Man-machine interface analysis of the flight design system

The objective of the current effort was to perform a broad analysis of the human factors issues involved in the design of the Flight Design System (FDS). The analysis was intended to include characteristics of the system itself, such as: (1) basic structure and functional capabilities of FDS; (2) user backgrounds, capabilities, and possible modes of use; (3) FDS interactive dialogue, problem solving aids; (4) system data management capabilities; and to include, as well, such system related matters as: (1) flight design team structure; (2) roles of technicians; (3) user training; and (4) methods of evaluating system performance. Wherever possible, specific recommendations are made. In other cases, the issues which seem most important are identified. In some cases, additional analyses or experiments which might provide resolution are suggested

Scheduling language and algorithm development study. Volume 3, phase 2: As-built specifications for the prototype language and module library

Detailed specifications of the prototype language and module library are presented. The user guide to the translator writing system is included

siRNA carrying an (E)-vinylphosphonate moiety at the 5' end of the guide strand augments gene silencing by enhanced binding to human Argonaute-2

Efficient gene silencing by RNA interference (RNAi) in vivo requires the recognition and binding of the 5'- phosphate of the guide strand of an siRNA by the Argonaute protein. However, for exogenous siRNAs it is limited by the rapid removal of the 5'- phosphate of the guide strand by metabolic enzymes. Here, we have determined the crystal structure of human Argonaute-2 in complex with the metabolically stable 5'-(E)-vinylphosphonate (5'-E-VP) guide RNA at 2.5-A resolution. The structure demonstrates how the 5' binding site in the Mid domain of human Argonaute-2 is able to adjust the key residues in the 5'-nucleotide binding pocket to compensate for the change introduced by the modified nucleotide. This observation also explains improved binding affinity of the 5'-E-VP -modified siRNA to human Argonaute-2 in-vitro, as well as the enhanced silencing in the context of the trivalent N-acetylgalactosamine (GalNAc)-conjugated siRNA in mice relative to the un-modified siRNA

Scheduling language and algorithm development study. Volume 3: Detailed functional specifications for the language and module library

The detailed functional specifications presented are written as requirements for software implementation of the language and the program modules, and are aimed at a specific audience

Scheduling language and algorithm development study. Volume 2: Use of the basic language and module library

The capabilities of the specified scheduling language and the program module library are outlined. The summary is written with the potential user in mind and, therefore, provides maximum insight on how the capabilities will be helpful in writing scheduling programs. Simple examples and illustrations are provided to assist the potential user in applying the capabilities of his problem

Gas hydrate on the northern Cascadia margin: regional geophysics and structural framework

Integrated Ocean Drilling Program Expedition 311 is based on extensive site survey data and historic research at the northern Cascadia margin since 1985. This research includes various regional geophysical surveys using a broad spectrum of seismic techniques, coring and logging by the Ocean Drilling Program Leg 146, heat flow measurements, shallow piston coring, and bottom video observations across a cold-vent field, as well as novel controlled-source electromagnetic and seafloor compliance surveying techniques. The wealth of data available allowed construction of structural cross-sections of the margin, development of models for the formation of gas hydrate in an accretionary prism, and estimation of gas hydrate and free gas concentrations. Expedition 311 established for the first time a transect of drill sites across the northern Cascadia margin to study the evolution of gas hydrate formation over the entire gas hydrate stability field of the accretionary complex. This paper reviews the tectonic framework at the northern Cascadia margin and summarizes the scientific studies that led to the drilling objectives of Expedition 311 Cascadia gas hydrate

Replacement of the Trabecular Meshwork Cells—A Way Ahead in IOP Control?

