Cognitive and gait in Wilson's disease: a cognitive and motor dual-task study.

Background: Cognitive and motor dual-tasks play important roles in daily life. Dual-task interference impacting gait performance has been observed not only in healthy subjects but also in subjects with neurological disorders. Approximately 44-75% of Wilson's disease (WD) patients have gait disturbance. According to our earlier research, 59.7% of WD patients have cognitive impairment. However, there are few studies on how cognition affects the gait in WD. Therefore, this study aims to explore the influence of cognitive impairment on gait and its neural mechanism in WD patients and to provide evidence for the clinical intervention of gait disturbance. Methods: We recruited 63 patients who were divided into two groups based on their scores on the Addenbrooke's cognitive examination III (ACE-III) scale: a non-cognitive impairment group and a cognitive impairment group. In addition to performing the timed up and go (TUG) single task and the cognitive and motor dual-task digital calculation and animal naming tests, the Tinetti Balance and Gait Assessment (POMA), Berg Balance Scale (BBS), and brain MRI severity scale of WD (bMRIsc-WD) were evaluated. The dual-task cost (DTC) was also computed. Between the two groups, the results of the enhanced POMA, BBS, and bMRIsc-WD scales, as well as gait performance measures such as TUG step size, pace speed, pace frequency, and DTC value, were compared. Results: (1) Among the 63 patients with WD, 30 (47.6%) patients had gait disturbance, and the single task TUG time was more than 10 s. A total of 43 patients had cognitive impairment, the incidence rate is 44.4%. Furthermore, 28 (44.4%) patients had cognitive impairment, 39 (61.9%) patients had abnormal brain MRI. (2) The Tinetti gait balance scale and Berg balance scale scores of patients with cognitive impairment were lower than those of patients without cognitive impairment (p < 0.05), and the pace, step size, and pace frequency in the single task TUG were slower than those of patients without cognitive impairment (p < 0.05). There was no change in the pace frequency between the dual-task TUG and the non-cognitive impairment group, but the pace speed and step size in the dual-task TUG were smaller than non-cognitive impairment group (p < 0.05). There was no difference in DTC values between cognitive impairment group and non-cognitive impairment group when performing dt-TUG number calculation and animal naming respectively (p > 0.05). However, regardless of cognitive impairment or not, the DTC2 values of number calculation tasks is higher than DTC1 of animal naming tasks in dt-TUG (p < 0.05). (3) Pace speed and step size were related to the total cognitive score, memory, language fluency, language understanding, and visual space factor score of the ACE-III (p < 0.05), and step frequency was correlated with memory and language comprehension factors (p < 0.05). There was no correlation between the attention factor scores of the ACE-III and TUG gait parameters of different tasks (p > 0.05). Brain atrophy, the thalamus, caudate nucleus, and cerebellum were correlated with cognitive impairment (p < 0.05), the lenticular nucleus was related to the step size, brain atrophy was related to the pace speed, and the thalamus, caudate nucleus, and midbrain were involved in step frequency in WD patients (p < 0.05). Conclusion: WD patients had a high incidence of cognitive impairment and gait disorder, the pace speed and step size can reflect the cognitive impairment of WD patients, cognitive impairment affects the gait disorder of WD patients, and the different cognitive and motor dual-tasks were involved in affecting gait parameters. The joint participation of cognitive impairment and lesion brain area may be the principal neural mechanism of gait abnormality in WD patients.

miR-486-5p inhibits cell growth of papillary thyroid carcinoma by targeting fibrillin-1.

Previous studies have demonstrated that miR-486-5p functions as a tumor suppressor or oncogene in various types of cancer. In the present study, we showed that miR-486-5p was significantly down-regulated in papillary thyroid carcinoma (PTC) tissues and cell lines, whereas miR-486-5p down-regulation inhibited PTC cell proliferation and increased apoptosis. Conversely, under-expression of miR-486-5p enhanced PTC cell proliferation and decreased apoptosis. Fibrillin-1 (FBN1) was shown to be a direct target of miR-486-5p and inversely regulated by miR-486-5p. FBN1 silencing led to decreased PTC cell proliferation and enhanced apoptosis in vitro, similar to that mediated by miR-486-5p. Furthermore, miR-486-5p over-expression or FBN1 knock-down inhibited, while up-regulation of FBN1 boosted xenograft tumor formation in vivo. Our data suggest that miR-486-5p induces PTC cell growth inhibition and apoptosis by targeting and suppressing FBN1. Thus, miR-486-5p/FBN1 might provide a promising therapeutic target for PTC treatment.

[Research on the correlation between Chinese medical syndrome types and objective indices of Wilson's disease].

