IAA17, whereas the roots of K41-mutated IAA17 transgenic plants were not significantly different from wild-type roots. Biochemical data indicated that K41-mutated IAA17 or IAA17 in the AtMMS21 knockout mutant was more likely to be degraded compared with nonmutated IAA17 in wild-type plants. In conclusion, our data revealed a role for SUMOylation in the maintenance of IAA17 protein stability, which contributes to improving our understanding of the mechanisms of auxin signaling.

Post-translational modification: a strategic response to high temperature in plants.

With the increasing global warming, high-temperature stress is affecting plant growth and development with greater frequency. Therefore, an increasing number of studies examining the mechanism of temperature response contribute to a more optimal understanding of plant growth under environmental pressure. Post-translational modification (PTM) provides the rapid reconnection of transcriptional programs including transcription factors and signaling proteins. It is vital that plants quickly respond to changes in the environment in order to survive under stressful situations. Herein, we discuss several types of PTMs that occur in response to warm-temperature and high-temperature stress, including ubiquitination, SUMOylation, phosphorylation, histone methylation, and acetylation. This review provides a valuable resolution to this issue to enable increased crop productivity at high temperatures.

Signatures of mRNA Alternative Polyadenylation in Arabidopsis Leaf Development.

Alternative polyadenylation (APA) of pre-mRNA is an important co-transcriptional mechanism that modulates gene expression, leading to transcriptomic and functional diversities. The role of APA in Arabidopsis leaf development, however, remains elusive. We applied a poly(A)-tag sequencing (PAT-seq) technique to characterize APA-mediated regulation events in cotyledon and in five stages of true leaf development. Over 60% APA was identified in genes expressed in leaves, consistent with the results in previous publications. However, a reduced APA level was detected in younger leaves, reaching 44% in the 18th true leaf. Importantly, we also found that >70% of the poly(A) site usages were altered in the second true leaf relative to the cotyledon. Compared with the cotyledon, more genes in the second true leaf tended to use the distal site of 3'UTR, but this was not found in pairwise comparison among other true leaves. In addition, a significant APA gene was found to be decreased in a pairwise comparison among true leaves, including differentially expressed genes. The APA genes identified herein were associated with specific biological processes, including metabolic and cellular processes and response to stimuli and hormones. These results provide a new insight into the regulation of Arabidopsis leaf development through APA.

Alternative polyadenylated mRNAs behave as asynchronous rhythmic transcription in Arabidopsis.

Alternative polyadenylation (APA) is a widespread post-transcriptional modification method that changes the 3' ends of transcripts by altering poly(A) site usage. However, the longitudinal transcriptomic 3' end profile and its mechanism of action are poorly understood. We applied diurnal time-course poly(A) tag sequencing (PAT-seq) for Arabidopsis and identified 3284 genes that generated both rhythmic and arrhythmic transcripts. These two classes of transcripts appear to exhibit dramatic differences in expression and translation activisty. The asynchronized transcripts derived by APA are embedded with different poly(A) signals, especially for rhythmic transcripts, which contain higher AAUAAA and UGUA signal proportions. The Pol II occupancy maximum is reached upstream of rhythmic poly(A) sites, while it is present directly at arrhythmic poly(A) sites. Integrating H3K9ac and H3K4me3 time-course data analyses revealed that transcriptional activation of histone markers may be involved in the differentiation of rhythmic and arrhythmic APA transcripts. These results implicate an interplay between histone modification and RNA 3'-end processing, shedding light on the mechanism of transcription rhythm and alternative polyadenylation.

The Roles of TRIMs in Antiviral Innate Immune Signaling.

The Tripartite motif (TRIM) protein family, which contains over 80 members in human sapiens, is the largest subfamily of the RING-type E3 ubiquitin ligase family. It is implicated in regulating various cellular functions, including cell cycle process, autophagy, and immune response. The dysfunction of TRIMs may lead to numerous diseases, such as systemic lupus erythematosus (SLE). Lots of studies in recent years have demonstrated that many TRIM proteins exert antiviral roles. TRIM proteins could affect viral replication by regulating the signaling pathways of antiviral innate immune responses. Besides, TRIM proteins can directly target viral components, which can lead to the degradation or functional inhibition of viral protein through degradative or non-degradative mechanisms and consequently interrupt the viral lifecycle. However, new evidence suggests that some viruses may manipulate TRIM proteins for their replication. Here, we summarize the latest discoveries on the interactions between TRIM protein and virus, especially TRIM proteins' role in the signaling pathway of antiviral innate immune response and the direct "game" between them.

