Biomarkers in 5q-associated spinal muscular atrophy-a narrative review.

5q-associated spinal muscular atrophy (SMA) is a rare genetic disease caused by mutations in the SMN1 gene, resulting in a loss of functional SMN protein and consecutive degeneration of motor neurons in the ventral horn. The disease is clinically characterized by proximal paralysis and secondary skeletal muscle atrophy. New disease-modifying drugs driving SMN gene expression have been developed in the past decade and have revolutionized SMA treatment. The rise of treatment options led to a concomitant need of biomarkers for therapeutic guidance and an improved disease monitoring. Intensive efforts have been undertaken to develop suitable markers, and numerous candidate biomarkers for diagnostic, prognostic, and predictive values have been identified. The most promising markers include appliance-based measures such as electrophysiological and imaging-based indices as well as molecular markers including SMN-related proteins and markers of neurodegeneration and skeletal muscle integrity. However, none of the proposed biomarkers have been validated for the clinical routine yet. In this narrative review, we discuss the most promising candidate biomarkers for SMA and expand the discussion by addressing the largely unfolded potential of muscle integrity markers, especially in the context of upcoming muscle-targeting therapies. While the discussed candidate biomarkers hold potential as either diagnostic (e.g., SMN-related biomarkers), prognostic (e.g., markers of neurodegeneration, imaging-based markers), predictive (e.g., electrophysiological markers) or response markers (e.g., muscle integrity markers), no single measure seems to be suitable to cover all biomarker categories. Hence, a combination of different biomarkers and clinical assessments appears to be the most expedient solution at the time.

Temperature-Dependent Spin Transport and Current-Induced Torques in Superconductor-Ferromagnet Heterostructures.

We investigate the injection of quasiparticle spin currents into a superconductor via spin pumping from an adjacent ferromagnetic metal layer. To this end, we use NbN-Ni_{80}Fe_{20}(Py) heterostructures with a Pt spin sink layer and excite ferromagnetic resonance in the Permalloy layer by placing the samples onto a coplanar waveguide. A phase sensitive detection of the microwave transmission signal is used to quantitatively extract the inductive coupling strength between the sample and the coplanar waveguide, interpreted in terms of inverse current-induced torques, in our heterostructures as a function of temperature. Below the superconducting transition temperature T_{c}, we observe a suppression of the dampinglike torque generated in the Pt layer by the inverse spin Hall effect, which can be understood by the changes in spin current transport in the superconducting NbN layer. Moreover, below T_{c} we find a large fieldlike current-induced torque.

Magnetization transfer ratio: a quantitative imaging biomarker for 5q spinal muscular atrophy.

BACKGROUND AND PURPOSE: We quantified peripheral nerve lesions in adults with 5q-linked spinal muscular atrophy (SMA) type 3 by analysing the magnetization transfer ratio (MTR) of the sciatic nerve, and tested its potential as a novel biomarker for macromolecular changes. METHODS: Eighteen adults with SMA 3 (50% SMA 3a, 50% SMA 3b) and 18 age-/sex-matched healthy controls prospectively underwent magnetization transfer contrast imaging in a 3-Tesla magnetic resonance scanner. Two axial three-dimensional gradient echo sequences, with and without an off-resonance saturation rapid frequency pulse, were performed at the right distal thigh. Sciatic nerve regions of interest were manually traced on 10 consecutive axial slices in the images generated without off-resonance saturation, and then transferred to corresponding slices generated by the sequence with the off-resonance saturation pulse. Subsequently, MTR and cross-sectional areas (CSAs) of the sciatic nerve were analysed. In addition, detailed neurologic, physiotherapeutic and electrophysiologic examinations were conducted in all patients. RESULTS: Sciatic nerve MTR and CSA reliably differentiated between healthy controls and SMA 3, 3a or 3b. MTR was lower in the SMA 3 (P < 0.0001), SMA 3a (P < 0.0001) and SMA 3b groups (P = 0.0020) than in respective controls. In patients with SMA 3, MTR correlated with all clinical scores, and arm nerve compound motor action potentials (CMAPs). CSA was lower in the SMA 3 (P < 0.0001), SMA 3a (P < 0.0001) and SMA 3b groups (P = 0.0006) than in controls, but did not correlate with clinical scores or electrophysiologic results. CONCLUSIONS: Magnetization transfer ratio is a novel imaging marker that quantifies macromolecular nerve changes in SMA 3, and positively correlates with clinical scores and CMAPs.

