Sacrificial Ionic Bonds Need To Be Randomly Distributed To Provide Shear Deformability

Multivalent ions are known to allow for reversible cross-linking in soft biological materials, providing stiffness and extensibility via sacrificial bonds. We present a simple model where stiff nanoscale elements carrying negative charges are coupled in shear by divalent mobile cations in aqueous media. Such a shear coupling through a soft glue has, indeed, been proposed to operate in biological nanocomposites. While the coupling is elastic and brittle when the negative charges are periodically arranged, sufficient randomness in their distribution allows for large irreversible deformation. Dependent on their function, biological as well as technical materials have to possess different, often contradictory, properties. In load-bearing materials, such as bone, a high stiffness has to be reconciled with an elevated toughness. A high stiffness, defined as the initial slope of the stress-strain curve, means that the material deforms only little with applied load. On the other hand, toughness is a measure of how much energy has to be put into the material to break it. In one-component materials, stiffness and toughness are typically contradictory properties. A strategy often followed by natur

Metal-coordination: using one of nature's tricks to control soft material mechanics

Growing evidence supports a critical role of dynamic metal-coordination crosslinking in soft biological material properties such as self-healing and underwater adhesion. Using bio-inspired metal-coordinating polymers, initial efforts to mimic these properties have shown promise. Here we demonstrate how bio-inspired aqueous polymer network mechanics can be easily controlled via metal-coordination crosslink dynamics; metal ion-based crosslink stability control allows aqueous polymer network relaxation times to be finely tuned over several orders of magnitude. In addition to further biological material insights, our demonstration of this compositional scaling mechanism should provide inspiration for new polymer material property-control designs.National Science Foundation (U.S.). Materials Research Science and Engineering Centers (Program) (DMR-0820054)Danish Council for Independent Research (Natural Sciences for a Post-Doctoral Fellowship 272-08-0087)University of Chicago. Materials Research Science and Engineering Center (DMR 0820054

TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is one of four inhibitors of the matrix metalloproteinases, which are capable of degrading most components of the extracellular matrix. However, in recent years, TIMP-1 has been recognised as a multifunctional protein, playing a complex role in cancer. In this regard, several studies have demonstrated an antiapoptotic effect of TIMP-1 in a number of different cell types. Since chemotherapy works by inducing apoptosis in cancer cells, we raised the hypothesis that TIMP-1 promotes resistance against chemotherapeutic drugs. In order to investigate this hypothesis, we have established TIMP-1 gene-deficient and TIMP-1 wild-type fibrosarcoma cells from mouse lung tissue. We have characterised these cells with regard to TIMP-1 genotype, TIMP-1 expression, malignant transformation and sensitivity to chemotherapy-induced apoptosis. We show that TIMP-1 gene deficiency increases the response to chemotherapy considerably, confirming that TIMP-1 protects the cells from apoptosis. This is to our knowledge the first study investigating TIMP-1 and chemotherapy-induced apoptosis employing a powerful model system comprising TIMP-1 gene-deficient cells and their genetically identical wild-type controls. For future studies, this cell system can be used to uncover the mechanisms and signalling pathways involved in the TIMP-1-mediated inhibition of apoptosis as well as to investigate the possibility of using TIMP-1 inhibitors to optimise the effect of conventional chemotherapy

Association between Plasma Antibody Response and Protection in Rainbow Trout Oncorhynchus mykiss Immersion Vaccinated against Yersinia ruckeri

A key hallmark of the vertebrate adaptive immune system is the generation of antigen-specific antibodies from B cells. Fish are the most primitive gnathostomes (jawed vertebrates) possessing an adaptive immune system. Vaccination of rainbow trout against enteric redmouth disease (ERM) by immersion in Yersinia ruckeri bacterin confers a high degree of protection to the fish. The immune mechanisms responsible for protection may comprise both cellular and humoral elements but the role of specific immunoglobulins in this system has been questioned and not previously described. The present study demonstrates significant increase in plasma antibody titers following immersion vaccination and significantly reduced mortality during Y. ruckeri challenge

Screening for colorectal cancer: possible improvements by risk assessment evaluation?

Emerging results indicate that screening improves survival of patients with colorectal cancer. Therefore, screening programs are already implemented or are being considered for implementation in Asia, Europe and North America. At present, a great variety of screening methods are available including colono- and sigmoidoscopy, CT- and MR-colonography, capsule endoscopy, DNA and occult blood in feces, and so on. The pros and cons of the various tests, including economic issues, are debated. Although a plethora of evaluated and validated tests even with high specificities and reasonable sensitivities are available, an international consensus on screening procedures is still not established. The rather limited compliance in present screening procedures is a significant drawback. Furthermore, some of the procedures are costly and, therefore, selection methods for these procedures are needed. Current research into improvements of screening for colorectal cancer includes blood-based biological markers, such as proteins, DNA and RNA in combination with various demographically and clinically parameters into a “risk assessment evaluation” (RAE) test. It is assumed that such a test may lead to higher acceptance among the screening populations, and thereby improve the compliances. Furthermore, the involvement of the media, including social media, may add even more individuals to the screening programs. Implementation of validated RAE and progressively improved screening methods may reform the cost/benefit of screening procedures for colorectal cancer. Therefore, results of present research, validating RAE tests, are awaited with interest

A Liposome-Based Mycobacterial Vaccine Induces Potent Adult and Neonatal Multifunctional T Cells through the Exquisite Targeting of Dendritic Cells

