•Hand muscle denervation was studied in adult spinal muscular atrophy (SMA) patients with MUNIX.•Adult SMA patients had a pathophysiological remarkable denervation pattern of hand muscles, a ...‘reversed split hand’.•MUNIX is a biomarker for upcoming questions in adult SMA.
There is still insufficient knowledge about natural history in adult spinal muscular atrophy, thus valid markers for treatment and disease monitoring are urgently needed.
We studied hand muscle innervation pattern of 38 adult genetically confirmed 5q spinal muscular atrophy (SMA) patients by the motor unit number index (MUNIX) method. Data were compared to healthy controls and amyotrophic lateral sclerosis (ALS) patients and systematically correlated to typical disease-relevant scores and other clinical as well as demographic characteristics.
Denervation of hand muscles in adult SMA was not evenly distributed. By calculation of the MUNIX ratios, we identified a specific hand muscle wasting pattern for SMA which is different to the split hand in ALS. Furthermore, MUNIX parameters strongly correlated with established disease course parameters independent of disease stages.
We found a pathophysiological remarkable denervation pattern of hand muscles, a ‘reversed split hand’. MUNIX of single hand muscles correlated well with disease severity and thus represents an easily available biomarker for adult SMA.
Our data show the power of the MUNIX method as a biomarker for upcoming questions in adult SMA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Until very recently, helium had remained the last naturally occurring element that was known not to form stable solid compounds. Here we propose and demonstrate that there is a general driving force ...for helium to react with ionic compounds that contain an unequal number of cations and anions. The corresponding reaction products are stabilized not by local chemical bonds but by long-range Coulomb interactions that are significantly modified by the insertion of helium atoms, especially under high pressure. This mechanism also explains the recently discovered reactivity of He and Na under pressure. Our work reveals that helium has the propensity to react with a broad range of ionic compounds at pressures as low as 30 GPa. Since most of the Earth's minerals contain unequal numbers of positively and negatively charged atoms, our work suggests that large quantities of He might be stored in the Earth's lower mantle.
Repeat expansion in
C9orf72
causes amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Expanded sense and antisense repeat RNA transcripts in
C9orf72
are translated into five ...dipeptide-repeat proteins (DPRs) in an AUG-independent manner. We previously identified the heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor of the sense repeat RNA that reduces its translation into DPRs. Furthermore, we found that hnRNPA3 is depleted from the nucleus and partially mislocalized to cytoplasmic poly-GA inclusions in
C9orf72
patients, suggesting that poly-GA sequesters hnRNPA3 within the cytoplasm. We now demonstrate that hnRNPA3 also binds to the antisense repeat RNA. Both DPR production and deposition from sense and antisense RNA repeats are increased upon hnRNPA3 reduction. All DPRs induced DNA double strand breaks (DSB), which was further enhanced upon reduction of hnRNPA3. Poly-glycine–arginine and poly-proline-arginine increased foci formed by phosphorylated Ataxia Telangiectasia Mutated (pATM), a major sensor of DSBs, whereas poly-glycine–alanine (poly-GA) evoked a reduction of pATM foci. In dentate gyri of
C9orf72
patients, lower nuclear hnRNPA3 levels were associated with increased DNA damage. Moreover, enhanced poly-GA deposition correlated with reduced pATM foci. Since cytoplasmic pATM deposits partially colocalized with poly-GA deposits, these results suggest that poly-GA, the most frequent DPR observed in
C9orf72
patients, differentially causes DNA damage and that poly-GA selectively sequesters pATM in the cytoplasm inhibiting its recruitment to sites of DNA damage. Thus, mislocalization of nuclear hnRNPA3 caused by poly-GA leads to increased poly-GA production, which partially depletes pATM, and consequently enhances DSB.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aging affects most living organisms and includes the processes that reduce health and survival. The chronological and the biological age of individuals can differ remarkably, and there is a lack of ...reliable biomarkers to monitor the consequences of aging. In this review we give an overview of commonly mentioned and frequently used potential aging-related biomarkers. We were interested in biomarkers of aging in general and in biomarkers related to cellular senescence in particular. To answer the question whether a biological feature is relevant as a potential biomarker of aging or senescence in the scientific community we used the PICO strategy known from evidence-based medicine. We introduced two scoring systems, aimed at reflecting biomarker relevance and measurement effort, which can be used to support study designs in both clinical and research settings.
