Journal of nature and science最新文献

We previously identified a human monoclonal antibody, termed HIgM12 that stimulates spontaneous locomotor activity in a chronically demyelinating mouse model of multiple sclerosis. When tested as a molecular substrate, HIgM12 stimulated neurite outgrowth in vitro. We recently reported that polysialic acid (PSA) attached to the neural cell adhesion molecule (NCAM) is one of the cellular antigens for HIgM12. Fluorescent double-labeling of astrocytes using HIgM12 and commercially available anti-PSA antibody showed dramatic co-localization. Neural tissue homogenates and primary CNS cultures from mice lacking the three major NCAM splice variants NCAM180, NCAM140 and NCAM120 (NCAM KO) were no longer able to bind HIgM12. Furthermore, enzymatic digestion of PSA on wild type (WT) glia abolished HIgM12-binding. Moreover, neurons and glia from NCAM KO animals did not attach to HIgM12-coated nitrocellulose in neurite outgrowth assays. We conclude that HIgM12 targets PSA attached to NCAM, and that the PSA moiety mediates neuronal and glial adhesion and subsequent neurite outgrowth in our in vitro assay. Therefore, this anti-PSA antibody may serve as a future therapeutic to stimulate functional improvement in multiple sclerosis patients and other neurodegenerative diseases.

Introduction: Ventricular tachycardia and ventricular fibrillation are the two most dangerous arrhythmias. Both are related to reentrant electrical activity in the ventricles. Many studies of arrhythmias consider a homogeneous sheet of cardiac tissue. Since normal ventricular myocardium is inhomogeneous and inhomogeneities play an important role in the induction of reentry, we investigate the effect of a localized inhomogeniety developed at the border between normal and ischemic region.

Methods: We used the bidomain model to represent the electrical properties of cardiac tissue and a modified version of the dynamic Luo-Rudy (LRd) model to represent the active properties of the membrane. To investigate the effect of a localized inhomogeneity, the extracellular potassium [K]_e concentration is raised to 10 mM from normal [K]_e (4 mM) on the right half of the tissue.

Results and discussion: A train of cathodal stimuli are applied from the lower left corner of the tissue with different basic cycle lengths (BCL). At certain BCL, the spatial heterogeneity created with regional elevation of [K]_e can lead to action potential instability (alternans) in the normal and border regions, and 2:1 conduction block in the ischemic region. We observed the reentry when local heterogeneity in [K]_e is changed from 10 to 12 mM on the right half of the virtual ventricular myocardium sheet.

Conclusion: Electrical alternans occur during high heart rates and are observed in patients suffering from ventricular tachycardia. It is an early indication of left ventricular systolic impairment. This study will help to evaluate alternans as a predictor and guide for antiarrhythmic therapy.

Objective: Minimal definitive literature identifies patients with radicular pain who would benefit most from epidural steroid injection (ESI). This study investigated if electromyographic (EMG) confirmation of radiculopathy with active or chronic denervation predicts a positive treatment outcome following ESI.

Design: Longitudinal cohort study of adults who underwent EMG and subsequent transforaminal ESI within 6 months. The proportion of individuals who experienced >50% pain relief and mean change in daily morphine equivalents (DME) were calculated.

Results: 170 individuals with respective mean (Standard Deviation) age and duration of symptoms of 55 (15) years and 36 (56) months were included. Mean time to <30 day and >30 day follow-up post-injection were 18 (6) and 99 (130) days, respectively. At >30 day follow-up, a larger proportion of EMG-confirmed individuals (37.7%) reported >50% pain reduction compared to EMG-negative individuals (17.8%) (p=0.03). This was significant for lumbosacral (40% vs. 15%, p=0.01) but not cervical symptoms (p>0.05). Mean decrease in DME at long-term follow-up in EMG-confirmed compared to EMG-negative individuals trended toward significance (-4 vs. -1, p=0.11). There was no significant relationship between myotomal spontaneous activity and pain or opioid use.

Conclusions: Needle EMG predicts long-term pain reduction from transforaminal ESI in patients with lumbosacral radiculopathy, regardless of the presence of active denervation.

According to the 'amyloid cascade hypothesis of Alzheimer's disease' first proposed about 16 years ago, the accumulation of Aβ peptides in the human central nervous system (CNS) is the primary influence driving Alzheimer's disease (AD) pathogenesis, and Aβ peptide accretion is the result of an imbalance between Aβ peptide production and clearance. In the last 18 months multiple laboratories have reported two particularly important observations: (i) that because the microbes of the human microbiome naturally secrete large amounts of amyloid, lipopolysaccharides (LPS) and other related pro-inflammatory pathogenic signals, these may contribute to both the systemic and CNS amyloid burden in aging humans; and (ii) that the clearance of Aβ peptides appears to be intrinsically impaired by deficits in the microglial plasma-membrane enriched triggering receptor expressed in microglial/myeloid-2 cells (TREM2). This brief general commentary-perspective paper: (i) will highlight some of these very recent findings on microbiome-secreted amyloids and LPS and the potential contribution of these microbial-derived pro-inflammatory and neurotoxic exudates to age-related inflammatory and AD-type neurodegeneration in the host; and (ii) will discuss the contribution of a defective microglial-based TREM2 transmembrane sensor-receptor system to amyloidogenesis in AD that is in contrast to the normal, homeostatic clearance of Aβ peptides from the human CNS.

Objective: Progressive myopia in humans and lid-sutured myopia in primates have been considered to be different processes. This report seeks to establish the connection between progressive myopia in humans and lid suture myopia in macaque monkeys.

