TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita

Patients with dyskeratosis congenita (DC), a heterogeneous inherited bone marrow failure syndrome, have abnormalities in telomere biology, including very short telomeres and germline mutations in DKC1, TERC, TERT, or NOP10, but approximately 60% of DC patients lack an identifiable mutation. With the very short telomere phenotype and a highly penetrant, rare disease model, a linkage scan was performed on a family with autosomal-dominant DC and no mutations in DKCI, TERC, or TERT. Evidence favoring linkage was found at 2p24 and 14q11.2, and this led to the identification of TINF2 (14q11.2) mutations, K280E, in the proband and her five affected relatives and TINF2 R282H in three additional unrelated DC probands, including one with Revesz syndrome; a fifth DC proband had a R282S mutation. TINF2 mutations were not present in unaffected relatives, DC probands with mutations in DKC1, TERC, or TERT or 298 control subjects. We demonstrate that a fifth gene, TINF2, is mutated in classical DC and, for the first time, in Revesz syndrome. This represents the first shelterin complex mutation linked to human disease and confirms the role of very short telomeres as a diagnostic test for DC.

Reclaiming Indigenous Narratives through Critical Discourses and the Autonomy of the Trickster

How do prevailing narratives about Native Americans, particularly in the medium of film, conspire to promote the perspective of the dominant culture? What makes the appropriation of Indigenous images so metaphorically popular? In the past hundred years, little has changed in the forms of representation favored by Hollywood. The introductory chapter elucidates the problem and outlines the scope of this study. As each subsequent chapter makes clear, the problem is as relevant today as it has been throughout the entire course of filmic history. Chapter Two analyzes representational trends and defines each decade according to its favorite stereotype. The binary of the bloodthirsty savage is just as prevalent as it was during the 1920s and 30s. The same holds true for the drunken scapegoat and the exotic maiden, which made their cinematic debuts in the 1940s and 50s. But Hollywood has added new types as well. The visionary peacemaker and environmental activist have also made an appearance within the last forty years. What matters most is not the realism of these images, but rather the purposes to which they can be put toward validating whatever concerns the majority filmmakers wish to promote. Whether naïvely or not, such representations continue to evacuate Indigenous agency to the advantage of the majority. A brief historical overview confirms this legacy. Various disciplines have sought to interrogate this problem. Chapter three investigates the field of postcolonial studies, which makes inquiry into the various ways these narratives are produced, marketed, and consumed. It also raises the key questions of for whom, and by whom, these narratives are constructed. Additional consideration is given to their value as commodities in the mass marketplace. Typically the products of a boutique-multiculturalism, their storylines are apt to promote the prevailing point of view. Critical theory provides a foundational framework for chapter four. What is the blockbuster formula and how do the instruments of capital promote it? Concepts such as culture industry and repressive tolerance examine both the function and form of the master narrative, as well as its use to control the avenues of dissent. Moreover, the public sphere and its diminishment highlight the challenges inherent in the widespread promotion of an alternative set of narratives. Nonetheless, challenges to prevailing narratives do exist, particularly in the form of Trickster narratives. Often subject to persistent misrecognition, the Trickster demonstrates a potent form of agency that undeniably dismantles the hegemony of Western cinema. The final chapter examines some of the Trickster's more subtle and obscure productions. Usually subjugated to the realm of the mystical, rather than the mythical, these misinterpreted forms have the power to speak in circles around a majority audience. Intended for an Other audience, they are coded in a language that delivers a type of direction through indirection, promoting a poignant agency all their own.

