291,457 research outputs found
Application of the Anomeric Samarium Route for the Convergent Synthesis of the <i>C</i>-Linked Trisaccharide α-d-Man-(1→3)-[α-d-Man-(1→6)]-d-Man and the Disaccharides α-d-Man-(1→3)-d-Man and α-d-Man-(1→6)-d-Man
No full textStudies are reported on the assembly of the branched C-trisaccharide, α-d-Man-(1→3)-[α-d-Man-(1→6)]-d-Man, representing the core region of the asparagine-linked oligosaccharides. The key step
in this synthesis uses a SmI2-mediated coupling of two mannosylpyridyl sulfones to a C3,C6-diformyl
branched monosaccharide unit, thereby assembling all three sugar units in one reaction and with
complete stereocontrol at the two anomeric carbon centers. Subsequent tin hydride-based deoxygenation followed by a deprotection step produces the target C-trimer. In contrast to many of the
other C-glycosylation methods, this approach employes intact carbohydrate units as C-glycosyl
donors and acceptors, which in many instances parallels the well-studied O-glycosylation reactions.
The synthesis of the C-disaccharides α-d-Man-(1→3)-d-Man and α-d-Man-(1→6)-d-Man is also
described, they being necessary for the following conformational studies of all three carbohydrate
analogues both in solution and bound to several mannose-binding proteins
Application of the Anomeric Samarium Route for the Convergent Synthesis of the <i>C</i>-Linked Trisaccharide α-d-Man-(1→3)-[α-d-Man-(1→6)]-d-Man and the Disaccharides α-d-Man-(1→3)-d-Man and α-d-Man-(1→6)-d-Man
No full textStudies are reported on the assembly of the branched C-trisaccharide, α-d-Man-(1→3)-[α-d-Man-(1→6)]-d-Man, representing the core region of the asparagine-linked oligosaccharides. The key step
in this synthesis uses a SmI2-mediated coupling of two mannosylpyridyl sulfones to a C3,C6-diformyl
branched monosaccharide unit, thereby assembling all three sugar units in one reaction and with
complete stereocontrol at the two anomeric carbon centers. Subsequent tin hydride-based deoxygenation followed by a deprotection step produces the target C-trimer. In contrast to many of the
other C-glycosylation methods, this approach employes intact carbohydrate units as C-glycosyl
donors and acceptors, which in many instances parallels the well-studied O-glycosylation reactions.
The synthesis of the C-disaccharides α-d-Man-(1→3)-d-Man and α-d-Man-(1→6)-d-Man is also
described, they being necessary for the following conformational studies of all three carbohydrate
analogues both in solution and bound to several mannose-binding proteins
The Padova Type 2 Diabetes Simulator from Triple-Tracer Single-Meal Studies: In Silico Trials Also Possible in Rare but Not-So-Rare Individuals
No full textBackground: In silico trials in type 2 diabetes (T2D) would be useful for testing diabetes treatments and accelerating the development of new antidiabetic drugs. In this study, we present a T2D simulator able to reproduce the variability observed in a T2D population. The simulator also allows to safely experiment on virtual subjects with severe (and possibly rare) pathological conditions. Methods: A meal simulation model of glucose, insulin, and C-peptide systems, made of 15 differential equations and 39 parameters, has been identified using a system decomposition and forcing function Bayesian strategy on data of 51 T2D subjects undergoing a single triple-tracer mixed meal. One hundred T2D in silico subjects have been generated from the joint distribution of estimated model parameters. A case study is presented to illustrate the simulator use for testing a virtual drug (improving insulin action and secretion) in a subpopulation of rare, extremely impaired, T2D subjects. Results: The model well fitted T2D data and parameters were estimated with precision. Simulated plasma glucose, insulin, and C-peptide well matched the data (e.g., median [25th-75th percentile] glucose area under the curves of 6.9 [6.1-8.5] 104 mg/dL·min in silico vs. 7.0 [5.6-8.2] 104 mg/dL·min in vivo). The potential use of the simulator was shown in a case study, in which the (virtual) antidiabetic drug dose was optimized for very insulin-resistant T2D subjects. Conclusions: We have developed a T2D simulator that captures the behavior of T2D population during a meal, both in terms of average and intersubject variability. The simulator represents a cost-effective way to test new antidiabetic drugs, before moving to human trials
