Frontal and Cerebellar Atrophy Supports FTSD-ALS Clinical Continuum

Background: Frontotemporal Spectrum Disorder (FTSD) and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases often considered as a continuum from clinical, epidemiologic, and genetic perspectives. We used localized brain volume alterations to evaluate common and specific features of FTSD, FTSD-ALS, and ALS patients to further understand this clinical continuum. Methods: We used voxel-based morphometry on structural magnetic resonance images to localize volume alterations in group comparisons: patients (20 FTSD, seven FTSD-ALS, and 18 ALS) versus healthy controls (39 CTR), and patient groups between themselves. We used mean whole-brain cortical thickness (CT¯¯¯¯¯) to assess whether its correlations with local brain volume could propose mechanistic explanations of the heterogeneous clinical presentations. We also assessed whether volume reduction can explain cognitive impairment, measured with frontal assessment battery, verbal fluency, and semantic fluency. Results: Common (mainly frontal) and specific areas with reduced volume were detected between FTSD, FTSD-ALS, and ALS patients, confirming suggestions of a clinical continuum, while at the same time defining morphological specificities for each clinical group (e.g., a difference of cerebral and cerebellar involvement between FTSD and ALS). CT¯¯¯¯¯ values suggested extensive network disruption in the pathological process, with indications of a correlation between cerebral and cerebellar volumes and CT¯¯¯¯¯ in ALS. The analysis of the neuropsychological scores indeed pointed toward an important role for the cerebellum, along with fronto-temporal areas, in explaining impairment of executive, and linguistic functions. Conclusion: We identified common elements that explain the FTSD-ALS clinical continuum, while also identifying specificities of each group, partially explained by different cerebral and cerebellar involvement

Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication

Specific patterns of white matter alterations help distinguishing Alzheimer's and vascular dementia

Alzheimer disease (AD) and vascular dementia (VaD) together represent the majority of dementia cases. Since their neuropsychological profiles often overlap and white matter lesions are observed in elderly subjects including AD, differentiating between VaD and AD can be difficult. Characterization of these different forms of dementia would benefit by identification of quantitative imaging biomarkers specifically sensitive to AD or VaD. Parameters of microstructural abnormalities derived from diffusion tensor imaging (DTI) have been reported to be helpful in differentiating between dementias, but only few studies have used them to compare AD and VaD with a voxelwise approach. Therefore, in this study a whole brain statistical analysis was performed on DTI data of 93 subjects (31 AD, 27 VaD and 35 healthy controls - HC) to identify specific white matter patterns of alteration in patients affected by VaD and AD with respect to HC. Parahippocampal tracts were found to be mainly affected in AD, while VaD showed more spread white matter damages associated with thalamic radiations involvement. The genu of the corpus callosum was predominantly affected in VaD, while the splenium was predominantly affected in AD revealing the existence of specific patterns of alteration useful in distinguishing between VaD and AD. Therefore, DTI parameters of these regions could be informative to understand the pathogenesis and support the etiological diagnosis of dementia. Further studies on larger cohorts of subjects, characterized for brain amyloidosis, will allow to confirm and to integrate the present findings and, furthermore, to elucidate the mechanisms of mixed dementia. These steps will be essential to translate these advances to clinical practice

Within-Host Dynamics of the Hepatitis C Virus Quasispecies Population in HIV-1/HCV Coinfected Patients

HIV/HCV coinfected individuals under highly active antiretroviral therapy (HAART) represent an interesting model for the investigation of the role played by the immune system in driving the evolution of the HCV quasispecies. We prospectively studied the intra-host evolution of the HCV heterogeneity in 8 coinfected subjects, selected from a cohort of 32 patients initiating HAART: 5 immunological responders (group A) and 3 immunological non-responders (group B), and in two HCV singly infected controls not assuming drugs (group C). For all these subjects at least two serial samples obtained at the first observation (before HAART) and more than 1 year later, underwent clonal sequence analysis of partial E1/E2 sequences, encompassing the whole HVR1. Evolutionary rates, dated phylogenies and population dynamics were co-estimated by using a Bayesian Markov Chain Monte Carlo approach, and site specific selection pressures were estimated by maximum likelihood-based methods. The intra-host evolutionary rates of HCV quasispecies was 10 times higher in subjects treated with HAART than in controls without immunodeficiency (1.9 and 2.3×10−3 sub/site/month in group A and B and 0.29×10−3 sub/site/month in group C individuals). The within-host Bayesian Skyline plot analysis showed an exponential growth of the quasispecies populations in immunological responders, coinciding with a peak in CD4 cell counts. On the contrary, quasispecies population remained constant in group B and in group C controls. A significant positive selection pressure was detected in a half of the patients under HAART and in none of the group C controls. Several sites under significant positive selection were described, mainly included in the HVR1. Our data indicate that different forces, in addition to the selection pressure, drive an exceptionally fast evolution of HCV during HAART immune restoration. We hypothesize that an important role is played by the enlargement of the viral replicative space