Nanomedicines for the delivery of glucocorticoids and nucleic acids as potential alternatives in the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects 0.5-1% of the world population. Current treatments include on one hand non-steroidal anti-inflammatory drugs and glucocorticoids (GCs) for treating pain and on the other hand disease-modifying anti-rheumatic drugs such as methotrexate, Janus kinase inhibitors or biologics such as antibodies targeting mainly cytokine expression. More recently, nucleic acids such as siRNA, miRNA, or anti-miRNA have shown strong potentialities for the treatment of RA. This review discusses the way nanomedicines can target GCs and nucleic acids to inflammatory sites, increase drug penetration within inflammatory cells, achieve better subcellular distribution and finally protect drugs against degradation. For GCs such a targeting effect would allow the treatment to be more effective at lower doses and to reduce the administration frequency as well as to induce much fewer side-effects. In the case of nucleic acids, particularly siRNA, knocking down proteins involved in RA, could importantly be facilitated using nanomedicines. Finally, the combination of both siRNA and GCs in the same carrier allowed for the same cell to target both the GCs receptor as well as any other signaling pathway involved in RA. Nanomedicines appear to be very promising for the delivery of conventional and novel drugs in RA therapeutics. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures.

Transcriptome Analyses of FY Mutants Reveal Its Role in mRNA Alternative Polyadenylation.

A crucial step for mRNA polyadenylation is poly(A) signal recognition by trans-acting factors. The mammalian cleavage and polyadenylation specificity factor (CPSF) complex components CPSF30 and WD repeat-containing protein33 (WDR33) recognize the canonical AAUAAA for polyadenylation. In Arabidopsis (Arabidopsis thaliana), the flowering time regulator FY is the homolog of WDR33. However, its role in mRNA polyadenylation is poorly understood. Using poly(A) tag sequencing, we found that >50% of alternative polyadenylation (APA) events are altered in fy single mutants or double mutants with oxt6 (a null mutant of AtCPSF30), but mutation of the FY WD40-repeat has a stronger effect than deletion of the plant-unique Pro-Pro-Leu-Pro-Pro (PPLPP) domain. fy mutations disrupt AAUAAA or AAUAAA-like poly(A) signal recognition. Notably, A-rich signal usage is suppressed in the WD40-repeat mutation but promoted in PPLPP-domain deficiency. However, fy mutations do not aggravate the altered signal usage in oxt6 Furthermore, the WD40-repeat mutation shows a preference for 3' untranslated region shortening, but the PPLPP-domain deficiency shows a preference for lengthening. Interestingly, the WD40-repeat mutant exhibits shortened primary roots and late flowering with alteration of APA of related genes. Importantly, the long transcripts of two APA genes affected in fy are related to abiotic stress responses. These results reveal a conserved and specific role of FY in mRNA polyadenylation.

The efficacy and safety of total glucosides of peony in the treatment of primary Sjögren's syndrome: a multi-center, randomized, double-blinded, placebo-controlled clinical trial.

