The existence of immunological memory in invertebrates remains a contentious topic. Exposure of Daphnia magna crustaceans to a noninfectious dose of the bacterium Pasteuria ramosa has been reported ...to reduce the chance of future infection upon exposure to higher doses. Using clonal hosts and parasites, we tested whether initial exposure of the host to the parasite (priming), followed by clearing of the parasite with antibiotic, protects the host from a second exposure (challenge). Our experiments included three treatments: priming and challenge with the same or with a different parasite clone, or no priming. Two independent experiments showed that both the likelihood of infection and the degree of parasite proliferation did not differ between treatments, supporting the conclusion that there is no immunological memory in this system. We discuss the possibility that previous discordant reports could result from immune or stress responses that did not fade following initial priming.
•We tested immune priming in invertebrates, a contentious topic.•Previous studies did not take into account specificity and memory effects.•We tested if exposure of Daphnia to a natural parasite can have a vaccination effect.•Prior exposure did not reduce likelihood or parasite load of future infection.•We did not confirm immune priming confers a long lasting protection to Daphnia.
Purpose
To develop a method to automatically detect multiple sclerosis (MS) lesions, located both in white matter (WM) and in the cortex, in patients with low disability and early disease stage.
...Materials and Methods
We developed a lesion detection method, based on the k‐nearest neighbor (k‐NN) technique, to detect lesions as small as 0.0036 mL. This method uses the image intensity information from up to four different 3D magnetic resonance imaging (MRI) sequences (magnetization‐prepared rapid gradient‐echo, MPRAGE; magnetization‐prepared two inversion‐contrast rapid gradient‐echo, MP2RAGE; 3D fluid‐attenuated inversion recovery, FLAIR; and 3D double‐inversion recovery, DIR), acquired on a 3T scanner. To these intensity features we added the information obtained by the spatial coordinates and tissue prior probabilities provided by the International Consortium for Brain Mapping (ICBM). Quantitative assessment was done in 39 early‐stage MS patients with a “leave‐one‐out” cross‐validation.
Results
The best lesion detection rate (DR) performance in WM was obtained using MP2RAGE, FLAIR, and DIR intensities (77% for lesions ≥0.0036 mL; 85% for lesions ≥0.005 mL). Similar results were obtained excluding the DIR intensity as well as when using only MPRAGE and FLAIR (DR = 75%, P = 0.5720). However, the combination of FLAIR with DIR and MP2RAGE appeared to be the best for detecting cortical lesions (DR = 62%), compared to the other combination of sequences (P < 0.001).
Conclusion
For WM lesion detection, similar results were observed when only conventional clinical sequences (FLAIR, MPRAGE) were used compared to a combination of conventional and “advanced” sequences (MP2RAGE, DIR). Cortical lesion detection increased significantly when “advanced” sequences were used. J. Magn. Reson. Imaging 2015. J. Magn. Reson. Imaging 2016;43:1445–1454.
Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with ...multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies.
For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry.
We obtained 10 133 blood samples from 5390 people (median samples per patient 1 IQR 1–2 in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 IQR 3·0–8·0). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35–4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08–6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry.
The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials.
Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche.
ABSTRACT In a six-year program started in 2014 July, the Extended Baryon Oscillation Spectroscopic Survey (eBOSS) will conduct novel cosmological observations using the BOSS spectrograph at Apache ...Point Observatory. These observations will be conducted simultaneously with the Time Domain Spectroscopic Survey (TDSS) designed for variability studies and the Spectroscopic Identification of eROSITA Sources (SPIDERS) program designed for studies of X-ray sources. In particular, eBOSS will measure with percent-level precision the distance-redshift relation with baryon acoustic oscillations (BAO) in the clustering of matter. eBOSS will use four different tracers of the underlying matter density field to vastly expand the volume covered by BOSS and map the large-scale-structures over the relatively unconstrained redshift range 0.6 < z < 2.2. Using more than 250,000 new, spectroscopically confirmed luminous red galaxies at a median redshift z = 0.72, we project that eBOSS will yield measurements of the angular diameter distance dA(z) to an accuracy of 1.2% and measurements of H(z) to 2.1% when combined with the z > 0.6 sample of BOSS galaxies. With ∼195,000 new emission line galaxy redshifts, we expect BAO measurements of dA(z) to an accuracy of 3.1% and H(z) to 4.7% at an effective redshift of z = 0.87. A sample of more than 500,000 spectroscopically confirmed quasars will provide the first BAO distance measurements over the redshift range 0.9 < z < 2.2, with expected precision of 2.8% and 4.2% on dA(z) and H(z), respectively. Finally, with 60,000 new quasars and re-observation of 60,000 BOSS quasars, we will obtain new Ly forest measurements at redshifts z > 2.1; these new data will enhance the precision of dA(z) and H(z) at z > 2.1 by a factor of 1.44 relative to BOSS. Furthermore, eBOSS will provide improved tests of General Relativity on cosmological scales through redshift-space distortion measurements, improved tests for non-Gaussianity in the primordial density field, and new constraints on the summed mass of all neutrino species. Here, we provide an overview of the cosmological goals, spectroscopic target sample, demonstration of spectral quality from early data, and projected cosmological constraints from eBOSS.