Methods: We followed the axial length of 4 lid-sutured macaque monkeys over an 18 month period. Their axial length is directly related to myopia. We also studied the myopia progression in corrected human subjects. Macaques and humans exhibit a linear time course of myopia progression when lid-sutured or corrected with lenses, respectively.

Results: A linear progression is observed in lid-sutured eyes of four macaques, r = 0.94, p < 0.05. Human progressive myopia and lid-suture myopia can be modeled by the same feedback process. In both cases the functional equivalent is the opening of the feedback loop.

Conclusions: The open loop feedback process predicts a linear progression of myopia. This prediction was confirmed in human subjects and it is now confirmed in our macaque subjects. This process also explains the very rapid rate of myopia progression of lid sutured eyes.

The two-component regulatory system, WalR/WalK is necessary for growth of different gram-positive bacteria, including Staphylococcus aureus. In present study, we confirmed the essentiality of both the histidine kinase protein WalK and the response regulator WalR for growth using S. aureus RN4220 strain and demonstrated that the histidine kinase protein WalK and the response regulator WalR function differently in regulation of staphylococcal autolysis. The down-regulation of walR expression effectively inhibited Triton X-100-induced lysis and had a weak impact on bacterial tolerance to penicillin induced cell lysis. In contrast, the down-regulation of walK expression had no influence on either Triton X-100- or penicillin-caused autolysis. Moreover, we determined the effect of WalR and WalK on bacterial hydrolase activity using a zymogram analysis. The results showed that the cell lysate of down-regulated walR expression mutant displayed several bands of decreased cell wall hydrolytic activities; however, the down-regulation of WalK had no dramatic impact on the hydrolytic activities. Furthermore, we examined the impact of WalR on the transcription of cidA associated with staphylococcal autolysis, and the results showed that the down-regulation of WalR led to decreased transcription of cidA in the log phase of growth. Taken together, the above results suggest that the essential WalR response regulator and the essential WalK histidine kinase might differently control bacterial lysis in RN4220 strain.

The death of immune cells in response to pathogens often dictates the outcome of an infection. In some contexts, pathogens specifically kill immune cells by producing highly potent toxins or by triggering host cell death pathways, thus ensuring successful infections. But for intracellular pathogens and viruses, the death of host cells normally is disastrous for their intracellular life cycle. Our recent experiments with the pathogen Legionella pneumophila revealed that the bacterial ribosomal protein RpsL is able to trigger lysosomal membrane permeabilization (LMP) and the subsequent macrophage cell death. Interestingly, a lysine to arginine mutation at the 88^th residue, which also confers resistance to the antibiotic streptomycin, substantially impaired the cell death inducing activity of RpsL and allowed L. pneumophila to succeed in intracellular replication, suggesting the convergence of resistance mechanisms to innate immunity and antibiotics. The discovery of lysosomal cell death as an immune response to a bacterial ligand has expanded the spectrum of reactions that host cells can mount against bacterial infection; these observations provide a model to study the pathways that lead to the induction of LMP, a currently poorly understood cellular process involved in the development of many diseases.

Objectives: This study evaluated the effect of incorporating increasing concentrations of sodium fluoride in incubation media, on the loss of dry mass and solubilization of collagen from demineralized dentin beams incubated for up to 7 days. The effect of fluoride on the inhibition of matrix-bound metalloproteinases (MMPs) was also measured.

Methods: Dentin beams were completely demineralized in 10% phosphoric acid. After baseline measurements of dry mass, the beams were divided into six groups (n=10) and incubated at 37°C either in buffered media containing sodium fluoride (NaF) at 75, 150, 300, 450, 600 ppm or in fluoride-free media (control) for seven days. Following incubation, dry mass was re-measured. The incubation media was hydrolyzed with HCl for the quantitation of hydroxyproline (HYP) as an index of solubilization of collagen by endogenous dentin proteases. Increasing concentrations of fluoride were also evaluated for their ability to inhibit rhMMP-9.

Results: Addition of NaF to the incubation media produced a progressive significant reduction (p<0.05) in the loss of mass of dentin matrices, with all concentrations demonstrating significantly less mass loss than the control group. Significantly less HYP release from the dentin beams was found in the higher fluoride concentration groups, while fluoride concentrations of 75 and 150 ppm significantly reduced rhMMP-9 activity by 6.5% and 79.2%, respectively.

Conclusions: The results of this study indicate that NaF inhibits matrix-bound MMPs and therefore may slow the degradation of dentin matrix by endogenous dentin MMPs.

In this short review, Puyang and her colleagues compared the results from three laboratories on the dendritic and functional degeneration of retinal ganglion cells (RGCs) in mouse models of experimental glaucoma [1-4]. Acute or chronic ocular hypertension was induced in mice, and different techniques were applied to identify RGC types. The dendritic alternations of RGCs were examined following the induction of ocular hypertension, and their light response properties were characterized by the multi-electrode array (MEA) recording. These studies support the notion that the morphological and functional degeneration of RGCs are subtype-dependent in experimental glaucoma.

The Alzheimer's Questionnaire (AQ) was developed to be brief and accurate informant-based assessment for primary care and geriatric physicians to use in screening for cognitive impairment. To date, several studies have been carried out and published establishing the diagnostic accuracy and psychometric validity of the AQ. This paper will provide a review of the studies that have been carried out to establish the AQ as a valid and accurate informant-based assessment of cognitive function.