ABSTRACT
The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.
Subject(s)
Nephritis, Interstitial/virology , Parvovirus/isolation & purification , Parvovirus/pathogenicity , Animals , Australia , Disease Progression , Female , Fibrosis/pathology , Fibrosis/virology , Humans , Kidney/metabolism , Kidney/physiology , Male , Mice , Mice, Inbred C57BL , Nephritis, Interstitial/physiopathology , North America , Parvoviridae Infections/metabolismABSTRACT
We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.
Subject(s)
Betacoronavirus/immunology , Clinical Laboratory Techniques/methods , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Immunity, Humoral , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Arizona/epidemiology , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Nucleocapsid Proteins , Female , Humans , Male , Middle Aged , Nucleocapsid Proteins/immunology , Pandemics , Phosphoproteins , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Prevalence , Protein Interaction Domains and Motifs , SARS-CoV-2 , Seroepidemiologic Studies , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Young AdultABSTRACT
The ß-barrel assembly machine (BAM) integrates ß-barrel proteins into the outer membrane (OM) of Gram-negative bacteria. An essential BAM subunit (BamA) catalyzes integration by promoting the formation of a hybrid-barrel intermediate state between its own ß-barrel domain and that of its client proteins. Here we show that in addition to catalyzing the integration of ß-barrel proteins, BamA functions as a polypeptide export channel. In vivo structural mapping via intermolecular disulfide crosslinking showed that the extracellular "passenger" domain of a member of the "autotransporter" superfamily of virulence factors traverses the OM through the BamA ß-barrel lumen. Furthermore, we demonstrate that a highly conserved residue within autotransporter ß-barrels is required to position the passenger inside BamA to initiate translocation and that during translocation, the passenger stabilizes the hybrid-barrel state. Our results not only establish a new function for BamA but also unify the divergent functions of BamA and other "Omp85" superfamily transporters.
Subject(s)
Bacterial Outer Membrane Proteins/metabolism , Bacterial Outer Membrane/metabolism , Escherichia coli K12/metabolism , Escherichia coli Proteins/metabolism , Bacterial Outer Membrane Proteins/genetics , Biological Transport , Conserved Sequence , Escherichia coli K12/genetics , Escherichia coli Proteins/genetics , Protein Conformation , Protein Folding , Structure-Activity Relationship , TryptophanABSTRACT
Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.
Subject(s)
Child Development Disorders, Pervasive/genetics , Chromosome Aberrations , Autistic Disorder/diagnosis , Autistic Disorder/genetics , Child , Child Development Disorders, Pervasive/diagnosis , Chromosome Breakage , Chromosome Deletion , DNA Copy Number Variations , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Nervous System/growth & development , Schizophrenia/genetics , Sequence Analysis, DNA , Signal TransductionABSTRACT
The C-terminal domain of the cellular prion protein (PrPC) contains two N-linked glycosylation sites, the occupancy of which impacts disease pathology. In this study, we demonstrate that glycans at these sites are required to maintain an intramolecular interaction with the N-terminal domain, mediated through a previously identified copper-histidine tether, which suppresses the neurotoxic activity of PrPC. NMR and electron paramagnetic resonance spectroscopy demonstrate that the glycans refine the structure of the protein's interdomain interaction. Using whole-cell patch-clamp electrophysiology, we further show that cultured cells expressing PrP molecules with mutated glycosylation sites display large, spontaneous inward currents, a correlate of PrP-induced neurotoxicity. Our findings establish a structural basis for the role of N-linked glycans in maintaining a nontoxic, physiological fold of PrPC.
