Impaired Functional Criticality of Human Brain during Alzheimer's Disease Progression

The progression of Alzheimer's Disease (AD) has been proposed to comprise three stages, subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD. Was brain dynamics across the three stages smooth? Was there a critical transition? How could we characterize and study functional criticality of human brain? Based on dynamical characteristics of critical transition from nonlinear dynamics, we proposed a vertex-wise Index of Functional Criticality (vIFC) of fMRI time series in this study. Using 42 SCD, 67 amnestic MCI (aMCI), 34 AD patients as well as their age-, sex-, years of education-matched 54 NC, our new method vIFC successfully detected significant patient-normal differences for SCD and aMCI, as well as significant negative correlates of vIFC in the right middle temporal gyrus with total scores of Montreal Cognitive Assessment (MoCA) in SCD. In comparison, standard deviation of fMRI time series only detected significant differences between AD patients and normal controls. As an index of functional criticality of human brain derived from nonlinear dynamics, vIFC could serve as a sensitive neuroimaging marker for future studies; considering much more vIFC impairments in aMCI compared to SCD and AD, our study indicated aMCI as a critical stage across AD progression

Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.

Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation

The role of EGFR mutation as a prognostic factor in survival after diagnosis of brain metastasis in non-small cell lung cancer: A systematic review and meta-analysis

Abstract Background The brain is a common site for metastasis in non-small-cell lung cancer (NSCLC). This study was designed to evaluate the relationship between the mutational of the epidermal growth factor receptor (EGFR) and overall survival (OS) in NSCLC patients with brain metastases. Methods Searches were performed in PubMed, EmBase, and the Cochrane Library to identify studies evaluating the association of EGFR mutation with OS in NSCLC patients through September 2017. Results 4373 NSCLC patients with brain metastases in 18 studies were involved. Mutated EGFR associated with significantly improved OS compared with wild type. Subgroup analyses suggested that this relationship persisted in studies conducted in Eastern, with retrospective design, with sample size ≥500, mean age of patients ≥65.0 years, percentage male < 50.0%, percentage of patients receiving tyrosine kinase inhibitor ≥30.0%. Finally, although significant publication bias was observed using the Egger test, the results were not changed after adjustment using the trim and fill method. Conclusions This meta-analysis suggests that EGFR mutation is an important predictive factor linked to improved OS for NSCLC patients with brain metastases. It can serve as a useful index in the prognostic assessment of NSCLC patients with brain metastases

Back to the Starting Point: on the Simulation of Initial Magnetic Fields and Spin Periods of Non-accretion Pulsars

Neutron stars (NSs) play essential roles in modern astrophysics. Magnetic fields and spin periods of newborn (zero age) NSs have large impact on the further evolution of NSs, which are however poorly explored in observation due to the difficulty of finding newborn NSs. In this work, we aim to infer the magnetic fields and spin periods (Bi and Pi) of zero-age NSs from the observed properties of NS population. We select non-accretion NSs (NANSs) whose evolution is solely determined by magnetic dipole radiation. We find that both Bi and Pi can be described by log-normal distribution and the fitting sensitively depends on our parameters.Comment: 8 pages, 5 figures, accepted for publication in Ap

Efficacy and safety of external-beam radiation therapy for hepatocellular carcinoma: An overview of current evidence according to the different target population

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In Vitro Activity of Plant Extracts and Alkaloids against Clinical Isolates of Extended-Spectrum b-Lactamase (ESBL)-Producing Strains

The antibacterial activity of 80% ethanol extracts of 10 medicinal plants collected in Yunnan (Southwest China), was tested against clinical isolates of extended-spectrum b-lactamase (ESBL)-producing strains. Their MIC values ranged between 1.56–12.50 mg/mL. The most active plant extract was Chelidonium majus L. (MIC = 1.56 mg/mL). Two potent isoquinoline alkaloids, 8-hydroxydihydrosanguinarine and 8-hydroxydihydrochelerythrine, were identified as the major active principles through bioassay-guided fractionation and identification of the active ethyl acetate fraction from C. majus, with minimum MIC/MBC values of 15.63/62.50 mg/mL

Functional Connectivity Changes Across the Spectrum of Subjective Cognitive Decline, Amnestic Mild Cognitive Impairment and Alzheimer’s Disease

The abnormality occurs at molecular, cellular as well as network levels in patients with Alzheimer’s disease (AD) prior to diagnosis. Most previous connectivity studies were conducted at 1 out of 3 (local, meso and global) scales in subjects covering only part of the entire AD spectrum (subjective cognitive decline, SCD; amnestic mild cognitive impairment, aMCI; and then fully manifest AD). Data interpretation within the framework of disease progression is therefore difficult. The current study included 3 age- and sex-matched cohorts: SCD (n = 32), aMCI (n = 37) and fully-established AD (n = 30). A group of healthy elderly subjects (n = 40) were included as a normal control (NC). Network connectivity was examined at the local (degree centrality), meso [subgraph centrality (SC)], and global (eigenvector and page-rank centralities) levels. As compared to NC, SCD subjects had isolated decrease of SC in primary (somatomotor and visual) networks. aMCI subjects had decreased centralities at all three scales in associative (frontoparietal control, dorsal attention, limbic and default) networks. AD subjects had increased centrality at the global scale in all seven networks. There was a positive association between Montreal Cognitive Assessment (MoCA) scores and DC in the frontoparietal control network in SCD, a negative relationship between Mini-Mental State Examination (MMSE) scores and EC in the somatomotor network in AD. These findings suggest that the primary network is impaired as early as in SCD. Impairment in the associative network also starts at the local level at this stage and may contribute to the cognitive decline. As associative network impairment extends from local to meso and global scales in aMCI, compensatory mechanisms in the primary network are activated

Different doses of intermittent theta burst stimulation for upper limb motor dysfunction after stroke: a study protocol for a randomized controlled trial

BackgroundUpper limb motor recovery is one of the important goals of stroke rehabilitation. Intermittent theta burst stimulation (iTBS), a new type of repetitive transcranial magnetic stimulation (rTMS), is considered a potential therapy. However, there is still no consensus on the efficacy of iTBS for upper limb motor dysfunction after stroke. Stimulus dose may be an important factor affecting the efficacy of iTBS. Therefore, we aim to investigate and compare the effects and neural mechanisms of three doses of iTBS on upper limb motor recovery in stroke patients, and our hypothesis is that the higher the dose of iTBS, the greater the improvement in upper limb motor function.MethodsThis prospective, randomized, controlled trial will recruit 56 stroke patients with upper limb motor dysfunction. All participants will be randomized in a 1:1:1:1 ratio to receive 21 sessions of 600 pulses active iTBS, 1,200 pulses active iTBS, 1,800 pulses active iTBS, or 1,800 pulses sham iTBS in addition to conventional rehabilitation training. The primary outcome is the Fugl-Meyer Assessment of the Upper Extremity (FMA-UE) score from baseline to end of intervention, and the secondary outcomes are the Wolf Motor Function Test (WMFT), Grip Strength (GS), Modified Barthel Index (MBI), and Stroke Impact Scale (SIS). The FMA-UE, MBI, and SIS are assessed pre-treatment, post-treatment, and at the 3-weeks follow-up. The WMFT, GS, and resting-state functional magnetic resonance imaging (rs-fMRI) data will be obtained pre- and post-treatment.DiscussionThe iTBS intervention in this study protocol is expected to be a potential method to promote upper limb motor recovery after stroke, and the results may provide supportive evidence for the optimal dose of iTBS intervention