Nonreciprocal Dzyaloshinskii-Moriya Magnetoacoustic Waves.

We study the interaction of surface acoustic waves with spin waves in ultrathin CoFeB/Pt bilayers. Because of the interfacial Dzyaloshinskii-Moriya interaction (DMI), the spin wave dispersion is nondegenerate for oppositely propagating spin waves in CoFeB/Pt. In combination with the additional nonreciprocity of the magnetoacoustic coupling itself, which is independent of the DMI, highly nonreciprocal acoustic wave transmission through the magnetic film is observed. We systematically characterize the magnetoacoustic wave propagation in a thickness series of CoFeB(d)/Pt samples as a function of magnetic field magnitude and direction, and at frequencies up to 7 GHz. We quantitatively model our results to extract the strength of the DMI and magnetoacoustic driving fields.

Groundwater controls on colloidal transport in forest stream waters.

Biogeochemical changes of whole catchments may, at least in part, be deduced from changes in stream water composition. We hypothesized that there are seasonal variations of natural nanoparticles (NNP; 1-100 nm) and fine colloids (<300 nm) in stream water, which differ in origin depending on catchment inflow parameters. To test this hypothesis, we assessed the annual dynamics of the elemental composition of NNP and fine colloids in multiple water compartments, namely in stream water, above and below canopy precipitation, groundwater and lateral subsurface flow from the Conventwald catchment, Germany. In doing so, we monitored meteorological and hydrological parameters, total element loads, and analyzed element concentrations of org C, Al, Si, P, Ca, Mn and Fe by Asymmetric Flow Field Flow Fractionation (AF4). The results showed that colloid element concentrations were < 5 µmol/L. Up to an average of 55% (Fe) of total element concentrations were not truly dissolved but bound to NNP and fine colloids. The colloid patterns showed seasonal variability with highest loads in winter. The presence of groundwater-derived colloidal Ca in stream water showed that groundwater mainly fed the streams throughout the whole year. Overall, the results showed that different water compartments vary in the NNP and fine colloidal composition making them a suitable tool to identify the streams NNP and fine colloid sources. Given the completeness of the dataset with respect to NNP and fine colloids in multiple water compartments of a single forest watershed this study adds to the hitherto underexplored role of NNP and fine colloids in natural forest watersheds.

A Curious Case of Cough in a Young Woman

Inflammatory myofibroblastic tumour (IMT) is a rare neoplasm derived from tissue of mesenchymal origin. This tumour occurs predominantly in the lung, though extrapulmonary sites have been documented throughout the body.1 Presentation can be variable depending on location of the tumour and can include constitutional symptoms (fever, weight loss), thrombocytosis, hypergammaglobulinemia, anemia, and mass effect on local structures.2 Majority of patients with intrapulmonary IMT remain asymptomatic but can have symptoms including chest pain, dyspnoea, cough or haemoptysis.3 Most cases of IMT present in younger individuals (under age 40).4 Although the aetiology of IMT is unclear, current hypotheses suggest an inflammatory response to infection or an underlying malignancy could promote such cellular changes. Alternatively, the inflammatory component itself may be a consequence of the development of these mesenchymal tumours.

Spin Transport in a Magnetic Insulator with Zero Effective Damping.

Applications based on spin currents strongly rely on the control and reduction of their effective damping and their transport properties. We here experimentally observe magnon mediated transport of spin (angular) momentum through a 13.4-nm thin yttrium iron garnet film with full control of the magnetic damping via spin-orbit torque. Above a critical spin-orbit torque, the fully compensated damping manifests itself as an increase of magnon conductivity by almost 2 orders of magnitude. We compare our results to theoretical expectations based on recently predicted current induced magnon condensates and discuss other possible origins of the observed critical behavior.

Systemic Inflammation and Multimodal Biomarkers in Amnestic Mild Cognitive Impairment and Alzheimer's Disease.