To evaluate the efficacy and safety of total glucosides of peony (TGP) in adults with primary Sjögren's syndrome (pSS). A multi-center, randomized, double-blinded, placebo-controlled study was conducted between March 2012 and July 2014 at ten Chinese hospitals. In total, 320 pSS patients-classified according to the 2002 American-European Consensus Group Criteria-were randomized (2:1 ratio) to receive TGP(600 mg, tid) in the TGP group or placebo for 24 weeks in the placebo group. Study personnel, investigators, and patients were blinded to the treatment grouping. The primary endpoint was the improvement of EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at week 24. The secondary endpoints were dry eyes/mouth/skin/nose/throat/vagina visual analogue scale (VAS), pain and discomfort VAS, fatigue VAS, mental discomfort VAS, patient global assessment (PGA), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), Schirmer's test, basal/stimulated salivary flow-rate values, and erythrocyte sedimentation rate (ESR). All adverse events were recorded during the trial period. ESSPRI improved more in the TGP than the placebo group (p < 0.001). Dry eyes/throat/vagina VAS, fatigue VAS, mental discomfort VAS, PGA, Schirmer's test, and ESR also improved more in the TGP group than in the placebo group (all p < 0.05). Stimulated salivary flow-rate values increased in the TGP group at week 12 but not at week 24. Adverse events in TGP group were 10.9%. TGP can alleviate some dryness symptoms as well as disease activity in pSS patients over 24 weeks. TGP was well tolerated by study subjects. TGP seems to be an effective and safe treatment for pSS.

Correction to: the efficacy and safety of total glucosides of peony in the treatment of primary Sjögren's syndrome: a multi-center, randomized, double-blinded, placebo-controlled clinical trial.

The authors regret that the Fig. 1 in the original version of this article contained an error. In the left column, 211 cases in the TGP group should be followed up for 8 weeks before 12 weeks. The correct figure presented in this article.

Impact of transgenic Cry1Ac + CpTI cotton on diversity and dynamics of rhizosphere bacterial community of different root environments.

The objective of this study was to characterize the diversity and dynamics of rhizosphere bacterial community, especially the response of dominant and rare bacterial taxa to the cultivation of Bt cotton for different root environments at different growth stages. qPCR analyses indicated that bacterial abundances of the taproots and lateral root rhizospheres of the Bt cotton SGK321 were significantly different at seedling and bolling stages. But no significant differences were detected between the same root zones from Bt and the conventional cotton varieties. Total bacterial genera had similar pattern with dominant genera in abundance, and with rare genera in richness to the changes of bacterial community, respectively. Although the rhizosphere bacterial diversity of the three cotton varieties changed in taproot and lateral root, no significant differences were detected in the same root environments between Bt and conventional cotton. Moreover, Soil pH was more correlated with variations in the bacterial community composition than Bt proteins. In conclusion, these results revealed no indication that rhizosphere bacterial community of Bt cotton had different response to increased Bt protein regarding the same root environment. In particular, dominant and rare bacterial taxa showed the variation in diversity and community composition in different root microhabitats.

Functional Connectivity Differences in the Insular Sub-regions in Migraine without Aura: A Resting-State Functional Magnetic Resonance Imaging Study.

Objective: The objective of this study was to investigate resting-state functional connectivity (FC) differences in insular sub-regions during the interictal phase in patients with migraine without aura (MWoA). Methods: Forty-nine MWoA patients (MWoA group) and 48 healthy individuals (healthy control group) were recruited for this study. All of the subjects underwent neurological examination and magnetic resonance imaging (MRI). The MRI data were processed using Brat 1.0 software to obtain a whole-brain FC diagram and using Rest 1.8 software to obtain the FC z-score of the sub-regions of both insulas (six sub-regions on each side). Therefore, there were a total of 12 regions of interest (ROIs) that were used as seed points for the statistical analysis. Results: There was abnormal FC between the insular sub-regions and multiple brain regions in the MWoA patients compared with the healthy control group, and a clear laterality was also observed. In addition, the FC z-score of certain sub-regions was negatively correlated with the disease duration. Conclusion: Different insular sub-regions are functionally associated with different regions of the brain and therefore have different functions. In MWoA, the FC between the insular sub-regions and other brain regions was mostly reduced, while a small amount was increased; additionally, the FC may be ipsilateral with a right-side advantage. Variations in the FC of insular sub-regions can be observed as an important indicator of MWoA.

A promising dual mode SPECT/CT imaging platform based on 99mTc-labeled multifunctional dendrimer-entrapped gold nanoparticles.

Multifunctional 99mTc-labeled dendrimer-entrapped gold nanoparticles (99mTc-Au DENPs) were designed and synthesized. Our results show that the type of surface groups (acetyl or hydroxyl) significantly impact the biodistribution profile of the 99mTc-Au DENPs, thereby allowing for preferential SPECT/CT imaging of different organs.

