Nickel and helium evidence for melt above the core–mantle boundary

High ^(3)He/^(4)He ratios in some basalts have generally been interpreted as originating in an incompletely degassed lower-mantle source. This helium source may have been isolated at the core–mantle boundary region since Earth’s accretion. Alternatively, it may have taken part in whole-mantle convection and crust production over the age of the Earth; if so, it is now either a primitive refugium at the core–mantle boundary or is distributed throughout the lower mantle. Here we constrain the problem using lavas from Baffin Island, West Greenland, the Ontong Java Plateau, Isla Gorgona and Fernandina (Galapagos). Olivine phenocryst compositions show that these lavas originated from a peridotite source that was about 20 per cent higher in nickel content than in the modern mid-ocean-ridge basalt source. Where data are available, these lavas also have high ^(3)He/^(4)He. We propose that a less-degassed nickel-rich source formed by core–mantle interaction during the crystallization of a melt-rich layer or basal magma ocean, and that this source continues to be sampled by mantle plumes. The spatial distribution of this source may be constrained by nickel partitioning experiments at the pressures of the core–mantle boundary

Insights gained from the reverse engineering of gene networks in keloid fibroblasts

<p>Abstract</p> <p>Background</p> <p>Keloids are protrusive claw-like scars that have a propensity to recur even after surgery, and its molecular etiology remains elusive. The goal of reverse engineering is to infer gene networks from observational data, thus providing insight into the inner workings of a cell. However, most attempts at modeling biological networks have been done using simulated data. This study aims to highlight some of the issues involved in working with experimental data, and at the same time gain some insights into the transcriptional regulatory mechanism present in keloid fibroblasts.</p> <p>Methods</p> <p>Microarray data from our previous study was combined with microarray data obtained from the literature as well as new microarray data generated by our group. For the physical approach, we used the fREDUCE algorithm for correlating expression values to binding motifs. For the influence approach, we compared the Bayesian algorithm BANJO with the information theoretic method ARACNE in terms of performance in recovering known influence networks obtained from the KEGG database. In addition, we also compared the performance of different normalization methods as well as different types of gene networks.</p> <p>Results</p> <p>Using the physical approach, we found consensus sequences that were active in the keloid condition, as well as some sequences that were responsive to steroids, a commonly used treatment for keloids. From the influence approach, we found that BANJO was better at recovering the gene networks compared to ARACNE and that transcriptional networks were better suited for network recovery compared to cytokine-receptor interaction networks and intracellular signaling networks. We also found that the NFKB transcriptional network that was inferred from normal fibroblast data was more accurate compared to that inferred from keloid data, suggesting a more robust network in the keloid condition.</p> <p>Conclusions</p> <p>Consensus sequences that were found from this study are possible transcription factor binding sites and could be explored for developing future keloid treatments or for improving the efficacy of current steroid treatments. We also found that the combination of the Bayesian algorithm, RMA normalization and transcriptional networks gave the best reconstruction results and this could serve as a guide for future influence approaches dealing with experimental data.</p

Analysis of a sprint ski race and associated laboratory determinants of world-class performance

This investigation was designed to analyze the time-trial (STT) in an international cross-country skiing sprint skating competition for (1) overall STT performance and relative contributions of time spent in different sections of terrain, (2) work rate and kinematics on uphill terrain, and (3) relationships to physiological and kinematic parameters while treadmill roller ski skating. Total time and times in nine different sections of terrain by 12 world-class male sprint skiers were determined, along with work rate and kinematics for one specific uphill section. In addition, peak oxygen uptake (VO2peak), gross efficiency (GE), peak speed (Vpeak), and kinematics in skating were measured. Times on the last two uphill and two final flat sections were correlated to overall STT performance (r = ~−0.80, P < 0.001). For the selected uphill section, speed was correlated to cycle length (r = −0.75, P < 0.01) and the estimated work rate was approximately 160% of peak aerobic power. VO2peak, GE, Vpeak, and peak cycle length were all correlated to STT performance (r = ~−0.85, P < 0.001). More specifically, VO2peak and GE were correlated to the last two uphill and two final flat section times, whereas Vpeak and peak cycle length were correlated to times in all uphill, flat, and curved sections except for the initial section (r = ~−0.80, P < 0.01). Performances on uphill and flat terrain in the latter part were the most significant determinants of overall STT performance. Peak oxygen uptake, efficiency, peak speed, and peak cycle length were strongly correlated to overall STT performance, as well as to performance in different sections of the race

Role of Muscarinic Acetylcholine Receptors in Serial Feature-Positive Discrimination Task during Eyeblink Conditioning in Mice.