Glaucoma is one of the leading causes of vision loss worldwide, characterised with irreversible optic nerve damage and progressive vision loss. Primary open-angle glaucoma (POAG) is a subset of glaucoma, characterised by normal anterior chamber angle and raised intraocular pressure (IOP). Reducing IOP is the main modifiable factor in the treatment of POAG, and the trabecular meshwork (TM) is the primary site of aqueous humour outflow (AH) and the resistance to outflow. The structure and the composition of the TM are key to its function in regulating AH outflow. Dysfunction and loss of the TM cells found in the natural ageing process and more so in POAG can cause abnormal extracellular matrix (ECM) accumulation, increased TM stiffness, and increased IOP. Therefore, repair or regeneration of TM’s structure and function is considered as a potential treatment for POAG. Cell transplantation is an attractive option to repopulate the TM cells in POAG, but to develop a cell replacement approach, various challenges are still to be addressed. The choice of cell replacement covers autologous or allogenic approaches, which led to investigations into TM progenitor cells, induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs) as potential stem cell source candidates. However, the potential plasticity and the lack of definitive cell markers for the progenitor and the TM cell population compound the biological challenge. Morphological and differential gene expression of TM cells located within different regions of the TM may give rise to different cell replacement or regenerative approaches. As such, this review describes the different approaches taken to date investigating different cell sources and their differing cell isolation and differentiation methodologies. In addition, we highlighted how these approaches were evaluated in different animal and ex vivo model systems and the potential of these methods in future POAG treatment

Sustained TL1A expression modulates effector and regulatory T-cell responses and drives intestinal goblet cell hyperplasia

The tumor necrosis factor (TNF) superfamily protein TNF-like 1A (TL1A) is the ligand for death receptor 3 (DR3). TL1A is induced on activated dendritic cells (DCs) and its expression has been linked to human inflammatory bowel disease. To address how TL1A might influence intestinal inflammation, we generated transgenic mice that constitutively express TL1A on DCs. TL1A transgenic mice developed striking goblet cell hyperplasia in the ileum that was associated with elevated interleukin (IL)-13 levels in the small intestine. IL-13- and IL-17-producing small intestinal lamina propria T cells were increased in TL1A transgenic mice. TL1A also enhanced regulatory T (Treg) cell turnover in vivo and directly stimulated Treg cell proliferation in vitro. The presence of TL1A attenuated the ability of Treg cells to suppress conventional T cells, an effect that required DR3 signaling in either conventional T cells or Treg cells. Our findings identify mechanisms by which chronic DR3 signaling could promote pathogenesis in inflammatory bowel disease.<br/

Relationship between vascular resistance and sympathetic nerve fiber density in arterial vessels in children with sleep disordered breathing

Sleep disordered breathing in children is associated with increased blood flow velocity and sympathetic overactivity. Sympathetic overactivity results in peripheral vasoconstriction and reduced systemic vascular compliance, which increases blood flow velocity during systole. Augmented blood flow velocity is recognized to promote vascular remodeling. Importantly, increased vascular sympathetic nerve fiber density and innervation in early life plays a key role in the development of early-onset hypertension in animal models. Examination of sympathetic nerve fiber density of the tonsillar arteries in children undergoing adenotonsillectomy for Sleep disordered breathing will address this question in humans.Thirteen children scheduled for adenotonsillectomy to treat sleep disordered breathing underwent pupillometry, polysomnography, flow-mediated dilation, resting brachial artery blood flow velocity (velocity time integral), and platelet aggregation. The dorsal lingual artery (tonsil) was stained and immunofluorescence techniques used to determine sympathetic nerve fiber density. Sympathetic nerve fiber density was correlated with increased resting velocity time integral (r=0.63; P<0.05) and a lower Neuronal Pupillary Index (r=-0.71, P<0.01), as well as a slower mean pupillary constriction velocity (mean, r=-0.64; P<0.05). A faster resting velocity time integral was associated with a slower peak pupillary constriction velocity (r=-0.77; P<0.01) and higher platelet aggregation to collagen antigen (r=0.64; P<0.05). Slower mean and peak pupillary constriction velocity were associated with higher platelet aggregation scores (P<0.05; P<0.01, respectively).These results indicate that sympathetic activity is associated with change in both the function and structure of systemic vasculature in children with sleep disordered breathing.Anna Kontos, Kurt Lushington, James Martin, Quenten Schwarz, Ryan Green, Ben, David Wabnitz, Xiangjun Xu, Elke M. Sokoya, Scott Willoughby, Mathias Baumert, Antonio Ferrante, Melissa La Forgia, Declan Kenned