ABSTRACT
The ability to adapt our locomotion in a feedforward (i.e., "predictive") manner is crucial for safe and efficient walking behavior. Equally important is the ability to quickly deadapt and update behavior that is no longer appropriate for the given context. It has been suggested that anxiety induced via postural threat may play a fundamental role in disrupting such deadaptation. We tested this hypothesis, using the "broken escalator" phenomenon: Fifty-six healthy young adults walked onto a stationary walkway ("BEFORE" condition, 5 trials), then onto a moving walkway akin to an airport travelator ("MOVING" condition, 10 trials), and then again onto the stationary walkway ("AFTER" condition, 5 trials). Participants completed all trials while wearing a virtual reality headset, which was used to induce postural threat-related anxiety (raised clifflike drop at the end of the walkway) during different phases of the paradigm. We found that performing the locomotor adaptation phase in a state of increased threat disrupted subsequent deadaptation during AFTER trials: These participants displayed anticipatory muscular activity as if expecting the platform to move and exhibited inappropriate anticipatory forward trunk movement that persisted during multiple AFTER trials. In contrast, postural threat induced during AFTER trials did not affect behavioral or neurophysiological outcomes. These findings highlight that actions learned in the presence of postural threat-induced anxiety are strengthened, leading to difficulties in deadapting these behaviors when no longer appropriate. Given the associations between anxiety and persistent maladaptive gait behaviors (e.g., "overly cautious" gait, functional gait disorders), the findings have implications for the understanding of such conditions.NEW & NOTEWORTHY Safe and efficient locomotion frequently requires movements to be adapted in a feedforward (i.e., "predictive") manner. These adaptations are not always correct, and thus inappropriate behavior must be quickly updated. Here we showed that increased threat disrupts this process. We found that locomotor actions learned in the presence of postural threat-induced anxiety are strengthened, subsequently impairing one's ability to update (or "deadapt") these actions when they are no longer appropriate for the current context.
Subject(s)
Learning , Walking , Young Adult , Humans , Walking/physiology , Learning/physiology , Gait/physiology , Locomotion/physiology , Anxiety , Postural Balance/physiologyABSTRACT
INTRODUCTION: The current obesity crisis has resulted in many people with excess adipose tissue suffering from chronic inflammation. This inflammation is largely due to the release of cytokines and chemokines from visceral fat. The aim of this study was to identify potential anti-inflammatory agents that might alleviate obesity-induced chronic inflammation. METHODS: To identify agents that might alleviate this obesity-induced chronic inflammation we have developed a simple protocol for incubating intact pieces of human visceral adipose tissue in 35 mm tissue culture plates, in the presence of low-dose lipopolysaccharide (LPS) and co-incubating these samples with potential anti-inflammatory agents. RNA-Seq analysis was performed to identify enriched gene expression signatures among the most significantly differentially expressed genes. RESULTS: From this screen, we have identified the short-chain fatty acid (SCFA) sodium butyrate and its triacylglyceride form, tributyrin, as effective agents, significantly reducing the production of LPS-induced inflammatory cytokines and chemokines from all adipose tissue samples tested. As well, these agents appear to be non-toxic at the concentrations tested. RNA-Seq analysis has revealed that IL36γ is one of the most upregulated genes in response to LPS and one of the most downregulated when sodium butyrate is added to human fat samples stimulated with LPS. IL-36γ ELISAs confirmed this holds true at the protein level as well. CONCLUSIONS: These studies suggest that the short-chain fatty acid, sodium butyrate, and its triacylglyceride form, tributyrin, might alleviate the chronic inflammation that is associated with many individuals with obesity.
ABSTRACT
OBJECTIVE: Acute calcium pyrophosphate (CPP) crystal arthritis is a distinct manifestation of calcium pyrophosphate crystal deposition (CPPD). No studies have specifically examined whether acute CPP crystal arthritis is associated with progressive structural joint damage. The objective of this retrospective cohort study was to evaluate the relative rate of hip and knee joint arthroplasties as an estimate of structural joint damage accrual, in a population of patients with acute CPP crystal arthritis. METHODS: Data were collected from Waikato District Health Board (WDHB) to identify an acute CPP crystal arthritis cohort with clinical episodes highly characteristic of acute CPP crystal arthritis. Data on hip and knee joint arthroplasties were collected from the New Zealand Orthopaedic Association's Joint Registry. The rate of arthroplasties in the cohort was compared with the age-ethnicity-matched New Zealand population. Additional analysis was performed for age, obesity (BMI) and ethnicity. RESULTS: The acute CPP crystal arthritis cohort included 99 patients; 63 were male and the median age was 77 years (interquartile range, 71-82). The obesity rate was 36% with a median BMI of 28.4 kg/m2 (interquartile range, 25.8-32.2), comparable to the New Zealand population. The standardized surgical rate ratio in the cohort vs the age-ethnicity-matched New Zealand population was 2.54 (95% CI: 1.39, 4.27). CONCLUSION: Our study identified a considerable increase in the rate of hip and knee joint arthroplasties in patients with episodes of acute CPP crystal arthritis. This suggests CPP crystal arthritis may be a chronic condition, leading to progressive joint damage.
