A single amino acid mutation in an ABC transporter gene causes resistance to Bt toxin Cry1Ab in the silkworm, \u3cem\u3eBombyx mori\u3c/em\u3e

Bt toxins derived from the arthropod bacterial pathogen Bacillus thuringiensis are widely used for insect control as insecticides or in transgenic crops. Bt resistance has been found in field populations of several lepidopteran pests and in laboratory strains selected with Bt toxin. Widespread planting of crops expressing Bt toxins has raised concerns about the potential increase of resistance mutations in targeted insects. By using Bombyx mori as a model, we identified a candidate gene for a recessive form of resistance to Cry1Ab toxin on chromosome 15 by positional cloning. BGIBMGA007792-93, which encodes an ATP-binding cassette transporter similar to human multidrug resistance protein 4 and orthologous to genes associated with recessive resistance to Cry1Ac in Heliothis virescens and two other lepidopteran species, was expressed in the midgut. Sequences of 10 susceptible and seven resistant silkworm strains revealed a common tyrosine insertion in an outer loop of the predicted transmembrane structure of resistant alleles. We confirmed the role of this ATP-binding cassette transporter gene in Bt resistance by converting a resistant silkworm strain into a susceptible one by using germline transformation. This study represents a direct demonstration of Bt resistance gene function in insects with the use of transgenesis

Primitive templated catalysis of a peptide ligation by self-folding RNAs

RNA–polypeptide complexes (RNPs), which play various roles in extant biological systems, have been suggested to have been important in the early stages of the molecular evolution of life. At a certain developmental stage of ancient RNPs, their RNA and polypeptide components have been proposed to evolve in a reciprocal manner to establish highly elaborate structures and functions. We have constructed a simple model system, from which a cooperative evolution system of RNA and polypeptide components could be developed. Based on the observation that several RNAs modestly accelerated the chemical ligation of the two basic peptides. We have designed an RNA molecule possessing two peptide binding sites that capture the two peptides. This designed RNA can also accelerate the peptide ligation. The resulting ligated peptide, which has two RNA-binding sites, can in turn function as a trans-acting factor that enhances the endonuclease activity catalyzed by the designed RNA

Local microbleeding facilitates IL-6– and IL-17–dependent arthritis in the absence of tissue antigen recognition by activated T cells

Local microbleeding induces the accumulation of Th17 cells and the development of IL-17– and IL-6–dependent arthritis in the absence of cognate antigen recognition by CD4+ T cells

Drug retention rates and relevant risk factors for drug discontinuation due to adverse events in rheumatoid arthritis patients receiving anticytokine therapy with different target molecules

Objective: To compare reasons for discontinuation and drug retention rates per reason among anticytokine therapies, infliximab, etanercept and tocilizumab, and the risk of discontinuation of biological agents due to adverse events (AE) in patients with rheumatoid arthritis (RA). Method: This prospective cohort study included Japanese RA patients who started infliximab (n=412, 636.0 patientyears (PY)), etanercept (n=442, 765.3 PY), or tocilizumab (n=168, 206.5 PY) as the first biological therapy after their enrolment in the Registry of Japanese Rheumatoid Arthritis Patients for Long-term Safety (REAL) database. Drug retention rates were calculated using the Kaplan-Meier method. To compare risks of drug discontinuation due to AE for patients treated with these biological agents, the Cox proportional hazard model was applied. Results: The authors found significant differences among the three therapeutic groups in demography, clinical status, comorbidities and usage of concomitant drugs. Development of AE was the most frequent reason for discontinuation of biological agents in the etanercept and tocilizumab groups, and the second most frequent reason in the infliximab group. Discontinuation due to good control was observed most frequently in the infliximab group. Compared with etanercept, the use of infliximab (HR 1.69; 95% CI 1.14 to 2.51) and tocilizumab (HR 1.98; 95% CI 1.04 to 3.76) was significantly associated with a higher risk of discontinuation of biological agents due to AE. Conclusions: Reasons for discontinuation are significantly different among biological agents. The use of infliximab and tocilizumab was significantly associated with treatment discontinuation due to AE compared with etanercept

Osteocrin is a specific ligand of the natriuretic peptide clearance receptor that modulates bone growth

Osteocrin (Ostn) is a recently discovered secreted protein produced by cells of the osteoblast lineage that shows a well conserved homology with members of the natriuretic peptide (NP) family. We hypothesized that Ostn could interact with the NP receptors, thereby modulating NP actions on the skeleton. Ostn binds specifically and saturably to the NP peptide receptor-C (NPR-C) receptor with a K-d of similar to 5 nM with no binding to the GC-A or GC-B receptors. Deletion of several of the residues deemed important for NP binding to NPR-C led to abolition of Ostn binding, confirming the presence of a "natriuretic motif." Functionally, Ostn was able to augment C-type natriuretic peptide-stimulated cGMP production in both pre-chondrocytic (ATDC5) and osteoblastic (UMR106) cells, suggesting increased NP levels due to attenuation of NPR-C associated NP clearance. Ostn-transgenic mice displayed elongated bones and a marked kyphosis associated with elevated bone cGMP levels, suggesting that elevated natriuretic peptide activity contributed to the increased bone length possibly through an increase in growth plate chondrocyte proliferation. Thus, we have demonstrated that Ostn is a naturally occurring ligand of the NPR-C clearance receptor and may act to locally modulate the actions of the natriuretic system in bone by blocking the clearance action of NPR-C, thus locally elevating levels of C-type natriuretic peptide

Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer

The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease

Safety and effectiveness of monthly intravenous ibandronate injections in a prospective, postmarketing, and observational study in Japanese patients with osteoporosis

Objectives: This postmarketing, observational study evaluated the safety and effectiveness of monthly intravenous (IV) ibandronate in Japanese patients with osteoporosis. Methods: Eligible patients received monthly IV ibandronate 1 mg for 12 months. Adverse drug reactions (ADRs) were evaluated. Changes in bone mineral density (BMD) and bone turnover markers (BTMs) were assessed using matched t-test analysis. Cumulative fracture rates were analyzed by Kaplan-Meier methodology. Results: In total, 1062 patients were enrolled, of whom 1025 (n = 887 women, n = 138 men) were treated. Mean patient age was 77 years. Seventy-five ADRs were reported in 54 patients (5.26%). Four patients (0.39%) experienced serious ADRs, including one case of osteonecrosis of the jaw. Acute-phase reactions occurred in 21 patients (2.04%), and half of them arose after the first ibandronate injection. No new safety concerns were identified. Significant increases in BMD at 12 months relative to baseline were observed at the lumbar spine (4.84%, n = 187; 95% confidence interval [CI], 3.47%–6.21%), femoral neck (2.73%, n = 166; 95% CI, 1.46%–4.01%), and total hip (1.93%, n = 133; 95% CI, 0.80%–3.07%). Significant reductions were observed in all BTMs at 12 months (n = 174 in tartrate-resistant acid phosphatase-5b, n = 101 in procollagen type 1 N-terminal propeptide at baseline). The cumulative incidence of nontraumatic, new vertebral and nonvertebral fractures was 3.16% (95% CI, 2.12%–4.70%). Analyses in women only showed similar results to the overall population. Conclusions: These findings confirm the favorable safety and consistent effectiveness of ibandronate, and indicate that monthly IV ibandronate would be beneficial in daily practice for the treatment of Japanese patients with osteoporosis. Keywords: Ibandronate, Intravenous, Japan, Osteoporosis, Prospective observational stud