A decrease in ARDS mortality was only seen in observational studies from 1984 to 1993. Mortality did not decrease between 1994 (when a consensus definition was published) and 2006, and is lower in RCTs than observational studies.
Quantum mechanical (QM) calculations
of noncovalent interactions
are uniquely useful as tools to test and improve molecular mechanics
force fields and to model the forces involved in biomolecular binding
and folding. Because the more computationally tractable QM methods
necessarily include approximations, which risk degrading accuracy,
it is essential to evaluate such methods by comparison with high-level
reference calculations. Here, we use the extensive Benchmark Energy
and Geometry Database (BEGDB) of CCSD(T)/CBS reference results to
evaluate the accuracy and speed of widely used QM methods for over
1200 chemically varied gas-phase dimers. In particular, we study the
semiempirical PM6 and PM7 methods; density functional theory (DFT)
approaches B3LYP, B97-D, M062X, and ωB97X-D; and symmetry-adapted
perturbation theory (SAPT) approach. For the PM6 and DFT methods,
we also examine the effects of post hoc corrections for hydrogen bonding
(PM6-DH+, PM6-DH2), halogen atoms (PM6-DH2X), and dispersion (DFT-D3
with zero and Becke–Johnson damping). Several orders of the
SAPT expansion are also compared, ranging from SAPT0 up to SAPT2+3,
where computationally feasible. We find that all DFT methods with
dispersion corrections, as well as SAPT at orders above SAPT2, consistently
provide dimer interaction energies within 1.0 kcal/mol RMSE across
all systems. We also show that a linear scaling of the perturbative
energy terms provided by the fast SAPT0 method yields similar high
accuracy, at particularly low computational cost. The energies of
all the dimer systems from the various QM approaches are included
in the Supporting Information, as are the full SAPT2+(3) energy decomposition
for a subset of over 1000 systems. The latter can be used to guide
the parametrization of molecular mechanics force fields on a term-by-term
basis.
This study reports on the remarkable attractive interaction between
organic azides and the portal carbonyls of cucurbiturils. Five homologous
bis-α,ω-azidoethylammonium alkanes were prepared, where the
number of methylene groups between the ammonium groups ranges from 4 to 8. Their
interactions with cucurbit[6]uril were studied by NMR, IR and
X-ray crystallography, and by computational methods. Remarkably, while the
distance between the portal plane and most atoms at the guest end groups
increase progressively with the molecular size, the β-nitrogen atoms
maintain a constant distance from the portal plane in all homologs, pointing at
a strong attractive interaction between the azide group and the portal. Both
crystallography and NMR support a specific electrostatic interaction between the
carbonyl and the azide β-nitrogen, which stabilizes the canonical
resonance form with positive charge on the β-nitrogen and negative
charge on the γ-nitrogen. Quantum computational analyses strongly
support electrostatics, in the form of orthogonal dipole-dipole interaction, as
the main driver for this attraction. The alternative mechanism of
n→π* orbital delocalization does not seem to play a
significant role in this interaction. The computational studies also indicate
that the interaction is not limited to azides, but generalizes to other
isoelectronic heteroallene functions, such as isocyanate and isothiocyanate.
This essentially unexploited attractive interaction could be more broadly
utilized as a tool not only in relation to cucurbituril chemistry, but also for
the design of novel supramolecular architectures.
There is a definable body of SSH knowledge that forms the academic underpinning for important physician competencies and is outside the experience of most medical educators. Curricular change incorporating such content is necessary if we are to strengthen the non-Medical Expert physician competencies. Our findings, particularly our cross-cutting themes, also provide a pedagogically useful mechanism for holistically teaching the underpinnings of physician competence. We are now implementing our findings into medical curricula.
Aggregation of misfolded α-synuclein (α-syn) is the major component of Lewy bodies and neurites in Parkinson’s disease (PD) and related α-synucleinopathies. Some α-syn mutations (e.g., A53T) in familial PD recapitulate the α-syn pathology in transgenic mice, which supports the importance of pathologic α-syn in driving the pathogenesis of α-synucleinopathies. Lymphocyte activation gene 3 (Lag3) is a receptor of α-syn fibrils facilitating pathologic α-syn spread; however, the role of Lag3 in mediating the pathogenesis in α-syn transgenic mice is not clear. Here, we report that depletion of Lag3 in human α-syn A53T transgenic (hA53T) mice significantly reduces the level of detergent-insoluble α-syn aggregates and phosphorylated ser129 α-syn, and inhibits activation of microglia and astrocytes. The absence of Lag3 significantly delays disease progression and reduces the behavioral deficits in hA53T transgenic mice leading to prolonged survival. Taken together, these results show that Lag3 contributes to the pathogenesis in the α-syn A53T transgenic mouse model.
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