Subject(s)
Chondrocalcinosis , Humans , Male , Aged , Female , Calcium Pyrophosphate , Retrospective Studies , Knee Joint/surgery , ObesityABSTRACT
BACKGROUND: Recent multicenter, multivendor MRI-based R2* vs. liver iron concentration (LIC) calibrations (i.e., MCMV calibrations) may facilitate broad clinical dissemination of R2*-based LIC quantification. However, these calibrations are based on a centralized offline R2* reconstruction, and their applicability with vendor-provided R2* maps is unclear. PURPOSE: To determine R2* ranges of agreement between the centralized and three MRI vendors' R2* reconstructions. STUDY TYPE: Prospective. SUBJECTS: Two hundred and seven subjects (mean age 37.6 ± 19.6 years; 117 male) with known or suspected iron overload from four academic medical centers. FIELD STRENGTH/SEQUENCE: Standardized multiecho spoiled gradient echo sequence at 1.5 T and 3.0 T for R2* mapping and a multiple spin-echo sequence at 1.5 T for LIC quantification. MRI vendors: GE Healthcare, Philips Healthcare, and Siemens Healthineers. ASSESSMENT: R2* maps were generated using both the centralized and vendor reconstructions, and ranges of agreement were determined. R2*-LIC linear calibrations were determined for each site, field strength, and reconstruction and compared with the MCMV calibrations. STATISTICAL TESTS: Bland-Altman analysis to determine ranges of agreement. Linear regression, analysis of covariance F tests, and Tukey's multiple comparison testing to assess reproducibility of calibrations across sites and vendors. A P value <0.05 was considered significant. RESULTS: The upper limits of R2* ranges of agreement were approximately 500, 375, and 330 s-1 for GE, Philips, and Siemens reconstructions, respectively, at 1.5 T and approximately 700 and 800 s-1 for GE and Philips, respectively, at 3.0 T. Within the R2* ranges of agreement, vendor R2*-LIC calibrations demonstrated high reproducibility (no significant differences between slopes or intercepts; P ≥ 0.06) and agreed with the MCMV calibrations (overlapping 95% confidence intervals). DATA CONCLUSION: Based on the determined upper limits, R2* measurements obtained from vendor-provided R2* maps may be reliably and practically used to quantify LIC less than approximately 8-13 mg/g using the MCMV calibrations and similar acquisition parameters as this study. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.
ABSTRACT
Several competing neuro-computational theories of autism have emerged from predictive coding models of the brain. To disentangle their subtly different predictions about the nature of atypicalities in autistic perception, we performed computational modelling of two sensorimotor tasks: the predictive use of manual gripping forces during object lifting and anticipatory eye movements during a naturalistic interception task. In contrast to some accounts, we found no evidence of chronic atypicalities in the use of priors or weighting of sensory information during object lifting. Differences in prior beliefs, rates of belief updating, and the precision weighting of prediction errors were, however, observed for anticipatory eye movements. Most notably, we observed autism-related difficulties in flexibly adapting learning rates in response to environmental change (i.e., volatility). These findings suggest that atypical encoding of precision and context-sensitive adjustments provide a better explanation of autistic perception than generic attenuation of priors or persistently high precision prediction errors. Our results did not, however, support previous suggestions that autistic people perceive their environment to be persistently volatile.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Humans , Learning , Eye Movements , BrainABSTRACT
We report the effect of shape anisotropy and material properties on the directed assembly of binary suspensions composed of magnetizable ellipsoids. In a Monte Carlo simulation, we implement the ellipsoid-dipole model to calculate the pairwise dipolar interaction energy as a function of position and orientation. The analysis explores dilute suspensions of paramagnetic and diamagnetic ellipsoids with different aspect ratios in a superparamagnetic medium. We analyze the local order of binary structures as a function of particle aspect ratio, medium permeability, and dipolar interaction strength. Our results show that local order and symmetry are tunable under the influence of a uniform magnetic field when one component of the structure is dilute with respect to the other. The simulation results match previously reported experiments on the directed assembly of binary suspension of spheres. Additionally, we report the conditions on particle aspect ratios and medium properties for various structures with rotational symmetries, as well as open and enclosed structures under the influence of a uniform magnetic field.
