Amphipathic alpha-helix AH2 is a major determinant for the oligomerization of hepatitis C virus nonstructural protein 4B.

Nonstructural protein 4B (NS4B) is a key organizer of hepatitis C virus (HCV) replication complex formation. It induces a specific membrane rearrangement, designated membranous web, that serves as a scaffold for the HCV replication complex. However, the mechanisms underlying membranous web formation are poorly understood. Based on fluorescence resonance energy transfer (FRET) and confirmatory coimmunoprecipitation analyses, we provide evidence for an oligomerization of NS4B in the membrane environment of intact cells. Several conserved determinants were found to be involved in NS4B oligomerization, through homotypic and heterotypic interactions. N-terminal amphipathic ?-helix AH2, comprising amino acids 42 to 66, was identified as a major determinant for NS4B oligomerization. Mutations that affected the oligomerization of NS4B disrupted membranous web formation and HCV RNA replication, implying that oligomerization of NS4B is required for the creation of a functional replication complex. These findings enhance our understanding of the functional architecture of the HCV replication complex and may provide new angles for therapeutic intervention. At the same time, they expand the list of positive-strand RNA virus replicase components acting as oligomers.

Winning time in land warfare : a reading of the classical strategists prior to the age of mechanization

We live in an age where rationalization and demands of efficiency taint every aspect of our lives both as individuals and as a society. Even warfare cannot escape the increased speed of human interaction. Time is a resource to be managed. It has to be optimized, saved and won in military affairs as well. The purpose of this research paper is to analyze the dogmatic texts of military thought to search for answers what the classics of strategy saw in the interrelations of temporality and warfare and if their thoughts remain meaningful in the contemporary conjunction. Since the way a society functions is reflected in the way it conducts its wars, there naturally are differences between an agrarian, industrial and information society. Theorists of different eras emphasize things specific to their times, but warfare, like any human interaction, is always bounded by temporality. Not only is the pace of warfare dependent on the progress of the society, but time permeates warfare in all its aspects. This research paper focuses on two specific topics that arose from the texts themselves; how should time be managed and manipulated in warfare and how to economize and “win” it from the enemy. A method where lengthy quotations are used to illustrate the main point of the strategists has been chosen for this research paper. While Clausewitz is the most prominent source of quotations, thoughts from ancient India and China are represented as well to prove that the combination of right force in the right place at the right time is still the way of the victorious. Tactics change in the course of time but the principles of strategy remain unaltered and are only adapted to suit new situations. While ancient and pre-modern societies had their focus on finding auspicious moments for battle in the flow of kronos-time based on divinities, portents and auguries, we can trace elements of manipulation of time in warfare from the earliest surviving texts. While time as a fourth dimension of the battlespace emerged only in the modern era, all through the history of military thought it has had a profound meaning. In the past time could be squandered, today it always has to be won. This paper asks the question “why”.

Can a consecutive double turn conformation be considered as a peptide based molecular scaffold for supramolecular helix in the solid state?

Helices and sheets are ubiquitous in nature. However, there are also some examples of self-assembling molecules forming supramolecular helices and sheets in unnatural systems. Unlike supramolecular sheets there are a very few examples of peptide sub-units that can be used to construct supramolecular helical architectures using the backbone hydrogen bonding functionalities of peptides. In this report we describe the design and synthesis of two single turn/bend forming peptides (Boc-Phe-Aib-Ile-OMe 1 and Boc-Ala-Leu-Aib-OMe 2) (Aib: alpha-aminoisobutyric acid) and a series of double-turn forming peptides (Boc-Phe-Aib-IIe-Aib-OMe 3, Boc-Leu-Aib-Gly-Aib-OMe 4 and Boc-gamma-Abu-Aib-Leu-Aib-OMe 5) (gamma-Abu: gamma-aminobutyric acid). It has been found that, in crystals, on self-assembly, single turn/bend forming peptides form either a supramolecular sheet (peptide 1) or a supramolecular helix (peptide 2). unlike self-associating double turn forming peptides, which have only the option of forming supramolecular helical assemblages. (c) 2005 Elsevier Ltd. All rights reserved.

