julilili42/papers huggingface dataset:
F56 Quantifying fine-motor impairment in ataxia: digital parameters of q-motor spiral drawing correlate with clinical severity, function & ADLs – lessons for HD
2022-09-01

<h3>Background and Objective</h3> Upper-limb function is insufficiently explored as digital-motor outcome in ataxia. The Archimedes spiral-drawing-task might serve as a meaningful outcome requiring fine-motor skills of everyday-living. We implemented Archimedes-spiral-drawing in the trial-ready quantitative-motor (Q-Motor) system and explored underlying movement kinematics as digital outcomes. <h3>Methods</h3> Cross-sectional single-center validation study in 46 patients with predominantly degenerative cross-genotype cerebellar-ataxias (mean-age: 50 years; mean-SARA: 12 points), and 48 age- and sex-matched controls. Subjects were instructed to draw – as accurate as possible at self-paced speed - two Archimedes spirals with their dominant hand on a paper template while traced by a Polhemus FASTRAK digitizer with a pencil lead attachment. Thirty-five parameters were validated against the Scale for the assessment and rating of ataxia (SARA), activities of daily living (FARS ADL), and the 9-hole peg-test (9HPT). <h3>Results</h3> Parameters in the spatial domain, namely the summed 10th decile, standard deviation and maximum of the error distribution (distance from template), discriminated best between ataxia and controls (AUC: 0.83-0.89), and showed the strongest correlation with FARS-ADL (rho: 0.38-0.47). In contrast, parameters in the frequency (Fourier power, 1-4 Hz, Spearman rho: 0.75) and spatiotemporal domain (90th percentile of speed, rho: 0.72) correlated most with the total SARA (specifically a composite of upper-limb items), as well as the 9HPT (rho: 0.59-0.74). <h3>Discussion and Conclusion</h3> Quantitative analysis of Archimedes-spiral-drawing allows to capture fine-motor impairment, with differential correlations to clinical severity, function, and ADL across domains in ataxia – encouraging its exploration in HD. Longitudinal analyses are ongoing to investigate sensitivity to change.
F59 A novel Q-Motor task: isometric force matching – results from the TRACK-HD study
2022-09-01

<h3>Background</h3> Quantitative digital motor assessments such as the Q-Motor Finger Tapping have been shown to detect progression (TRACK-HD) and drug effects in multiple clinical trials. We here report cross-sectional results of the novel Isometric Force Matching task that had been introduced in the TRACK-HD study as part of the Q-Motor assessment battery to assess grasping force in a more defined environment. <h3>Aims</h3> To evaluate the potential of the Q-Motor Force Matching task as quantitative endpoint to objectively assess motor dysfunction in clinical studies in HD. <h3>Methods</h3> A target force level and current sensor force level were displayed on a computer screen. Participants of the TRACK-HD study (year 2011, gene carriers=220, controls=110) were instructed to grasp a force sensor-equipped device, which was firmly attached to a table surface, in precision grip, and to adjust the applied force to best match the displayed target force level using visual feedback. For group comparisons, we used a CAG-Age dependent parametric survival model (Langbehn 2004). <h3>Results</h3> Q-Motor Force Matching shows high correlations with clinical scales, CAG-Age product scores and imaging variables. Differentiation between gene carriers and non-gene carriers was very good (p&lt;0.001) for groups of gene carriers with a Survival Score of &lt;=0.75. <h3>Conclusions</h3> We could show that Q-Motor Isometric Force Matching assessment is feasible in multicenter clinical studies in HD and can differentiate between patient groups. The task design allows to also add cognitive challenges, which we want to explore in further experiments, along with longitudinal performance. <h3>Acknowledgment</h3> TRACK-HD study team and CHDI-Foundation
F70 Early manifestation and rapid symptom progression in a case of homozygous trinucleotide expansion in the TBP-gene in autosomal dominant spinocerebellar ataxia type 17
2022-09-01

