ProNodal acts via FGFR3 to govern duration of Shh expression in the prechordal mesoderm

The secreted glycoprotein sonic hedgehog (Shh) is expressed in the prechordal mesoderm, where it plays a crucial role in induction and patterning of the ventral forebrain. Currently little is known about how Shh is regulated in prechordal tissue. Here we show that in the embryonic chick, Shh is expressed transiently in prechordal mesoderm, and is governed by unprocessed Nodal. Exposure of prechordal mesoderm microcultures to Nodal-conditioned medium, the Nodal inhibitor CerS, or to an ALK4/5/7 inhibitor reveals that Nodal is required to maintain both Shh and Gsc expression, but whereas Gsc is largely maintained through canonical signalling, Nodal signals through a non-canonical route to maintain Shh. Further, Shh expression can be maintained by a recombinant Nodal cleavage mutant, proNodal, but not by purified mature Nodal. A number of lines of evidence suggest that proNodal acts via FGFR3. ProNodal and FGFR3 co-immunoprecipitate and proNodal increases FGFR3 tyrosine phosphorylation. In microcultures, soluble FGFR3 abolishes Shh without affecting Gsc expression. Further, prechordal mesoderm cells in which Fgfr3 expression is reduced by Fgfr3 siRNA fail to bind to proNodal. Finally, targeted electroporation of Fgfr3 siRNA to prechordal mesoderm in vivo results in premature Shh downregulation without affecting Gsc. We report an inverse correlation between proNodal-FGFR3 signalling and pSmad1/5/8, and show that proNodal-FGFR3 signalling antagonises BMP-mediated pSmad1/5/8 signalling, which is poised to downregulate Shh. Our studies suggest that proNodal/FGFR3 signalling governs Shh duration by repressing canonical BMP signalling, and that local BMPs rapidly silence Shh once endogenous Nodal-FGFR3 signalling is downregulated

Estimating the nuclear level density with the Monte Carlo shell model

A method for making realistic estimates of the density of levels in even-even nuclei is presented making use of the Monte Carlo shell model (MCSM). The procedure follows three basic steps: (1) computation of the thermal energy with the MCSM, (2) evaluation of the partition function by integrating the thermal energy, and (3) evaluating the level density by performing the inverse Laplace transform of the partition function using Maximum Entropy reconstruction techniques. It is found that results obtained with schematic interactions, which do not have a sign problem in the MCSM, compare well with realistic shell-model interactions provided an important isospin dependence is accounted for.Comment: 14 pages, 3 postscript figures. Latex with RevTex. Submitted as a rapid communication to Phys. Rev.

Protocol for a systematic review and thematic synthesis of patient experiences of central venous access devices in anti-cancer treatment

Background: Three types of central venous access devices (CVADs)—peripherally inserted central catheters (PICCs), skin-tunnelled central catheters (Hickman-type devices), and implantable chest wall Ports (Ports)—are routinely used in the intravenous administration of anti-cancer treatment. These devices avoid the need for peripheral cannulation and allow for home delivery of treatment. Assessments of these devices have tended to focus on medical and economic factors, but there is increased interest in the importance of patient experiences and perspectives in this area. The aim of this systematic review is to synthesise existing research regarding patient experiences of these CVADs to help clinicians guide, prepare, and support patients receiving CVADs for the administration of anti-cancer treatment. Method: A systematic search of MEDLINE, Embase, and CINAHL research databases will be carried out along with a supplementary reference list search. This review will include quantitative, qualitative, and mixed methods studies published in peer-review journals, reporting some aspect(s) of patient experiences or perspectives regarding the use of PICC, Hickman, or Port CVADs for the administration of anti-cancer drugs. The methodological quality and risk of bias of included papers will be assessed using the Mixed Methods Appraisal Tool (MMAT). Relevant outcome data will be extracted from included studies and analysed using a thematic synthesis approach. Discussion: The results section of the review will comprise thematic synthesis of quantitative studies, thematic synthesis of qualitative studies, and the aggregation of the two. Results will aim to offer an account of current understandings of patient experiences and perspective regarding PICC, Hickman-type, and Port devices in the context of anti-cancer treatment. Confidence in cumulative evidence will be assessed using the Confidence in the Evidence from Reviews of Qualitative research (CERQual) approach

A Common Variant Associated with Dyslexia Reduces Expression of the KIAA0319 Gene

Numerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s) remains unknown but may modulate gene expression, given that (1) a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2) the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s) responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001), confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits

Hepatitis B virus infection as a neglected tropical disease

PCM is funded by a Wellcome Trust Intermediate Fellowship Grant (ref 110110/Z/15/Z).Publisher PDFPeer reviewe

Reassessing climate and pre-Columbian drivers of paleofire activity in the Bolivian Amazon