Design of a turn-linker-turn foldamer by incorporating meta-amino benzoic acid in the middle of a helix forming hexapeptide sequence: A helix breaking approach

Single crystal X-ray diffraction studies reveal that the incorporation of meta-amino benzoic acid in the middle of a helix forming hexapeptide sequence such as in peptide I Boc-Ile(1)-Aib(2)-Val(3)-m-ABA(4)-Ile(5)-Aib(6)-Leu(7)-OMe (Aib: alpha-amino isobutyric acid: m-ABA: meta-amino benzoic acid) breaks the helix propagation to produce a turn-linker-turn (T-L-T) foldamer in the solid state. In the crystalline state two conformational isomers of peptide I self-assemble in antiparallel fashion through intermolecular hydrogen bonds and aromatic pi-pi interactions to form a molecular duplex. The duplexes are further interconnected through intermolecular hydrogen bonds to form a layer of peptides. The layers are stacked one on top of the other through van der Waals interactions to form hydrophilic channels filled with solvent methanol. (C) 2009 Elsevier B.V. All rights reserved.

Supramolecular helix and beta-sheet through self-assembly of two isomeric tetrapeptides in crystals and formation of filaments and ribbons in the solid state

Single crystal X-ray diffraction studies show that the beta-turn structure of tetrapeptide I, Boc-Gly-Phe-Aib-Leu-OMe (Aib: alpha-amino isobutyric acid) self-assembles to a supramolecular helix through intermolecular hydrogen bonding along the crystallographic a axis. By contrast the beta-turn structure of an isomeric tetrapeptide II, Boc-Gly-Leu-Aib-Phe-OMe self-assembles to a supramolecular beta-sheet-like structure via a two-dimensional (a, b axis) intermolecular hydrogen bonding network and pi-pi interactions. FT-IR studies of the peptides revealed that both of them form intermolecularly hydrogen bonded supramolecular structures in the solid state. Field emission scanning electron micrographs (FE-SEM) of the dried fibrous materials of the peptides show different morphologies, non-twisted filaments in case of peptide I and non-twisted filaments and ribbon-like structures in case of peptide II.

Winning and losing in the creative industries: an analysis of creative graduates' career opportunities across creative disciplines

Following earlier work looking at overall career difficulties and low economic rewards faced by graduates in creative disciplines, the paper takes a closer look into the different career patterns and economic performance of “Bohemian” graduates across different creative disciplines. While it is widely acknowledged in the literature that careers in the creative field tend to be unstructured, often relying on part-time work and low wages, our knowledge of how these characteristics differ across the creative industries and occupational sectors is very limited. The paper explores the different trajectory and career patterns experienced by graduates in different creative disciplinary fields and their ability to enter creative occupations. Data from the Higher Education Statistical Agency (HESA) are presented, articulating a complex picture of the reality of finding a creative occupation for creative graduates. While students of some disciplines struggle to find full-time work in the creative economy, for others full-time occupation is the norm. Geography plays a crucial role also in offering graduates opportunities in creative occupations and higher salaries. The findings are contextualised in the New Labour cultural policy framework and conclusions are drawn on whether the creative industries policy construct has hidden a very problematic reality of winners and losers in the creative economy.

Delivery of AAV2/9-microdystrophin genes incorporating helix 1 of the coiled-coil motif in the C-terminal domain of dystrophin improves muscle pathology and restores the level of α1-syntrophin and α-dystrobrevin in skeletal muscles of mdx mice. Level of α1-Syntrophin and α-Dystrobrevin in Skeletal Muscles of mdx Mice

Duchenne muscular dystrophy is a severe X-linked inherited muscle wasting disorder caused by mutations in the dystrophin gene. Adeno-associated virus (AAV) vectors have been extensively used to deliver genes efficiently for dystrophin expression in skeletal muscles. To overcome limited packaging capacity of AAV vectors (<5 kb), truncated recombinant microdystrophin genes with deletions of most of rod and carboxyl-terminal (CT) domains of dystrophin have been developed. We have previously shown the efficiency of mRNA sequence–optimized microdystrophin (ΔR4-23/ΔCT, called MD1) with deletion of spectrin-like repeat domain 4 to 23 and CT domain in ameliorating the pathology of dystrophic mdx mice. However, the CT domain of dystrophin is thought to recruit part of the dystrophin-associated protein complex, which acts as a mediator of signalling between extracellular matrix and cytoskeleton in muscle fibers. In this study, we extended the ΔR4-23/ΔCT microdystrophin by incorporating helix 1 of the coiled-coil motif in the CT domain of dystrophin (MD2), which contains the α1-syntrophin and α-dystrobrevin binding sites. Intramuscular injection of AAV2/9 expressing CT domain–extended microdystrophin showed efficient dystrophin expression in tibialis anterior muscles of mdx mice. The presence of the CT domain of dystrophin in MD2 increased the recruitment of α1-syntrophin and α-dystrobrevin at the sarcolemma and significantly improved the muscle resistance to lengthening contraction–induced muscle damage in the mdx mice compared with MD1. These results suggest that the incorporation of helix 1 of the coiled-coil motif in the CT domain of dystrophin to the microdystrophins will substantially improve their efficiency in restoring muscle function in patients with Duchenne muscular dystrophy.

