Autoantibodies against eukaryotic translation elongation factor 1 delta in two patients with autoimmune cerebellar ataxia

BackgroundAutoantibodies are useful biomarkers for the early detection and diagnosis of autoimmune cerebellar ataxia (ACA).ObjectiveTo identify novel autoantibody candidates in ACA patients.MethodsPatients with cerebellar ataxia of unknown cause were recruited from July 2018 to February 2023. Anti-neural autoantibodies in patient samples were detected by tissue-based indirect immunofluorescence assay (TBA) on rat cerebellum sections. TBA-positive samples were further screened for well-established anti-neural autoantibodies using commercial kits. Tissue-immunoprecipitation (TIP) and subsequent mass spectrometric (MS) analysis were used to explore the target antigens of autoantibodies in samples that were TBA-positive but negative for known autoantibodies. The specific binding between autoantibodies and the identified target antigen was confirmed by neutralization experiments, recombinant cell-based indirect immunofluorescence assay (CBA), and western blotting experiments.ResultsThe eukaryotic translation elongation factor 1 delta (EEF1D) protein was identified as a target antigen of autoantibodies in samples from a 43-year-old female ACA patient, while the specific binding of autoantibodies and EEF1D was confirmed by subsequent experiments. A second anti-EEF1D autoantibody-positive ACA patient, a 59-year-old female, was detected in simultaneous screening. The main clinical manifestations in each of the two patients were cerebellar syndrome, such as unsteady walking and limb ataxia. Both patients received immunotherapy, including corticosteroids, intravenous immunoglobulin, and mycophenolate mofetil. Their outcomes provided evidence to support the effectiveness of immunotherapy, but the cerebellar atrophy that occurred before treatment may be irreversible.ConclusionIn the current study, we identified anti-EEF1D autoantibody as a novel autoantibody candidate in ACA. Its pathological roles and diagnostic value need to be further verified in larger-scale studies

Cronobacter sakazakii clinical isolates overcome host barriers and evade the immune response

Cronobacter sakazakii is the most frequently clinically isolated species of the Cronobacter genus. However the virulence factors of C. sakazakii including their ability to overcome host barriers remains poorly studied. In this study, ten clinical isolates of C. sakazakii were assessed for their ability to invade and translocate through human microvascular endothelial cells (HBMEC). Their ability to avoid phagocytosis in human macrophages U937 and human brain microglial cells was investigated. Additionally, they were tested for serum sensitivity and the presence of the Cronobacter plasminogen activation gene (cpa) gene, which is reported to confer serum resistance. Our data showed that the clinical C. sakazakii strains invaded and translocated through Caco-2 and HBMEC cell lines and some strains showed significantly higher levels of invasion and translocation. Moreover, C. sakazakii was able to persist and even multiply in phagocytic macrophage and microglial cells. All strains, except one, were able to withstand human serum exposure, the single serum sensitive strain was also the only one which did not encode for the cpa gene. These results demonstrate that C. sakazakii clinical host immune response indicating their capacity to cause diseases such as necrotizing enterocolitis (NEC) and meningitis. Our data showed for the first time the ability of C. sakazakii clinical isolates to survive and multiply within human microglial cells. Additionally, it was shown that C. sakazakii clinical strains have the capacity to translocate through the Caco-2 and HBMEC cell lines paracellularly

An integrated study of geochemistry and mineralogy of the Upper Tukau Formation, Borneo Island (East Malaysia): Sediment provenance, depositional setting and tectonic implications