<h3>Background</h3> Spinocerebellar ataxia type 17 (SCA17) is a rare, autosomal-dominantly inherited neurodegenerative disease caused by a CAG/CAA repeat expansion in the TATA-box-binding protein (TBP) gene. Clinically, SCA17 is quite variable and includes cerebellar and hypokinetic-rigid symptoms, chorea as well as cognitive impairment. Thus, the disease is also called a Huntington disease phenocopy (HDL-4). <h3>Case History</h3> A 39-year-old female patient presented with cognitive impairment and behavioural symptoms with affect lability and impulsivity that had been present since the age of 35 and had progressed rapidly over time. Clinical findings included stance and gait ataxia, saccadic gaze, chanting speech and generalized chorea. The family history was unremarkable. Brain imaging showed isolated cerebellar atrophy with normal visualisation of the basal ganglia. The molecular-genetic diagnostics for Huntington's disease was unremarkable. In the extended human genetic examination, a homozygous expanded allele with 44 CAG/CAA repeats in the TBP gene was detected, thus confirming the diagnosis of SCA17. Within 2 years, the patient showed a clear increase in cognitive changes and behavioural disturbance. <h3>Conclusions</h3> In the present case, a homozygous expanded allele with 44 CAG/CAA repeats in the TBP gene leads to an early age of manifestation, in contrast to SCA17 patients with comparable heterozygous intermediate repeat expansions with reduced penetrance. Furthermore, the index patient showed faster progression of symptoms, suggesting that SCA17 homozygous trinucleotide expansions are associated with a more severe disease course even with intermediate repeat expansions.
F57 Quantitative motor assessment of upper limb ataxia with q-motor: a cross-sectional validation study including novel ataxia tasks – lessons learnt for HD
2022-09-01

<h3>Background and Objective</h3> With its relevance for everyday function, upper-limb-coordination is an insufficiently explored domain for digital-motor-outcomes in ataxia. Leveraging the trial-ready quantitative-motor (Q-Motor) system, we developed and validated a comprehensive task battery to capture upper-limb-ataxia. <h3>Methods</h3> Cross-sectional single-center-study (46 patients with predominantly degenerative cross-genotype cerebellar-ataxias (mean-age: 50 years; mean-SARA: 12 points), and 48 age- and sex-matched controls. Q-Motor assessments with a force transducer and an electromagnetic position sensor comprised both existing bilateral-tasks particularly promising for ataxia (foot-tapping, finger-tapping, diadochokinesia, grip-lift) (47 parameters/side), and tasks newly designed to capture ataxia (multi-directional two-dimensional-target-pointing, spiral-drawing) with the dominant hand (450 parameters, including spatial, temporal, spatiotemporal, and texture measures). <h3>Results</h3> Target hits per second (AUC: 0.97) and frequency of foot-tapping, finger-tapping or diadochokinesia (AUC: 0.91-0.94) were excellent discriminators between ataxia and controls. Target hits per second and finger-tapping-frequency correlated strongly with the SARA (Spearman rho: -0.87 and -0.81), and even specifically with the sum of its upper limb items (-0.85 and -0.72). For diadochokinesia, temporal variability showed the strongest correlation with SARA (0.71) and its upper-limb composite (0.67, all p&lt;0.001). Parameters in upper-limb tasks had moderate to strong correlations with activities-of-daily-living-function (FARS ADL, |rho|: 0.5-0.6), and dexterity as assessed by the 9-hole peg-test (0.53-0.78, all p&lt;0.001). <h3>Discussion and Conclusion</h3> Severity of upper-limb ataxia can be captured by Q-Motor with physiologically interpretable and functionally relevant measures of a finger-tapping, diadochokinesia, and a novel two-dimensional target-pointing-task of interest also for HD. Longitudinal assessments are ongoing to explore their responsiveness to change in a clinical trial setting.
A24 Mutant huntingtin impairs musculoskeletal and brain growth via disturbing testosterone biosynthesis in male huntington disease animals
2022-09-01