Modelling the warm H(2) infrared emission of the Helix nebula cometary knots

Molecular hydrogen emission is commonly observed in planetary nebulae. Images taken in infrared H(2) emission lines show that at least part of the molecular emission is produced inside the ionized region. In the best studied case, the Helix nebula, the H(2) emission is produced inside cometary knots (CKs), comet-shaped structures believed to be clumps of dense neutral gas embedded within the ionized gas. Most of the H(2) emission of the CKs seems to be produced in a thin layer between the ionized diffuse gas and the neutral material of the knot, in a mini-photodissociation region (mini-PDR). However, PDR models published so far cannot fully explain all the characteristics of the H(2) emission of the CKs. In this work, we use the photoionization code AANGABA to study the H(2) emission of the CKs, particularly that produced in the interface H(+)/H(0) of the knot, where a significant fraction of the H(2) 1-0 S(1) emission seems to be produced. Our results show that the production of molecular hydrogen in such a region may explain several characteristics of the observed emission, particularly the high excitation temperature of the H(2) infrared lines. We find that the temperature derived from H(2) observations, even of a single knot, will depend very strongly on the observed transitions, with much higher temperatures derived from excited levels. We also proposed that the separation between the H alpha and [N II] peak emission observed in the images of CKs may be an effect of the distance of the knot from the star, since for knots farther from the central star the [N II] line is produced closer to the border of the CK than H alpha.

Winning the Accreditation Game: The Library as Key Player and Hidden Gold Mine

Libraries are a central hub of information resources supporting college and university curricula. Several library strategies, cross-campus collaborations, and philosophical considerations of electronic and print offerings led to successful accreditations in business and engineering programs.

Winning in Brazil: how institutional voids affect the entry decision making process of foreign venture capital firms coming to Brazil

The master thesis for the achievement of the academic status master of science in international management (MPGI) will aim to solve the research question of how institutional voids affect the entry decision-making process of foreign venture capital firms coming to Brazil. This is a timely matter since in the past years there has been a sudden eruption of foreign VC involvement in Brazil. Based on the actionable framework by Khanna and Palpeu (2010) we conducted quantitative as well as qualitative research with two sets of interview partners in a two-phase analysis. We interviewed experts from VC firms, foreign VC firms based in Brazil and perspective VC firms that are looking to come to Brazil. We started with the former, derived lessons learned and analyzed how they affect the latter in reaching a decision. As we expected we found that depending on the industry that ventures are in, institutional voids can either pose an opportunity or a threat and hence attract or push away potential VC firms entering Brazil. Opportunities exist especially when exploiting institutional voids, for example through ventures in the marketplace efficiency. Threats are posed by investments in for instance hard infrastructure, where the economic, political and judicial systems as well as corruption and bureaucracy play demanding roles.

The use of bone scintigraphy to detect active Hansen's disease in mutilated patients

Mutilation of extremities was very frequent in patients affected by leprosy in the past; although it is now much less common, it is still seen, mainly in patients with long-term disease. In general, mutilation of the nose and ears is caused by the bacillus and mutilation of the hands and feet a consequence of chronic trauma. Leprosy must be chronically treated and any decision to interrupt therapy is based on laboratory tests and biopsy. Scintigraphy is a non-invasive procedure which could be of great value in to determining disease activity. We studied eight patients (five males and three females, aged 64-73 years) who presented with mutilation of the nose (2), ear (1), feet (3) or foot and hand (2), Conventional three-phase bone scintigraphy (750 MBq) and X-ray examinations of the affected areas were performed in all patients. Bone scintigraphy was abnormal in four patients (the presence of bacilli was confirmed by biopsy in two of them), and normal in the other four. In all patients except for the one with ear mutilation, radiography only showed the absence of bone. We conclude that bone scintigraphy is very useful to determine disease activity in cases of mutilation caused by leprosy. It seems to be superior to conventional radiography and may enable bone biopsies to be avoided.