There is increasing evidence suggesting that one of the most relevant pathophysiological features of Alzheimer's disease (AD) is neuroinflammation, which plays an important role in the production and regulation of AD-related proteins (amyloid beta (Aß) and Tau) and exacerbates AD pathology. Neuroinflammation can also be induced by systemic influences (factors from outside the central nervous system). However, the role of systemic inflammation in AD pathophysiology is much less understood. Thus, our main objective in this study was to verify whether the presence of serum cytokines (IL-1ß, IL-6, IL-10, IL-12, and TNF-α) affects different AD biomarkers: Aß1-42 and Tau protein levels, hippocampal volumes (HV), and default mode network functional connectivity (DMN FC) in healthy elderly controls, amnestic mild cognitive impairment (aMCI) patients due to AD, and mild AD patients. To accomplish this, we acquired 3-T MRI, blood, and cerebrospinal fluid (CSF) samples from 42 healthy controls, 55 aMCI patients due to AD, and 33 mild AD patients. Comparing the groups, we found that the mild AD patients presented smaller HV, disrupted DMN FC, and proportionally less IL-1ß than the controls. The aMCI patients only differed from the controls in DMN FC. In intra-group comparison, aMCI and mild AD with detectable levels of cytokines (TNF-α, IL-1ß, IL-10, and IL-12) had decreased DMN FC. On the other hand, patients with detectable levels of IL-10 and IL-12 presented a more favorable AD biomarkers profile (larger HV, more CSF Aß1-42, and less p-Tau), indicating a possible protective role of these ILs. Our findings indicate a possible relationship between systemic inflammation with DMN FC disruption, hippocampal atrophy, and CSF protein levels in the subjects with mild AD and aMCI.

[Clinical indications for high-resolution MRI diagnostics of the peripheral nervous system]. / Klinische Indikationen hochauflösender MRT-Diagnostik des peripheren Nervensystems.

CLINICAL/METHODICAL ISSUE: Peripheral neuropathies are common and diagnostically often challenging disorders. Difficulties particularly exist in lesion localization and recognition of complex spatial lesion patterns. STANDARD DIAGNOSTIC METHODS: Medical history taking, neurological examination, neurophysiological tests and nerve ultrasonography represent the gold standard in the diagnosis of peripheral nerve lesions but have known methodical limitations. METHODICAL INNOVATIONS: The use of 3 Tesla magnetic resonance neurography (MRN) is an additional diagnostic imaging tool recently developed for the high-resolution visualization of long segments of peripheral nerves. Reasonable clinical indications for MRN are exemplarily presented. PERFORMANCE: Using MRN a direct visualization and thus precise localization of focal and non-focal peripheral nerve lesions of various origins can be achieved with high spatial resolution down to the anatomical level of nerve fascicles. ACHIEVEMENTS: Using MRN large anatomical areas of the peripheral nervous system (PNS) can be covered in a single examination session, spatial nerve lesion patterns can be evaluated and the underlying causes can often be detected. PRACTICAL RECOMMENDATIONS: The MRN is a valuable supplement to the diagnostic work-up of the PNS, especially in cases that cannot be clarified with standard diagnostic methods. Evaluation of the spatial nerve lesion pattern gives additional information on the origin of the underlying disease. Reasonable indications for MRN are the assessment of proximal nerve structures including the brachial and lumbosacral nerve plexi, the clarification of inconclusive diagnostic results, preoperative, postoperative and posttraumatic assessments, the identification of fascicular nerve lesions and the differential diagnosis of an alleged somatoform disorder.

Mineral mediated isotope fractionation of soil water.

