389 research outputs found
Molecular modeling of an antigenic complex between a viral peptide and a class I major histocompatibility glycoprotein
Computer simulation of the
conformations of short antigenic peptides (&lo
residues) either free or bound to their receptor,
the major histocompatibility complex (MHC)-
encoded glycoprotein H-2 Ld, was employed to
explain experimentally determined differences
in the antigenic activities within a set of related
peptides. Starting for each sequence from the
most probable conformations disclosed by a
pattern-recognition technique, several energyminimized
structures were subjected to molecular
dynamics simulations (MD) either in vacuo
or solvated by water molecules. Notably, antigenic
potencies were found to correlate to the
peptides propensity to form and maintain an
overall a-helical conformation through regular
i,i + 4 hydrogen bonds. Accordingly, less active
or inactive peptides showed a strong tendency
to form i,i+3 hydrogen bonds at their Nterminal
end. Experimental data documented
that the C-terminal residue is critical for interaction
of the peptide with H-2 Ld. This finding
could be satisfactorily explained by a 3-D
Q.S.A.R. analysis postulating interactions between
ligand and receptor by hydrophobic
forces. A 3-D model is proposed for the complex
between a high-affinity nonapeptide and the H-
2 Ld receptor. First, the H-2 Ld molecule was
built from X-ray coordinates of two homologous
proteins: HLA-A2 and HLA-Aw68, energyminimized
and studied by MD simulations. With
HLA-A2 as template, the only realistic simulation
was achieved for a solvated model with minor
deviations of the MD mean structure from
the X-ray conformation. Water simulation of the
H-2 Ld protein in complex with the antigenic
nonapeptide was then achieved with the template-
derived optimal parameters. The bound
peptide retains mainly its a-helical conformation
and binds to hydrophobic residues of H-2
Ld that correspond to highly polymorphic positions
of MHC proteins. The orientation of the
nonapeptide in the binding cleft is in accordance
with the experimentally determined distribution
of its MHC receptor-binding residues
(agretope residues). Thus, computer simulation was successfully employed to explain functional
data and predicts a-helical conformation
for the bound peptid
A novel phase variant of the cholera pathogen shows stress-adaptive cryptic transcriptomic signatures
© 2016 The Author(s). Background: In a process known as phase variation, the marine bacterium and cholera pathogen Vibrio cholerae alternately expresses smooth or rugose colonial phenotypes, the latter being associated with advanced biofilm architecture and greater resistance to ecological stress. To define phase variation at the transcriptomic level in pandemic V. cholerae O1 El Tor strain N16961, we compared the RNA-seq-derived transcriptomes among the smooth parent N16961, its rugose derivative (N16961R) and a smooth form obtained directly from the rugose at high frequencies consistent with phase variation (N16961SD). Results: Differentially regulated genes which clustered into co-expression groups were identified for specific cellular functions, including acetate metabolism, gluconeogenesis, and anaerobic respiration, suggesting an important link between these processes and biofilm formation in this species. Principal component analysis separated the transcriptome of N16961SD from the other phase variants. Although N16961SD was defective in biofilm formation, transcription of its biofilm-related vps and rbm gene clusters was nevertheless elevated as judged by both RNA-seq and RT-qPCR analyses. This transcriptome signature was shared with N16961R, as were others involving two-component signal transduction, chemotaxis, and c-di-GMP synthesis functions. Conclusions: Precise turnarounds in gene expression did not accompany reversible phase transitions (i.e., smooth to rugose to smooth) in the cholera pathogen. Transcriptomic signatures consisting of up-regulated genes involved in biofilm formation, environmental sensing and persistence, chemotaxis, and signal transduction, which were shared by N16961R and N16961SD variants, may implicate a stress adaptation in the pathogen that facilitates transition of the N16961SD smooth form back to rugosity should environmental conditions dictate
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Orthostatic Tremor is Responsive to Bilateral Thalamic Deep Brain Stimulation: Report of Two Cases Performed Asleep
Background: Orthostatic tremor (OT) is a hyperkinetic movement disorder characterized by rapid tremor in the lower extremities or trunk upon standing.
