Hormonal regulation of ovarian bursa fluid in mice and involvement of aquaporins.

In rodent species, the ovary and the end of oviduct are encapsulated by a thin membrane called ovarian bursa. The biological functions of ovarian bursa remain unexplored despite its structural arrangement in facilitating oocytes transport into oviduct. In the present study, we observed a rapid fluid accumulation and reabsorption within the ovarian bursa after ovarian stimulation (PMSG-primed hCG injection), suggesting that the ovarian bursa might play an active role in regulating local fluid homeostasis around the timing of ovulation. We hypothesized that the aquaporin proteins, which are specialized channels for water transport, might be involved in this process. By screening the expression of aquaporin family members (Aqp1-9) in the ovarian tissue and isolated ovarian bursa (0, 1, 2 and 5 h after hCG injection), we found that AQP2 and AQP5 mRNA showed dynamic changes after hCG treatment, showing upregulation at 1-2 h followed by gradually decrease at 5 h, which is closely related with the intra-bursa fluid dynamics. Further immunofluorescence examinations of AQP2 and AQP5 in the ovarian bursa revealed that AQP2 is specifically localized in the outer layer (peritoneal side) while AQP5 localized in the inner layer (ovarian side) of the bursa, such cell type specific and spatial-temporal expressions of AQP2 and 5 support our hypothesis that they might be involved in efficient water transport through ovarian bursa under ovulation related hormonal regulation. The physiological significance of aquaporin-mediated water transport in the context of ovarian bursa still awaits further clarification

Gauge invariant definition of the jet quenching parameter

In the framework of Soft-Collinear Effective Theory, the jet quenching parameter, $\hat{q}$, has been evaluated by adding the effect of Glauber gluon interactions to the propagation of a highly-energetic collinear parton in a medium. The result, which holds in covariant gauges, has been expressed in terms of the expectation value of two Wilson lines stretching along the direction of the four-momentum of the parton. In this paper, we show how that expression can be generalized to an arbitrary gauge by the addition of transverse Wilson lines. The transverse Wilson lines are explicitly computed by resumming interactions of the parton with Glauber gluons that appear only in non-covariant gauges. As an application of our result, we discuss the contribution to $\hat{q}$ coming from transverse momenta of order $g^2T$ in a medium that is a weakly-coupled quark-gluon plasma.Comment: 31 pages, 7 figures; journal versio

The Global Programme to Eliminate Lymphatic Filariasis: Health Impact after 8 Years

Lymphatic filariasis (LF) is a vector-borne, chronically disabling parasitic infection causing elephantiasis, lymphedema, and hydrocele. The infection is endemic in 83 countries worldwide, with more than 1.2 billion people at risk and 120 million already infected. Since 1998, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) has targeted elimination of LF by 2020. In its first 8 operational years, the program has scaled-up to provide more than 1.9 billion treatments through annual, single-dose mass drug administration (MDA) to ∼570 million individuals living in 48 LF-endemic countries. Not only do the GPELF drugs prevent the spread of LF, they also stop the progression of disease in those already infected. In addition, since two of the three drugs used for LF elimination have broad anti-parasite properties, treated populations are freed from both intestinal worms and from skin infections with onchocerca, lice, and scabies. To better understand the public health benefit of this ongoing global health initiative, we undertook an analysis of Programme data made available to WHO by participating countries. Our conservative estimates show that the GPELF has had an unprecedented public health impact on both LF and other neglected tropical diseases; it justly deserves the accolade of ‘a best buy’ in global health

Base-Pairing Versatility Determines Wobble Sites in tRNA Anticodons of Vertebrate Mitogenomes

BACKGROUND: Vertebrate mitochondrial genomes typically have one transfer RNA (tRNA) for each synonymous codon family. This limited anticodon repertoire implies that each tRNA anticodon needs to wobble (establish a non-Watson-Crick base pairing between two nucleotides in RNA molecules) to recognize one or more synonymous codons. Different hypotheses have been proposed to explain the factors that determine the nucleotide composition of wobble sites in vertebrate mitochondrial tRNA anticodons. Until now, the two major postulates--the "codon-anticodon adaptation hypothesis" and the "wobble versatility hypothesis"--have not been formally tested in vertebrate mitochondria because both make the same predictions regarding the composition of anticodon wobble sites. The same is true for the more recent "wobble cost hypothesis". PRINCIPAL FINDINGS: In this study we have analyzed the occurrence of synonymous codons and tRNA anticodon wobble sites in 1553 complete vertebrate mitochondrial genomes, focusing on three fish species with mtDNA codon usage bias reversal (L-strand is GT-rich). These mitogenomes constitute an excellent opportunity to study the evolution of the wobble nucleotide composition of tRNA anticodons because due to the reversal the predictions for the anticodon wobble sites differ between the existing hypotheses. We observed that none of the wobble sites of tRNA anticodons in these unusual mitochondrial genomes coevolved to match the new overall codon usage bias, suggesting that nucleotides at the wobble sites of tRNA anticodons in vertebrate mitochondrial genomes are determined by wobble versatility. CONCLUSIONS/SIGNIFICANCE: Our results suggest that, at wobble sites of tRNA anticodons in vertebrate mitogenomes, selection favors the most versatile nucleotide in terms of wobble base-pairing stability and that wobble site composition is not influenced by codon usage. These results are in agreement with the "wobble versatility hypothesis"