<h3></h3> Body weight (BW) loss and reduced body mass index (BMI) are the most common peripheral alterations in Huntington disease (HD) and have been found in HD mutation carriers and HD animal models before manifestation of neurological symptoms. This suggests that, at least in the early disease stage, these changes could be due to abnormal tissue growth rather than tissue atrophy. Also, BW and BMI are reported to be more affected in males than females in HD animal models and patients. Here, we confirmed sex-dependent growth alterations in the BACHD rat model for HD and investigated the associated contributing factors. We assessed body weight longitudinally and musculoskeletal and brain growth as well as growth-related hormones transversally in male and female rats. Our results showed growth abnormalities along with decreased plasma testosterone and insulin-like growth factor 1 (IGF-1) levels only in males. Moreover, we demonstrated correlations between growth parameters, IGF-1 and testosterone. Our analyses further revealed an aberrant transcription of testosterone biosynthesis-related genes in the testes of BACHD rats with undisturbed luteinizing hormone (LH)/cAMP/PKA signalling, which plays a key role in regulating the transcription process of some of these genes. In line with these results in BACHD rats, analyses in the R6/2 mouse model of HD showed sex-specific BW reduction in males, reduced circulating levels of testosterone and dysregulation of testosterone biosynthesis-related genes. Our findings support the view that mutant huntingtin may induce abnormal growth in males via dysregulation of gene transcription in the testis, which in turn can affect testosterone biosynthesis.
A35 Calpains contribute to the molecular pathogenesis of spinocerebellar ataxia type 17
2022-09-01

<h3>Background</h3> Spinocerebellar ataxia type 17 (SCA17), also known as Huntington disease-like 4 (HDL4), is a neurodegenerative disease caused by a polyglutamine (polyQ)-encoding CAG repeat expansion in the TATA box-binding protein (TBP) gene. While its pathomechanism remains unclarified, polyQ-expanded TBP fragments of unclarified origin were shown to mediate the mutant protein's toxicity. <h3>Aims</h3> Calpains, a family of calcium-dependent proteases, are protagonists in disease protein cleavage, a hallmark of many neurodegenerative disorders. Therefore, we examined the potential contribution of calpains to TBP fragmentation in SCA17. <h3>Methods</h3> We analyzed whether TBP is a substrate of calpain-mediated proteolysis via in silico, in vitro and cell-based strategies. Using SCA17 cell and rat models, we investigated if the calpain system is perturbed upon polyQ-expanded TBP expression and which consequences a dysregulation has on vital neuronal proteins. Underlying molecular pathways were investigated by RNA sequencing of SCA17 cells. Moreover, we tested whether calpain inhibition ameliorates molecular disease hallmarks in SCA17 cells. <h3>Results</h3> We demonstrate that calpains cleave TBP, and emerging C-terminal fragments become mislocalized to the cytoplasm. SCA17 cells and rats exhibited calpain overactivation, with excessive fragmentation and depletion of neuronal proteins in vivo. Transcriptome analysis of SCA17 cells revealed synaptogenesis and calcium signaling perturbations, indicating the potential cause of overactivated calpains. Calpain inhibition reduced TBP cleavage and aggregation, consequently improving cell viability. <h3>Conclusions</h3> Our work highlights calpains and their activating pathways as therapeutic targets in neurodegenerative disorders - such as Huntington disease - and presents these proteases as novel actors in the molecular pathogenesis of SCA17.
I12 The novel alpha-2 adrenoceptor inhibitor beditin reduces cytotoxicity and huntingtin aggregates in cell models of Huntington’s disease
2022-09-01

<h3>Background</h3> Cellular hallmarks of Huntington Disease include aggregate formation in neurons and neuronal loss. Encouraging findings on neuroprotection in AD and PD have led us to explore the effects of a novel α2-adrenoceptor (α2A-AR) antagonist, Beditin, in HD cell models. α2-ARs have been implicated in the reduction of oxidative stress, neuroprotection and reduction of excitotoxicity. <h3>Aim</h3> We sought to assess the neuroprotective properties of α2-AR inhibition with beditin in cell models of HD. <h3>Methods</h3> α2A-AR levels were assessed in cell models of HD and brain homogenates of R6/2 mice. In STHdhQ111/Q111 cells, effects of beditin were assessed by LDH and TUNEL cytotoxicity assays. Levels of mHTT and autophagy markers were analyzed by western blot and HTT levels by TR-FRET. Aggregation was analyzed by fluorescence microscopy and filter trap in an HEK293T eGFP-exon1-fragment overexpression model. <h3>Results/Outcome</h3> α2A-AR levels were found to be increased in STHdh Q111/Q111 cells. Beditin did not only decrease cytotoxicity in this cell line, but it also showed effects on the levels of HTT fragments. It further reduced aggregation in an overexpression cell model. mTOR independent induction of autophagy was observed, possibly contributing to the mHTT reducing effects. <h3>Conclusion</h3> In line with findings in AD and PD, we could confirm the neuroprotective effects of α2-AR inhibition and showed a reduction of aggregates in an in vitro model. The study suggests α2-ARs as a therapeutic target in HD and pharmacological manipulation of the receptor by beditin can be used to further characterize the molecular mechanisms underlying the observed effects.
F60 Q-Motor foot tapping: novel setup to increase reliability
2022-09-01