OBJECTIVE: To explore the correlation between Chinese medical syndrome types of Wilson's disease (WD) and clinical materials as well as physical and chemical indices. METHODS: Totally 116 WD patients were typed by Chinese medical syndrome. The correlation between Chinese medical syndrome types and clinical materials as well as physical and chemical indices were analyzed using binary stepwise Logistic regression by SPSS 19.0 Software, taking the common Chinese medical syndrome types as the dependent variable and clinical materials as well as physical and chemical indices as the independent variables. RESULTS: Gan-Galibladder dampness-heat syndrome (GGDHS, 35.3%). Gan-stagnation and Pi-deficiency syndrome (GSPDS, 13.8%), Gan-Shen yin deficiency syndrome (GSYDS, 13.8%), and phlegm-dampness retention syndrome (PDRS, 12.1%) were most often seen. GGDHS was positively correlated with grade of K-F ring, total bilirubin (TBIL), alanine transaminase (ALT), laminin (LN) (P < 0.01). GSYDS was positively correlated with TBIL (P < 0.01). PDRS was positively correlated with clinical types, ceruloplasmin (CP), aspartate aminotransferase (AST), and total protein (TP) (P < 0.01, P < 0.05). Qi blood deficiency syndrome was positively correlated with disease course, blood ammonia, blood urea nitrogen (BUN), and LN (P < 0.01, P < 0.05). CONCLUSIONS: Chinese medical syndrome types were correlated with clinical materials, physical and chemical indices in WD patients, which could provide experimental reference for Chinese medical syndrome typing. GGDHS, GSPDS, GSYDS, and PDRS were most often seen.

Identification of residues of functional importance within the central turn motifs present in the cytoplasmic tails of integrin alphaIIb and alphaV subunits.

INTRODUCTION: Previous studies demonstrated that cell-permeable alphaIIb cytoplasmic peptides can modulate the activation of alphaIIbbeta3. An integrin activation motif was mapped to its membrane proximal region and a double proline mutant peptide and receptor indicated that its central turn motif had inhibitory capacity. However, the residues critical for inhibition of alphaIIbbeta3 activation were not identified. Using central turn peptides derived from alphaIIb and alphaV, residues critical for suppression of integrin activation were identified and the importance of these residues in protein-protein interactions was assessed. MATERIALS AND METHODS: Cell-permeable peptides were used to determine the capacity of the central turn peptides to suppress alphaIIbbeta3 and alphaVbeta3 activation. Far Western analysis was used to characterize the capacity of the peptides to interact with CIB1 and surface plasmon resonance was used to characterize the binding of an antibody to the cytoplasmic tails of alphaIIb and alphaV. RESULTS AND CONCLUSIONS: The central turn peptide from alphaV, alphaV(993-1001), has full inhibitory capacity while that derived from alphaIIb requires additional residues located adjacent to alphaIIb(995-1003). Within these two sequences there is a switch in the position of an asparaginine and leucine residue for a valine and glutamine (alphaIIb, RNRPPLEED; alphaV, RVRPPQEEQ). This switch had a dramatic effect on their inhibitory capacity and on protein-protein interactions. The two arginine and glutamic residues, juxtapositioned at identical locations in both subunits, appeared to be important in specifying the orientation by which proteins can dock to this region in alphaIIb and alphaV.

Calcium stiffens archaeal Rad51 recombinase from Methanococcus voltae for homologous recombination.

Archaeal RadA or Rad51 recombinases are close homologues of eukaryal Rad51 and DMC1. These and bacterial RecA orthologues play a key role in DNA repair by forming helical nucleoprotein filaments in which a hallmark strand exchange reaction between homologous DNA substrates occurs. Recent studies have discovered the stimulatory role by calcium on human and yeast recombinases. Here we report that the strand exchange activity but not the ATPase activity of an archaeal RadA/Rad51 recombinase from Methanococcus voltae (MvRadA) is also subject to calcium stimulation. Crystallized MvRadA filaments in the presence of CaCl(2) resemble that of the recently reported ATPase active form in the presence of an activating dose of KCl. At the ATPase center, one Ca(2+) ion takes the place of two K(+) ions in the K(+)-bound form. The terminal phosphate of the nonhydrolyzable ATP analogue is in a staggered conformation in the Ca(2+)-bound form. In comparison, an eclipsed conformation was seen in the K(+)-bound form. Despite the changes in the ATPase center, both forms harbor largely ordered L2 regions in essentially identical conformations. These data suggest a unified stimulation mechanism by potassium and calcium because of the existence of a conserved ATPase center promiscuous in binding cations.