Different mean thickness implicates involvement of the cortex in migraine.

The results of neuroimaging studies on migraines have shown that the functions and functional connectivity networks of some brain regions are altered in migraine patients, and different brain structure volumes have also been observed in recent years. However, it is still not known whether the mean thickness of the cortex is different in migraine patients.A total of 48 migraine without aura (MWoA) patients in interictal phase and 48 healthy controls were enrolled in this study. All subjects received neurological and magnetic resonance imaging (MRI) examinations. Automatic segmentation processing of high-resolution MRI structure images was performed using FreeSurfer software.The mean cortical thickness of many brain regions in the frontal lobe, temporal lobe, occipital lobe, parietal lobe, and insula in the migraine patient group was significantly decreased compared with that in the healthy control group. The mean cortical thickness of the insula anterior was positively correlated with the duration of the disease course, while the mean cortical thickness of insula superior and insula inferior was negatively correlated with the duration of the disease course.The results showed that MWoA results from a complex interactive reaction involving many brain regions and many brain network systems together. However, it is still not clear whether the difference in the brain structure of migraine patients is the result or the cause of headache, which is a topic that must be better elucidated. Therefore, longitudinal neuroimaging studies on migraine patients with large samples sizes should be performed using more advanced neuroimaging techniques.

Iron-induced neuronal damage in a rat model of post-traumatic stress disorder.

Previous studies have shown that iron redistribution and deposition in the brain occurs in some neurodegenerative diseases, and oxidative damage due to abnormal iron level is a primary cause of neuronal death. In the present study, we used the single prolonged stress (SPS) model to mimic post-traumatic stress disorder (PTSD), and examined whether iron was involved in the progression of PTSD. The anxiety-like behaviors of the SPS group were assessed by the elevated plus maze (EPM) and open field tests, and iron levels were measured by inductively coupled plasma optical emission spectrometer (ICP-OES). Expression of glucocorticoid receptors and transferrin receptor 1 (TfR1) and ferritin (Fn) was detected by Western blot and immunohistochemistry in selected brain areas; TfR1 and Fn mRNA expression were detected by quantitative-polymerase chain reaction (Q-PCR). Ultrastructures of the hippocampus were observed under a transmission electron microscope. Our results showed that SPS exposure induced anxiety-like symptoms and increased the level of serum cortisol and the concentration of iron in key brain areas such as the hippocampus, prefrontal cortex, and striatum. The stress induced region-specific changes in both protein and mRNA levels of TfR1 and Fn. Moreover, swelling mitochondria and cell apoptosis were observed in neurons in brain regions with iron accumulation. We concluded that SPS stress increased iron in some cognition-related brain regions and subsequently cause neuronal injury, indicating that the iron may function in the pathology of PTSD.

LAPONITE®-stabilized iron oxide nanoparticles for in vivo MR imaging of tumors.

We report the synthesis, characterization and utilization of LAPONITE®-stabilized magnetic iron oxide nanoparticles (LAP-Fe3O4 NPs) as a high performance contrast agent for in vivo magnetic resonance (MR) detection of tumors. In this study, Fe3O4 NPs were synthesized by a facile controlled coprecipitation route in LAP solution, and the formed LAP-Fe3O4 NPs have great colloidal stability and about 2-fold increase of T2 relaxivity than Fe3O4 NPs (from 247.6 mM(-1) s(-1) to 475.9 mM(-1) s(-1)). Moreover, cytotoxicity assay and cell morphology observation demonstrate that LAP-Fe3O4 NPs display good biocompatibility in the given Fe concentration range, and in vivo biodistribution results prove that NPs can be metabolized and cleared out of the body. Most importantly, LAP-Fe3O4 NPs can not only be used as a contrast agent for MR imaging of cancer cells in vitro due to the effective uptake by tumor cells, but also significantly enhance the contrast of a xenografted tumor model. Therefore, the developed LAP-based Fe3O4 NPs with good colloidal stability and exceptionally high transverse relaxivity may have tremendous potential in MR imaging applications.