Case Report: We report two patients presenting with OT, whose symptoms improved markedly following asleep bilateral thalamic deep brain stimulation (DBS) surgery.
Discussion: Medically refractory OT can respond favorably to asleep bilateral DBS surgery similar to awake surgery, and may have the advantages of less psychological trauma to the patient, shorter procedure times, and less exposure to anesthesia
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Deletion of the Complement C5a Receptor Alleviates the Severity of Acute Pneumococcal Otitis Media following Influenza A Virus Infection in Mice
There is considerable evidence that influenza A virus (IAV) promotes adherence, colonization, and superinfection by S. pneumoniae (Spn) and contributes to the pathogenesis of otitis media (OM). The complement system is a critical innate immune defense against both pathogens. To assess the role of the complement system in the host defense and the pathogenesis of acute pneumococcal OM following IAV infection, we employed a well-established transtympanically-induced mouse model of acute pneumococcal OM. We found that antecedent IAV infection enhanced the severity of acute pneumococcal OM. Mice deficient in complement C1qa (C1qaâ/â) or factor B (Bf â/â) exhibited delayed viral and bacterial clearance from the middle ear and developed significant mucosal damage in the eustachian tube and middle ear. This indicates that both the classical and alternative complement pathways are critical for the oto-immune defense against acute pneumococcal OM following influenza infection. We also found that Spn increased complement activation following IAV infection. This was characterized by sustained increased levels of anaphylatoxins C3a and C5a in serum and middle ear lavage samples. In contrast, mice deficient in the complement C5a receptor (C5aR) demonstrated enhanced bacterial clearance and reduced severity of OM. Our data support the concept that C5a-C5aR interactions play a significant role in the pathogenesis of acute pneumococcal OM following IAV infection. It is possible that targeting the C5a-C5aR axis might prove useful in attenuating acute pneumococcal OM in patients with influenza infection
Dynamic Managerial Compensation: A Variational Approach
We study the optimal dynamics of incentives for a manager whose ability to generate cash flows changes stochastically with time and is his private information. We show that distortions (aka, wedges) under optimal contracts may either increase or decrease over time. In particular, when the manager's risk aversion and ability persistence are small, distortions decrease, on average, over time. For sufficiently high degrees of risk aversion and ability persistence, instead, distortions increase, on average, with tenure. Our results follow from a novel variational approach that permits us to tackle directly the "full program," thus bypassing some of the difficulties of the "first-order approach" encountered in the dynamic mechanism design literature
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Reference-dependent analysis of capital structure and REIT performance
Using prospect theory, we develop a theoretical framework to examine the relationship between leverage and Real Estate Investment Trust (REIT) returns by introducing the concept of reference point. We postulate that firmsâ capital structure decisions are affected by target leverage (i.e., the reference point) as well as the observed leverage. Market conditions combined with firmsâ capital structure will put firms in either loss or gain domains, where firms behave differently. In general, the leverage-return relationship is positive in the gain domain and negative in the loss domain. Firms are then subject to asymmetric risk preference in different domains. Our empirical evidence shows strong support for the theoretical model. Compared to the conventional approach where only observed leverage is used, our model is more flexible and realistic in revealing the underlying structure of the leverageâreturns relationship.We are grateful for financial support from the National Natural Science Foundation of China (Project #71231005) and the Senior Membersâ Research Grant from Newnham College, University of Cambridge
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Diphenylamine-substituted osmanaphthalyne complexes: structural, bonding, and redox properties of unusual donorâbridgeâacceptor systems
Diarylamine-substituted osmanaphthalyne complexes