ABSTRACT
Pentraxin-related protein 3 (PTX3), commonly produced by myeloid and endothelial cells, is a humoral pattern recognition protein of the innate immune system. Because PTX3 plasma levels of patients with chronic lymphocytic leukemia (CLL) are high and most circulating cells in patients with CLL are CLL cells, we reasoned that CLL cells produce PTX3. Western immunoblotting revealed that low-density cells from seven of seven patients with CLL produce high levels of PTX3, flow cytometry analysis revealed that the PTX3-producing cells are B lymphocytes coexpressing CD19 and CD5, and confocal microscopy showed that PTX3 is present in the cytoplasm of CLL cells. Because STAT3 is constitutively activated in CLL cells, and because we identified putative STAT3 binding sites within the PTX3 gene promoter, we postulated that phosphorylated STAT3 triggers transcriptional activation of PTX3. Immunoprecipitation analysis of CLL cells' chromatin fragments showed that STAT3 Abs precipitated PTX3 DNA. STAT3 knockdown induced a marked reduction in PTX3 expression, indicating a STAT3-induced transcriptional activation of the PTX3 gene in CLL cells. Using an EMSA, we established and used a dual-reporter luciferase assay to confirm that STAT3 binds the PTX3 gene promoter. Downregulation of PTX3 enhanced apoptosis of CLL cells, suggesting that inhibition of PTX3 might benefit patients with CLL.
Subject(s)
C-Reactive Protein , Leukemia, Lymphocytic, Chronic, B-Cell , STAT3 Transcription Factor , Serum Amyloid P-Component , C-Reactive Protein/genetics , C-Reactive Protein/metabolism , Endothelial Cells/metabolism , Humans , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Serum Amyloid P-Component/genetics , Serum Amyloid P-Component/metabolismABSTRACT
The responses of tropical forests to environmental change are critical uncertainties in predicting the future impacts of climate change. The positive phase of the 2015-2016 El Niño Southern Oscillation resulted in unprecedented heat and low precipitation in the tropics with substantial impacts on the global carbon cycle. The role of African tropical forests is uncertain as their responses to short-term drought and temperature anomalies have yet to be determined using on-the-ground measurements. African tropical forests may be particularly sensitive because they exist in relatively dry conditions compared with Amazonian or Asian forests, or they may be more resistant because of an abundance of drought-adapted species. Here, we report responses of structurally intact old-growth lowland tropical forests inventoried within the African Tropical Rainforest Observatory Network (AfriTRON). We use 100 long-term inventory plots from six countries each measured at least twice prior to and once following the 2015-2016 El Niño event. These plots experienced the highest temperatures and driest conditions on record. The record temperature did not significantly reduce carbon gains from tree growth or significantly increase carbon losses from tree mortality, but the record drought did significantly decrease net carbon uptake. Overall, the long-term biomass increase of these forests was reduced due to the El Niño event, but these plots remained a live biomass carbon sink (0.51 ± 0.40 Mg C ha-1 y-1) despite extreme environmental conditions. Our analyses, while limited to African tropical forests, suggest they may be more resistant to climatic extremes than Amazonian and Asian forests.