An integrated study using bulk chemical composition, mineralogy and mineral chemistry of sedimentary rocks from the Tukau Formation of Borneo Island (Sarawak, Malaysia) is presented in order to understand the depositional and tectonic settings during the Neogene. Sedimentary rocks are chemically classified as shale, wacke, arkose, litharenite and quartz arenite and consist of quartz, illite, feldspar, rutile and anatase, zircon, tourmaline, chromite and monazite. All of them are highly matured and were derived from a moderate to intensively weathered source. Bulk and mineral chemistries suggest that these rocks were recycled from sedimentary to metasedimentary source regions with some input from granitoids and mafic-ultramafic rocks. The chondrite normalized REE signature indicates the presence of felsic rocks in the source region. Zircon geochronology shows that the samples were of Cretaceous and Triassic age. Comparable ages of zircon from the Tukau Formation sedimentary rocks, granitoids of the Schwaner Mountains (southern Borneo) and Tin Belt of the Malaysia Peninsular suggest that the principal provenance for the Rajang Group were further uplifted and eroded during the Neogene. Additionally, presence of chromian spinels and their chemistry indicate a minor influence of mafic and ultramafic rocks present in the Rajang Group. From a tectonic standpoint, the Tukau Formation sedimentary rocks were deposited in a passive margin with passive collisional and rift settings. Our key geochemical observation on tectonic setting is comparable to the regional geological setting of northwestern Borneo as described in the literature

D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile

Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis characterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile. Amyloid fibrils comprise the D25V-variant only, showing that wild-type apolipoprotein C-III does not contribute to amyloid deposition in vivo. The mutation profoundly impacts helical structure stability of D25V-variant, which is remarkably fibrillogenic under physiological conditions in vitro producing typical amyloid fibrils in its lipid-free form. D25V apolipoprotein C-III is a new human amyloidogenic protein and the first conferring cardioprotection even in the unfavourable context of renal failure, extending the evidence for an important cardiovascular protective role of apolipoprotein C-III deficiency. Thus, fibrate therapy, which reduces hepatic APOC3 transcription, may delay amyloid deposition in affected patients

Rheumatoid meningitis: a rare neurological complication of rheumatoid arthritis

ObjectiveTo describe the clinical and neuroimaging characteristics of rheumatoid meningitis (RM) in Chinese patients. MethodsThe patients admitted to our hospital with the diagnosis of RM in the past 8 years were retrospectively analyzed. ResultsSix patients with RM were identified among 933 patients admitted with rheumatoid arthritis (RA). The symptoms of meningitis occurred after onset of arthritis in five patients and before onset in one. Headache (n=6), hyperacute focal neurological deficits (n=4) and seizures (n=3) were the most prevalent symptoms. The nadir modified Rankin Scale score was ≥3 in five patients. Rheumatoid factor was elevated in all patients, and interleukin-6 levels in cerebrospinal fluid were dramatically elevated in three of four tested patients. Magnetic resonance imaging of the brain revealed that the meninges were affected in all patients and the cerebral parenchyma was affected in one patient. The lesions were generally located in the frontoparietal region and showed restricted diffusion along the adjacent subarachnoid space. RM occurred during disease-modifying therapy in four patients. In the acute episode, three patients improved on tocilizumab and the other three improved on pulse corticosteroids. For maintenance therapy, two patients received combined therapy of tocilizumab and other immunosuppressive agents, one received adalimumab and methotrexate, and two received low-dose oral corticosteroids with an immunosuppressive agent. Five patients had a good outcome, and one died of Pneumocystis jirovecii pneumonia after stabilization of his neurologic conditions. No relapse of RM occurred on immunotherapy during follow-up. ConclusionsChinese patients with RM share some remarkable clinical and neuroimaging features and respond well to appropriate immunotherapy. Tocilizumab could be a treatment option for this severe complication of RA

Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations

Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Consequently, the degree to which facial traits share a common genetic basis across diverse sets of humans remains largely unknown. We therefore investigated the genetic basis of facial morphology in an East African cohort. We applied an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children. This approach segments the face into hierarchically arranged, multivariate features that capture the shape variation after adjusting for age, sex, height, weight, facial size and population stratification. Genome scans of these multivariate shape phenotypes revealed significant (p < 2.5 × 10−8) signals at 20 loci, which were enriched for active chromatin elements in human cranial neural crest cells and embryonic craniofacial tissue, consistent with an early developmental origin of the facial variation. Two of these associations were in highly conserved regions showing craniofacial-specific enhancer activity during embryological development (5q31.1 and 12q21.31). Six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance (p < 6.25 × 10−10). Cross-population comparisons indicated 10 association signals were shared with Europeans (seven sharing the same associated SNP), and facilitated fine-mapping of causal variants at previously reported loci. Taken together, these results may point to both shared and population-specific components to the genetic architecture of facial variation

