Order-to-Disorder Transition and Hydrogen Bonding in the Jahn-Teller Active NH4CrF3 Fluoroperovskite.

Large quantities of high-purity NH4CrF3 have been synthesized using a wet-chemical method, and its structural chemistry and magnetic properties are investigated in detail for the first time. NH4CrF3 is a tetragonal fluoroperovskite that displays an ordering of the ammonium (NH4+) groups at room temperature and C-type orbital ordering. The ammonium groups order and display distinct signs of hydrogen bonds to nearby fluoride anions by buckling the Cr-F-Cr angle away from 180°. The ammonium ordering remains up to 405 K, much higher than in other ammonium fluoroperovskites, indicating a correlation between the flexibility of the Jahn-Teller ion, the hydrogen bond formation, and the ammonium ordering. At 405 K, an order-to-disorder transition occurs, where the ammonium groups disorder, corresponding to a transition to higher symmetry. This is accompanied by a contraction of the unit cell from breaking hydrogen bonds, similar to the phenomenon observed in water ice melting. The compound orders antiferromagnetically with a Neél temperature of 60 K, an effective paramagnetic moment of 4.3 µB, and a Weiss temperature of -33 K. An A-type antiferromagnetic structure is identified by neutron diffraction, with an ordered moment of 3.72(2) µB.

Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR.

Genome-scale screening experiments in cancer produce long lists of candidate genes that require extensive interpretation for biological insight and prioritization for follow-up studies. Interrogation of gene lists frequently represents a significant and time-consuming undertaking, in which experimental biologists typically combine results from a variety of bioinformatics resources in an attempt to portray and understand cancer relevance. As a means to simplify and strengthen the support for this endeavor, we have developed oncoEnrichR, a flexible bioinformatics tool that allows cancer researchers to comprehensively interrogate a given gene list along multiple facets of cancer relevance. oncoEnrichR differs from general gene set analysis frameworks through the integration of an extensive set of prior knowledge specifically relevant for cancer, including ranked gene-tumor type associations, literature-supported proto-oncogene and tumor suppressor gene annotations, target druggability data, regulatory interactions, synthetic lethality predictions, as well as prognostic associations, gene aberrations and co-expression patterns across tumor types. The software produces a structured and user-friendly analysis report as its main output, where versions of all underlying data resources are explicitly logged, the latter being a critical component for reproducible science. We demonstrate the usefulness of oncoEnrichR through interrogation of two candidate lists from proteomic and CRISPR screens. oncoEnrichR is freely available as a web-based service hosted by the Galaxy platform (https://oncotools.elixir.no), and can also be accessed as a stand-alone R package (https://github.com/sigven/oncoEnrichR).

The immuneML ecosystem for machine learning analysis of adaptive immune receptor repertoires.

Adaptive immune receptor repertoires (AIRR) are key targets for biomedical research as they record past and ongoing adaptive immune responses. The capacity of machine learning (ML) to identify complex discriminative sequence patterns renders it an ideal approach for AIRR-based diagnostic and therapeutic discovery. To date, widespread adoption of AIRR ML has been inhibited by a lack of reproducibility, transparency, and interoperability. immuneML (immuneml.uio.no) addresses these concerns by implementing each step of the AIRR ML process in an extensible, open-source software ecosystem that is based on fully specified and shareable workflows. To facilitate widespread user adoption, immuneML is available as a command-line tool and through an intuitive Galaxy web interface, and extensive documentation of workflows is provided. We demonstrate the broad applicability of immuneML by (i) reproducing a large-scale study on immune state prediction, (ii) developing, integrating, and applying a novel deep learning method for antigen specificity prediction, and (iii) showcasing streamlined interpretability-focused benchmarking of AIRR ML.

Perovskite to postperovskite transition in NaFeF3.

The GdFeO3-type perovskite NaFeF3 transforms to CaIrO3-type postperovskite at pressures as low as 9 GPa at room temperature. The details of such a transition were investigated by in situ synchrotron powder diffraction in a multianvil press. Fit of the p-V data showed that the perovskite phase is more compressible than related chemistries with a strongly anisotropic response of the lattice metrics to increasing pressure. The reduction in volume is accommodated by a rapid increase of the octahedral tilting angle, which reaches a critical value of 26° at the transition boundary. The postperovskite form, which is fully recoverable at ambient conditions, shows a regular geometry of the edge-sharing octahedra and its structural properties are comparable to those found in CaIrO3-type MgSiO3 at high pressure and temperature. Theoretical studies using density functional theory at the GGA + U level were also performed and describe a scenario where both perovskite and postperovskite phases can be considered Mott-Hubbard insulators with collinear magnetic G- and C-type antiferromagnetic structures, respectively. Magnetic measurements are in line with the theoretical predictions with both forms showing the typical behavior of canted antiferromagnets.

Nimodipine inhibits TMB-8 potentiation of AMPA-induced hippocampal neurodegeneration.

