Inhibition of autoimmune diabetes by TLR2 tolerance

We have reported that apoptotic β cells undergoing secondary necrosis, called "late apoptotic (LA) β cells," stimulated APCs and induced diabetogenic T cell priming through TLR2, which might be one of the initial events in autoimmune diabetes. Indeed, diabetogenic T cell priming and the development of autoimmune diabetes were significantly inhibited in TLR2-null NOD mice, suggesting the possibility that TLR2 blockade could be used to inhibit autoimmune diabetes. Because prolonged TLR stimulation can induce TLR tolerance, we investigated whether repeated TLR2 administration affects responses to LA β cells and inhibits autoimmune diabetes in NOD mice by inducing TLR2 tolerance. Treatment of primary peritoneal macrophages with a TLR2 agonist, Pam3CSK(4), suppressed cytokine release in response to LA insulinoma cells or further TLR2 stimulation. The expression of signal transducer IRAK-1 and -4 proteins was decreased by repeated TLR2 stimulation, whereas expression of IRAK-M, an inhibitory signal transducer, was enhanced. Chronic Pam3CSK(4) administration inhibited the development of diabetes in NOD mice. Diabetogenic T cell priming by dendritic cells and upregulation of costimulatory molecules on dendritic cells by in vitro stimulation were attenuated by Pam3CSK(4) administration in vivo. Pam3CSK(4) inhibited diabetes after adoptive transfer of diabetogenic T cells or recurrence of diabetes after islet transplantation by pre-existing sensitized T cells. These results showed that TLR2 tolerance can be achieved by prolonged treatment with TLR2 agonists, which could inhibit priming of naive T cells, as well as the activity of sensitized T cells. TLR2 modulation could be used as a novel therapeutic modality against autoimmune diabetes.     

Differences in bird communities in postfire silvicultural practices stands within pine forest of South Korea

We examined differences in bird communities in relation to characteristics of habitat structure in a pine forest, Samcheok, South Korea. An unburned stand, a stand burned 7 years earlier and then naturally restored, and a stand where Japanese red pine Pinus densiflora seedlings were planted after the fire were used for the survey. Habitat structure was dramatically changed by postfire silvicultural practices. Number of stand trees, shrubs, seedlings, snags, and vegetation coverage were significantly different among study stands. We made 1,421 detections of 46 bird species during 23 separate line transect surveys per stand between February 2007 and December 2008. The mean number of observed bird species and individuals, bird species diversity index (H′), and Simpson’s diversity index (D _s) were highest in the unburned stand and lowest in the pine seedling stand. There were more species and individuals of forest-dwelling birds in the unburned stand than both burned stands. Canopy and cavity nesters, foliage searchers, bark gleaners, and timber drillers were significantly higher in the unburned stand. In the pine seedling stand, densities of birds that prefer open field and shrub cover were higher. Stand structure was simplified in the pine seedling stand by postfire practices. Because of differences in habitat structure and bird communities, postfire practices in the burned stand should be re-evaluated. Also, management strategies for pine forest after forest fires are needed based on results of long-term experiments.     

Activity-dependent α-Cleavage of Nectin-1 Is Mediated by A Disintegrin and Metalloprotease 10 (ADAM10)

Nectin-1 is known to undergo ectodomain shedding by α-secretase and subsequent proteolytic processing by γ-secretase. How secretase-mediated cleavage of nectin-1 is regulated in neuronal cells and how nectin-1 cleavage affects synaptic adhesion is poorly understood. We have investigated α-and γ-secretase-mediated processing of nectin-1 in primary cortical neurons and identified which protease acts as a α-secretase. We report here that NMDA receptor activation, but not stimulation of AMPA or metabotropic glutamate receptors, resulted in robust α- and γ-secretase cleavage of nectin-1 in mature cortical neurons. Cleavage of nectin-1 required influx of Ca²⁺ through the NMDA receptor, and activation of calmodulin, but was not dependent on calcium/calmodulin-dependent protein kinase II (CaMKII) activation. We found that ADAM10 is the major secretase responsible for nectin-1 ectodomain cleavage in neurons and the brain. These observations suggest that α- and γ-secretase processing of nectin-1 is a Ca²⁺/calmodulin-regulated event that occurs under conditions of activity-dependent synaptic plasticity and ADAM10 and γ-secretase are responsible for these cleavage events.     

Structural hybridization of pyrrolidine-based T-type calcium channel inhibitors and exploration of their analgesic effects in a neuropathic pain model

Highly effective and safe drugs for the treatment of neuropathic pain are urgently required and it was shown that blocking T-type calcium channels can be a promising strategy for drug development for neuropathic pain. We have developed pyrrolidine-based T-type calcium channel inhibitors by structural hybridization and subsequent assessment of in vitro activities against Ca_v3.1 and Ca_v3.2 channels. Profiling of in vitro ADME properties of compounds was also carried out. The representative compound 17h showed comparable in vivo efficacy to gabapentin in the SNL model, which indicates T-type calcium channel inhibitors can be developed as effective therapeutics for neuropathic pain.     