Use of skin graft punch graft type for the healing of leg ulcers in treated Hansen's disease patients

Hansen's disease is an infectious illness caused by Mycobacterium leprae. It affects preferentially the skin and the peripheral nervous system leading to incapacities, such as leg ulcers, which happens due to the direct action of the bacillus on the organs or its indirect action on the peripheral nervous system. Leg ulcers can occur by two physiopathologic processes. There are many treatments for general leg ulcers, which include the ones caused by Hansen's disease sequels. Among them, surgical treatment shows to be effective when using skin graft, which can be performed by several techniques. Considering the low number of techniques known for treating leg ulcers in Hansen's disease sequels, the aims of this work were to standardize alternative techniques, to detect the main bacteria found in ulcer secretion cultures, to analyze the patients profile and the ulcers, to describe the histophatologies found, and to correlate these data with those of literature from all over the world. Skin graft punch type was carried out and analyzed; males had a mean age of 59.4 years old and females, 54.2 years old. Patients were 73.6% male and 26.3% female. Lepromatous type was present in 89.4% patients and tuberculoid type was seen in 10.5% of them. Associated systemic diseases were observed in 26.3% patients. Mean time of ulcers evolution was 11.6 years in male and 12.8 years in women. The average diameter of ulcers in the pre-treatment period was 8.5 X 9.5 cm in male and 10.2 X 6.8 cm in women. After the graft, their average diameters were 3.2 X 2.7 cm in male and 5.1 X 5.6 cm in women. Statistical analysis showed that there was no significant correlation between the ulcer diameter and its reduction or not in the post-surgery period (p=0.269732). The mean age of patients whose ulcers diameter did not change or reduced by only 20% was 63.5 years. Using the Spearman's coefficient, it was possible to observe that there was no significant correlation between the patients' age and the ulcers diameter reduction after the skin graft (p=0.222531). Evolution time of ulcers that did not present any satisfactory result in the post-surgery period was 12.1 years. The Spearman's coefficient showed that there was no significant correlation between the ulcers evolution time and the ulcers diameter reduction in the post-surgery period (p=0.191655). Cultures presented 50% of cases with Pseudomonas aeruginosa. Statistical analysis showed there is no correlation between the bacterial types found and the ulcer evolution in the post-surgery period (p=0.697531). The average of the ulcers diameter reduction was 42.4%, and in 26.3% of the patients the lesions disappeared after the skin graft.

Winning On for the Gipper: Diversity Strategies and Initiative at Notre Dame

One of the enduring images linked to the University of Notre Dame is that of injured football player George Gipp imploring Coach Knute Rockne to "Win One for the Gipper. " Similarly, people of color and conscience at Notre Dame struggle with formidable challenges in implementing diversity into areas of faculty retention, university initiatives and community outreach, all while remaining sane. The panelists will discuss innovative successes and continuing efforts that can be adapted by others seeking a game plan for diversity.

Effect of Solvent-Induced Coil to Helix Conformational Change on the Two-Photon Absorption Spectrum of Poly(3,6-phenanthrene)

This paper investigates the effect of solvent-induced conformational changes of poly(3,6-phenanthrene) on their two-photon absorption (2PA). Such effect was studied employing the wavelength-tunable femtosecond Z-scan technique and modeled using the sum-over-essential states approach. We observed a strong reduction of the 2PA cross-section when the sample was prepared in hexane (poor solvent) in comparison to chloroform (good solvent), which is related to the conformation adopted by the polymer in each case. In chloroform it adopts a random coil conformation, as opposed to the one-handed helix conformation in hexane. Our results pointed out that the coil to helix conformation change decreases the degree of molecular planarity of the polymer pi-conjugated backbone, which is primarily responsible for their optical nonlinearity, contributing to diminishing the effective transition dipole moments and, consequently, the 2PA cross-section. Moreover, by studying the nonlinear response with different light polarization, we showed that, although the solvent-induced conformational change does not alter the molecular symmetry of the polymer, it modifies considerably the direction of the transition dipole moments between the excited states.