Metabolic synergies in the biotransformation of organic and metallic toxic compounds by a saprotrophic soil fungus

The saprotrophic fungus Penicillium griseofulvum was chosen as model organism to study responses to a mixture of hexachlorocyclohexane (HCH) isomers (α-HCH, β-HCH, γ-HCH, δ-HCH) and of potentially toxic metals (vanadium, lead) in solid and liquid media. The P. griseofulvum FBL 500 strain was isolated from polluted soil containing high concentrations of HCH isomers and potentially toxic elements (Pb, V). Experiments were performed in order to analyse the tolerance/resistance of this fungus to xenobiotics, and to shed further light on fungal potential in inorganic and organic biotransformations. The aim was to examine the ecological and bioremedial potential of this fungus verifying the presence of mechanisms that allow it to transform HCH isomers and metals under different, extreme, test conditions. To our knowledge, this work is the first to provide evidence on the biotransformation of HCH mixtures, in combination with toxic metals, by a saprotrophic non-white-rot fungus and on the metabolic synergies involved

X-Shooting ULLYSES: Massive stars at low metallicity: I. Project description

Observations of individual massive stars, super-luminous supernovae, gamma-ray bursts, and gravitational wave events involving spectacular black hole mergers indicate that the low-metallicity Universe is fundamentally different from our own Galaxy. Many transient phenomena will remain enigmatic until we achieve a firm understanding of the physics and evolution of massive stars at low metallicity (Z). The Hubble Space Telescope has devoted 500 orbits to observing ∼250 massive stars at low Z in the ultraviolet (UV) with the COS and STIS spectrographs under the ULLYSES programme. The complementary X-Shooting ULLYSES (XShootU) project provides an enhanced legacy value with high-quality optical and near-infrared spectra obtained with the wide-wavelength coverage X-shooter spectrograph at ESOa's Very Large Telescope. We present an overview of the XShootU project, showing that combining ULLYSES UV and XShootU optical spectra is critical for the uniform determination of stellar parameters such as effective temperature, surface gravity, luminosity, and abundances, as well as wind properties such as mass-loss rates as a function of Z. As uncertainties in stellar and wind parameters percolate into many adjacent areas of astrophysics, the data and modelling of the XShootU project is expected to be a game changer for our physical understanding of massive stars at low Z. To be able to confidently interpret James Webb Space Telescope spectra of the first stellar generations, the individual spectra of low-Z stars need to be understood, which is exactly where XShootU can deliver

COordination of Standards in MetabOlomicS (COSMOS): facilitating integrated metabolomics data access

Metabolomics has become a crucial phenotyping technique in a range of research fields including medicine, the life sciences, biotechnology and the environmental sciences. This necessitates the transfer of experimental information between research groups, as well as potentially to publishers and funders. After the initial efforts of the metabolomics standards initiative, minimum reporting standards were proposed which included the concepts for metabolomics databases. Built by the community, standards and infrastructure for metabolomics are still needed to allow storage, exchange, comparison and re-utilization of metabolomics data. The Framework Programme 7 EU Initiative ‘coordination of standards in metabolomics’ (COSMOS) is developing a robust data infrastructure and exchange standards for metabolomics data and metadata. This is to support workflows for a broad range of metabolomics applications within the European metabolomics community and the wider metabolomics and biomedical communities’ participation. Here we announce our concepts and efforts asking for re-engagement of the metabolomics community, academics and industry, journal publishers, software and hardware vendors, as well as those interested in standardisation worldwide (addressing missing metabolomics ontologies, complex-metadata capturing and XML based open source data exchange format), to join and work towards updating and implementing metabolomics standards

Phylogeography of Sardinian Cave Salamanders (Genus Hydromantes) Is Mainly Determined by Geomorphology

Detecting the factors that determine the interruption of gene flow between populations is key to understanding how speciation occurs. In this context, caves are an excellent system for studying processes of colonization, differentiation and speciation, since they represent discrete geographical units often with known geological histories. Here, we asked whether discontinuous calcareous areas and cave systems represent major barriers to gene flow within and among the five species of Sardinian cave salamanders (genus Hydromantes) and whether intraspecific genetic structure parallels geographic distance within and among caves. We generated mitochondrial cytochrome b gene sequences from 184 individuals representing 48 populations, and used a Bayesian phylogeographic approach to infer possible areas of cladogenesis for these species and reconstruct historical and current dispersal routes among distinct populations. Our results show deep genetic divergence within and among all Sardinian cave salamander species, which can mostly be attributed to the effects of mountains and discontinuities in major calcareous areas and cave systems acting as barriers to gene flow. While these salamander species can also occur outside caves, our results indicate that there is a very poor dispersal of these species between separate cave systems