The \u3cem\u3emir-51\u3c/em\u3e Family of MicroRNAs Functions in Diverse Regulatory Pathways in \u3cem\u3eCaenorhbditis elegans\u3c/em\u3e

The mir-51 family of microRNAs (miRNAs) in C. elegans are part of the deeply conserved miR-99/100 family. While loss of all six family members (mir-51-56) in C. elegans results in embryonic lethality, loss of individual mir-51 family members results in a suppression of retarded developmental timing defects associated with the loss of alg-1. The mechanism of this suppression of developmental timing defects is unknown. To address this, we characterized the function of the mir-51 family in the developmental timing pathway. We performed genetic analysis and determined that mir-51 family members regulate the developmental timing pathway in the L2 stage upstream of hbl-1. Loss of the mir-51 family member, mir-52, suppressed retarded developmental timing defects associated with the loss of let-7 family members and lin-46. Enhancement of precocious defects was observed for mutations in lin-14, hbl-1, and mir-48(ve33), but not later acting developmental timing genes. Interestingly, mir-51 family members showed genetic interactions with additional miRNA-regulated pathways, which are regulated by the let-7 and mir-35 family miRNAs, lsy-6, miR-240/786, and miR-1. Loss of mir-52 likely does not suppress miRNA-regulated pathways through an increase in miRNA biogenesis or miRNA activity. We found no increase in the levels of four mature miRNAs, let-7, miR-58, miR-62 or miR-244, in mir-52 or mir-52/53/54/55/56 mutant worms. In addition, we observed no increase in the activity of ectopic lsy-6 in the repression of a downstream target in uterine cells in worms that lack mir-52. We propose that the mir-51 family functions broadly through the regulation of multiple targets, which have not yet been identified, in diverse regulatory pathways in C. elegans

SCOPe: Structural Classification of Proteins--extended, integrating SCOP and ASTRAL data and classification of new structures.

Structural Classification of Proteins-extended (SCOPe, http://scop.berkeley.edu) is a database of protein structural relationships that extends the SCOP database. SCOP is a manually curated ordering of domains from the majority of proteins of known structure in a hierarchy according to structural and evolutionary relationships. Development of the SCOP 1.x series concluded with SCOP 1.75. The ASTRAL compendium provides several databases and tools to aid in the analysis of the protein structures classified in SCOP, particularly through the use of their sequences. SCOPe extends version 1.75 of the SCOP database, using automated curation methods to classify many structures released since SCOP 1.75. We have rigorously benchmarked our automated methods to ensure that they are as accurate as manual curation, though there are many proteins to which our methods cannot be applied. SCOPe is also partially manually curated to correct some errors in SCOP. SCOPe aims to be backward compatible with SCOP, providing the same parseable files and a history of changes between all stable SCOP and SCOPe releases. SCOPe also incorporates and updates the ASTRAL database. The latest release of SCOPe, 2.03, contains 59 514 Protein Data Bank (PDB) entries, increasing the number of structures classified in SCOP by 55% and including more than 65% of the protein structures in the PDB

The Election Controversy Among Lutherans in the Twentieth Century: An Examination of the Underlying Problems

The Election Controversy of the nineteenth re-shaped the face of confessional Lutheranism in America. The Evangelical Lutheran Synodical Conference of North America, the leading voice of confessional Lutheranism in America, bore the brunt of the dispute and ultimately dissolved. This dissertation examines the Election Controversy with special attention to the twentieth century attempts to resolve it in order to discover the underlying problems that have prevented the opposing sides from reaching a resolution. The dissertation is written from the viewpoint of the Wisconsin Synod, one of the synods involved in the controversy but often ignored in the discussion of it. The study is needed because contemporary observers do not have a good understanding of confessional Lutheranism and Lutheranism\u27s historic emphasis on doctrinal purity. The dissertation demonstrates that the underlying causes of the controversy and the failures to resolve it were departures from Luther\u27s approach to theology and from the historic Lutheran stress on doctrine and doctrinal agreement for the expression of church fellowship

Genetic Identification of Development Pathways Regulated by Conserved microRNAs in Caenorhabditis elegans

microRNAs (miRNAs) are approximately 22 nucleotide non-coding RNAs that function to repress genes by binding to complementary sites in target mRNAs and play critical roles in development and disease. It is predicted that more than 60% of human genes are regulated by miRNAs, however, little is known about the individual functions of miRNAs. I used the nematode worm, Caenorhabditis elegans, as a model to identify developmental processes and pathways regulated by conserved miRNAs. Genetic examination of miRNA function is hindered by lack of obvious phenotypes attributed to loss of individual miRNA genes. Phenotypes attributable to loss of individual miRNA genes were identified by examining worms mutant for individual miRNA genes and alg-1, which encodes an Argonaute protein that functions in the miRNA pathway in C. elegans. This analysis identified functions for 80% of miRNA genes examined. miRNAs were found to regulate diverse processes, including embryonic development, directional migration of the gonad, and developmental timing. The goal of the second half of this study was to determine the mechanism whereby loss of members of the mir-51 miRNA family suppresses the developmental timing defects of alg-1 mutant worms. Genetic evidence indicates the mir-51 family regulates the L2 to L3 transition through regulation of hbl-1 expression. Interestingly, the mir-51 family genetically interacts in pathways regulated by the let-7 and miR-35 families, as well as lsy-6, miR-240/786, and miR-1. Evidence herein indicates that the mir-51 family does not regulate these pathways through miRNA biogenesis or activity. Instead it is possible that the miR-51 family regulates multiple targets in diverse developmental pathways

Mitoparans: mitochondriotoxic cell penetrating peptides and novel inducers of apoptosis.