ON THE DIGITAL-POLITICAL TOPOGRAPHY OF MUSIC

The persuasive power of music is often relegated to the dimension of pathos: that which moves us emotionally. Yet, the music commodity is now situated in and around the liminal spaces of digitality. To think about how music functions, how it argues across media, and how it moves us, we must examine its material and immaterial realities as they present themselves to us and as we so create them. This dissertation rethinks the relationship between rhetoric and music by examining the creation, performance, and distribution of music in its material and immaterial forms to demonstrate its persuasive power. While both Plato and Aristotle understood music as a means to move men toward virtue, Aristotle tells us in his Laws, through the Athenian Stranger, that the very best kinds of music can help guide us to truth. From this starting point, I assess the historical problem of understanding the rhetorical potential of music as merely that which directs or imitates the emotions: that which “Soothes the savage breast,” as William Congreve writes. By furthering work by Vickers and Farnsworth, who suggest that the Baroque fascination with applying rhetorical figures to musical figures is an insufficient framework for assessing the rhetorical potential of music, I demonstrate the gravity of musical persuasion in its political weight, in its violence—the subjective violence of musical torture at Guantanamo and the objective, ideological violence of music—and in what Jacques Attali calls the prophetic nature of music. I argue that music has a significant function, and as a non-discursive form of argumentation, works on us beyond affect. Moreover, with the emergence of digital music distribution and domestic digital recording technologies, the digital music commodity in its material and immaterial forms allows for ruptures in the former methods of musical composition, production, and distribution and in the political potential of music which Jacques Attali describes as being able to foresee new political realities. I thus suggest a new theoretical framework for thinking about rhetoric and music by expanding on Lloyd Bitzer’s rhetorical situation, by offering the idea of “openings” to the existing exigence, audience, and constraints. The prophetic and rhetorical power of music in the aleatoric moment can help provide openings from which new exigencies can be conceived. We must, therefore, reconsider the role of rhetorical-musical composition for the citizen, not merely as a tool for entertainment or emotional persuasion, but as an arena for engaging with the political.

Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency

CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

Retaining perivascular tissue of human saphenous vein grafts protects against surgical and distension-induced damage and preserves endothelial nitric oxide synthase and nitric oxide synthase activity

OBJECTIVE: Conventional harvesting of saphenous vein used for coronary artery bypass surgery induces a vasospasm that is overcome by high-pressure distension. Saphenous vein harvested with its cushion of perivascular tissue by a "no touch" technique does not undergo vasospasm and distension is not required, leading to an improved graft patency. The aim of this study is to investigate the effect of surgical damage and high-pressure distension on endothelial integrity and endothelial nitric oxide synthase expression and activity in saphenous vein harvested with and without perivascular tissue. METHODS: Saphenous veins from patients (n = 26) undergoing coronary artery bypass surgery were prepared with and without perivascular tissue. We analyzed the effect of 300 mm Hg distension on morphology and endothelial nitric oxide synthase/nitric oxide synthase activity using a combination of immunohistochemistry, Western blot analysis, reverse transcriptase polymerase chain reaction, and enzyme assay in distended (with and without perivascular tissue) compared with nondistended (with and without perivascular tissue) segments. RESULTS: Distension induced substantial damage to the luminal endothelium (assessed by CD31 staining) and vessel wall. Endothelial nitric oxide synthase expression and activity were significantly reduced by high-pressure distension and removal of, or damage to, perivascular tissue. The effect of distension was significantly less for those with perivascular tissue than for those without perivascular tissue in most cases. CONCLUSION: The success of the saphenous vein used as a bypass graft is affected by surgical trauma and distension. Veins removed with minimal damage exhibit increased patency rates. We show that retention of perivascular tissue on saphenous vein prepared for coronary artery bypass surgery by the "no touch" technique protects against distension-induced damage, preserves vessel morphology, and maintains endothelial nitric oxide synthase/nitric oxide synthase activity.

Fog-water collection for community use

Fog is a potential source of water that could be exploited using the innovative technology of fog collection. Naturally, the potential of fog has proven its significance in cloud forests that are thriving from fog interception. Historically, the remains of artificial structures in different countries prove that fog has been collected as an alternative and/or supplementary water source. In the beginning of the 19th century, fog collection was investigated as a potential natural resource. After the mid-1980s, following success in Chile, fog-water collection commenced in a number of developing countries. Most of these countries are located in arid and semi-arid regions with topographic and climatic conditions that favour fog-water collection. This paper reviews the technology of fog collection with initial background information on natural fog collection and its historical development. It reviews the climatic and topographic features that dictate fog formation (mainly advection and orographic) and the innovative technology to collect it, focusing on the amount collected, the quality of fog water, and the impact of the technology on the livelihoods of beneficiary communities. By and large, the technology described is simple, cost-effective, and energy-free. However, fog-water collection has disadvantages in that it is seasonal, localised, and the technology needs continual maintenance. Based on the experience in several countries, the sustainability of the technology could be guaranteed if technical, economic, social, and management factors are addressed during its planning and implementation.