Current views on insect feed and its future

Population growth and the subsequent increased demand for food, along with the rise in cost of feed, have led insect feed to be considered as an alternative to conventional animal feed. Insect feed is a sustainable and nutritious option; however, it does carry the risk of lower microbiological safety than conventional feed. Although there is some hesitancy from farmers in adapting insect feed due to fear of market rejection of insect‐fed animals, surveys seem to show positive attitudes of people towards insect feed when they informed of the benefits. Traditional methods of harvesting insects is not a sustainable method of production, and therefore further research will be needed to access appropriate methods of mass‐producing insects without putting a strain on the natural ecosystem. This review discusses the benefits and risks of using insect feed, its acceptance, type of animals that can be fed by insects, and future directions of insect feed.     

In vivo Tracking of Dendritic Cell using MRI Reporter Gene,Ferritin

The noninvasive imaging of dendritic cells (DCs) migrated into lymph nodes (LNs) can provide helpful information on designing DCs-based immunotherapeutic strategies. This study is to investigate the influence of transduction of human ferritin heavy chain (FTH) and green fluorescence protein (GFP) genes on inherent properties of DCs, and the feasibility of FTH as a magnetic resonance imaging (MRI) reporter gene to track DCs migration into LNs. FTH-DCs were established by the introduction of FTH and GFP genes into the DC cell line (DC2.4) using lentivirus. The changes in the rate of MRI signal decay (R₂*) resulting from FTH transduction were analyzed in cell phantoms as well as popliteal LN of mice after subcutaneous injection of those cells into hind limb foot pad by using a multiple gradient echo sequence on a 9.4 T MR scanner. The transduction of FTH and GFP did not influence the proliferation and migration abilities of DCs. The expression of co-stimulatory molecules (CD40, CD80 and CD86) in FTH-DCs was similar to that of DCs. FTH-DCs exhibited increased iron storage capacity, and displayed a significantly higher transverse relaxation rate (R₂*) as compared to DCs in phantom. LNs with FTH-DCs exhibited negative contrast, leading to a high R₂* in both in vivo and ex vivo T₂*-weighted images compared to DCs. On histological analysis FTH-DCs migrated to the subcapsular sinus and the T cell zone of LN, where they highly expressed CD25 to bind and stimulate T cells. Our study addresses the feasibility of FTH as an MRI reporter gene to track DCs migration into LNs without alteration of their inherent properties. This study suggests that FTH-based MRI could be a useful technique to longitudinally monitor DCs and evaluate the therapeutic efficacy of DC-based vaccines.     

Industrial attributes of β-glucanase produced by Bacillus sp. CSB55 and its potential application as bio-industrial catalyst

Bioprocess and Biosystems Engineering - The β-glucanase produced from Bacillus sp. CSB55 not only depicts the potent industrial characteristics but also relates as bio-industrial catalyst...     

A Modified Valley Restrained Monte Carlo Method to Efficiently Search the Low Energy Structures of Peptides

Abstract

A new Monte Carlo sampling scheme, namely the Modified Valley Restrained Monte Carlo procedure, is used to obtain the global energy minimum conformations for polypeptides, such as Met-enkephalin and Melittin. For each peptide, we found close agreement with previous results from both theoretical and experimental studies. The simple idea for controlling the step size according to the Valley Function, provides useful suggestions in searching the global energy minimum structures, and furthermore helps solve the multiple minima problem.     

Intermittent Hypoxia Can Aggravate Motor Neuronal Loss and Cognitive Dysfunction in ALS Mice

Background

Patients with ALS may be exposed to variable degrees of chronic intermittent hypoxia. However, all previous experimental studies on the effects of hypoxia in ALS have only used a sustained hypoxia model and it is possible that chronic intermittent hypoxia exerts effects via a different molecular mechanism from that of sustained hypoxia. No study has yet shown that hypoxia (either chronic intermittent or sustained) can affect the loss of motor neurons or cognitive function in an in vivo model of ALS.

Objective

To evaluate the effects of chronic intermittent hypoxia on motor and cognitive function in ALS mice.

Methods

Sixteen ALS mice and 16 wild-type mice were divided into 2 groups and subjected to either chronic intermittent hypoxia or normoxia for 2 weeks. The effects of chronic intermittent hypoxia on ALS mice were evaluated using the rotarod, Y-maze, and wire-hanging tests. In addition, numbers of motor neurons in the ventral horn of the spinal cord were counted and western blot analyses were performed for markers of oxidative stress and inflammatory pathway activation.

Results

Compared to ALS mice kept in normoxic conditions, ALS mice that experienced chronic intermittent hypoxia had poorer motor learning on the rotarod test, poorer spatial memory on the Y-maze test, shorter wire hanging time, and fewer motor neurons in the ventral spinal cord. Compared to ALS-normoxic and wild-type mice, ALS mice that experienced chronic intermittent hypoxia had higher levels of oxidative stress and inflammation.

Conclusions

Chronic intermittent hypoxia can aggravate motor neuronal death, neuromuscular weakness, and probably cognitive dysfunction in ALS mice. The generation of oxidative stress with activation of inflammatory pathways may be associated with this mechanism. Our study will provide insight into the association of hypoxia with disease progression, and in turn, the rationale for an early non-invasive ventilation treatment in patients with ALS.