Acknowledgments The authors would like to thank Keith Holding at the University of Wolverhampton for his outstanding technical support. This work was supported in part by Samantha Dickson Brain Tumour Trust.Introduction: The amphipathic helical peptide mastoparan (MP; H-INLKALAALAKKIL-NH2) inserts into biological membranes to modulate the activity of heterotrimeric G proteins and other targets. Moreover, whilst cell free models of apoptosis demonstrate MP to facilitate mitochondrial permeability transition and release of apoptogenic cytochrome c, MP-induced death of intact cells has been attributed to its non-specific membrane destabilising properties (necrotic mechanisms). However, MP and related peptides are known to activate other signalling systems, including p42/p44 MAP kinases and could therefore, also modulate cell fate and specific apoptotic events. The ability of MP to facilitate mitochondrial permeability in cell free systems has lead to proposals that MP could be of utility in tumour therapeutics provided that it conferred features of cellular penetration and mitochondrial localization. We have recently reported that our highly potent amphipathic MP analogue mitoparan (mitP; [Lys5,8Aib10]MP; Aib = -aminoisobutyric acid) specifically promotes apoptosis of human cancer cells, as was confirmed by in situ TUNEL staining and activation of caspase-3. Moreover, we have also demonstrated that mitP penetrates plasma membranes and redistributes to co-localize with mitochondria. Complementary studies, using isolated mitochondria, further demonstrated that mitP, through co-operation with a protein of the permeability transition pore complex voltage-dependent anion channel (VDAC), induced swelling and permeabilization of mitochondria, leading to the release of the apoptogenic factor cytochrome c. An expanding field of peptide and cell penetrating peptide (CPP) research has focussed on the selective targeting of tumours by engineering constructs that incorporate cell-specific or tissue–specific address motifs. Peptidyl address motifs could enhance the selectivity of drug delivery whilst the improved cellular uptake offered by CPP enhances bioavailability. Thus and as a potential therapeutic strategy, we extended our findings to design target-specific mitP analogues. The integrin-specific address motif RGD and a Fas ligand mimetic WEWT were incorporated by N-terminal acylation of mitP to produce novel tandem-linked chimeric peptides

Variables Influencing Publication in the Field of Social Work

The manuscript presents a descriptive summary of variables influencing professional publication in four major journals: Social Work, Social Service Review, Social Casework and Clinical Social Work Journal. Data were drawn from a random sampling of the years 1960 to 1976. The following descriptive variables were analyzed: degree, sex, occupation, organizational affiliation, and geographic location of author; topic of article; and single VS multiple authorship. Implications the data have for the production of knowledge in social work and future research questions are briefly educidated

Loss of Individual MicroRNAs Causes Mutant Phenotypes in Sensitized Genetic Backgrounds in \u3cem\u3eC. elegans\u3c/em\u3e

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate the translation and/or stability of their mRNA targets. Previous work showed that for most miRNA genes of C. elegans, single-gene knockouts did not result in detectable mutant phenotypes. This may be due, in part, to functional redundancy between miRNAs. However, in most cases, worms carrying deletions of all members of a miRNA family do not display strong mutant phenotypes. They may function together with unrelated miRNAs or with non-miRNA genes in regulatory networks, possibly to ensure the robustness of developmental mechanisms. To test this, we examined worms lacking individual miRNAs in genetically sensitized backgrounds. These include genetic backgrounds with reduced processing and activity of all miRNAs or with reduced activity of a wide array of regulatory pathways. With these two approaches, we identified mutant phenotypes for 25 out of 31 miRNAs included in this analysis. Our findings describe biological roles for individual miRNAs and suggest that the use of sensitized genetic backgrounds provides an efficient approach for miRNA functional analysis

Skating on a Film of Air: Drops Impacting on a Surface

Drops impacting on a surface are ubiquitous in our everyday experience. This impact is understood within a commonly accepted hydrodynamic picture: it is initiated by a rapid shock and a subsequent ejection of a sheet leading to beautiful splashing patterns. However, this picture ignores the essential role of the air that is trapped between the impacting drop and the surface. Here we describe a new imaging modality that is sensitive to the behavior right at the surface. We show that a very thin film of air, only a few tens of nanometers thick, remains trapped between the falling drop and the surface as the drop spreads. The thin film of air serves to lubricate the drop enabling the fluid to skate on the air film laterally outward at surprisingly high velocities, consistent with theoretical predictions. Eventually this thin film of air must break down as the fluid wets the surface. We suggest that this occurs in a spinodal-like fashion, and causes a very rapid spreading of a wetting front outwards; simultaneously the wetting fluid spreads inward much more slowly, trapping a bubble of air within the drop. Our results show that the dynamics of impacting drops are much more complex than previously thought and exhibit a rich array of unexpected phenomena that require rethinking classical paradigms.Comment: 4 pages, 4 figure

Drag-n-fly: a Proposal in Response to a Low Reynolds Number Station Keeping Mission

The Drag-n-Fly is a remotely piloted, low Reynolds number vehicle. It was designed to maintain level controlled flight and fly a closed course at flight speeds corresponding to Reynolds numbers of less than 2 x 10(exp 5) and as close to 1 x 10(exp 5) as possible. The success of the mission will be associated with achieving the lowest mean chord Reynolds number possible and maximizing loiter time on the course. The flight plan for the Drag-n-Fly calls for the vehicle to ascent to a cruise altitude of 25 ft. The airfoil selected for the Drag-n-Fly is a Spica chosen for its high lift coefficient at low Reynolds number. The propulsion system for the Drag-n-Fly consists of a 10 inch diameter propeller mounted on the front of the vehicle. Structural support for the Drag-n-Fly comes from four box beams running the length of the fuselage. The tail and horizontal stabilizers are located far aft of the lifting surface in order to assure proper static stability. The present design for the Drag-n-Fly will meet the criteria for the present mission