Conformation of Glycomimetics in the Free and Protein-Bound State: Structural and Binding Features of the <i>C</i>-glycosyl Analogue of the Core Trisaccharide α-d-Man-(1 → 3)-[α-d-Man-(1 → 6)]-d-Man
No full textThe conformational properties of the C-glycosyl analogue of the core trisaccharide α-d-Man-(1
→ 3)-[α-d-Man-(1 → 6)]-d-Man in solution have been carefully analyzed by a combination of NMR
spectroscopy and time-averaged restrained molecular dynamics. It has been found that both the α-1,3-
and the α-1,6-glycosidic linkages show a major conformational averaging. Unusual Φ ca. 60° orientations
for both Φ torsion angles are found. Moreover, a major conformational distinction between the natural
compound and the glycomimetic affects to the behavior of the ω16 torsion angle around the α-1 → 6-linkage.
Despite this increased flexibility, the C-glycosyl analogue is recognized by three mannose binding lectins,
as shown by NMR (line broadening, TR−NOE, and STD) and surface plasmon resonance (SPR) methods.
Moreover, a process of conformational selection takes place, so that these lectins probably bind the
glycomimetic similarly to the way they recognize the natural analogue. Depending upon the architecture
and extension of the binding site of the lectin, loss or gain of binding affinity with respect to the natural
analogue is found
‘The Churchillian Paradigm and the “Other British Isles”: An Examination of Second World War Remembrance in Man, Orkney, and Jersey’
No full textThis dissertation studies Second World War ‘sites of memory’ in the islands of Jersey, Orkney and the Isle of Man, to determine if each island celebrates the war’s events as Britain does, or if they have charted their own mnemonic course. It builds on the work of Angus Calder, Malcolm Smith, and Mark Connelly, who have explored how popular conception of the Second World War in Britain has been structured around a certain set of commemorative motifs, most of which centre on Winston Churchill and the events of 1940. The British war narrative is now commonly referred to as the ‘Churchillian paradigm’ or ‘finest-hour myth’, and continues to be the driving force in commemoration and memorialization on the British mainland. The three islands in this study are culturally and historically distinct from Britain, and each has strong notions of its own ‘island identity’. Each also possesses a tangential and divisive domestic experience of war, one which is often minimized in the iconography of the Churchillian paradigm. Jersey was occupied by Nazi Germany from 1940 to 1945, Orkney was home to several thousand Italian POWs who built important infrastructure in the island, and the Isle of Man was home to 14,000 German, Finnish, Japanese, and Italian internees in what one critic has called ‘a bespattered page’ in the nation’s history. By examining ‘sites of memory’— museums, heritage sites, commemorations, celebrations, philately, and use of public space—this dissertation shows that each island simultaneously accepts and rejects elements of the finest-hour myth in their collective memory. Each island displays its unique (though often quite negative) heritage in order to differentiate itself from Britain, while at the same time allowing them, at certain events, to participate in celebration of Britain’s ‘greatest victory’. In this way, islands’ use ‘Britishness’ pragmatically, by basking in traditionally ‘British’ commemorative tropes, while at the same time deepening their own cultural and historical sovereignty
(The) man, his body, and his society: masculinity and the male experience in English and Scottish medicine c.1640-c.1780.