Human cerebral calcification has been related to deregulation of intracellular calcium homeostasis. In rat basal ganglia, nimodipine and TMB-8, two commonly used calcium antagonists, worsen the chronic AMPA-induced lesion, whereas only nimodipine potentiates calcification. To investigate whether similar effects are present in the hippocampus, AMPA dose-response and calcium movement blockade were performed. A dose-related increase of both hippocampal lesion and calcification was evident in a saturable mode, mostly different from the continuous globus pallidus response previously observed. The value of 2.7 nmol AMPA, selected as yielding 60% of maximum calcification, was coinjected with nimodipine or/and TMB-8 to determine their influence on tissue damage. TMB-8 increased the AMPA lesion in terms of calcified area, and nimodipine reversed this increase, with no effect alone. These results, divergent from those for the globus pallidus, reveal differences in extra- and intracellular calcium movement between the two neurodegenerative processes. Future work focused on other brain areas is required to understand how control of calcium stores may influence neurodegenerative disease evolution.

Matrix metalloproteinase-2 is involved in myelination of dorsal root ganglia neurons.

Matrix metalloproteinases (MMPs) comprise a large family of endopeptidases that are capable of degrading all extracellular matrix components. There is increasing evidence that MMPs are not only involved in tissue destruction but may also exert beneficial effects during axonal regeneration and nerve remyelination. Here, we provide evidence that MMP-2 (gelatinase A) is associated with the physiological process of myelination in the peripheral nervous system (PNS). In a myelinating co-culture model of Schwann cells and dorsal root ganglia neurons, MMP-2 expression correlated with the degree of myelination as determined by immunocytochemistry, zymography, and immunosorbent assay. Modulation of MMP-2 activity by chemical inhibitors led to incomplete and aberrant myelin formation. In vivo MMP-2 expression was detected in the cerebrospinal fluid (CSF) of patients with Guillain-Barré syndrome as well as in CSF and sural nerve biopsies of patients with chronic inflammatory demyelinating polyneuropathy. Our findings suggest an important, previously unrecognized role for MMP-2 during myelination in the PNS. Endogenous or exogenous modulation of MMP-2 activity may be a relevant target to enhance regeneration in demyelinating diseases of the PNS.

Similar calcification process in acute and chronic human brain pathologies.

Cellular microcalcification observed in a diversity of human pathologies, such as vascular dementia, Alzheimer's disease, Parkinson's disease, astrogliomas, and posttraumatic epilepsy, also develops in rodent experimental models of central nervous system (CNS) neurodegeneration. Central to the neurodegenerative process is the inability of neurons to regulate intracellular calcium levels properly, and this is extensible to fine regulation of the CNS. This study provides evidence of a common pattern of brain calcification taking place in several human pathologies, and in the rat with glutamate-derived CNS lesions, regarding the chemical composition, physical characteristics, and histological environment of the precipitates. Furthermore, a common physical mechanism of deposit formation through nucleation, lineal growth, and aggregation is presented, under the modulation of protein deposition and elemental composition factors. Insofar as calcium precipitation reduces activity signals at no energy expense, the presence in human and rodent cerebral brain lesions of a common pattern of calcification may reflect an imbalance between cellular signals of activity and energy availability for its execution. If this is true, this new step of calcium homeostasis can be viewed as a general cellular adaptative mechanism to reduce further brain damage.

Tissue mRNA expression in rat of newly described matrix metalloproteinases.

Matrix metalloproteinases (MMPs) comprise a large group of endoproteinases that degrade all protein components of the extracellular matrix. Functionally, MMPs contribute to several different physiological as well as pathological conditions. The number of newly described MMPs has increased in recent years, although current knowledge about their expression pattern in various tissues remains incomplete. Here we analyzed the relative mRNA expression of the most recently described MMPs--MT5-MMP (MMP-24), MT6-MMP (MMP-25), MMP-27 and epilysin (MMP-28)--in a broad selection of rat tissues using real time-PCR. MMP-24 mRNA was found to be widely expressed with predominance in the central nervous system. MMP-25 mRNA, in contrast, exhibited peak expression levels in testis, kidney and skeletal muscle, differing from previously described distribution patterns in humans. mRNAs for MMP-27 and MMP-28 were generally expressed at a lower level. All four MMPs studied were detected at higher mRNA levels in bone and kidney, suggesting a possible role of these MMPs in physiological processes within these two organs. The present study highlights the differential distribution pattern of newly described MMPs among different tissues and underlines differences in the mRNA expression between different species.