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.

Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor.

Debris flow magnitudes: a global catalog

The episodic occurrence of debris flow events in response to stochastic precipitation and wildfire events makes hazard prediction challenging. Previous work has shown that frequency-magnitude distributions of non-fire-related debris flows follow a power law, but less is known about the distribution of post-fire debris flows. As a first step in parameterizing hazard models, we use frequency-magnitude distributions and cumulative distribution functions to compare volumes of post-fire debris flows to non-fire-related debris flows. Due to the large number of events required to parameterize frequency-magnitude distributions, and the relatively small number of post-fire event magnitudes recorded in the literature, we collected data on 73 recent post-fire events in the field. The resulting catalog of 988 debris flow events is presented as an appendix to this article. We found that the empirical cumulative distribution function of post-fire debris flow volumes is composed of smaller events than that of non-fire-related debris flows. In addition, the slope of the frequency-magnitude distribution of post-fire debris flows is steeper than that of non-fire-related debris flows, evidence that differences in the post-fire environment tend to produce a higher proportion of small events. We propose two possible explanations: 1) post-fire events occur on shorter return intervals than debris flows in similar basins that do not experience fire, causing their distribution to shift toward smaller events due to limitations in sediment supply, or 2) fire causes changes in resisting and driving forces on a package of sediment, such that a smaller perturbation of the system is required in order for a debris flow to occur, resulting in smaller event volumes.

Performance of financial institutions in Bhutan

The Kingdom of Bhutan is a small landlocked country in South Asia, located in the eastern Himalayas, and bordered by India and China. Bhutan is a small and fragile economy with a population of about 687,000. Nevertheless, its banking system plays an essential role in the growth and development of the country. This paper analyzes the financial performance, the development and growth of bank and non-bank financial institutions of Bhutan for the period 1999-2008 using both traditional and data envelopment analysis (DEA). The DEA analysis shows that financial institutions in are efficient and Bhutan National Bank has been the most efficient one. Overall, the paper finds that the ROE of the financial institutions in Bhutan are comparable to the international banks.

Commercialization of agriculture in the Himalayas

Increased market integration and commercialization of traditional agriculture in the Himalayas is part of a development strategy towards growth and better standard of living. More than 97 percent households depend upon agricultural and allied activities for livelihood which constitutes 30 percent of the household income. Given the importance of commercialization of agriculture to improve the productivity, per capita income and thereby the standard of living in the Himalayas, we examine the factors affecting the commercialization of agriculture on the basis of primary survey data. The results reveal that the land size, gender of the household head, livestock assets, ethnicity, education and location are important determinants of commercialization. Although commercialization of agriculture is considered as stimulated private-sector activity, public policy is essential to facilitate driving forces viz., trade and market reforms, rural infrastructure, and the institutional framework for legal and contractual arrangements between farmers and processors.

Managing Soil Organic Carbon: A Farm Perspective

Farming practices that lead to declining returns and inputs of carbon to soils pose a threat to key soil functions. The EU FP 7 interdisciplinary project Smart SOIL is using scientific testing and modeling to identify management practices that can optimize soil carbon storage and crop productivity. A consultation with advisors and policymakers in six European case study regions seeks to identify barriers to, and incentives for, uptake of such practices. Results from preliminary interviews are reported. Overall advisor and farmer awareness of management practices specifically directed towards soil carbon. is low. Most production- related decisions are taken in the short term, but managing soil carbon needs a long- term approach. Key barriers to uptake of practices include: perceived scientifi c uncertainty about the effi cacy of practices; lack of real life ?best practice? examples to show farmers; diffi culty in demonstrating the positive effects of soil carbon management practices and economic benefi ts over a long time scale; and advisors being unable to provide suitable advice due to inadequate information or training. Most farmers are unconvinced of the economic benefi ts of practices for managing soil carbon. Incentives are therefore needed, either as subsidies or as evidence of the cost effectiveness of practices. All new measures and advice should be integrated into existing programmes to avoid a fragmented policy approach.