Rate-dependent Ca2+ signalling underlying the force-frequency response in rat ventricular myocytes: A coupled electromechanical modeling study

Rate-dependent effects on the Ca2+ sub-system in a rat ventricular myocyte are investigated. Here, we employ a deterministic mathematical model describing various Ca2+ signalling pathways under voltage clamp (VC) conditions, to better understand the important role of calmodulin (CaM) in modulating the key control variables Ca2+/calmodulin-dependent protein kinase-II (CaMKII), calcineurin (CaN), and cyclic adenosine monophosphate (cAMP) as they affect various intracellular targets. In particular, we study the frequency dependence of the peak force generated by the myofilaments, the force-frequency response (FFR). Our cell model incorporates frequency-dependent CaM-mediated spatially heterogenous interaction of CaMKII and CaN with their principal targets (dihydropyridine (DHPR) and ryanodine (RyR) receptors and the SERCA pump). It also accounts for the rate-dependent effects of phospholamban (PLB) on the SERCA pump; the rate-dependent role of cAMP in up-regulation of the L-type Ca2+ channel (ICa;L); and the enhancement in SERCA pump activity via phosphorylation of PLB.Our model reproduces positive peak FFR observed in rat ventricular myocytes during voltage-clamp studies both in the presence/absence of cAMP mediated -adrenergic stimulation. This study provides quantitative insight into the rate-dependence of Ca2+-induced Ca2+-release (CICR) by investigating the frequency-dependence of the trigger current (ICa;L) and RyR-release. It also highlights the relative role of the sodium-calcium exchanger (NCX) and the SERCA pump at higher frequencies, as well as the rate-dependence of sarcoplasmic reticulum (SR) Ca2+ content. A rigorous Ca2+ balance imposed on our investigation of these Ca2+ signalling pathways clarifies their individual roles. Here, we present a coupled electromechanical study emphasizing the rate-dependence of isometric force developed and also investigate the temperature-dependence of FFR. Our model provides mechanistic biophysically based explanations for the rate-dependence of CICR, generating useful and testable hypotheses. Although rat ventricular myocytes exhibit a positive peak FFR in the presence/absence of beta-adrenergic stimulation, they show a characteristic increase in the positive slope in FFR due to the presence of Norepinephrine or Isoproterenol. Our study identifies cAMP-mediated stimulation, and rate-dependent CaMKII-mediated up-regulation of ICa;L as the key mechanisms underlying the aforementioned positive FFR

Identification of Histological Patterns in Clinically Affected and Unaffected Palm Regions in Dupuytren's Disease

Dupuytren's disease is a fibro-proliferative disease characterized by a disorder of the extracellular matrix (ECM) and high myofibroblast proliferation. However, studies failed to determine if the whole palm fascia is affected by the disease. The objective of this study was to analyze several components of the extracellular matrix of three types of tissues—Dupuytren's diseased contracture cords (DDC), palmar fascia clinically unaffected by Dupuytren's disease contracture (NPF), and normal forehand fascia (NFF). Histological analysis, quantification of cells recultured from each type of tissue, mRNA microarrays and immunohistochemistry for smooth muscle actin (SMA), fibrillar ECM components and non-fibrillar ECM components were carried out. The results showed that DDC samples had abundant fibrosis with reticular fibers and few elastic fibers, high cell proliferation and myofibroblasts, laminin and glycoproteins, whereas NFF did not show any of these findings. Interestingly, NPF tissues had more cells showing myofibroblasts differentiation and more collagen and reticular fibers, laminin and glycoproteins than NFF, although at lower level than DDC, with similar elastic fibers than DDC. Immunohistochemical expression of decorin was high in DDC, whereas versican was highly expressed NFF, with no differences for aggrecan. Cluster analysis revealed that the global expression profile of NPF was very similar to DDC, and reculturing methods showed that cells corresponding to DDC tissues proliferated more actively than NPF, and NPF more actively than NFF. All these results suggest that NPF tissues may be affected, and that a modification of the therapeutic approach used for the treatment of Dupuytren's disease should be considered.This work was supported by CTS-115 (Tissue Engineering Group), University of Granada/Spain

Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer

Purpose: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. Methods: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. Results: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9 %) and 31 (1.2 %) in the denosumab and ZA groups, respectively. In total, 32 (6.9 %) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1 %, in patients continuing and switching to denosumab, respectively. Conclusion: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports

Evolution and Optimality of Similar Neural Mechanisms for Perception and Action during Search

A prevailing theory proposes that the brain's two visual pathways, the ventral and dorsal, lead to differing visual processing and world representations for conscious perception than those for action. Others have claimed that perception and action share much of their visual processing. But which of these two neural architectures is favored by evolution? Successful visual search is life-critical and here we investigate the evolution and optimality of neural mechanisms mediating perception and eye movement actions for visual search in natural images. We implement an approximation to the ideal Bayesian searcher with two separate processing streams, one controlling the eye movements and the other stream determining the perceptual search decisions. We virtually evolved the neural mechanisms of the searchers' two separate pathways built from linear combinations of primary visual cortex receptive fields (V1) by making the simulated individuals' probability of survival depend on the perceptual accuracy finding targets in cluttered backgrounds. We find that for a variety of targets, backgrounds, and dependence of target detectability on retinal eccentricity, the mechanisms of the searchers' two processing streams converge to similar representations showing that mismatches in the mechanisms for perception and eye movements lead to suboptimal search. Three exceptions which resulted in partial or no convergence were a case of an organism for which the targets are equally detectable across the retina, an organism with sufficient time to foveate all possible target locations, and a strict two-pathway model with no interconnections and differential pre-filtering based on parvocellular and magnocellular lateral geniculate cell properties. Thus, similar neural mechanisms for perception and eye movement actions during search are optimal and should be expected from the effects of natural selection on an organism with limited time to search for food that is not equi-detectable across its retina and interconnected perception and action neural pathways

HIPPIE: Integrating Protein Interaction Networks with Experiment Based Quality Scores

Protein function is often modulated by protein-protein interactions (PPIs) and therefore defining the partners of a protein helps to understand its activity. PPIs can be detected through different experimental approaches and are collected in several expert curated databases. These databases are used by researchers interested in examining detailed information on particular proteins. In many analyses the reliability of the characterization of the interactions becomes important and it might be necessary to select sets of PPIs of different confidence levels. To this goal, we generated HIPPIE (Human Integrated Protein-Protein Interaction rEference), a human PPI dataset with a normalized scoring scheme that integrates multiple experimental PPI datasets. HIPPIE's scoring scheme has been optimized by human experts and a computer algorithm to reflect the amount and quality of evidence for a given PPI and we show that these scores correlate to the quality of the experimental characterization. The HIPPIE web tool (available at http://cbdm.mdc-berlin.de/tools/hippie) allows researchers to do network analyses focused on likely true PPI sets by generating subnetworks around proteins of interest at a specified confidence level

Differences in MEF2 and NFAT Transcriptional Pathways According to Human Heart Failure Aetiology

BACKGROUND:Ca(2+) handling machinery modulates the activation of cardiac transcription pathways involved in heart failure (HF). The present study investigated the effect of HF aetiology on Ca(+2) handling proteins and NFAT1, MEF2C and GATA4 (transcription factors) in the same cardiac tissue. METHODOLOGY AND PRINCIPAL FINDINGS:A total of 83 hearts from ischemic (ICM, n = 43) and dilated (DCM, n = 31) patients undergoing heart transplantation and controls (CNT, n = 9) were analyzed by western blotting. Subcellular distribution was analyzed by fluorescence and electron microscopy. When we compared Ca(+2) handling proteins according to HF aetiology, ICM showed higher levels of calmodulin (24%, p<0.01), calcineurin (26%, p<0.01) and Ca(2+)/Calmodulin-dependent kinase II (CaMKIIδ(b) nuclear isoform 62%, p<0.001) than the CNT group. However, these proteins in DCM did not significantly increase. Furthermore, ICM showed a significant elevation in MEF2C (33%, p<0.01), and GATA4 (49%, p<0.05); also NFAT1 (66%, p<0.001) was increased, producing the resultant translocation of this transcriptional factor into the nuclei. These results were supported by fluorescence and electron microscopy analysis. Whereas, DCM only had a significant increase in GATA4 (52%, p<0.05). Correlations between NFAT1 and MEF2C in both groups (ICM r = 0.38 and DCM r = 0.59, p<0.05 and p<0.01, respectively) were found; only ICM showed a correlation between GATA4 and NFAT1 (r = 0.37, p<0.05). CONCLUSIONS/SIGNIFICANCE:This study shows an increase of Ca(2+) handling machinery synthesis and their cardiac transcription pathways in HF, being more markedly increased in ICM. Furthermore, there is a significant association between MEF2, NFAT1 and GATA4. These proteins could be therapeutic targets to improve myocardial function