Subject(s)
Climate Change , Rainforest , Trees/growth & development , Tropical Climate , Carbon Cycle , Droughts , El Nino-Southern Oscillation , Hot Temperature , Humans , SeasonsABSTRACT
OBJECTIVE: This scoping review aims to explore published literature testing Virtual Reality (VR) interventions for improving upper limb motor performance in children and adolescents with Developmental Coordination Disorder (DCD). Our primary focus was on the types of VR systems used and the measurement tools employed within the International Classification of Functioning, Disability and Health Children and Youth Version (ICF-CY) domains in these studies. METHODS: A comprehensive search of six electronic databases up to 11th January 2024 was conducted using predefined terms. Inclusion and exclusion criteria were applied to determine study eligibility, with two authors independently assessing titles, abstracts, and full-text articles. RESULTS: Out of 788 potential studies, 14 met the eligibility criteria. Studies predominantly utilized non-immersive VR (nVR) systems, for example, commercial platforms such as Nintendo Wii. Most interventions targeted general motor coordination or balance, with only four studies specifically focusing on upper limb motor performance. The Movement Assessment Battery for Children-2 was the predominant assessment tool. However, the use of game scores and trial durations raised concerns about the accuracy of assessments. The majority of studies reported no significant improvement in upper limb motor performance following VR interventions, though some noted improvements in specific tasks or overall outcomes. CONCLUSION: The findings suggest that, while nVR interventions are being explored for paediatric motor rehabilitation, their impact on enhancing upper limb motor performance in children with DCD is unclear. The variability in intervention designs, outcome measures, and the predominant focus on general motor skills rather than specific upper limb improvements highlight the need for more targeted research in this area. IMPACT: This review underscores the importance of developing precise and clinically relevant measurement tools in a broader range of VR technologies to optimize the use of VR in therapy for children with DCD. Future research should aim for more rigorous study designs and emerging immersive technologies to maximize therapeutic benefits.
Subject(s)
Motor Skills Disorders , Upper Extremity , Virtual Reality Exposure Therapy , Adolescent , Child , Humans , International Classification of Functioning, Disability and Health , Motor Skills/physiology , Motor Skills Disorders/rehabilitation , Motor Skills Disorders/diagnosis , Upper Extremity/physiopathology , Video Games , Virtual Reality , Virtual Reality Exposure Therapy/methodsABSTRACT
PURPOSE: Collaborations between basic science educators (BE) and clinical educators (CE) in medical education are common and necessary to create integrated learning materials. However, few studies describe experiences of or processes used by educators engaged in interdisciplinary teamwork. We use the lens of boundary crossing to explore processes described by BE and CE that support the co-creation of integrated learning materials, and the impact that this work has on them. MATERIALS AND METHODS: We conducted qualitative content analysis on program evaluation data from 27 BE and CE who worked on 12 teams as part of a multi-institutional instructional design project. RESULTS: BE and CE productively engaged in collaboration using boundary crossing mechanisms. These included respecting diverse perspectives and expertise and finding efficient processes for completing shared work that allow BE and CE to build on each other's contributions. BE and CE developed confidence in connecting clinical concepts with causal explanations, and willingness to engage in and support such collaborations at their own institutions. CONCLUSIONS: BE and CE report the use of boundary crossing mechanisms that support collaboration in instructional design. Such practices could be harnessed in future collaborations between BE and CE.