High pressure ices Hermann, Andreas; Ashcroft, N. W; Hoffmann, Roald
Proceedings of the National Academy of Sciences - PNAS,
01/2012, Volume:
109, Issue:
3
Journal Article
Peer reviewed
Open access
H2O will be more resistant to metallization than previously thought. From computational evolutionary structure searches, we find a sequence of new stable and meta-stable structures for the ground ...state of ice in the 1–5 TPa (10 to 50 Mbar) regime, in the static approximation. The previously proposed Pbcm structure is superseded by a Pmc21 phase at p = 930 GPa, followed by a predicted transition to a P21 crystal structure at p = 1.3 TPa. This phase, featuring higher coordination at O and H, is stable over a wide pressure range, reaching 4.8 TPa. We analyze carefully the geometrical changes in the calculated structures, especially the buckling at the H in O-H-O motifs. All structures are insulating—chemistry burns a deep and (with pressure increase) lasting hole in the density of states near the highest occupied electronic levels of what might be component metallic lattices. Metallization of ice in our calculations occurs only near 4.8 TPa, where the metallic C2/m phase becomes most stable. In this regime, zero-point energies much larger than typical enthalpy differences suggest possible melting of the H sublattice, or even the entire crystal.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Insights gained from a comparison of aminometalation reactions with lithium amides, potassium amides and mixed lithium/potassium amides are presented. A combination of structural characterization, ...DFT calculations and electrophile reactions of aminometalated intermediates has shown the advantages of using a mixed metal strategy. While potassium amides fail to add, the lithium amides are uncontrollable and eliminated, yet the mixed K/Li amides deliver the best of both systems. Aminopotassiation proceeds to form the alkylpotassium species which has enhanced stability over its lithium counterpart allowing for its isolation and thereby its further characterization.
The use of a mixed‐metal system consisting of LiNR2/KOR increases the selectivity of the aminometalation of styrene derivatives in favour of a potassiated intermediate over a polymerization product. Crystal structures along with quantum chemical calculations and experimental investigations demonstrate the additional advantages of potassium over lithium or sodium for the stability of metalated phenylethylamines.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of ...specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation, plays a pivotal role in various pathological conditions, including neurodegenerative diseases. ...While reasonable evidence for ferroptosis exists, e.g., in Parkinson's disease or Alzheimer's disease, there are only a few reports on amyotrophic lateral sclerosis (ALS), a fast progressive and incurable neurodegenerative disease characterized by progressive motor neuron degeneration. Interestingly, initial studies have suggested that ferroptosis might be significantly involved in ALS. Key features of ferroptosis include oxidative stress, glutathione depletion, and alterations in mitochondrial morphology and function, mediated by proteins such as GPX4, xCT, ACSL4 FSP1, Nrf2, and TfR1. Induction of ferroptosis involves small molecule compounds like erastin and RSL3, which disrupt system Xc
and GPX4 activity, respectively, resulting in lipid peroxidation and cellular demise. Mutations in fused in sarcoma (
) are associated with familial ALS. Pathophysiological hallmarks of FUS-ALS involve mitochondrial dysfunction and oxidative damage, implicating ferroptosis as a putative cell-death pathway in motor neuron demise. However, a mechanistic understanding of ferroptosis in ALS, particularly FUS-ALS, remains limited. Here, we investigated the vulnerability to ferroptosis in FUS-ALS cell models, revealing mitochondrial disturbances and increased susceptibility to ferroptosis in cells harboring ALS-causing FUS mutations. This was accompanied by an altered expression of ferroptosis-associated proteins, particularly by a reduction in xCT expression, leading to cellular imbalance in the redox system and increased lipid peroxidation. Iron chelation with deferoxamine, as well as inhibition of the mitochondrial calcium uniporter (MCU), significantly alleviated ferroptotic cell death and lipid peroxidation. These findings suggest a link between ferroptosis and FUS-ALS, offering potential new therapeutic targets.
Both helium and ammonia are main components of icy giant planets. While ammonia is very reactive, helium is the most inert element in the universe. It is of great interest whether ammonia and helium ...can react with each other under planetary conditions, and if so, what kinds of structures and states of matter can form. Here, using crystal structure prediction methods and first-principles calculations, we report three new stable stoichiometries and eight new stable phases ofHe−NH3compounds under pressures up to 500 GPa. These structures may exhibit perovskitelike structures forHeNH3andHe2NH3, and a host-guest crystal structure forHe(NH3)2. Superionic states are found in all theseHe−NH3compounds under high pressures and temperatures in which the hydrogen atoms are diffusive while the nitrogen and helium atoms remain fixed. Such dynamical behavior in helium ammonia compounds is quite different from that in helium water compounds, where weakly interacting helium is more diffusive than stronger bound hydrogen. The low-density host-guest phase of space groupI4cmis found to be stable at very low pressures (about 3 GPa) and it enters into a plastic state, characterized by freely rotating ammonia molecules. The present results suggest that plastic or superionic helium ammonia compounds may exist under planetary conditions, and helium contributes crucially to the exotic physics and chemistry observed under extreme conditions.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM, UPUK
Chorea is a common movement disorder which can be caused by a large variety of diseases including neurodegenerative diseases, metabolic diseases, and autoimmune diseases, or can be secondary to ...structural changes. The basal ganglia seem to be mainly involved in the pathophysiology indicating the vulnerability of this region. The diagnosis can be challenging, especially if chorea occurs during the treatment of neuropsychiatric conditions, and in these cases, it is difficult to distinguish between medication side effects (i.e., tardive dyskinesia) and the development of a neurodegenerative disease. Most therapeutic approaches are predominantly symptomatic, with a focus on multidisciplinary care for many patients. Nevertheless, some underlying diseases can be successfully treated and must not be missed. In this review, we summarize recent new developments in the differential diagnosis of chorea syndromes and suggest a pathway for a successful diagnosis of chorea in infancy, childhood, and adulthood for daily practice.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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