RATIONALE: The ability to recover the isotopic signature of water added to soil samples that have previously been oven-dried decreases with the increasing presence of silt and clay. The effects on the isotopic signature of water associated with physicochemical soil properties are not yet fully understood, for either hydration or dehydration of soil samples. METHODS: The soil sample chemistry and the crystallinity of minerals were measured by X-ray fluorescence and X-ray diffraction. The organic carbon and the cation-exchange capacity were also determined. Water of known isotopic signature was used to spike an oven-dried substrate and subsequently extracted by cryogenic vacuum extraction at a temperature of 105°C. In addition, the soils were oven-dried at 205°C and water extractions were also performed at 205°C. The isotopic signatures of the water samples were determined by cavity-ring-down spectrometry. RESULTS: The isotope effects caused by the cryogenic vacuum extraction method applied to soils with elevated clay content were reduced. First, by increasing the extraction temperature to 205°C, we improved the precision of the cryogenic vacuum extraction method and the recovery of the known isotopic signature of the spike water. Secondly, the post-correction of data based on the physicochemical soil properties and a common extraction temperature of 105°C improved the measurement trueness. CONCLUSIONS: The isotopic signature of soil water is influenced by mineral-water interaction. During the hydration of clay, different minerals deplete free water in heavy isotopes. The extracted soil water (dehydration water) gathered from clay-rich soils is generally more depleted in the heavy isotopes than the spike water, making results obtained for different soil types difficult to compare. Isotope effects observed at the mineral-water interface highlight potential explanations for eco-hydrological separation of water pools. Copyright © 2016 John Wiley & Sons, Ltd.

Physico-chemical characteristics affect the spatial distribution of pesticide and transformation product loss to an agricultural brook.

Diffuse entry of pesticide residues from agriculture into rivers is spatially unevenly distributed. Therefore, the identification of critical source areas (CSAs) may support water quality management in agricultural catchments. In contrast to former studies, we followed the hypothesis that not only hydrological and topographical characteristics but also physico-chemical properties of pesticide residues have a major influence on their loss to rivers and on corresponding formation of CSAs. We designed a virtual experiment, i.e. a numerical experiment as close as possible to environmental conditions, in a headwater catchment where pronounced spatial differences in hydrological transport processes were identified in the past. 144 scenarios with different combinations of adsorption coefficients (KOC = 10-1000 ml/g) and transformation half-lives (DT50 = 3-60 days) for pesticide parent compounds (PCs) and their transformation products (TPs) were simulated using the catchment-scale spatially distributed reactive transport model ZIN-AgriTra. Export fractions of substances in the virtual experiment ranged from 0.001-15% for pesticides and 0.001-1.8% for TPs. The results of the scenario investigations suggest that more of the calculated export mass variability could be attributed to KOC than to DT50 for both PCs and TPs. CSAs for TPs were spatially more equally distributed in the catchment than for PC export which was likely an effect of changing physico-chemical properties during transformation. The ranking of highest export fields was different between PCs and TPs for most of the investigated scenarios but six fields appeared among the top ten export fields in 95% of the scenarios, which shows the influence of site characteristics such as tile drains or soil properties in the catchment. Thus, the highest export fields were determined by a combination of site characteristics and substance characteristics. Therefore, despite the challenge of widely differing physico-chemical characteristics of pesticides on the market, these characteristics are an important consideration when delineating pesticide residue CSAs.

Peripheral Nerve Diffusion Tensor Imaging: Assessment of Axon and Myelin Sheath Integrity.

PURPOSE: To investigate the potential of diffusion tensor imaging (DTI) parameters as in-vivo biomarkers of axon and myelin sheath integrity of the median nerve in the carpal tunnel as validated by correlation with electrophysiology. METHODS: MRI examinations at 3T including DTI were conducted on wrists in 30 healthy subjects. After manual segmentation of the median nerve quantitative analysis of fractional anisotropy (FA) as well as axial, radial and mean diffusivity (AD, RD, and MD) was carried out. Pairwise Pearson correlations with electrophysiological parameters comprising sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) as markers of axon integrity, and distal motor latency (dml) and sensory nerve conduction velocity (sNCV) as markers of myelin sheath integrity were computed. The significance criterion was set at P=0.05, Bonferroni corrected for multiple comparisons. RESULTS: DTI parameters showed a distinct proximal-to-distal profile with FA, MD, and RD extrema coinciding in the center of the carpal tunnel. AD correlated with CMAP (r=0.50, p=0.04, Bonf. corr.) but not with markers of myelin sheath integrity. RD correlated with sNCV (r=-0.53, p=0.02, Bonf. corr.) but not with markers of axon integrity. FA correlated with dml (r=-0.63, p=0.002, Bonf. corr.) and sNCV (r=0.68, p=0.001, Bonf. corr.) but not with markers of axon integrity. CONCLUSION: AD reflects axon integrity, while RD (and FA) reflect myelin sheath integrity as validated by correlation with electrophysiology. DTI parameters consistently indicate a slight decrease of structural integrity in the carpal tunnel as a physiological site of median nerve entrapment. DTI is particularly sensitive, since these findings are observed in healthy participants. Our results encourage future studies to evaluate the potential of DTI in differentiating axon from myelin sheath injury in patients with manifest peripheral neuropathies.