Subject(s)
Cooperative Behavior , Faculty, Medical , Humans , Education, Medical/organization & administration , Qualitative Research , Program Evaluation , Science/educationABSTRACT
The interception (or avoidance) of moving objects is a common component of various daily living tasks; however, it remains unclear whether precise alignment of foveal vision with a target is important for motor performance. Furthermore, there has also been little examination of individual differences in visual tracking strategy and the use of anticipatory gaze adjustments. We examined the importance of in-flight tracking and predictive visual behaviors using a virtual reality environment that required participants (n = 41) to intercept tennis balls projected from one of two possible locations. Here, we explored whether different tracking strategies spontaneously arose during the task, and which were most effective. Although indices of closer in-flight tracking (pursuit gain, tracking coherence, tracking lag, and saccades) were predictive of better interception performance, these relationships were rather weak. Anticipatory gaze shifts toward the correct release location of the ball provided no benefit for subsequent interception. Nonetheless, two interceptive strategies were evident: 1) early anticipation of the ball's onset location followed by attempts to closely track the ball in flight (i.e., predictive strategy); or 2) positioning gaze between possible onset locations and then using peripheral vision to locate the moving ball (i.e., a visual pivot strategy). Despite showing much poorer in-flight foveal tracking of the ball, participants adopting a visual pivot strategy performed slightly better in the task. Overall, these results indicate that precise alignment of the fovea with the target may not be critical for interception tasks, but that observers can adopt quite varied visual guidance approaches.
Subject(s)
Individuality , Motion Perception , Humans , Male , Female , Young Adult , Motion Perception/physiology , Adult , Psychomotor Performance/physiology , Fixation, Ocular/physiology , Virtual Reality , Saccades/physiology , Fovea Centralis/physiology , Eye Movements/physiologyABSTRACT
Obesity-related cancers account for 40% of the cancer cases observed in the USA and obesity is overtaking smoking as the most widespread modifiable risk factor for carcinogenesis. Here, we use the hallmarks of cancer framework to delineate how obesity might influence the carcinogenic hallmarks in somatic cells. We discuss the effects of obesity on (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) resisting cell death; (d) enabling replicative immortality; (e) inducing angiogenesis; (f) activating invasion and metastasis; (g) reprogramming energy metabolism; and (h) avoiding immune destruction, together with its effects on genome instability and tumour-promoting inflammation. We present the current understanding and controversies in this evolving field, and highlight some areas in need of further cross-disciplinary focus. For instance, the relative importance of the many potentially causative obesity-related factors is unclear for each type of malignancy. Even within a single tumour type, it is currently unknown whether one obesity-related factor consistently plays a predominant role, or if this varies between patients or, even in a single patient with time. Clarifying how the hallmarks are affected by obesity may lead to novel prevention and treatment strategies for the increasingly obese population.
Subject(s)
Carcinogenesis , Neoplasms , Humans , Neoplasms/metabolism , Neovascularization, Pathologic/pathology , Obesity/complications , Signal TransductionABSTRACT
Previous studies found cDC1s to be protective in early stage anti-GBM disease through Tregs, but pathogenic in late stage Adriamycin nephropathy through CD8+ T cells. Flt3 ligand is a growth factor essential for cDC1 development and Flt3 inhibitors are currently used for cancer treatment. We conducted this study to clarify the role and mechanisms of effects of cDC1s at different time points in anti-GBM disease. In addition, we aimed to utilize drug repurposing of Flt3 inhibitors to target cDC1s as a treatment of anti-GBM disease. We found that in human anti-GBM disease, the number of cDC1s increased significantly, proportionally more than cDC2s. The number of CD8+ T cells also increased significantly and their number correlated with cDC1 number. In XCR1-DTR mice, late (day 12-21) but not early (day 3-12) depletion of cDC1s attenuated kidney injury in mice with anti-GBM disease. cDC1s separated from kidneys of anti-GBM disease mice were found to have a pro-inflammatory phenotype (i.e. express high level of IL-6, IL-12 and IL-23) in late but not early stage. In the late depletion model, the number of CD8+ T cells was also reduced, but not Tregs. CD8+ T cells separated from kidneys of anti-GBM disease mice expressed high levels of cytotoxic molecules (granzyme B and perforin) and inflammatory cytokines (TNF-α and IFN-γ), and their expression reduced significantly after cDC1 depletion with diphtheria toxin. These findings were reproduced using a Flt3 inhibitor in wild type mice. Therefore, cDC1s are pathogenic in anti-GBM disease through activation of CD8+ T cells. Flt3 inhibition successfully attenuated kidney injury through depletion of cDC1s. Repurposing Flt3 inhibitors has potential as a novel therapeutic strategy for anti-GBM disease.