No full textThis thesis examines the relationship(s) between medicine, the body and societal codes of masculinity in England and Scotland between c.1640 and c.1780. It responds to the way in which the men in histories of post-1660 masculinity are often disembodied, and to the comparative absence of men’s gendered experiences from the history of medicine. Its findings show that in both centuries the experience of being a man with a body that was the site of health and sickness was an open, candid, and often communal, one, inside and outside of the formal medical encounter. Thus, and on both sides of 1700, ill men had full freedom in the pursuit and acceptance of medical, familial and social assistance, while their physical suffering, and associated emotional distress, was met with sympathy. With their sick bodies the sites of honest self-examination and open discussion, it was in part this very public nature of their sicknesses that allowed men, as a gender and as individuals, independence and agency in their non-commercial health care. Indeed, later-seventeenth- and eighteenth-century men suffered no constraints in their ability to respond to the vulnerabilities of their bodies, even where this involved behaviours or attributes allegedly associated with women and femininity, or inconsistent with ideals of active, independent, masculinity.
These findings indicate, therefore, great continuity across the period 1640-1780, and not only in masculine ideals of and involving the male corporeality. There seems to have been significant consistency across time in men’s social and medical experiences of both sickness and their pre-emptive preparation for it, and in an apparent collective self-confidence concerning their corporeal masculinity, their sex, and, possibly, even their sexual potential. Indeed, these sources suggest that seventeenth- and eighteenth-century men had a resilient sense of self-identity (and personal masculinity), conceptually separable from the corporeal body and its known fragilities
Minimal and Maximal Models to Quantitate Glucose Metabolism: Tools to Measure, to Simulate and to Run in Silico Clinical Trials
No full textSeveral models have been proposed to describe the glucose system at whole-body, organ/tissue and cellular level, designed to measure non-accessible parameters (minimal models), to simulate system behavior and run in silico clinical trials (maximal models). Here, we will review the authors’ work, by putting it into a concise historical background. We will discuss first the parametric portrait provided by the oral minimal models—building on the classical intravenous glucose tolerance test minimal models—to measure otherwise non-accessible key parameters like insulin sensitivity and beta-cell responsivity from a physiological oral test, the mixed meal or the oral glucose tolerance tests, and what can be gained by adding a tracer to the oral glucose dose. These models were used in various pathophysiological studies, which we will briefly review. A deeper understanding of insulin sensitivity can be gained by measuring insulin action in the skeletal muscle. This requires the use of isotopic tracers: both the classical multiple-tracer dilution and the positron emission tomography techniques are discussed, which quantitate the effect of insulin on the individual steps of glucose metabolism, that is, bidirectional transport plasma-interstitium, and phosphorylation. Finally, we will present a cellular model of insulin secretion that, using a multiscale modeling approach, highlights the relations between minimal model indices and subcellular secretory events. In terms of maximal models, we will move from a parametric to a flux portrait of the system by discussing the triple tracer meal protocol implemented with the tracer-to-tracee clamp technique. This allows to arrive at quasi-model independent measurement of glucose rate of appearance (Ra), endogenous glucose production (EGP), and glucose rate of disappearance (Rd). Both the fast absorbing simple carbs and the slow absorbing complex carbs are discussed. This rich data base has allowed us to build the UVA/Padova Type 1 diabetes and the Padova Type 2 diabetes large scale simulators. In particular, the UVA/Padova Type 1 simulator proved to be a very useful tool to safely and effectively test in silico closed-loop control algorithms for an artificial pancreas (AP). This was the first and unique simulator of the glucose system accepted by the U.S. Food and Drug Administration as a substitute to animal trials for in silico testing AP algorithms. Recent uses of the simulator have looked at glucose sensors for non-adjunctive use and new insulin molecules
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
That Man Stone Collection
No full textPhotograph of the Creek Council House, Okmulgee, Indian Territory, c. 1896. Copy photo by That Man Stone Co., c. pre-1938
That Man Stone Collection
No full textPhotograph of the Creek Council House, Okmulgee, Indian Territory, c. 1890. Copy photo by That Man Stone Co., c. pre-1938
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