Contribution of sea-ice loss to Arctic amplification is regulated by Pacific Ocean decadal variability

The pace of Arctic warming is about double that at lower latitudes – a robust phenomenon known as Arctic amplification (AA)1. Many diverse climate processes and feedbacks cause AA2-7, including positive feedbacks associated with diminished sea ice6,7. However, the precise contribution of sea-ice loss to AA remains uncertain7,8. Through analyses of both observations and model simulations, we show that the contribution of sea-ice loss to wintertime AA appears dependent on the phase of the Pacific Decadal Oscillation (PDO). Our results suggest that for the same pattern and amount of sea-ice loss, consequent Arctic warming is larger during the negative PDO phase, relative to the positive phase, leading to larger reductions in the poleward gradient of tropospheric thickness and to more pronounced reductions in the upper-level westerlies. Given the oscillatory nature of the PDO, this relationship has the potential to increase skill in decadal-scale predictability of Arctic and sub-Arctic climate. Our results indicate that Arctic warming in response to the ongoing long-term sea-ice decline9,10 is greater (reduced) during periods of negative (positive) PDO phase. We speculate that the observed recent shift to the positive PDO phase, if maintained and all other factors being equal, could act to temporarily reduce the pace of wintertime Arctic warming in the near future.J.A.S. was funded by a UK Natural Environment Research Council (NERC) grants NE/J019585/1 and NE/M006123/1. J.A.F. was supported by an NSF/ARCSS grant (1304097) and NASA grant (NNX14AH896). The model simulations were performed on the ARCHER UK National Supercomputing Service. We thank the NOAA ESRL and Met Office Hadley Centre for provision of observational and reanalysis data sets. We also thank D. Ackerley for helping to diagnose the cause of model crashes, C. Deser for commenting on the manuscript prior to submission, and two anonymous reviewers for constructive criticism

Innovative solutions to sticky situations: Antiadhesive strategies for treating bacterial infections

ABSTRACT Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.</jats:p

Gd(III) complexes intercalated into hydroxy double salts as potential MRI contrast agents

The ion exchange intercalation of two Gd-based magnetic resonance imaging contrast agents into hydroxy double salts (HDSs) is reported. The presence of Gd3+ diethylenetriaminepentaacetate and Gd3+ diethylenetriaminepenta(methylenephosphonate) complexes in the HDS lattice after intercalation was confirmed by microwave plasma-atomic emission spectroscopy. The structural aspects of the HDS-Gd composites were studied by X-ray diffraction, with the intercalates having an interlayer spacing of 14.5–18.6 Å. Infrared spectroscopy confirmed the presence of characteristic vibration peaks associated with the Gd3+ complexes in the intercalation compounds. The proton relaxivities of the Gd3+ complex-loaded composites were 2 to 5-fold higher in longitudinal relaxivity, and up to 10-fold higher in transverse relaxivity, compared to solutions of the pure complexes. These data demonstrate that the new composites reported here are potentially potent MRI contrast agents

Bacterial curli protein promotes the conversion of PAP248-286 into the amyloid SEVI: cross-seeding of dissimilar amyloid sequences

Fragments of prostatic acid phosphatase (PAP248-286) in human semen dramatically increase HIV infection efficiency by increasing virus adhesion to target cells. PAP248-286 only enhances HIV infection in the form of amyloid aggregates termed SEVI (Semen Enhancer of Viral Infection), however monomeric PAP248-286 aggregates very slowly in isolation. It has therefore been suggested that SEVI fiber formation in vivo may be promoted by exogenous factors. We show here that a bacterially-produced extracellular amyloid (curli or Csg) acts as a catalytic agent for SEVI formation from PAP248-286 at low concentrations in vitro, producing fibers that retain the ability to enhance HIV (Human Immunodeficiency Virus) infection. Kinetic analysis of the cross-seeding effect shows an unusual pattern. Cross-seeding PAP248-286 with curli only moderately affects the nucleation rate while significantly enhancing the growth of fibers from existing nuclei. This pattern is in contrast to most previous observations of cross-seeding, which show cross-seeding partially bypasses the nucleation step but has little effect on fiber elongation. Seeding other amyloidogenic proteins (IAPP (islet amyloid polypeptide) and Aβ1−40) with curli showed varied results. Curli cross-seeding decreased the lag-time of IAPP amyloid formation but strongly inhibited IAPP elongation. Curli cross-seeding exerted a complicated concentration dependent effect on Aβ1−40 fibrillogenesis kinetics. Combined, these results suggest that the interaction of amyloidogenic proteins with preformed fibers of a different type can take a variety of forms and is not limited to epitaxial nucleation between proteins of similar sequence. The ability of curli fibers to interact with proteins of dissimilar sequences suggests cross-seeding may be a more general phenomenon than previously supposed