Genomes of animals as different as sponges and humans show conservation of global architecture. Here we show that multiple genomic features including transposon diversity, developmental gene ...repertoire, physical gene order, and intron-exon organization are shattered in the tunicate Oikopleura, belonging to the sister group of vertebrates and retaining chordate morphology. Ancestral architecture of animal genomes can be deeply modified and may therefore be largely nonadaptive. This rapidly evolving animal lineage thus offers unique perspectives on the level of genome plasticity. It also illuminates issues as fundamental as the mechanisms of intron gain.
Invertebrate immune response may be primed by a current infection in a sustained manner, leading to the failure of a secondary infection with the same pathogen. The present study focuses on the ...Schistosomiasis vector snail Biomphalaria glabrata, in which a specific genotype-dependent immunological memory was demonstrated as a shift from a cellular to a humoral immune response.
Herein, we investigate the complex molecular bases associated with this genotype-dependant immunological memory response. We demonstrate that Biomphalaria regulates a polymorphic set of immune recognition molecules and immune effector repertoires to respond to different strains of Schistosoma parasites. These results suggest a combinatorial usage of pathogen recognition receptors (PRRs) that distinguish different strains of parasites during the acquisition of immunological memory. Immunizations also show that snails become resistant after exposure to parasite extracts. Hemolymph transfer and a label-free proteomic analysis proved that circulating hemolymph compounds can be produced and released to more efficiently kill the newly encountered parasite of the same genetic lineage.
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•Immunological memory (IM) has been now demonstrated in numerous invertebrate models.•A high level of specificity of IM has been demonstrated in Biomphalaria glabrata snails.•Efficiency of IM seems to be supported by a potential combinatorial usage of PRRs.•PRRs and cytolytic/cytotoxic compounds were mandatory for parasite killing.
The infection process of many diseases can be divided into series of steps, each one required to successfully complete the parasite's life and transmission cycle. This approach often reveals that the ...complex phenomenon of infection is composed of a series of more simple mechanisms. Here we demonstrate that a population biology approach, which takes into consideration the natural genetic and environmental variation at each step, can greatly aid our understanding of the evolutionary processes shaping disease traits. We focus in this review on the biology of the bacterial parasite Pasteuria ramosa and its aquatic crustacean host Daphnia, a model system for the evolutionary ecology of infectious disease. Our analysis reveals tremendous differences in the degree to which the environment, host genetics, parasite genetics and their interactions contribute to the expression of disease traits at each of seven different steps. This allows us to predict which steps may respond most readily to selection and which steps are evolutionarily constrained by an absence of variation. We show that the ability of Pasteuria to attach to the host's cuticle (attachment step) stands out as being strongly influenced by the interaction of host and parasite genotypes, but not by environmental factors, making it the prime candidate for coevolutionary interactions. Furthermore, the stepwise approach helps us understanding the evolution of resistance, virulence and host ranges. The population biological approach introduced here is a versatile tool that can be easily transferred to other systems of infectious disease.
To assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament ...light chain (sNfL) levels, a marker of neuroaxonal damage.
In 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases.
In univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68;
< 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4;
= 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (β
, 16.3; 95% confidence interval CI, 4.6-28.0;
< 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; β
, 30.4; 95% CI, 15.6-45.2;
< 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (β
, 1.1; 95% CI, 0.3-1.9;
< 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center:
= 0.004 and
= 0.0002, respectively).
Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.
•Optimized de novo transcriptome assembly allows the study of highly diversified molecules.•We increased over two fold the number of bonafide FREP gene subfamilies.•FREP12 are constitutively highly ...diversified.•C-type lectin-related proteins (CREPs) combine an IgSF domain with a C-type lectin domain.•Galectin-related protein (GREP) combines two IgSF domains with a Galectin domain.•FREPs, CREPs and GREP constitute the VIgL family.
Technical limitations have hindered comprehensive studies of highly variable immune response molecules that are thought to have evolved due to pathogen-mediated selection such as fibrinogen-related proteins (FREPs) from Biomphalaria glabrata. FREPs combine upstream immunoglobulin superfamily (IgSF) domains with a C-terminal fibrinogen-related domain (FreD) and participate in reactions against trematode parasites. From RNAseq data we assembled a de novo reference transcriptome of B. glabrata to investigate the diversity of FREP transcripts. This study increased over two fold the number of bonafide FREP subfamilies and revealed important sequence diversity within FREP12 subfamily. We also report the discovery of related molecules that feature one or two IgSF domains associated with different C-terminal lectin domains, named C-type lectin-related proteins (CREPs) and Galectin-related protein (GREP). Together, the highly similar FREPs, CREPs and GREP were designated VIgL (Variable Immunoglobulin and Lectin domain containing molecules).
Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients ...experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA.
From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses.
In total, 445 patients with MS (64.9% female; mean SD age at baseline 45.0 11.4 years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change MD-APC -1.41;
= 0.004) and higher PRL load (incidence rate ratio IRR 1.93;
= 0.005). Increased spinal cord atrophy (MD-APC -1.39;
= 0.0008) and PRL burden (IRR 1.95;
= 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all
≤ 0.002).
Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.
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