A combined IR/IR and IR/UV spectroscopy study on the proton transfer coordinate of isolated 3-hydroxychromone in the electronic ground and excited state.

In this paper the excited state proton transfer (ESPT) of isolated 3-hydroxychromone (3-HC), the prototype of the flavonols, is investigated for the first time by combined IR/UV spectroscopy in molecular beam experiments. The IR/UV investigations are performed both for the electronically excited and electronic ground state indicating a spectral overlap of transitions of the 3-HC monomer and clusters with water in the electronic ground state, whereas in the excited state only the IR frequencies of the proton-transferred monomer structure are observed. Due to the loss of isomer and species selectivity with respect to the UV excitations IR/IR techniques are applied in order to figure out the assignment of the vibrational transitions in the S0 state. In this context the quadruple resonance IR/UV/IR/UV technique (originally developed to distinguish different isomers in the electronically excited state) could be applied to identify the OH stretching vibration of the monomer in the electronic ground state. In agreement with calculations the OH stretching frequency differs significantly from the corresponding values of substituted hydroxychromones.

NDRG1 prognosticates the natural course of disease in WHO grade II glioma.

There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment.

An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.

Clinical integration of next-generation sequencing technology.

Recent advances in next-generation sequencing (NGS) methods and technology have substantially reduced costs and operational complexity leading to production of benchtop sequencers and commercial software solutions for implementation in small research and clinical laboratories. This article addresses requirements and limitations to successful implementation of these systems, including (1) calibration and validation of the instrumentation, experimental paradigm, and primary readout, (2) secure data transfer, storage, and secondary processing, (3) implementation of software tools for targeted analysis, and (4) training of research and clinical personnel to evaluate data fidelity and interpret the molecular significance of the genomic output.

Spin pumping with coherent elastic waves.

We show that the resonant coupling of phonons and magnons can be exploited to generate spin currents at room temperature. Surface acoustic wave pulses with a frequency of 1.55 GHz and duration of 300 ns provide coherent elastic waves in a ferromagnetic thin-film-normal-metal (Co/Pt) bilayer. We use the inverse spin Hall voltage in the Pt as a measure for the spin current and record its evolution as a function of time and external magnetic field magnitude and orientation. Our experiments show that a spin current is generated in the exclusive presence of a resonant elastic excitation. This establishes acoustic spin pumping as a resonant analogue to the spin Seebeck effect.

Infrared/ultraviolet quadruple resonance spectroscopy to investigate structures of electronically excited states.

Molecular beam investigations in combination with IR/UV spectroscopy offer the possibility to obtain structural information on isolated molecules and clusters. One of the demanding tasks is the discrimination of different isomers, e.g., by the use of isomer specific UV excitations. If this discrimination fails due to overlaying UV spectra of different isomers, IR/IR methods offer another possibility. Here, we present a new IR/UV/IR/UV quadruple resonance technique to distinguish between different isomers especially in the electronically excited state. Due to the IR spectra, structural changes and photochemical pathways in excited states can be assigned and identified. The method is applied to the dihydrated cluster of 3-hydroxyflavone which has been investigated as photochemically relevant system and proton wire model in the S(1) state. By applying the new IR/UV/IR/UV technique, we are able to show experimentally that both in the electronic ground (S(0)) and the electronically excited state (S(1)) two isomers have to be assigned.

Scaling behavior of the spin pumping effect in ferromagnet-platinum bilayers.

We systematically measured the dc voltage V(ISH) induced by spin pumping together with the inverse spin Hall effect in ferromagnet-platinum bilayer films. In all our samples, comprising ferromagnetic 3d transition metals, Heusler compounds, ferrite spinel oxides, and magnetic semiconductors, V(ISH) invariably has the same polarity, and scales with the magnetization precession cone angle. These findings, together with the spin mixing conductance derived from the experimental data, quantitatively corroborate the present theoretical understanding of spin pumping in combination with the inverse spin Hall effect.