We investigated the role of muscarinic acetylcholine receptors (mAChRs) in eyeblink serial feature-positive discrimination learning in mice using the mAChR antagonist. A 2-s light cue was delivered 5 or 6 s before the presentation of a 350-ms tone paired with a 100-ms periorbital electrical shock (cued trial) but not before the tone-alone presentation (non-cued trial). Mice received 30 cued and 30 non-cued trials each day in a random order. We found that saline-injected control mice were successfully discriminating between cued and non-cued trials within a few days of conditioning. The mice responded more frequently to the tone in cued trials than in non-cued trials. Analysis of conditioned response (CR) dynamics revealed that the CR onset latency was shorter in cued trials than in non-cued trials, despite the CR peak amplitude not differing significantly between the two conditions. In contrast, scopolamine-injected mice developed an equal number of CRs with similar temporal patterns irrespective of the presence of the cue during the 7 days of conditioning, indicating in a failure to acquire conditional discrimination. In addition, the scopolamine administration to the control mice after they had successfully acquired discrimination did not impair the conditional discrimination and expression of pre-acquired CR. These results suggest that mAChRs may play a pivotal role in memory formation in the conditional brain state associated with the feature cue; however they are unlikely to be involved in the development of discrimination after conditional memory had formed in the serial feature-positive discrimination task during eyeblink conditioning

HIV-Neutralizing Activity of Cationic Polypeptides in Cervicovaginal Secretions of Women in HIV-Serodiscordant Relationships

HIV exposed seronegative (HESN) women represent the population most in need of a prophylactic antiviral strategy. Mucosal cationic polypeptides can potentially be regulated for this purpose and we here aimed to determine their endogenous expression and HIV neutralizing activity in genital secretions of women at risk of HIV infection.Cervicovaginal secretions (CVS) of Kenyan women in HIV-serodiscordant relationships (HESN, n = 164; HIV seropositive, n = 60) and low-risk controls (n = 72) were assessed for the cationic polypeptides HNP1–3, LL-37 and SLPI by ELISA and for HIV neutralizing activity by a PBMC-based assay using an HIV primary isolate. Median levels of HNP1–3 and LL-37 in CVS were similar across study groups. Neither HSV-2 serostatus, nor presence of bacterial vaginosis, correlated with levels of HNP1–3 or LL-37 in the HESN women. However, an association with their partner's viral load was observed. High viral load (>10,000 HIV RNA copies/ml plasma) correlated with higher levels of HNP1–3 and LL-37 (p = 0.04 and 0.03, respectively). SLPI was most abundant in the low-risk group and did not correlate with male partner's viral load in the HESN women. HIV neutralizing activity was found in CVS of all study groups. In experimental studies, selective depletion of cationic polypeptides from CVS rendered the remaining CVS fraction non-neutralizing, whereas the cationic polypeptide fraction retained the activity. Furthermore, recombinant HNP1–3 and LL-37 could induce neutralizing activity when added to CVS lacking intrinsic activity.These findings show that CVS from HESN, low-risk, and HIV seropositive women contain HIV neutralizing activity. Although several innate immune proteins, including HNP1–3 and LL-37, contribute to this activity these molecules can also have inflammatory properties. This balance is influenced by hormonal and environmental factors and in the present HIV serodiscordant couple cohort study we show that a partner's viral load is associated with levels of such molecules

Reductions in co-contraction following neuromuscular re-education in people with knee osteoarthritis

Background Both increased knee muscle co-contraction and alterations in central pain processing have been suggested to play a role in knee osteoarthritis pain. However, current interventions do not target either of these mechanisms. The Alexander Technique provides neuromuscular re-education and may also influence anticipation of pain. This study therefore sought to investigate the potential clinical effectiveness of the AT intervention in the management of knee osteoarthritis and also to identify a possible mechanism of action. Methods A cohort of 21 participants with confirmed knee osteoarthritis were given 20 lessons of instruction in the Alexander Technique. In addition to clinical outcomes EMG data, quantifying knee muscle co-contraction and EEG data, characterising brain activity during anticipation of pain, were collected. All data were compared between baseline and post-intervention time points with a further 15-month clinical follow up. In addition, biomechanical data were collected from a healthy control group and compared with the data from the osteoarthritis subjects. Results: Following AT instruction the mean WOMAC pain score reduced by 56% from 9.6 to 4.2 (P<0.01) and this reduction was maintained at 15 month follow up. There was a clear decrease in medial co-contraction at the end of the intervention, towards the levels observed in the healthy control group, both during a pre-contact phase of gait (p<0.05) and during early stance (p<0.01). However, no changes in pain-anticipatory brain activity were observed. Interestingly, decreases in WOMAC pain were associated with reductions in medial co-contraction during the pre-contact phase of gait. Conclusions: This is the first study to investigate the potential effectiveness of an intervention aimed at increasing awareness of muscle behaviour in the clinical management of knee osteoarthritis. These data suggest a complex relationship between muscle contraction, joint loading and pain and support the idea that excessive muscle co-contraction may be a maladaptive response in this patient group. Furthermore, these data provide evidence that, if the activation of certain muscles can be reduced during gait, this may lead to positive long-term clinical outcomes. This finding challenges clinical management models of knee osteoarthritis which focus primarily on muscle strengthening