Subject(s)
Anti-Glomerular Basement Membrane Disease , CD8-Positive T-Lymphocytes , Drug Repositioning , fms-Like Tyrosine Kinase 3 , Animals , Humans , Mice , Anti-Glomerular Basement Membrane Disease/drug therapy , CD8-Positive T-Lymphocytes/metabolism , Dendritic Cells/metabolism , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Kidney/metabolism , Signal TransductionABSTRACT
BACKGROUND: Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known. METHODS: In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m2 of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULTS: Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m2; median urine albumin:creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m2 per year [95% confidence interval {CI}, -4.11 to -2.55] and -3.23 ml per minute per 1.73 m2 per year [95% CI, -3.98 to -2.47], respectively; mean difference, -0.10 ml per minute per 1.73 m2 per year [95% CI, -1.18 to 0.97]; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group. CONCLUSIONS: In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.).
Subject(s)
Allopurinol/therapeutic use , Diabetes Mellitus, Type 1/drug therapy , Diabetic Nephropathies/drug therapy , Enzyme Inhibitors/therapeutic use , Glomerular Filtration Rate/drug effects , Gout Suppressants/therapeutic use , Uric Acid/blood , Xanthine Oxidase/antagonists & inhibitors , Aged , Allopurinol/adverse effects , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/physiopathology , Diabetic Nephropathies/physiopathology , Disease Progression , Double-Blind Method , Enzyme Inhibitors/adverse effects , Female , Gout Suppressants/adverse effects , Humans , Male , Middle Aged , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/physiopathology , Renin-Angiotensin System , Treatment FailureABSTRACT
Background MRI is a standard of care tool to measure liver iron concentration (LIC). Compared with regulatory-approved R2 MRI, R2* MRI has superior speed and is available in most MRI scanners; however, the cross-vendor reproducibility of R2*-based LIC estimation remains unknown. Purpose To evaluate the reproducibility of LIC via single-breath-hold R2* MRI at both 1.5 T and 3.0 T with use of a multicenter, multivendor study. Materials and Methods Four academic medical centers using MRI scanners from three different vendors (three 1.5-T scanners, one 2.89-T scanner, and two 3.0-T scanners) participated in this prospective cross-sectional study. Participants with known or suspected liver iron overload were recruited to undergo multiecho gradient-echo MRI for R2* mapping at 1.5 T and 3.0 T (2.89 T or 3.0 T) on the same day. R2* maps were reconstructed from the multiecho images and analyzed at a single center. Reference LIC measurements were obtained with a commercial R2 MRI method performed using standardized 1.5-T spin-echo imaging. R2*-versus-LIC calibrations were generated across centers and field strengths using linear regression and compared using F tests. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic performance of R2* MRI in the detection of clinically relevant LIC thresholds. Results A total of 207 participants (mean age, 38 years ± 20 [SD]; 117 male participants) were evaluated between March 2015 and September 2019. A linear relationship was confirmed between R2* and LIC. All calibrations within the same field strength were highly reproducible, showing no evidence of statistically significant center-specific differences (P > .43 across all comparisons). Calibrations for 1.5 T and 3.0 T were generated, as follows: for 1.5 T, LIC (in milligrams per gram [dry weight]) = -0.16 + 2.603 × 10-2 R2* (in seconds-1); for 2.89 T, LIC (in milligrams per gram) = -0.03 + 1.400 × 10-2 R2* (in seconds-1); for 3.0 T, LIC (in milligrams per gram) = -0.03 + 1.349 × 10-2 R2* (in seconds-1). Liver R2* had high diagnostic performance in the detection of clinically relevant LIC thresholds (area under the ROC curve, >0.98). Conclusion R2* MRI enabled accurate and reproducible quantification of liver iron overload over clinically relevant ranges of liver iron concentration (LIC). The data generated in this study provide the necessary calibrations for broad clinical dissemination of R2*-based LIC quantification. ClinicalTrials.gov registration no.: NCT02025543 © RSNA, 2022 Online supplemental material is available for this article.