<h3>Background</h3> Q-Motor provided reliable quantitative endpoints in TRACK-HD and several clinical trials. Finger tapping was the most sensitive assessment of disease progression and to detect treatment effects. Recently a foot tapping test was introduced to expand Q-Motor to the lower extremity. However, subjects had difficulties to properly lift the foot from the force sensor. <h3>Aims</h3> To assess the feasibility of using a novel foot tapping apparatus that requires subjects to lift their foot properly. <h3>Methods</h3> Two novel setups were constructed with the force sensor above the foot, one using a rigid (G1), one with a non-rigid bar (G2) to carry the sensor. Both setups were compared with the old setup carrying the sensor underneath the foot (G3). 6 healthy controls were asked to perform the foot tapping task on each setup on 4 consecutive days. They tapped with the foot on the force sensor as fast as possible for 10 seconds with 5 repetitions at each foot. <h3>Results</h3> The 'Tap-Speed-Inter-Onset-Interval-Mean-Foot' is the main endpoint of foot tapping. It is the average time between the start of each successive tap. A density plot showed normally distributed data only for G2 and G3, thus G1 was not analyzed further. The data showed that the new inverted test setup (G2) provided less variability and better reproducibility over time. <h3>Conclusions</h3> The novel foot tapping task is feasible and provided more reliable data. The new setup with the non-rigid bar merits further exploration in upcoming studies and should be tested in a larger cohort of subjects over longer periods.
“Savage War” as “People’s War”: Nineteenth-Century African Wars, European Perceptions, and the Future of Warfare
2022-09-01

This article first looks at how British, French, and German officers assessed the specifics of nineteenth-century colonial warfare and how they distinguished it from wars in Europe. Part 2 explores, on the basis of war reports from the nineteenth century and secondary literature, the significance of specifically African war traditions from precolonial times and how these came into play when, in the second half of the century, within a few decades the European colonial powers divided the continent among themselves with enormous brutality in their “scramble for Africa.” In their mental baggage Europeans brought ideas about war as having to “take a different form in Africa,” to quote a Prussian observer of the Franco-Moroccan War. What did this imply for their own style of warfare? Part 3 intervenes in the politically charged debate about how the European experience of nineteenth-century colonial warfare shaped war, and genocide, in twentieth-century Europe. The wars in nineteenth-century Africa, both precolonial and colonial, were not “contained” (gehegt) wars, to use Carl Schmitt’s term. Following 1815, in most of Europe the containment of warfare—that is, the separation of combatants and the civilian population—worked for a hundred years. After that, no more. Why? Does the experience of colonial warfare offer an explanation? This article tests an explanation that hinges on an unconventional comparison of what Europeans called “savage war” in Africa and “people’s war” (Volkskrieg) in Europe.
Light Stimulation of Neurons on Organic Photocapacitors Induces Action Potentials with Millisecond Precision (Adv. Mater. Technol. 9/2022)
2022-09-01

Photocapacitors In article number 2101159, Eric Daniel Głowacki, Theresa Rienmüller, Rainer Schindl, and co-workers present thin and flexible organic electrolytic photocapacitors (OEPCs) suitable for neuro-stimulation. Like photovoltaic cells, these organic semiconductors have a photosensitive pn-layer. OEPCs generate in an electrolytic environment an electric field when illuminated with visible red light, which is capable of inducing action potential firing in excitable cells.
P16 TAPBPR shapes the hepatitis B immunopeptidome presented on HLA class I molecules
2022-09-01