A 50,000-year-old sediment core record from Laguna Chaplin is reanalyzed to explore potential paleoecological methods to detect the extent of pre-Columbian disturbance in the Bolivian Amazon. High-resolution (sub-centennial) macrocharcoal data are analyzed using statistical algorithm software including Regime Shift Detection and CHAR Analysis to detect changes in past fire regimes. These data are compared with existing charcoal records from throughout the Bolivian lowlands to provide a regional scale context of past biomass burning. During the mid-Holocene, changes in precipitation are the dominant driver of fire activity and biomass burning at Laguna Chaplin and across the Bolivian lowlands. During the late Holocene, increased fire activity across ecosystems ranging from fire-adapted to fire-intolerant forests is attributed to the apex of pre-Columbian activity. These data suggest human-caused ignitions during the late Holocene are the driving factor of regional scale fire activity in the Bolivian lowlands. After ca. 650 cal yr BP, there is an increase in biomass burning and fire frequency synchronous with the expansion of Moraceae/Urticaceae pollen (>50%) at Laguna Chaplin. This occurs during the time-transgressive southward expansion of the rainforest boundary, during the apex of pre-Columbian activity in the region. The increase in biomass burning at Laguna Chaplin is reflected at other sites in the region with known human occupation histories. The presence of Zea mays ca. 970 to 170 cal yr BP indicates maize cultivation is practiced in the immediate vicinity surrounding Laguna Chaplin. The simultaneous increase in fire activity with the expansion of the less flammable humid rainforest vegetation suggests human fire management practices. These data are interpreted as the use of frequent, low severity, human-caused fires to clear the croplands from encroaching rainforest vegetation. Despite evidence of pre-Columbian fire management during the late Holocene, vegetation and fire data indicate the extent of human-landscape modification and fire management at Laguna Chaplin, is not enough to inhibit the climate-driven regional forest expansion of the savanna-rainforest ecotonal boundary to its most southern extent in the last 50,000 years. This study demonstrates the utility of applying a multi-proxy, high-resolution paleoecological method to disentangle climate and pre-Columbian disturbance in the Bolivian Amazon

Strategies to inhibit tumour associated integrin receptors: rationale for dual and multi-antagonists

YesThe integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions; thrombosis, angiogenesis and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress towards development of antagonists targeting two or more members of the RGD-binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics

Percutaneous subclavian artery stent-graft placement following failed ultrasound guided subclavian venous access

BACKGROUND: Ultrasound guidance for central and peripheral venous access has been proven to improve success rates and reduce complications of venous cannulation. Appropriately trained and experienced operators add significantly to diminished patient morbidity related to venous access procedures. We discuss a patient who required an arterial stent-graft to prevent arterial hemorrhage following inadvertent cannulation of the proximal, ventral, right subclavian artery related to unsuccessful ultrasound guided access of the subclavian vein. CASE PRESENTATION: During pre-operative preparation for aortic valve replacement and aorto-coronary bypass surgery an anesthetist attempted ultrasound guided venous access. The ultrasound guided attempt to access the right jugular vein failed and the ultrasound guided attempt at accessing the subclavian vein resulted in inappropriate placement of an 8.5 F sheath in the arterial system. Following angiographic imaging and specialist consultations, an arterial stent-graft was deployed in the right subclavian artery rather than perform an extensive anterior chest wall resection and dissection to extract the arterial sheath. The patient tolerated the procedure, without complication, despite occlusion of the right internal mammary artery and the right vertebral artery. There were no neurologic sequelae. There was no evidence of hemorrhage after subclavian artery sheath extraction and stent-graft implantation. CONCLUSION: The attempted ultrasound guided puncture of the subclavian vein resulted in placement of an 8.5 F subclavian artery catheter. Entry of the catheter into the proximal subclavian artery beneath the medial clavicle, the medial first rib and the manubrium suggests that the operator, most likely, did not directly visualize the puncture needle enter the vessel with the ultrasound. The bones of the anterior chest impede the ultrasound beam and the vessels in this area would not be visible to ultrasound imaging. Appropriate training and supervised experience in ultrasound guided venous access coupled with quality ultrasound equipment would most likely have significantly diminished the likelihood of this complication. The potential for significant patient morbidity, and possible mortality, was prevented by implantation of an arterial stent-graft

Kualitas Hidup Pasien Diabetes Melitus Tipe 2 di Puskesmas Se Kota Kupang

Diabetes Mellitus is well known as a chronic disease which can lead to a decrease in quality of life in all domains. The study aims to explore the diabetic type 2 patient\u27s quality of life and find out the factors affecting in type 2 diabetic mellitus patients. The cross-sectional study design is used that included 65 patient with type 2 diabetes mellitus, in 11 public health centers of Kupang City. Data were collected by using Short Form Survey (SF-36) that assessed 8-scale health profile. Independent sample t-test is used to analyze the correlation between the factors affecting and the quality of life. the study showed that the QoL of DM patients decreased in all 8- health profile including physical functioning, social functioning, mental health, general health, pain, change in the role due to physical problems and emotional problems. The Study also showed there was a relationship between gender, duration of suffering from Diabetes mellitus, and complications to the quality of life. Male perceived a better quality of life than female

A Framework for Linking Projects and Project Management Methods

Software development processes such as the Waterfall process and Extreme Programming are project management methods (PMMs) which are well known and widely used. However, conventional project management (PM) lacks the process concepts expressed in PMMs, and the connection between PMMs and PM is not much explored in the literature. We present data models for PM and PMM, in a framework that can articulate the PM-to-PMM relationship, illustrating with simple examples. A java/XML implementation of this framework can create and then revise a "PMM aware" project, conforming to a specified PMM. In terms of the framework, we describe a simple project data visualization and associated method that can be used to synthesize a PMM for a project instance that was initially created without reference to any PMM