Gait patterns in Prader-Willi and Down syndrome patients

<p>Abstract</p> <p>Background</p> <p>Prader-Willi (PWS) and Down Syndrome (DS) are two genetic disorders characterised by some common clinical and functional features. A quantitative description and comparison of their patterns would contribute to a deeper understanding of the determinants of motor disability in these two syndromes. The aim of this study was to measure gait pattern in PWS and DS in order to provide data for developing evidence-based deficit-specific or common rehabilitation strategies.</p> <p>Methods</p> <p>19 PWS patients (17.7-40 yr) and 21 DS patients (18-39 yr) were evaluated with an optoelectronic system and force platforms for measuring kinematic and kinetic parameters during walking. The results were compared with those obtained in a group of normal-weight controls (Control Group: CG; 33.4 + 9.6 yr).</p> <p>Results and Discussion</p> <p>The results show that PWS and DS are characterised by different gait strategies. Spatio-temporal parameters indicated a cautious, abnormal gait in both groups, but DS walked with a less stable strategy than PWS. As for kinematics, DS showed a significantly reduced hip and knee flexion, especially at initial contact and ankle range of motion than PWS. DS were characterised by lower ranges of motion (p < 0.05) in all joints than CG and PWS. As for ankle kinetics, both PWS and DS showed a significantly lower push-off during terminal stance than CG, with DS yielding the lowest values. Stiffness at hip and ankle level was increased in DS. PWS showed hip stiffness values close to normal. At ankle level, stiffness was significantly decreased in both groups.</p> <p>Conclusions</p> <p>Our data show that DS walk with a less physiological gait pattern than PWS. Based on our results, PWS and DS patients need targeted rehabilitation and exercise prescription. Common to both groups is the aim to improve hypotonia, muscle strength and motor control during gait. In DS, improving pelvis and hip range of motion should represent a major specific goal to optimize gait pattern.</p

Is visual estimation of passive range of motion in the pediatric lower limb valid and reliable

<p>Abstract</p> <p>Background</p> <p>Visual estimation (VE) is an essential tool for evaluation of range of motion. Few papers discussed its validity in children orthopedics' practice. The purpose of our study was to assess validity and reliability of VE for passive range of motions (PROMs) of children's lower limbs.</p> <p>Methods</p> <p>Fifty typically developing children (100 lower limbs) were examined. Visual estimations for PROMs of hip (flexion, adduction, abduction, internal and external rotations), knee (flexion and popliteal angle) and ankle (dorsiflexion and plantarflexion) were made by a pediatric orthopaedic surgeon (POS) and a 5^thyear resident in orthopaedics. A last year medical student did goniometric measurements. Three weeks later, same measurements were performed to assess reliability of visual estimation for each examiner.</p> <p>Results</p> <p>Visual estimations of the POS were highly reliable for hip flexion, hip rotations and popliteal angle (ρ_c≥ 0.8). Reliability was good for hip abduction, knee flexion, ankle dorsiflexion and plantarflexion (ρ_c≥ 0.7) but poor for hip adduction (ρ_c= 0.5). Reproducibility for all PROMs was verified. Resident's VE showed high reliability (ρ_c≥ 0.8) for hip flexion and popliteal angle. Good correlation was found for hip rotations and knee flexion (ρ_c≥ 0.7). Poor results were obtained for ankle PROMs (ρ_c< 0.6) as well as hip adduction and abduction, the results of which not being reproducible. Influence of experience was clearly demonstrated for PROMs of hip rotations, adduction and abduction as well as ankle plantarflexion.</p> <p>Conclusion</p> <p>Accuracy of VE of passive hip flexion and knee PROMs is high regardless of the examiner's experience. Same accuracy can be found for hip rotations and abduction whenever VE is performed by an experienced examiner. Goniometric evaluation is recommended for passive hip adduction and for ankle PROMs.</p

Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma : preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates

Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D (KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.Peer reviewe

Caspase-8 activity has an essential role in CD95/Fas-mediated MAPK activation

Stimulation of CD95/Fas/APO-1 results in the induction of both apoptotic and non-apoptotic signaling pathways. The processes regulating these two opposing pathways have not been thoroughly elucidated to date. In this study, using quantitative immunoblots, imaging, and mathematical modeling, we addressed the dynamics of the DED proteins of the death-inducing signaling complex (DISC), procaspase-8, and cellular FLICE inhibitory proteins (c-FLIPs) to the onset of CD95-mediated ERK1/2 and p38 mitogen-activated protein kinase (MAPK) activation. We found that CD95 DISC-induced caspase-8 activity is important for the initiation of ERK1/2 and p38 MAPK activation. The long c-FLIP isoform, c-FLIPL, and the short c-FLIP isoform, c-FLIPR, inhibited MAPK induction by blocking caspase-8 processing at the DISC. Furthermore, we built a mathematical model describing CD95 DISC-mediated MAPK activation and apoptosis. The model quantitatively defined the dynamics of DED proteins, procaspase-8, and c-FLIP, which lead to caspase-8 activation and induction of apoptotic and non-apoptotic signaling pathways. In conclusion, the combination of biochemical analysis with mathematical modeling provides evidence for an important role of caspase-8 in CD95-mediated activation of MAPKs, while c-FLIP exerts a regulatory function in this process

Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer

The folate derivatives folic acid (FA) and folinic acid (FNA) decrease the in vivo and in vitro activities of antifolate drugs in Plasmodium falciparum. However, the effects of 5-methyl-tetrahydrofolate (5-Me-THF) and tetrahydrofolate (THF), the two dominant circulating folate forms in humans, have not been explored yet. We have investigated the effects of FA, FNA, 5-Me-THF, and THF on the in vitro activity of the antimalarial antifolates pyrimethamine and chlorcycloguanil and the anticancer antifolates methotrexate (MTX), aminopterin, and trimetrexate (TMX), against P. falciparum. The results indicate that these anticancers are potent against P. falciparum, with IC50 < 50 nM. 5-Me-THF does not significantly decrease the activity of all tested drugs, and none of the tested folate derivatives significantly decrease the activity of these anticancers. Thus, malaria folate metabolism has features different from those in human, and the exploitation of this difference could lead to the discovery of new drugs to treat malaria. For instance, the combination of 5-Me-THF with a low dose of TMX could be used to treat malaria. In addition, the safety of a low dose of MTX in the treatment of arthritis indicates that this drug could be used alone to treat malaria

Early growth response-1 is a regulator of DR5-induced apoptosis in colon cancer cells

BACKGROUND: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour cell apoptosis by binding to death receptor 4 (DR4) and DR5. DR4 and DR5 activation however can also induce inflammatory and pro-survival signalling. It is not known how these different cellular responses are regulated and what the individual role of DR4 vs DR5 is in these processes.METHODS: DNA microarray study was carried out to identify genes differentially expressed after DR4 and DR5 activation. RT-PCR and western blotting was used to examine the expression of early growth response gene-1 (Egr-1) and the proteins of the TRAIL signalling pathway. The function of Egr-1 was studied by siRNA-mediated knockdown and overexpression of a dominant-negative version of Egr-1.RESULTS: We show that the immediate early gene, Egr-1, regulates TRAIL sensitivity. Egr-1 is constitutively expressed in colon cancer cells and further induced upon activation of DR4 or DR5. Our results also show that DR4 mediates a type II, mitochondrion-dependent apoptotic pathway, whereas DR5 induces a mitochondrion-independent, type I apoptosis in HCT15 colon carcinoma cells. Egr-1 drives c-FLIP expression and the short splice variant of c-FLIP (c-FLIPS) specifically inhibits DR5 activation.CONCLUSION: Selective knockdown of c-FLIPS sensitises cells to DR5-induced but not DR4-induced apoptosis and Egr-1 exerts an effect as an inhibitor of the DR5-induced apoptotic pathway, possibly by regulating the expression of c-FLIPS. British Journal of Cancer (2010) 102, 754-764. doi:10.1038/sj.bjc.6605545 www.bjcancer.com Published online 19 January 2010 (C) 2010 Cancer Research U