Quantitative grip force assessment of muscular weakness in chronic inflammatory demyelinating polyneuropathy

Background: In patients suffering from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) disease severity is assessed by Medical Research Counsil (MRC) Scale or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. However, none of these methods is appropriate to objectively assess muscle weakness or to detect very small subclinical changes. More objective and quantitative measures are needed in order to evaluate treatment efficiency or to detect subclinical affection of upper limps for early diagnosis. The goal of our study was to objectively quantify muscular weakness in CIDP patients with the non-invasive Quantitative Motor (Q-Motor) test of Grip Force Assessment (QGFA) as well as the Involuntary Movement Assessment (QIMA) and to search for differences between typical and atypical CIDP variants. In addition, we hypothesized that Q-Motor findings correlate with disease severity scales such as MRC or INCAT score. Methods: In this cross-sectional exploratory proof-of-concept study subjects with confirmed diagnosis of typical or atypical CIDP were examined and compared to healthy controls (HC). For Q-Motor tests all subjects had to lift a device (250 g and 500 g) equipped with an electromagnetic sensor that measured grip force (GF) and three-dimensional changes in position and orientation. The measures "grip force variability" (GFV), "position index" (PI) and "orientation index" (OI) were provided to assess involuntary movements due to muscular weakness. Results: 33 patients with CIDP and 28 HC were included. All measures were significantly elevated in CIDP patients for both devices in the right and left hand compared to healthy controls. Subgroup analysis revealed no differences between typical and atypical CIDP variants. INCAT score only weakly correlated with OI and PI. However, there was a stronger correlation between MRC and QIMA parameters in both hands. Conclusion: Q-Motor assessments were capable to objectively assess muscular weakness in CIDP. In particular, QIMA measures detected subclinical generalized muscle weakness even in patients with milder disability. Sensitivity and rater-independence of Q-Motor assessments support a further exploration of QIMA measures as potential endpoints for future clinical trials in CIDP

NF-κB essential modulator (NEMO) interaction with linear and Lys-63 ubiquitin chains contributes to NF-κB activation.

The IκB kinase (IKK) complex acts as a gatekeeper of canonical NF-κB signaling in response to upstream stimulation. IKK activation requires sensing of ubiquitin chains by the essential IKK regulatory subunit IKKγ/NEMO. However, it has remained enigmatic whether NEMO binding to Lys-63-linked or linear ubiquitin chains is critical for triggering IKK activation. We show here that the NEMO C terminus, comprising the ubiquitin binding region and a zinc finger, has a high preference for binding to linear ubiquitin chains. However, immobilization of NEMO, which may be reminiscent of cellular oligomerization, facilitates the interaction with Lys-63 ubiquitin chains. Moreover, selective mutations in NEMO that abolish association with linear ubiquitin but do not affect binding to Lys-63 ubiquitin are only partially compromising NF-κB signaling in response to TNFα stimulation in fibroblasts and T cells. In line with this, TNFα-triggered expression of NF-κB target genes and induction of apoptosis was partially compromised by NEMO mutations that selectively impair the binding to linear ubiquitin chains. Thus, in vivo NEMO interaction with linear and Lys-63 ubiquitin chains is required for optimal IKK activation, suggesting that both type of chains are cooperating in triggering canonical NF-κB signaling

Photoreceptor layer thinning in idiopathic Parkinson's disease

This study was undertaken to quantify retinal and intra-retinal layer thicknesses in Parkinson's disease (PD), and to evaluate whether retinal structural changes may be related to altered discrimination of color vision and to severity and duration of PD disease. We examined 97 PD patients and 32 healthy controls (HC) with spectral-domain optical coherence tomography (OCT), including intra-retinal layer segmentation. In total, we compared 111 retinal nerve fiber layer (RNFL)-scans and 114 macula scans from 68 PD patients with 62 RNFL and 63 macula scans from 32 HC. For clinical evaluation of disease severity, we used the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. To determine color discrimination, we performed the Farnsworth Munsell 100 Hue Test (FMT) in a subgroup of PD patients. We found significant combined outer nuclear and photoreceptor layer thinning in PD versus HC (118.6 vs. 123.5 µm, P = 0.001). Differences in RNFL, total macular volume, or the other retinal layer thicknesses were not detected. The OCT measures were not associated with disease severity, duration, or color vision. By showing photoreceptor cell layer thinning, our findings support previous in vivo and autopsy studies demonstrating retinal alterations in PD. Optical coherence tomography may help to assess morphological retinal changes in PD patients; however, the utility of OCT in routine clinical practice may be limited because many PD patients have difficulties complying with OCT investigation because of disease-related symptoms such as tremor, axial rigidity, or cognitive impairment

Quantitative RNA imaging in single live cells reveals age-dependent asymmetric inheritance.

Asymmetric inheritance of cellular content through cell division plays an important role in cell viability and fitness. The dynamics of RNA segregation are so far largely unaddressed. This is partly due to a lack of approaches to follow RNAs over multiple cellular divisions. Here, we establish an approach to quantify RNA dynamics in single cells across several generations in a microfluidics device by tagging RNAs with the diSpinach aptamer. Using S. cerevisiae as a model, we quantitatively characterize intracellular RNA transport from mothers into their buds. Our results suggest that, at cytokinesis, ENO2 diSpinach RNA is preferentially distributed to daughters. This asymmetric RNA segregation depends on the lifespan regulator Sir2 and decreases with increasing replicative age of mothers but does not result from increasing cell size during aging. Overall, our approach opens more opportunities to study RNA dynamics and inheritance in live budding yeast at the single-cell level