Calcineurin Inhibition at the Clinical Phase of Prion Disease Reduces Neurodegeneration, Improves Behavioral Alterations and Increases Animal Survival

Prion diseases are fatal neurodegenerative disorders characterized by a long pre-symptomatic phase followed by rapid and progressive clinical phase. Although rare in humans, the unconventional infectious nature of the disease raises the potential for an epidemic. Unfortunately, no treatment is currently available. The hallmark event in prion diseases is the accumulation of a misfolded and infectious form of the prion protein (PrPSc). Previous reports have shown that PrPSc induces endoplasmic reticulum stress and changes in calcium homeostasis in the brain of affected individuals. In this study we show that the calcium-dependent phosphatase Calcineurin (CaN) is hyperactivated both in vitro and in vivo as a result of PrPSc formation. CaN activation mediates prion-induced neurodegeneration, suggesting that inhibition of this phosphatase could be a target for therapy. To test this hypothesis, prion infected wild type mice were treated intra-peritoneally with the CaN inhibitor FK506 at the clinical phase of the disease. Treated animals exhibited reduced severity of the clinical abnormalities and increased survival time compared to vehicle treated controls. Treatment also led to a significant increase in the brain levels of the CaN downstream targets pCREB and pBAD, which paralleled the decrease of CaN activity. Importantly, we observed a lower degree of neurodegeneration in animals treated with the drug as revealed by a higher number of neurons and a lower quantity of degenerating nerve cells. These changes were not dependent on PrPSc formation, since the protein accumulated in the brain to the same levels as in the untreated mice. Our findings contribute to an understanding of the mechanism of neurodegeneration in prion diseases and more importantly may provide a novel strategy for therapy that is beneficial at the clinical phase of the disease

Appraising the intention of other people: Ecological validity and procedures for investigating effects of lighting for pedestrians

One of the aims of outdoor lighting public spaces such as pathways and subsidiary roads is to help pedestrians to evaluate the intentions of other people. This paper discusses how a pedestrians’ appraisal of another persons’ intentions in artificially lit outdoor environments can be studied. We review the visual cues that might be used, and the experimental design with which effects of changes in lighting could be investigated to best resemble the pedestrian experience in artificially lit urban environments. Proposals are made to establish appropriate operationalisation of the identified visual cues, choice of methods and measurements representing critical situations. It is concluded that the intentions of other people should be evaluated using facial emotion recognition; eye tracking data suggest a tendency to make these observations at an interpersonal distance of 15 m and for a duration of 500 ms. Photographs are considered suitable for evaluating the effect of changes in light level and spectral power distribution. To support investigation of changes in spatial distribution further investigation is needed with 3D targets. Further data are also required to examine the influence of glare

Isolation and Characterization of Cytotoxic, Aggregative Citrobacter freundii

Citrobacter freundii is an infrequent but established cause of diarrhea in humans. However, little is known of its genetic diversity and potential for virulence. We analyzed 26 isolates, including 12 from human diarrheal patients, 2 from human fecal samples of unknown diarrheal status, and 12 from animals, insects, and other sources. Pulsed field gel electrophoresis using XbaI allowed us to divide the 26 isolates into 20 pulse types, while multi-locus sequence typing using 7 housekeeping genes allowed us to divide the 26 isolates into 6 sequence types (STs) with the majority belonging to 4 STs. We analyzed adhesion and cytotoxicity to HEp-2 cells in these 26 strains. All were found to adhere to HEp-2 cells. One strain, CF74, which had been isolated from a goat, showed the strongest aggregative adhesion pattern. Lactate dehydrogenase (LDH) released from HEp-2 cells was evaluated as a measure of cytotoxicity, averaging 7.46%. Strain CF74 induced the highest level of LDH, 24.3%, and caused >50% cell rounding, detachment, and death. We named strain CF74 “cytotoxic and aggregative C. freundii.” Genome sequencing of CF74 revealed that it had acquired 7 genomic islands, including 2 fimbriae islands and a type VI secretion system island, all of which are potential virulence factors. Our results show that aggregative adherence and cytotoxicity play an important role in the pathogenesis of C. freundii