Tissue mRNA expression in rat of newly described matrix metalloproteinases

Matrix metalloproteinases (MMPs) comprise a large group of endoproteinases that degrade all protein components of the extracellular matrix. Functionally, MMPs contribute to several different physiological as well as pathological conditions. The number of newly described MMPs has increased in recent years, although current knowledge about their expression pattern in various tissues remains incomplete. Here we analyzed the relative mRNA expression of the most recently described MMPs _ MT5-MMP (MMP-24), MT6-MMP (MMP-25), MMP-27 and epilysin (MMP-28) _ in a broad selection of rat tissues using real time-PCR. MMP-24 mRNA was found to be widely expressed with predominance in the central nervous system. MMP-25 mRNA, in contrast, exhibited peak expression levels in testis, kidney and skeletal muscle, differing from previously described distribution patterns in humans. mRNAs for MMP-27 and MMP-28 were generally expressed at a lower level. All four MMPs studied were detected at higher mRNA levels in bone and kidney, suggesting a possible role of these MMPs in physiological processes within these two organs. The present study highlights the differential distribution pattern of newly described MMPs among different tissues and underlines differences in the mRNA expression between different species.

Heterogeneity between hippocampal and septal astroglia as a contributing factor to differential in vivo AMPA excitotoxicity.

Astroglial participation in the regional differences of vulnerability to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-induced neurodegeneration was investigated in the rat hippocampus and medial septum using L-alpha-aminoadipate (alpha-AA) as a specific astroglial toxin. alpha-AA was microinjected in the hippocampus and the medial septum and a time-course study was carried out between 2 hr and 3 days. When compared to controls, microinjection of alpha-AA in the hippocampus induced within 3 days a reversible loss of glial fibrillary acidic protein (GFAP) immunostaining and a microglial reaction without any neuronal loss, whereas in the medial septum it caused no effects on astroglial, microglial, or neuronal populations. Differences in hippocampus and medial septum vulnerability were also evidenced when alpha-AA was co-injected with AMPA and neurodegeneration was assessed in terms of neuronal loss, glial reactions, calcification, and atrophy of the area. In the hippocampus, alpha-AA increased AMPA excitotoxicity with marked disorganization of all hippocampal subfields, increased neuronal loss, a more important astroglial reaction, a larger area of microgliosis, and a greater abundance of calcium deposits. By contrast, in the medial septum alpha-AA did not modify any parameter of the AMPA-induced lesion. In conclusion, the presence of different astroglial populations in hippocampus and medial septum results in a different participation to AMPA excitotoxicity that may determine, at least in part, the specific regional vulnerability to neurodegeneration.

Nimodipine and TMB-8 potentiate the AMPA-induced lesion in the basal ganglia.

Acute injection of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) into the rat globus pallidus leads to calcium precipitation, neuronal death and gliosis. In order to determine whether L-type calcium channels and/or release of Ca(2+) from intracellular stores contribute to the effects of AMPA, nimodipine and 8-(N,N-diethylamino) octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8) were administered in combination with AMPA. Nimodipine, but not TMB-8, tended to exacerbate the calcification process initiated by AMPA; the AMPA/nimodipine/TMB-8 combination produced much more calcium deposition than AMPA (+62%, P<0.05). AMPA alone induced a slight but not significant astroglial reaction. Nimodipine slightly enhanced the astroglial reaction triggered by AMPA, whereas TMB-8 doubled it (P<0.001 versus AMPA). These data suggest that blockade of L-type calcium channels by nimodipine enhances calcium imbalance triggered by AMPA, and the calcium release from the endoplasmic reticulum does not participate in the AMPA-induced calcification.

Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis.

The precise immune mechanisms of neuronal death in anti-Hu-associated paraneoplastic encephalomyelitis (PEM) are unclear. We performed an immunohistochemical study on postmortem brain tissue from 11 patients with anti-Hu-associated PEM to further characterize the immune reaction and to ascertain possible mechanisms of neuronal death. To analyze inflammatory infiltrates, antibodies against lymphocyte subpopulations (CD3, CD20, CD4, CD8), macrophage and activated microglia (CD68), major histocompatibility complex (MHC) classes I and II (HLA-ABC and HLA-DR), and the intercellular adhesion molecules (ICAM) -1 and -3 were used. Cell death mechanisms were defined using antibodies against the cytotoxic protein TIA-1, the C9neo component of complement, the Fas receptor (CD95) and its ligand, the apoptosis effector activated caspase-3, and the apoptosis inhibitor Bcl-2. A great number of T cells expressing the cytotoxic protein TIA-1 was observed, mainly in clusters around neurons. ICAM-1 immunoreactivity was increased in the neuropil and reactive astrocytes in areas of inflammation within the central nervous system and in satellite cells of pathological dorsal root ganglia surrounding apparently normal sensory neurons. By contrast, Fas, FasL, C9neo, and activated caspase-3 immunoreactivities were negative in pathological areas. Bcl-2 immunoreactivity was found in satellite cells, but not in sensory neurons of normal and pathological dorsal root ganglia. Our data point out to an induction of a cytotoxic, non-apoptotic, neuronal death in anti-Hu-associated PEM. The increased ICAM-1 immunoreactivity may favor the infiltration of lymphocytes in the pathological areas.