BACKGROUND: In the search for more potent and safer tuberculosis vaccines, CAF01 was identified as a remarkable formulation. Based on cationic liposomes and including a synthetic mycobacterial glycolipid as TLR-independent immunomodulator, it induces strong and protective T helper-1 and T helper-17 adult murine responses to Ag85B-ESAT-6, a major mycobacterial fusion protein. Here, we assessed whether these properties extend to early life and how CAF01 mediates its adjuvant properties in vivo. METHODS/FINDINGS: Following adult or neonatal murine immunization, Ag85B-ESAT-6/CAF01 similarly reduced the post-challenge bacterial growth of M. bovis BCG, whereas no protection was observed using Alum as control. This protection was mediated by the induction of similarly strong Th1 and Th17 responses in both age groups. Multifunctional Th1 cells were already elicited after a single vaccine dose and persisted at high levels for at least 6 months even after neonatal priming. Unexpectedly, this potent adjuvanticity was not mediated by a massive targeting/activation of dendritic cells: in contrast, very few DCs in the draining lymph nodes were bearing the labeled antigen/adjuvant. The increased expression of the CD40 and CD86 activation markers was restricted to the minute portion of adjuvant-bearing DCs. However, vaccine-associated activated DCs were recovered several days after immunization. CONCLUSION: The potent adult and neonatal adjuvanticity of CAF01 is associated in vivo with an exquisite but prolonged DC uptake and activation, fulfilling the preclinical requirements for novel tuberculosis vaccines to be used in early life

Potentiating Effects of MPL on DSPC Bearing Cationic Liposomes Promote Recombinant GP63 Vaccine Efficacy: High Immunogenicity and Protection

Visceral leishmaniasis (VL), a vector-transmitted disease caused by Leishmania donovani, is potentially fatal if left untreated. Vaccination against VL has received limited attention compared with cutaneous leishmaniasis, although the need for an effective vaccine is pressing for the control of the disease. Earlier, we observed protective efficacy using leishmanial antigen (Ag) in the presence of either cationic liposomes or monophosphoryl lipid A-trehalose dicorynomycolate (MPL-TDM) against experimental VL through the intraperitoneal (i.p.) route of administration in the mouse model. However, this route of immunization is not adequate for human use. For this work, we developed vaccine formulations combining cationic liposomes with MPL-TDM using recombinant GP63 (rGP63) as protein Ag through the clinically relevant subcutaneous (s.c.) route. Two s.c. injections with rGP63 in association with cationic liposomes and MPL-TDM showed enhanced immune responses that further resulted in high protective levels against VL in the mouse model. This validates the combined use of MPL-TDM as an immunopotentiator and liposomes as a suitable vaccine delivery system

Baltic Salmon, Salmo salar, from Swedish River Lule Älv Is More Resistant to Furunculosis Compared to Rainbow Trout

BACKGROUND: Furunculosis, caused by Aeromonas salmonicida, continues to be a major health problem for the growing salmonid aquaculture. Despite effective vaccination programs regular outbreaks occur at the fish farms calling for repeated antibiotic treatment. We hypothesized that a difference in natural susceptibility to this disease might exist between Baltic salmon and the widely used rainbow trout. STUDY DESIGN: A cohabitation challenge model was applied to investigate the relative susceptibility to infection with A. salmonicida in rainbow trout and Baltic salmon. The course of infection was monitored daily over a 30-day period post challenge and the results were summarized in mortality curves. RESULTS: A. salmonicida was recovered from mortalities during the entire test period. At day 30 the survival was 6.2% and 34.0% for rainbow trout and Baltic salmon, respectively. Significant differences in susceptibility to A. salmonicida were demonstrated between the two salmonids and hazard ratio estimation between rainbow trout and Baltic salmon showed a 3.36 higher risk of dying from the infection in the former. CONCLUSION: The finding that Baltic salmon carries a high level of natural resistance to furunculosis might raise new possibilities for salmonid aquaculture in terms of minimizing disease outbreaks and the use of antibiotics

The effect of different training modes on skeletal muscle microvascular density and endothelial enzymes controlling NO availability

It is becoming increasingly apparent that a high vasodilator response of the skeletal muscle microvasculature to insulin and exercise is of critical importance for adequate muscle perfusion and long-term microvascular and muscle metabolic health. Previous research has shown that a sedentary lifestyle, obesity, and ageing lead to impairments in the vasodilator response, while a physically active lifestyle keeps both microvascular density and vasodilator response high. To investigate the molecular mechanisms behind these impairments and the benefits of exercise training interventions, our laboratory has recently developed quantitative immunofluorescence microscopy methods to measure protein content of eNOS and NAD(P)Hoxidase specifically in the endothelial layer of capillaries and arterioles of human skeletal muscle. As eNOS produces NO and NAD(P)Hoxidase superoxide anions (quenching NO) we propose that the eNOS/NAD(P)Hoxidase protein ratio is a marker of vasodilator capacity. The novel methods show that endurance training (ET) and high intensity interval training (HIT) generally regarded as a time efficient alternative to ET, increase eNOS protein content and the eNOS/NADP(H) oxidase protein ratio in previously sedentary lean and obese young men. Resistance exercise training had smaller but qualitatively similar effects. Western blot data of other laboratories suggest that endurance exercise training leads to similar changes in sedentary elderly men. Future research will be required to investigate the relative importance of other sources and tissues in the balance between NO and O2- production seen by the vascular smooth muscle layer of terminal arterioles