<h3>Background and Aims</h3> The presentation of virus derived peptides on HLA class I molecules is crucial for mounting antiviral immune responses. TAPBPR is a recently identified peptide editor involved in optimizing antigen selection on MHC class I molecules. Here, we present novel data on the impact of TAPBPR on the hepatitis B (HBV) immunopeptidome presented on HLA class I by using a mass spectrometry approach. <h3>Method</h3> HeLa cells (HLA-A*68:02, -B*15:03 and -Cw12) and TAPBPR knock-out HeLa cells (TAPBPRKO) overexpressing individual HBV proteins HBsAg, Pol, HBcAg and HBx were generated. These cells were expanded to 5x10<sup>8</sup> cells, lysed and peptides were eluted using a pan HLA class I antibody (W6/32). Analysis was performed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Mass spectra data were then searched against a database of possible peptides that could be derived from the host and/or pathogen proteomes, to identify HBV derived peptides presented on HLA class I. The HBV immunopeptidome in TAPBPRKO cells was compared to HeLa cells expressing wild type TAPBPR and individual HBV proteins. <h3>Results</h3> A greater number of HBV peptides were presented in TAPBPRKO cell lines compared to wild type cell lines, which was consistently observed between cells expressing different HBV proteins. This was despite the fact that no substantial change in the total cellular peptide count was observed between wild type and TAPBPRKO cells. Amino acids positions 2 and 9 were clearly preferred for binding in both wild type and TAPBPRKO cells, and a greater number of peptides were assigned to HLA-B*15:03 than HLA-A*68:02. Furthermore, semi quantitative analysis revealed that depletion of TAPBPR resulted in up-modulation of almost all HBV-derived peptides identified. In addition, changes in the hierarchy of the abundance of HBV peptides presented were observed in TAPBPRKO cells. Of the up-modulated peptides, only four have been identified previously and are catalogued on IEDB. A total of 26 HBV-derived peptides were identified, 22 (84.62%) of which were novel. Of the novel peptides 7 were only identified in the TAPBPRKO cell lines. <h3>Conclusion</h3> These findings strongly support a role of TAPBPR in HBV-derived peptide selection for presentation on HLA class I. However, it is still unclear whether this is advantageous for individuals with HBV expressing HLA alleles where TAPBPR mediates peptide exchange.
O02 Discovery of novel HLA class I presented hepatitis B peptides using an immunopeptidomics approach
2022-09-01

<h3>Background and Aims</h3> An estimated 250 million people worldwide are infected with chronic hepatitis B (HBV), the leading cause of hepatocellular carcinoma (HCC) worldwide. The display of HBV derived peptides on HLA class I molecules is crucial for immune cell mediated responses and control of HBV. Most HBV peptides that have previously been characterised are restricted to HLA alleles not representative of HBV high prevalence regions and were identified by computational methods which do not consider the antigen presentation pathway. <h3>Methods</h3> We used a mass spectrometry-based approach (immunopeptidomics) to discover novel HBV peptides presented on a diverse set of HLA allotypes. Cell lines expressing single HLA class I of choice (HLA-A*02:01, -B*08:01, -B*35:01 and Cw06:02) and individual HBV proteins, HBsAg, Pol, HBcAg and HBx were generated and expanded to 10<sup>8</sup> cells. Cells were lysed, peptides eluted using a pan HLA class I antibody (W6/32) and then analysed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Mass spectra data were then searched against a database of possible peptides that could be derived from the host and/or HBV proteomes, to identify HBV derived peptides presented on HLA class I. We then performed exogenous peptide loading on cells expressing single HLA class I using a selection of fluorescently- labelled HLA class I binding HBV peptides discovered using the approach above. <h3>Results</h3> A total of 55 unique HBV-derived peptides were discovered, 38 (69.09%) of which were novel peptides. Importantly, binding prediction using netMHCpan4.1 revealed that 32 peptides (58.18%) were predicted to be strong binders, whereas 23 peptides (41.82%) were predicted to be weak binders. We identified numerous novel HBV-derived antigens presented on HLA-B*08:01, -B*35:01 or Cw06:02. Twenty-three peptides were derived from HBsAg, 29 peptides were derived from Pol and three peptides were derived from HBcAg. No HBx derived peptides were identified. Subsequent testing of fluorescent-derivatives of a small panel of the HBV-derived antigens confirmed their ability to bind to the specific HLA. <h3>Conclusion</h3> An immunopeptidomics approach is a promising new technique for HBV peptide discovery, which considers all aspects of the antigen presentation pathway. Furthermore, the majority of these peptides are predicted to be strong binders to HLA class I. The large numbers of HBV peptides presented on HLA -B and -C allotypes that are both novel and predicted to be strong binders is encouraging for therapeutic vaccine design. These peptides have the potential to trigger immune responses from a broad array of immune cell types and across populations with a more diverse range of HLA class I allotypes.