that feature two redox centers linked by the rigid
skeleton of the metallacycle (C^C+), specifically,
[OsCl2(PPh3)2{(C^C+)NAr2}][BF4
] (Ar=Ph (1 a), p-MeOPh (1 b))
and their open-ring precursors [OsHCl2(PPh3)2{(CC(PPh3
+)=
CHPh)NR2}][BF4
] (Ar=Ph (2 a), p-MeOPh (2 b)), were successfully
synthesized and characterized by 1
H, 13C, and 31P NMR
spectroscopy, ESI-MS, and elemental analysis. The solid-state
molecular structures of complexes 1 a and 2 a were ascertained
by single-crystal X-ray diffraction. The OsC bond
length in both complexes 1 a and 2 a fell within the range
reported for similar osmanaphthalynes and osmium carbyne
complexes, respectively. The structural parameters determined
for complex 1 a, which were successfully reproduced
by theoretical calculations, point to a p-delocalized metallacycle
structure. The purple color of compounds 1 a and b
was explained by the diarylamine!Os(metallacycle) chargetransfer
absorption in the visible region. The neutral, oneelectron-oxidized
and one-electron-reduced states of compounds 1 a, b, and a reference complex that lacked the diarylamine substituent, [OsCl2(PPh3)2{(C^C+)}][BF4] (1â), were investigated by cyclic and square-wave voltammetry, UV/Vis/NIR spectroelectrochemistry, and DFT calculations. The spin
density in singly oxidized complexes [1 a]+ and [1 b]+ predominantly resided on the aminyl segment, with osmium involvement controlled by the diphenylamine substitution.
Spin density in stable, singly-reduced [1â] was distributed
mainly over the osmanaphthalyne metallacycle
âBritish is professional, American is urbanâ: attitudes towards English reference accents in Spain
The spread and diversification of English worldwide challenges the use of reference accents in EFL classrooms. Yet, learners often demonstrate greater recognition of, familiarity with and preference for inner-circle varieties of English speech, especially Received Pronunciation (RP) and General American (GenAm). This article investigates the attitudes of 71 university students in Spain towards these speech varieties. Using the verbal guise technique, it measures cognitive, affective and conative responses to speech stimuli. Qualitative comments, collected using questionnaires and interviews, help to interpret these evaluative responses. The findings suggest a desire to emulate RP, often associated with status and prestige, though greater solidarity and stronger affiliative feelings towards GenAm speakers. They highlight the complexity and dynamism of the language attitudes of EFL learners in the Spanish context
LSST: from Science Drivers to Reference Design and Anticipated Data Products
(Abridged) We describe here the most ambitious survey currently planned in
the optical, the Large Synoptic Survey Telescope (LSST). A vast array of
science will be enabled by a single wide-deep-fast sky survey, and LSST will
have unique survey capability in the faint time domain. The LSST design is
driven by four main science themes: probing dark energy and dark matter, taking
an inventory of the Solar System, exploring the transient optical sky, and
mapping the Milky Way. LSST will be a wide-field ground-based system sited at
Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m
effective) primary mirror, a 9.6 deg field of view, and a 3.2 Gigapixel
camera. The standard observing sequence will consist of pairs of 15-second
exposures in a given field, with two such visits in each pointing in a given
night. With these repeats, the LSST system is capable of imaging about 10,000
square degrees of sky in a single filter in three nights. The typical 5
point-source depth in a single visit in will be (AB). The
project is in the construction phase and will begin regular survey operations
by 2022. The survey area will be contained within 30,000 deg with
, and will be imaged multiple times in six bands, ,
covering the wavelength range 320--1050 nm. About 90\% of the observing time
will be devoted to a deep-wide-fast survey mode which will uniformly observe a
18,000 deg region about 800 times (summed over all six bands) during the
anticipated 10 years of operations, and yield a coadded map to . The
remaining 10\% of the observing time will be allocated to projects such as a
Very Deep and Fast time domain survey. The goal is to make LSST data products,
including a relational database of about 32 trillion observations of 40 billion
objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures
available from https://www.lsst.org/overvie
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