Integrating Ion Mobility Mass Spectrometry with Molecular Modelling to Determine the Architecture of Multiprotein Complexes

Current challenges in the field of structural genomics point to the need for new tools and technologies for obtaining structures of macromolecular protein complexes. Here, we present an integrative computational method that uses molecular modelling, ion mobility-mass spectrometry (IM-MS) and incomplete atomic structures, usually from X-ray crystallography, to generate models of the subunit architecture of protein complexes. We begin by analyzing protein complexes using IM-MS, and by taking measurements of both intact complexes and sub-complexes that are generated in solution. We then examine available high resolution structural data and use a suite of computational methods to account for missing residues at the subunit and/or domain level. High-order complexes and sub-complexes are then constructed that conform to distance and connectivity constraints imposed by IM-MS data. We illustrate our method by applying it to multimeric protein complexes within the Escherichia coli replisome: the sliding clamp, (β2), the γ complex (γ3δδ′), the DnaB helicase (DnaB6) and the Single-Stranded Binding Protein (SSB4)

GDNF Secreting Human Neural Progenitor Cells Protect Dying Motor Neurons, but Not Their Projection to Muscle, in a Rat Model of Familial ALS

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by rapid loss of muscle control and eventual paralysis due to the death of large motor neurons in the brain and spinal cord. Growth factors such as glial cell line derived neurotrophic factor (GDNF) are known to protect motor neurons from damage in a range of models. However, penetrance through the blood brain barrier and delivery to the spinal cord remains a serious challenge. Although there may be a primary dysfunction in the motor neuron itself, there is also increasing evidence that excitotoxicity due to glial dysfunction plays a crucial role in disease progression. Clearly it would be of great interest if wild type glial cells could ameliorate motor neuron loss in these models, perhaps in combination with the release of growth factors such as GDNF.Human neural progenitor cells can be expanded in culture for long periods and survive transplantation into the adult rodent central nervous system, in some cases making large numbers of GFAP positive astrocytes. They can also be genetically modified to release GDNF (hNPC(GDNF)) and thus act as long-term 'mini pumps' in specific regions of the rodent and primate brain. In the current study we genetically modified human neural stem cells to release GDNF and transplanted them into the spinal cord of rats over-expressing mutant SOD1 (SOD1(G93A)). Following unilateral transplantation into the spinal cord of SOD1(G93A) rats there was robust cellular migration into degenerating areas, efficient delivery of GDNF and remarkable preservation of motor neurons at early and end stages of the disease within chimeric regions. The progenitors retained immature markers, and those not secreting GDNF had no effect on motor neuron survival. Interestingly, this robust motor neuron survival was not accompanied by continued innervation of muscle end plates and thus resulted in no improvement in ipsilateral limb use.The potential to maintain dying motor neurons by delivering GDNF using neural progenitor cells represents a novel and powerful treatment strategy for ALS. While this approach represents a unique way to prevent motor neuron loss, our data also suggest that additional strategies may also be required for maintenance of neuromuscular connections and full functional recovery. However, simply maintaining motor neurons in patients would be the first step of a therapeutic advance for this devastating and incurable disease, while future strategies focus on the maintenance of the neuromuscular junction

Reduced Expression of the Vesicular Acetylcholine Transporter and Neurotransmitter Content Affects Synaptic Vesicle Distribution and Shape in Mouse Neuromuscular Junction

In vertebrates, nerve muscle communication is mediated by the release of the neurotransmitter acetylcholine packed inside synaptic vesicles by a specific vesicular acetylcholine transporter (VAChT). Here we used a mouse model (VAChT KDHOM) with 70% reduction in the expression of VAChT to investigate the morphological and functional consequences of a decreased acetylcholine uptake and release in neuromuscular synapses. Upon hypertonic stimulation, VAChT KDHOM mice presented a reduction in the amplitude and frequency of miniature endplate potentials, FM 1-43 staining intensity, total number of synaptic vesicles and altered distribution of vesicles within the synaptic terminal. In contrast, under electrical stimulation or no stimulation, VAChT KDHOM neuromuscular junctions did not differ from WT on total number of vesicles but showed altered distribution. Additionally, motor nerve terminals in VAChT KDHOM exhibited small and flattened synaptic vesicles similar to that observed in WT mice treated with vesamicol that blocks acetylcholine uptake. Based on these results, we propose that decreased VAChT levels affect synaptic vesicle biogenesis and distribution whereas a lower ACh content affects vesicles shape